Cystic Fibrosis

Genetic MONDO:0009061 Pathograph 70 Show in embeddings browser Respiratory Disease Inborn Error of Metabolism

Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder caused by mutations in the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator, a chloride and bicarbonate channel expressed in epithelial cells. CFTR dysfunction leads to dehydrated, viscous secretions in multiple organ systems, most critically the airways and pancreas. Nearly 2,000 CFTR variants have been identified, with the Phe508del (F508del) mutation present in nearly 90% of patients. The disease is characterized by progressive bronchiectasis, chronic bacterial lung infection, exocrine pancreatic insufficiency, male infertility due to congenital bilateral absence of the vas deferens, and elevated sweat chloride. Multidisciplinary care and CFTR modulator therapies have extended median survival beyond 40 years, with the advent of elexacaftor-tezacaftor-ivacaftor (Trikafta) representing a transformational advance for the majority of patients.

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Classifications

Harrison's Part

Channelopathy

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Mappings

MONDO

MONDO:0009061 cystic fibrosis

Orphanet ORPHA:586 cross-reference table lists MONDO:0009061 as an exact match.

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Definitions

CF Foundation Diagnostic Criteria (2017)

Consensus guidelines from the Cystic Fibrosis Foundation for establishing a diagnosis of CF in individuals from newborn to adult, requiring evidence of CFTR dysfunction via sweat chloride testing combined with clinical features or two disease-causing CFTR mutations.

CASE_DEFINITION Diagnosis of cystic fibrosis in all age groups

Diagnostic criteria for cystic fibrosis

CF diagnosis requires clinical features consistent with CF in at least one organ system OR positive newborn screen, PLUS evidence of CFTR dysfunction demonstrated by elevated sweat chloride (>=60 mmol/L) or identification of two CF-causing CFTR mutations.

Core clinical characteristics

Elevated sweat chloride
Recurrent respiratory infections
Exocrine pancreatic insufficiency
Male infertility
Meconium ileus

Show evidence (1 reference)

PMID:28129811 SUPPORT Human clinical

"It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test."

CF Foundation consensus guidelines establish sweat chloride testing as the cornerstone of CF diagnosis.

Newborn Screening Algorithm

Most CF cases in the US and many other countries are identified through newborn screening (NBS) programs that measure immunoreactive trypsinogen (IRT) in dried blood spots, followed by CFTR mutation panel or a second IRT measurement. Positive screens require diagnostic confirmation with sweat chloride testing.

DIAGNOSTIC_CRITERIA Newborn screening for cystic fibrosis

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Most cases of CF are identified through newborn screening (NBS)."

Clinical review confirms newborn screening as the primary route to CF diagnosis.

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Inheritance

Autosomal Recessive HP:0000007

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Clinical review confirms autosomal recessive inheritance pattern.

ORPHA:586 SUPPORT Other

"Autosomal recessive"

Orphanet lists cystic fibrosis inheritance as autosomal recessive.

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Subtypes

mutation class

Class I - No Protein Production

Nonsense mutations, frameshift mutations, and canonical splice site mutations that result in premature termination codons and no functional CFTR protein production due to mRNA degradation via nonsense-mediated decay. Examples include G542X, W1282X, R553X, and 621+1G>T. Class I mutations cause severe disease with pancreatic insufficiency.

G542X
W1282X
R553X

Show evidence (3 references)

PMID:26823392 SUPPORT REVIEW SYNTHESIS Other

"Class I encompasses frameshift, splicing, or nonsense mutations that introduce premature termination codons (PTC), resulting in severely reduced or absent CFTR expression."

Defines class I as premature-termination mutations with severely reduced or absent CFTR expression.

PMID:26823392 SUPPORT Other

"First, the level of the W1282X transcript is reduced by nonsense-mediated RNA decay"

Supports nonsense-mediated decay as the mechanism, for the class I example W1282X.

PMID:1376016 SUPPORT Human clinical

"the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T"

Places the class I examples G542X, R553X, W1282X and 621+1G>T among the severe alleles associated with pancreatic insufficiency.

Class II - Processing/Trafficking Defect

Mutations causing CFTR protein misfolding, endoplasmic reticulum retention, and proteasomal degradation. The most important example is F508del, present in nearly 90% of CF patients. Misfolded protein is recognized by ER quality control and targeted for ubiquitin-proteasome degradation, resulting in minimal CFTR at the cell surface. Corrector drugs (lumacaftor, tezacaftor, elexacaftor) partially rescue F508del trafficking.

F508del
N1303K
I507del

Show evidence (1 reference)

PMID:31697873 SUPPORT Human clinical

"nearly 90% of patients have at least one copy of the Phe508del CFTR mutation"

Confirms the high prevalence of the prototypical Class II mutation F508del.

Class III - Gating Defect

CFTR protein reaches the cell surface normally but channel gating is severely impaired, resulting in very low open probability. The prototypical example is G551D. Potentiator drugs (ivacaftor) increase channel open probability and produce dramatic clinical benefit.

G551D
S549N
G1244E

Show evidence (1 reference)

PMID:22047557 SUPPORT Human clinical

"The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001)."

Ivacaftor trial in G551D patients demonstrates therapeutic targeting of gating mutations.

Class IV - Conductance Defect

CFTR reaches the cell surface and channel opens, but chloride conductance through the channel pore is reduced. Typically associated with milder phenotype and pancreatic sufficiency. Examples include R117H, R334W, and R347P.

R117H
R334W
R347P

Show evidence (2 references)

PMID:26823392 SUPPORT REVIEW SYNTHESIS Other

"Class IV mutations alter the channel conductance by impeding the ion conduction pore, leading to a reduced unitary conductance"

Defines class IV as a conductance defect of the channel pore.

PMID:1376016 SUPPORT Human clinical

Places the class IV examples R117H, R334W and R347P among the mild alleles associated with pancreatic sufficiency, supporting the milder phenotype.

Class V - Reduced Quantity

Mutations that reduce the amount of normal CFTR protein produced, such as alternative splice site mutations that produce some normal transcript alongside aberrant transcript. Typically associated with milder phenotype and pancreatic sufficiency. Examples include 3849+10kbC>T and A455E.

3849+10kbC>T
A455E

Show evidence (2 references)

PMID:26823392 SUPPORT REVIEW SYNTHESIS Other

"Class V mutations do not change the conformation of the protein but alter its abundance by introducing promoter or splicing abnormalities"

Defines class V as reduced abundance of normal CFTR through promoter or splicing abnormalities.

PMID:1376016 SUPPORT Human clinical

Places the class V example A455E among the mild alleles associated with pancreatic sufficiency. The study did not test 3849+10kbC>T.

Class VI - Decreased Stability

CFTR protein reaches the cell surface and functions but has accelerated turnover and reduced plasma membrane stability. Rescued F508del protein (after corrector therapy) exhibits this additional defect, necessitating combination therapy with correctors and potentiators.

Show evidence (2 references)

PMID:26823392 SUPPORT REVIEW SYNTHESIS Other

"Class VI mutations destabilize the channel in post-ER compartments and/or at the plasma membrane (PM), by reducing its conformational stability"

Defines class VI as reduced stability of CFTR after it leaves the ER.

PMID:26823392 SUPPORT Other

"Unless the folding and conformational dynamics of the rescued ΔF508-CFTR are fully restored to that of the wild-type protein by pharmacological treatment, this mutation remains partially defective and requires correction of its gating and/or peripheral stability defect."

Supports the statement that corrector-rescued F508del keeps a stability defect and needs combined correction.

clinical phenotype

Classic Cystic Fibrosis

Severe disease phenotype with two severe CFTR mutations, pancreatic insufficiency, progressive bronchiectasis, elevated sweat chloride (>=60 mmol/L), and male infertility due to CBAVD. Represents the majority of CF patients.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Clinical review describes the classic CF phenotype of pancreatic insufficiency and chronic airway infection.

Atypical (Non-Classic) Cystic Fibrosis

Milder disease phenotype, often with at least one CFTR mutation conferring residual function (Class IV, V). May present with pancreatic sufficiency, milder lung disease, borderline or normal sweat chloride, and later age of diagnosis. Some patients are not diagnosed until adulthood.

Show evidence (1 reference)

PMID:33178516 SUPPORT BACKGROUND Human clinical

"There exists another clinically diverse group of individuals with cystic fibrosis who usually have onset in adulthood with minimal symptoms involving only a single organ, or more, and a negative sweat chloride test called atypical CF."

Introduction of a case report describing atypical CF as adult-onset, milder disease that can have a normal sweat chloride, supporting the milder phenotype and late diagnosis in the description. The case itself, diagnosed at 57, illustrates adult diagnosis.

CFTR related disorder

Congenital Bilateral Absence of the Vas Deferens (CBAVD)

Isolated congenital bilateral absence of the vas deferens causing obstructive azoospermia and male infertility, without other features of classic CF. Found in approximately 1-2% of infertile males. Most affected men carry at least one CFTR mutation, often including the 5T poly-T variant or R117H. Sweat chloride is typically normal or borderline. Lung and pancreatic function are preserved.

Comorbidities

Asthma <-> Cystic Fibrosis

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Mechanistic Hypotheses

Canonical CFTR Loss-of-Function Model

canonical_cftr_loss_of_function_model CANONICAL

Evidence balance 4 support

Biallelic CFTR pathogenic variants impair the cyclic-AMP-regulated apical anion channel that exports chloride and bicarbonate at epithelial surfaces. Loss of CFTR-mediated anion secretion (and secondary hyperabsorption of sodium and water) produces dehydrated, acidic, viscous airway surface liquid and pancreatic/biliary secretions. The resulting impaired mucociliary clearance, chronic bacterial airway infection, and obstructive secretions drive the progressive bronchiectatic lung disease, exocrine pancreatic insufficiency, hepatobiliary disease, elevated sweat chloride, and male infertility (CBAVD) characteristic of cystic fibrosis. CFTR modulator therapies (correctors/potentiators, exemplified by elexacaftor/tezacaftor/ivacaftor) that restore residual CFTR activity provide direct interventional validation of this canonical pathway.

Retained as CANONICAL following independent assessment of the 2026 OpenScientist hypothesis-search report (see kb/hypotheses/Cystic_Fibrosis/canonical_cftr_loss_of_function_model/assessments/openscientist-assessment-by-codex.md; reconciliation tracked in issue #7325). The core mechanism is well supported by convergent evidence: newborn CF-pig airway-surface-liquid acidification impairs bacterial killing before infection or inflammation, and randomized/registry CFTR-modulator trials (ETI: ppFEV1 +9.9 across 11,151 registry patients) provide direct human interventional validation. Several report-level claims required narrowing rather than verbatim promotion: (1) as of the 2013 CFTR2 analysis, few of the nearly 2,000 then-reported CFTR variants had empirical evidence of disease causation, so an unqualified ">2,000 disease-causing variants" count conflates reported with clinically classified variants; CFTR2 has interpreted substantially more variants since, so any exact count must be dated to its source snapshot rather than asserted in the present tense; (2) bicarbonate secretion has been shown to be rate-limiting for host defense in mixed porcine airway epithelia and cell-culture systems, but this does not establish bicarbonate as the universal rate-limiting determinant over chloride across all human tissues and genotypes; (3) human monocyte-derived macrophages show direct CFTR-dependent defects, but a cited CFTR-depleted zebrafish neutrophil-recruitment finding traced the effect to epithelial oxidative signaling rather than immune-cell-autonomous CFTR dysfunction, so the two should not be conflated as one parallel immune mechanism; (4) residual airway inflammation and molecular abnormalities persisting after highly effective modulator therapy reflect incomplete correction of CFTR function rather than proof that inflammation becomes independent of ongoing CFTR dysfunction; and (5) next-generation vanzacaftor evidence of differential response in two previously unresponsive genotypes is from intestinal organoids, not yet a demonstrated clinical rescue.

Deep research

OpenScientist citations 44 citations 2026-05-23T15:40:32.507768

Show evidence (4 references)

PMID:27140670 SUPPORT Human clinical

"Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs."

Elborn 2016 Lancet seminar identifies CFTR functional failure as the central mechanism producing mucus retention, chronic infection, and progressive airway inflammation — the canonical pathogenic chain for cystic fibrosis lung disease.

PMID:23974870 SUPPORT Human clinical

"Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis."

Corrects an OpenScientist report claim that treated all ~2,000 reported CFTR variants as disease-causing. The snippet's point is that most reported variants have never been empirically evaluated, not that they were evaluated and failed: of the 159 variants common enough to assess in this 39,696-person cohort, 127 (80%) did meet both clinical and functional criteria consistent with disease. The unsupported step is therefore the slide from ~2,000 reported to ~2,000 disease-causing, per issue #7325. Figures are the 2013 CFTR2 snapshot.

PMID:22763554 SUPPORT Model organism

"Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs."

Bidirectional perturbation of airway surface liquid pH in newborn pigs is the strongest single perturbational support for the canonical model: lowering pH reproduces the host-defence defect in wild-type animals and raising pH rescues it in CF animals, at an age when the lungs are still free of infection and inflammation. It establishes causal primacy for the CFTR-dependent step in that model, not every downstream human manifestation.

+ 1 more reference

Discussions and Knowledge Gaps

Why does airway inflammation persist after highly effective CFTR modulator therapy, and is any part of it genuinely independent of ongoing CFTR dysfunction?

KNOWLEDGE GAP OPEN hemt_era_residual_disease

Attached to

pathophysiology#Neutrophilic Airway Inflammation treatments#Elexacaftor-Tezacaftor-Ivacaftor (Trikafta/Kaftrio)

Sputum proteomes and cytokine profiles improve substantially on elexacaftor/tezacaftor/ivacaftor but remain distinct from healthy controls, and residual oxidative stress and infection persist at levels comparable to non-cystic-fibrosis bronchiectasis. In vitro, restoring roughly 60% of CFTR function does not normalize the lipid imbalance or the basal inflammatory cytokine profile of cystic fibrosis bronchial epithelium. What these observations establish is incomplete normalization, not independence from CFTR. Partial target restoration, irreversible structural injury, persistent infection and microbiome disruption, late treatment initiation, and cell-type-specific drug exposure are all still viable explanations, and the published data do not separate them. The distinction matters for therapy: a self-sustaining cascade would justify adjunct anti-inflammatory treatment on top of modulators, whereas incomplete correction argues for deeper or earlier CFTR restoration.

Proposed experiments

Longitudinal airway multi-omics in infant-initiated versus late-initiated modulator therapy

exp_cf_infant_vs_late_eti_multiomics

Follow two prospective cohorts starting elexacaftor/tezacaftor/ivacaftor, one before six months of age and one after established structural lung disease, with serial airway proteomics, cytokines, microbiome sequencing and imaging, against matched controls without cystic fibrosis.

Decision criterion

Convergence of the infant-initiated cohort on the control airway proteome and microbiome would attribute the residual signature to accumulated injury and timing; persistence of an inflammatory signature in that cohort despite equivalent restored CFTR function would support a component that no longer depends on ongoing CFTR dysfunction.

Would support

pathophysiology#Neutrophilic Airway Inflammation

Supporting outcome

A residual inflammatory and proteomic signature that persists in children treated from infancy, at the same restored CFTR function as later-treated patients, would show the inflammatory arm running partly independently of current CFTR activity.

Refuting outcome

Normalization of the airway proteome, cytokines and microbiome in the infant-initiated cohort would attribute the residual disease of later-treated patients to prior structural and microbial injury rather than to a CFTR-independent inflammatory program.

Show evidence (3 references)

PMID:42128740 SUPPORT Human clinical

"Despite these improvements, proteomic and cytokine profiles remained distinct from healthy controls."

Longitudinal sputum proteomics and cytokines in 30 people with cystic fibrosis before and during modulator therapy, compared with seven healthy controls, document that normalization is incomplete. Seven controls is a small comparison group, and the study does not test why the difference remains.

PMID:33613309 SUPPORT In vitro / ex vivo

"However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress."

Shows residual lipid and oxidative-stress abnormalities in cystic fibrosis bronchial epithelium after short-term modulator treatment. Because the correction reached only about 60% of non-cystic-fibrosis function over 72 hours, this is equally compatible with incomplete correction and with a CFTR-independent component.

PMID:40227282 SUPPORT Other

"However, despite these advancements, residual airway infection, oxidative stress and inflammation persist, with levels similar to other chronic lung conditions, like non-CF bronchiectasis."

Review framing the residual burden and the reason it is clinically consequential. It synthesizes published series rather than reporting new data, so it supports the existence of the gap and not any particular mechanism for it.

How much of cystic fibrosis lung disease is attributable to immune-cell-autonomous CFTR dysfunction, independently of the epithelial surface defect?

KNOWLEDGE GAP OPEN immune_cell_cftr_contribution

Attached to

pathophysiology#Macrophage CFTR Dysfunction

Macrophage CFTR is measurable, modulator-responsive, and associated with reduced phagocytosis, intracellular killing and efferocytosis, and ENaC is overexpressed in cystic fibrosis immune cells in a way that CFTR inhibition reproduces in non-cystic-fibrosis cells. All of this is ex vivo work on blood-derived cells. No study separates the immune contribution from the epithelial one in vivo, so the weight of this arm in human airway disease is unknown, and it cannot be assumed to hold for every immune lineage. A frequently cited zebrafish result does not close the gap either: those larvae were globally CFTR-depleted, and the excess neutrophil recruitment was traced to an epithelial oxidative response rather than to an immune-cell-autonomous defect. Resolving this determines whether immune-directed therapy, such as ENaC modulation in macrophages, is worth pursuing alongside CFTR modulators.

Proposed experiments

Reciprocal bone-marrow chimeras between CFTR-null and wild-type animals

exp_cf_bone_marrow_chimera

Transplant wild-type marrow into CFTR-null recipients and CFTR-null marrow into wild-type recipients in an animal model that develops airway disease, then compare bacterial burden, neutrophilic inflammation and airway histopathology against the two unmanipulated genotypes.

Decision criterion

An intermediate phenotype in both chimera directions would quantify a real immune-cell-autonomous contribution; a phenotype that tracks recipient airway genotype alone would place the mechanism entirely in the epithelium.

Would support

pathophysiology#Macrophage CFTR Dysfunction

Supporting outcome

Wild-type marrow reducing disease in CFTR-null recipients, and CFTR-null marrow producing inflammation in wild-type recipients, would establish an immune-cell-autonomous contribution and give its approximate size.

Refuting outcome

Disease severity determined solely by the recipient airway genotype, with no effect of donor marrow genotype, would show the macrophage defect to be a downstream marker rather than an independent driver.

Show evidence (1 reference)

PMID:39574739 SUPPORT In vitro / ex vivo

"Baseline expression of ENaC in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF controls and persisted after exposure to bacteria."

Reports ENaC overexpression across cystic fibrosis immune lineages, which the same work reproduces by inhibiting CFTR in non-cystic-fibrosis macrophages, making the ion-channel abnormality a candidate immune-cell-autonomous mechanism. This source is a bioRxiv preprint and has not been peer reviewed, and the assays are ex vivo, so it marks out the question rather than answering it.

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Pathophysiology

CFTR Dysfunction

Mutations in the CFTR gene reduce or eliminate CFTR channel function at epithelial surfaces. Defective CFTR impairs epithelial anion and water handling, creating dehydrated secretions that initiate respiratory, gastrointestinal, hepatobiliary, sweat-gland, and reproductive disease.

Epithelial cell CL:0000066

Chloride Transport GO:0006821 ↓ DECREASED bicarbonate transport GO:0015701 ↓ DECREASED

chloride channel activity GO:0005254 ↓ DECREASED

Experimental models

Patient-derived airway organoid theratyping model ORGANOID Measures genotype-specific epithelial CFTR dysfunction and rescue by modulators in patient-derived airway tissue.

NuLi/CuFi airway epithelial cell-line model CELL LINE Preserves genotype-specific CFTR-dependent ion-transport defects in a reusable airway epithelial system.

Computational models

O'Donoghue quantitative model of human nasal epithelial ion transport KINETIC Reduces apical CFTR chloride permeability and calculates the resulting transepithelial and membrane-potential responses.

Sandefur purinergic model of airway-surface-liquid homeostasis KINETIC MATLAB ode15s Reduces CFTR-mediated chloride secretion within a calibrated model of cultured human airway epithelium.

Downstream

Airway Surface Liquid Depletion Loss of epithelial chloride and bicarbonate secretion dehydrates airway surface liquid.

Airway Surface Liquid Acidification Loss of CFTR-mediated bicarbonate secretion lowers the pH of the airway surface liquid, a step separable from depletion of its volume.

Macrophage CFTR Dysfunction CFTR is expressed and functional in monocyte-derived macrophages, so the same genetic defect acts on innate immune cells in parallel with epithelium rather than only through them.

ENaC Hyperactivity and Sodium Hyperabsorption Loss of CFTR-mediated inhibition increases ENaC-dependent sodium and water absorption.

Impaired Pancreatic Organogenesis CFTR dysfunction during fetal pancreatic development may reduce pancreatic mass and islet number, establishing a developmental foundation for pancreatic disease.

Pancreatic Duct Obstruction Viscid epithelial secretions obstruct pancreatic ducts and initiate pancreatic injury.

Intestinal Obstruction Dehydrated intestinal secretions cause bowel obstruction.

Sweat Gland Dysfunction Failure of sweat-duct chloride reabsorption raises sweat chloride.

Vas Deferens Agenesis CFTR dysfunction contributes to male reproductive tract abnormalities and infertility.

Hepatobiliary Obstruction Viscid bile causes biliary obstruction and hepatobiliary disease.

Sinonasal Disease Impaired epithelial ion and fluid transport promotes chronic sinonasal disease.

Reduced Female Fertility Thick cervical mucus and impaired epithelial fluid transport reduce female fertility.

Show evidence (2 references)

PMID:9922375 SUPPORT Human clinical

"The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl- channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes..."

Comprehensive review establishes CFTR as chloride channel whose dysfunction causes cystic fibrosis.

PMID:9922375 SUPPORT Human clinical

"The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain."

Describes the five-domain architecture of CFTR critical to understanding mutation effects.

ENaC Hyperactivity and Sodium Hyperabsorption

In CF airways, reduced CFTR function disinhibits ENaC, increasing epithelial sodium and water absorption and worsening airway dehydration.

Bronchial epithelial cell CL:0002328

sodium ion transport GO:0006814 ↑ INCREASED

Experimental models

NuLi/CuFi airway epithelial cell-line model CELL LINE Supports mechanistic readouts of abnormal epithelial sodium transport downstream of CFTR loss.

Computational models

O'Donoghue quantitative model of human nasal epithelial ion transport KINETIC Infers the ENaC permeability change needed to reproduce CF basal and amiloride-sensitive nasal potential differences.

Sandefur purinergic model of airway-surface-liquid homeostasis KINETIC MATLAB ode15s Increased sodium absorption is required with reduced chloride secretion to reproduce the CF epithelial state.

Downstream

Airway Surface Liquid Depletion Increased Na+/H2O absorption further depletes airway surface liquid.

Show evidence (1 reference)

PMID:23878362 SUPPORT Human clinical

"CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased..."

Supports ENaC hyperactivity and increased Na+/water absorption in CF airway epithelium.

Airway Surface Liquid Depletion

Reduced epithelial anion secretion together with increased sodium absorption depletes the periciliary liquid layer and airway surface liquid.

Bronchial epithelial cell CL:0002328

mucus secretion GO:0070254 ⚠ ABNORMAL

Lung UBERON:0002048

Experimental models

CF airway-on-chip microphysiological model ORGAN ON CHIP Recapitulates dehydrated mucus-layer phenotypes downstream of epithelial ion-transport failure.

Computational models

Sandefur purinergic model of airway-surface-liquid homeostasis KINETIC MATLAB ode15s Predicts the lower resting ASL height in CF and its dependence on chloride secretion, sodium absorption, and extracellular nucleotide metabolism.

Kurbatova physiologically based model of mucociliary clearance PHYSIOLOGICAL Represents the depleted periciliary-liquid layer that changes mucus transport in CF airways.

Downstream

Impaired Mucociliary Clearance Airway liquid depletion causes ineffective mucus transport and mucus stasis.

Show evidence (1 reference)

PMID:23878362 SUPPORT Human clinical

Review describes ENaC hyperactivity and dehydration mechanism in CF airways.

Airway Surface Liquid Acidification

Loss of CFTR-mediated bicarbonate secretion lowers the pH of the thin airway surface liquid layer. Acidic airway surface liquid inhibits the antimicrobial activity of the secreted host-defence proteins it carries, so bacteria landing on the surface are killed less efficiently. This arm is separable from volume depletion and from mucus stasis: in newborn cystic fibrosis pigs it is present at birth, before any infection or inflammation. The amount of CFTR is rate-limiting for bicarbonate secretion over its whole range, unlike chloride secretion, which plateaus once a minority of cells express CFTR; that dose relationship has been established in mixed porcine airway epithelia and in cultured human bronchial epithelium rather than across human tissues, genotypes and disease stages, so it should not be read as a universal bicarbonate-over-chloride hierarchy.

Bronchial epithelial cell CL:0002328

bicarbonate transport GO:0015701 ↓ DECREASED Antibacterial activity of airway surface liquid GO:0042742 ↓ DECREASED

Lung UBERON:0002048

Downstream

Chronic Bacterial Infection Acidic airway surface liquid kills inhaled bacteria less efficiently, permitting colonization independently of mucus stasis.

Show evidence (3 references)

PMID:22763554 SUPPORT Model organism

"We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL."

Measures the acidification directly in newborn CF pigs and shows that pH itself, rather than any downstream consequence of infection, suppresses the antimicrobial activity of the airway surface liquid.

PMID:27114540 SUPPORT In vitro / ex vivo

"Thus, in contrast to Cl(-) secretion, the amount of CFTR is rate-limiting for HCO3 (-) secretion and for correcting host defense abnormalities."

Porcine airway epithelia with graded proportions of CFTR-expressing cells show that bicarbonate secretion, airway surface liquid pH and antimicrobial activity scale with CFTR abundance, whereas chloride secretion saturates early. This supports bicarbonate as a dose-limiting arm in this system; it does not establish the same hierarchy across human tissues and genotypes.

PMID:38573173 SUPPORT In vitro / ex vivo

"cAMP-stimulated non-CF ionocytes do not secrete Na+ or Cl- into the ASL, but rather modulate its pH by secreting bicarbonate via CFTR-linked Cl-/bicarbonate exchange."

Single-cell ion-transport measurements in primary human bronchial epithelium assign the pH-setting function to pulmonary ionocytes acting through CFTR-linked bicarbonate exchange, and the bulk fluid-secretion function to club cells. This separates the pH arm from the volume arm in human cells and identifies which cell type carries it.

Impaired Mucociliary Clearance

Dehydrated airway surfaces reduce effective mucus transport, allowing mucus to remain adherent on airway epithelium.

mucociliary clearance GO:0120197 ↓ DECREASED

Experimental models

CF airway-on-chip microphysiological model ORGAN ON CHIP Captures ciliary and mucus-transport abnormalities in differentiated CF airway epithelium.

Computational models

Kurbatova physiologically based model of mucociliary clearance PHYSIOLOGICAL Simulates impaired regional mucus transport and its response to reduced mucus viscosity after inhaled dornase alfa.

Downstream

Mucus Plugging Failed mucus transport promotes adherent mucus plugging.

Chronic Productive Cough

Show evidence (1 reference)

PMID:23878362 SUPPORT Human clinical

"Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus."

Supports impaired mucociliary clearance as a discrete downstream step after airway dehydration.

Mucus Plugging

Impaired mucus transport generates concentrated, adherent mucus plugs that persist in the airway lumen.

Bronchial epithelial cell CL:0002328

mucus secretion GO:0070254 ⚠ ABNORMAL

Downstream

Small-Airway Obstruction Luminal mucus plugs narrow and obstruct small airways.

Chronic Bacterial Infection Retained mucus supports persistent bacterial colonization and chronic endobronchial infection.

Allergic Bronchopulmonary Aspergillosis

Show evidence (1 reference)

PMID:22711878 SUPPORT Model organism

"We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice."

Study demonstrates the mechanistic link between CFTR dysfunction and abnormal mucus properties.

Small-Airway Obstruction

Progressive luminal obstruction and air trapping in small airways emerges from persistent mucus plugging.

Lung UBERON:0002048

Downstream

Bronchiectasis Persistent obstruction contributes to irreversible airway structural damage.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

"Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."

Supports small-airway obstruction as a central respiratory disease feature.

Chronic Bacterial Infection

The CF airway is chronically colonized by characteristic pathogens. Staphylococcus aureus typically predominates in early childhood, followed by Pseudomonas aeruginosa which becomes the dominant pathogen in adolescence and adulthood. P. aeruginosa transitions to a mucoid phenotype with alginate biofilm production, making eradication extremely difficult. Other important pathogens include Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and non-tuberculous mycobacteria.

Defense response to bacterium GO:0042742 ↕ DYSREGULATED

Experimental models

CF airway-on-chip microphysiological model ORGAN ON CHIP Provides a controllable airway context for infection and bacterial overgrowth phenotypes in CF epithelium.

Downstream

Neutrophilic Airway Inflammation Chronic infection drives persistent neutrophil-predominant airway inflammation.

Bronchiectasis Recurrent endobronchial infection contributes to progressive bronchiectatic damage.

Recurrent Respiratory Infections

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Clinical review identifies chronic endobronchial infection as a defining characteristic of CF.

Macrophage CFTR Dysfunction

CFTR is expressed and functional in monocyte-derived macrophages, and macrophages from people with cystic fibrosis show reduced phagocytosis, reduced intracellular killing of cystic fibrosis pathogens, and reduced efferocytosis of apoptotic neutrophils. Elexacaftor/tezacaftor/ivacaftor partially restores these effector functions while leaving inflammatory cytokine production unchanged, which places the defect at least partly within the immune cell rather than entirely downstream of the epithelial surface. The evidence is ex vivo, from blood-derived macrophages, so the independent contribution of this arm to airway disease in vivo is not quantified and it should not be generalized to every immune lineage.

Monocyte-derived macrophage CL:0000235

phagocytosis GO:0006909 ↓ DECREASED

Downstream

Chronic Bacterial Infection Reduced macrophage phagocytosis and intracellular killing of cystic fibrosis pathogens is expected to contribute to bacterial persistence alongside the epithelial surface defect.

Show evidence (1 reference)

PMID:36265882 SUPPORT In vitro / ex vivo

"CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged."

Blood-derived macrophages from 56 people with cystic fibrosis, assayed before and during modulator therapy, show CFTR-dependent effector deficits. That correction is partial and does not extend to cytokine production is the reason this node is curated as a parallel arm of uncertain weight rather than a fully corrected one.

Neutrophilic Airway Inflammation

The CF airway shows persistent neutrophil-predominant inflammation, with a protease-rich inflammatory milieu that amplifies local tissue injury.

Neutrophil CL:0000775

Inflammatory response GO:0006954 ↑ INCREASED neutrophil chemotaxis GO:0030593 ↑ INCREASED

Downstream

Neutrophil Elastase-Mediated Tissue Injury Protease-dominant neutrophilic inflammation drives extracellular airway tissue damage.

Show evidence (1 reference)

PMID:29258516 SUPPORT Human clinical

"The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF."

Review confirms neutrophil elastase as a key marker of inflammation in CF and bronchiectasis.

Neutrophil Elastase-Mediated Tissue Injury

Neutrophil elastase burden and protease-antiprotease imbalance contribute to structural airway tissue damage.

proteolysis GO:0006508 ↑ INCREASED

Downstream

Airway Remodeling Persistent proteolytic injury promotes abnormal airway wall remodeling.

Show evidence (1 reference)

PMID:29258516 SUPPORT Human clinical

"In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment."

Supports persistent NE activity as a biologically relevant marker in chronic suppurative airway disease with CF-based mechanistic context.

Airway Remodeling

Repeated infection-inflammation injury cycles alter airway wall architecture, producing thickening, scarring, and loss of normal elastic structure.

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Lung UBERON:0002048

Downstream

Bronchiectasis Structural remodeling culminates in irreversible bronchial dilation.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."

Supports progressive structural airway deterioration in CF lung disease.

Bronchiectasis

Progressive, irreversible bronchial dilation develops from chronic obstruction, infection, and inflammatory injury.

Lung UBERON:0002048

Downstream

Respiratory Failure End-stage bronchiectasis leads to hypoxemic and hypercapnic respiratory failure.

Hemoptysis

Pneumothorax

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."

Clinical review confirms progressive bronchiectasis leading to respiratory failure as the primary cause of mortality.

Respiratory Failure

End-stage CF lung disease results in progressive respiratory failure with hypoxemia, hypercapnia, and cor pulmonale. Respiratory failure is the leading cause of death in CF patients and the primary indication for lung transplantation.

Downstream

Digital Clubbing

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."

Respiratory failure is confirmed as the leading cause of CF mortality.

Impaired Pancreatic Organogenesis

CFTR dysfunction during fetal pancreatic development impairs the organogenesis of both endocrine and exocrine pancreatic tissue. Clinical evidence demonstrates that CF patients present with pancreatic pathology and glucose abnormalities as early as in utero. CFTR's role during pancreatic development may reduce pancreatic mass and islet cell number from birth, establishing a developmental foundation that predisposes to CF-related diabetes (CFRD) and exocrine insufficiency, distinct from post-natal destruction mechanisms.

Pancreatic ductal cell CL:0002079 Pancreatic acinar cell CL:0002064 Pancreatic beta cell CL:0000169

pancreas development GO:0031016 ↓ DECREASED

Pancreas UBERON:0001264

Downstream

CF-Related Diabetes Reduced islet mass and number from impaired organogenesis contribute to insulin insufficiency.

Show evidence (1 reference)

PMID:42262528 SUPPORT Human clinical

"An emerging body of evidence supports that CFRD may have developmental origins, as people with CF present with pancreatic pathology and glucose abnormalities as early as in utero. This therefore suggests that the CF transmembrane conductance regulator (CFTR) gene mutations that cause CF may..."

Primary literature establishes developmental origins of CF pancreatic pathology, with evidence of pancreatic dysfunction in utero.

Pancreatic Duct Obstruction

CFTR dysfunction in pancreatic ductal epithelium impairs bicarbonate and fluid secretion, leading to viscid secretions that obstruct pancreatic ducts.

Pancreatic ductal cell CL:0002079

bicarbonate transport GO:0015701 ↓ DECREASED

Pancreas UBERON:0001264

Downstream

Exocrine Pancreatic Tissue Destruction Persistent ductal obstruction promotes acinar injury and fibrosis.

Exocrine Pancreatic Insufficiency Ductal disease progresses to insufficient exocrine enzyme output.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Pediatric review confirms pancreatic insufficiency and dysfunction as core CF manifestations.

Exocrine Pancreatic Tissue Destruction

Ongoing duct obstruction and intrapancreatic injury damage exocrine tissue and promote fibrosis.

Pancreatic acinar cell CL:0002064

proteolysis GO:0006508 ↑ INCREASED

Pancreas UBERON:0001264

Downstream

Exocrine Pancreatic Insufficiency Loss of acinar tissue lowers digestive enzyme delivery to the gut.

CF-Related Diabetes Progressive pancreatic destruction contributes to insulin deficiency.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Supports destructive pancreatic dysfunction as part of the CF multiorgan phenotype.

Exocrine Pancreatic Insufficiency

Destruction of exocrine pancreatic tissue causes insufficient production of digestive enzymes including lipase, amylase, and proteases. Present in 85-90% of CF patients, pancreatic insufficiency causes fat and protein malabsorption leading to steatorrhea, failure to thrive, and fat-soluble vitamin deficiency (vitamins A, D, E, K). Pancreatic sufficiency is more common in patients with at least one mild (class IV-V) CFTR mutation.

Downstream

Fat Malabsorption Low pancreatic lipase causes fat malabsorption with steatorrhea.

Fat-Soluble Vitamin Deficiency Malabsorption of vitamins A, D, E, K causes deficiency states.

Protein-Calorie Malnutrition Impaired digestion and absorption lead to failure to thrive.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Clinical review identifies pancreatic insufficiency as a defining characteristic of cystic fibrosis.

Fat Malabsorption

Insufficient pancreatic lipase causes malabsorption of dietary fat, resulting in steatorrhea (fatty, bulky, foul-smelling stools), caloric loss, and deficiency of fat-soluble vitamins. Fat malabsorption is a major contributor to malnutrition and failure to thrive in CF.

lipid digestion GO:0044241 ↓ DECREASED

Downstream

Fat-Soluble Vitamin Deficiency Impaired intestinal fat absorption reduces uptake of vitamins A, D, E, and K.

Protein-Calorie Malnutrition Chronic caloric and nutrient loss worsens growth and nutritional status.

Steatorrhea

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Pediatric review confirms malabsorption as a clinical characteristic of CF.

Fat-Soluble Vitamin Deficiency

Malabsorption of fat-soluble vitamins A, D, E, and K leads to specific deficiency states. Vitamin A deficiency can cause night blindness, vitamin D deficiency contributes to CF bone disease, vitamin E deficiency may cause neurological symptoms, and vitamin K deficiency increases bleeding risk.

Downstream

CF Bone Disease Chronic vitamin D and K deficiency contributes to low bone mass and skeletal fragility.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Malabsorption leads to vitamin deficiencies as part of the CF nutritional phenotype.

Protein-Calorie Malnutrition

Combined effects of pancreatic insufficiency, increased metabolic demands from chronic infection and inflammation, and poor appetite lead to protein-calorie malnutrition, failure to thrive in children, and poor weight maintenance in adults. Nutritional status is strongly correlated with lung function and survival.

Downstream

CF Bone Disease Sustained undernutrition worsens bone accrual and skeletal strength.

Rectal Prolapse

Gastroesophageal Reflux

Delayed Puberty

Failure to Thrive

Short Stature

Show evidence (1 reference)

PMID:33178516 SUPPORT Human clinical

"It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."

Case report review confirms malabsorption and failure to thrive as classic CF presentations.

Intestinal Obstruction

Dehydrated intestinal secretions cause bowel obstruction at different ages. Meconium ileus occurs in 15-20% of CF neonates due to inspissated meconium in the distal ileum. In older children and adults, distal intestinal obstruction syndrome (DIOS) presents with similar pathophysiology in the ileocecal region. Constipation is also common due to dehydrated intestinal contents.

Downstream

Meconium Ileus

Distal Intestinal Obstruction Syndrome

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists bowel obstruction among established complications of CF.

Hepatobiliary Obstruction

CFTR dysfunction in cholangiocytes causes viscid bile secretions that obstruct intrahepatic bile ductules. This leads to focal biliary cirrhosis, which can progress to multilobular cirrhosis with portal hypertension in 5-10% of CF patients. CF liver disease is the third leading cause of death after respiratory failure and transplant complications.

Cholangiocyte CL:1000488

Liver UBERON:0002107

Downstream

Focal Biliary Cirrhosis

Portal Hypertension

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists hepatobiliary disease among established complications of CF.

Sweat Gland Dysfunction

In sweat glands, CFTR is required for chloride reabsorption in the sweat duct. Loss of CFTR function results in failure to reabsorb chloride from primary sweat, producing sweat with elevated chloride concentration. This is the basis of the diagnostic sweat chloride test. Excessive salt loss can cause hyponatremic dehydration, especially in hot weather or during exercise.

Chloride Transport GO:0006821 ↓ DECREASED

Downstream

Hyponatremic Dehydration Chronic sweat salt loss predisposes to hyponatremic volume depletion.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Diagnosis of CF is confirmed by demonstration of elevated sweat chloride."

Elevated sweat chloride reflects defective CFTR-mediated chloride reabsorption in sweat ducts.

Hyponatremic Dehydration

Excessive sweat sodium and chloride loss can produce clinically significant hyponatremic dehydration, especially with heat stress or inadequate salt intake.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists hyponatremic dehydration among established cystic fibrosis complications.

Vas Deferens Agenesis

CFTR is required for normal development of the Wolffian duct derivatives. Congenital bilateral absence of the vas deferens (CBAVD) occurs in approximately 97-98% of males with CF due to inspissation and atresia of the vas deferens during fetal development. CBAVD causes obstructive azoospermia and male infertility. Notably, CBAVD can occur as an isolated finding in males who carry one or two CFTR mutations with residual function, representing a CFTR-related disorder.

Downstream

Male Infertility

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review confirms infertility as an established complication of CF.

Sinonasal Disease

CFTR dysfunction in the sinonasal epithelium causes mucus retention and chronic inflammation in the paranasal sinuses. Chronic rhinosinusitis affects nearly all CF patients. Nasal polyposis occurs in 10-32% of CF patients and is unusual in children without CF, making it an important diagnostic clue.

Downstream

Nasal Polyposis

Chronic Sinusitis

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists sinusitis among established complications of CF.

CF Bone Disease

CF-related bone disease results from multiple converging mechanisms including vitamin D deficiency from fat malabsorption, chronic systemic inflammation with elevated cytokines (IL-6, TNF-alpha) that promote osteoclast activity, reduced physical activity, delayed puberty with reduced sex steroids, glucocorticoid use, and possibly direct CFTR effects on osteoblast function. Osteopenia and osteoporosis are common in adults with CF.

Downstream

Osteoporosis

Show evidence (2 references)

PMID:15613415 SUPPORT Other

"Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and..."

Consensus summary listing the converging risk factors in this node. It names bone-active cytokines without specifying IL-6 or TNF-alpha, and does not discuss a direct CFTR effect on osteoblasts, which the description marks as possible.

PMID:15613415 SUPPORT Other

"Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures."

Supports the statement that low bone density is common in adults with CF.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 1

Portal Hypertension OCCASIONAL HP:0001409

Occurs in patients who progress to multilobular cirrhosis. May require portosystemic shunting or liver transplantation.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Liver and pancreatic dysfunction in CF includes cirrhosis leading to portal hypertension.

Digestive 8

Exocrine Pancreatic Insufficiency VERY_FREQUENT HP:0001738

Present in 85-90% of CF patients, typically those with two severe CFTR mutations. Patients with at least one mild mutation may retain pancreatic sufficiency.

Show evidence (2 references)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Clinical review identifies pancreatic insufficiency as a defining characteristic of cystic fibrosis.

ORPHA:586 SUPPORT Other

"HP:0001738 | Exocrine pancreatic insufficiency | Very frequent (99-80%)"

Orphanet's HPO annotation independently supports exocrine pancreatic insufficiency as a very frequent cystic fibrosis phenotype.

Steatorrhea VERY_FREQUENT HP:0002570

A classic presenting symptom of CF in infancy and early childhood.

Show evidence (1 reference)

PMID:33178516 SUPPORT Human clinical

"It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."

Review confirms steatorrhea as a classic presentation of cystic fibrosis due to malabsorption.

Meconium Ileus OCCASIONAL HP:0004401

Present in 15-20% of CF newborns. May be complicated by volvulus, atresia, or perforation. Meconium ileus in a neonate is highly suggestive of CF.

Show evidence (2 references)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists bowel obstruction (including meconium ileus) among established complications of CF.

ORPHA:586 SUPPORT Other

"HP:0004401 | Meconium ileus | Occasional (29-5%)"

Orphanet's HPO annotation independently supports meconium ileus as an occasional cystic fibrosis phenotype.

Distal Intestinal Obstruction Syndrome OCCASIONAL HP:0005214

Occurs in approximately 10-15% of CF patients. Risk factors include pancreatic insufficiency, dehydration, and inadequate enzyme replacement.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Bowel obstruction including DIOS is an established complication in CF patients.

Rectal Prolapse OCCASIONAL HP:0002035

Less common since advent of newborn screening and early treatment.

Show evidence (1 reference)

ORPHA:586 SUPPORT Other

"HP:0002035 | Rectal prolapse | Occasional (29-5%)"

Orphanet's HPO annotation independently supports rectal prolapse as an occasional cystic fibrosis phenotype.

Gastroesophageal Reflux FREQUENT HP:0002020

Show evidence (2 references)

PMID:33202431 SUPPORT Human clinical

"The overall incidence of GERD was 46% (range, 19-81%), derived from seven studies (n = 212 patients)."

Systematic review supporting the FREQUENT frequency in children with CF.

PMID:33202431 SUPPORT Human clinical

"Gastroesophageal reflux disease (GERD) is associated with accelerated decline in lung health in children with cystic fibrosis (CF)."

Supports the statement that reflux may worsen lung disease.

Focal Biliary Cirrhosis OCCASIONAL HP:0002613

CF liver disease is the third leading cause of CF mortality. Ursodeoxycholic acid may slow progression.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists hepatobiliary disease among established complications of CF.

Fat-Soluble Vitamin Deficiency VERY_FREQUENT Malabsorption HP:0002024

Routine supplementation of fat-soluble vitamins is standard of care.

Show evidence (2 references)

PMID:33526571 SUPPORT Human clinical

Malabsorption from pancreatic insufficiency causes vitamin deficiencies.

ORPHA:586 SUPPORT Other

"HP:0002024 | Malabsorption | Very frequent (99-80%)"

Orphanet's HPO annotation independently supports malabsorption as a very frequent cystic fibrosis phenotype.

Endocrine 2

Delayed Puberty FREQUENT HP:0000823

More common when nutritional status is poor.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Malnutrition from pancreatic insufficiency contributes to delayed puberty in CF patients.

Genitourinary 2

Male Infertility VERY_FREQUENT HP:0003251

CBAVD can also occur as an isolated finding in males carrying one or two CFTR mutations, representing a CFTR-related disorder.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists infertility among the established complications of cystic fibrosis.

Reduced Female Fertility FREQUENT Female infertility HP:0008222

Not absolute infertility; many CF women conceive, especially with improved health status on modulator therapy.

Show evidence (2 references)

PMID:42167573 SUPPORT Other

"Infertility has historically affected approximately 37% of females with CF (FwCF) who attempt conception-more than twice the general population rate-driven by mechanisms including altered cervical mucus, ovulatory dysfunction, and impaired uterine pH."

Supports the frequency and the mechanisms in the description.

PMID:42167573 SUPPORT Other

"Since FDA approval of elexacaftor/tezacaftor/ivacaftor in 2019, pregnancy rates among FwCF have more than doubled."

Supports improved fertility with CFTR modulator therapy.

Head and Neck 2

Nasal Polyposis FREQUENT HP:0100582

Present in 10-32% of CF patients. In children, nasal polyps are uncommon outside of CF and should trigger sweat testing.

Chronic Sinusitis VERY_FREQUENT HP:0011109

Radiographic sinusitis is nearly universal; symptomatic disease varies.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists sinusitis among established complications of CF.

Immune 1

Recurrent Respiratory Infections VERY_FREQUENT HP:0002205

Chronic Pseudomonas aeruginosa and Staphylococcus aureus infections are hallmarks of CF lung disease.

Show evidence (2 references)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Clinical review identifies chronic airway infection as a defining characteristic of cystic fibrosis.

ORPHA:586 SUPPORT Other

"HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"

Orphanet's HPO annotation independently supports recurrent respiratory infections as a very frequent cystic fibrosis phenotype.

Limbs 1

Digital Clubbing FREQUENT HP:0001217

Develops with progression of lung disease; correlates with severity.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Progressive obstructive lung disease leads to chronic hypoxemia and clubbing.

Metabolism 1

Hyponatremic Dehydration OCCASIONAL Hyponatremia HP:0002902

Can be a presenting feature in infancy. Salt supplementation is recommended.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

Clinical review lists hyponatremic dehydration among established complications of CF.

Musculoskeletal 1

Osteoporosis OCCASIONAL HP:0000939

Bone density screening with DXA recommended for adults with CF.

Show evidence (3 references)

PMID:19949942 SUPPORT Human clinical

"The pooled prevalence of osteoporosis in adults with cystic fibrosis was 23.5% (95% CI, 16.6-31.0)."

Meta-analysis of 12 adult cohorts (1,055 patients); 23.5% places osteoporosis in the OCCASIONAL (5-29%) band.

PMID:19949942 SUPPORT Human clinical

"The pooled prevalences of radiological vertebral fractures and nonvertebral fractures were 14% (95% CI, 7.8-21.7) and 19.7% (95% CI, 6.0-38.8), respectively."

Supports increased fracture risk, including vertebral fractures. Rib fractures are not reported separately.

PMID:15613415 SUPPORT Other

"decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy"

CF Foundation consensus summary listing the risk factors named in the description.

Respiratory 4

Chronic Productive Cough VERY_FREQUENT HP:0031245

One of the classic presenting symptoms of CF along with steatorrhea and failure to thrive.

Show evidence (1 reference)

PMID:33178516 SUPPORT Human clinical

"It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."

Review confirms chronic productive cough as a classic presentation of cystic fibrosis.

Bronchiectasis VERY_FREQUENT HP:0002110

Progressive and eventually universal in CF patients; the primary driver of morbidity and mortality.

Show evidence (2 references)

PMID:30986316 SUPPORT Human clinical

"This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."

Clinical review confirms progressive bronchiectasis as a consequence of chronic airway infection in CF.

ORPHA:586 SUPPORT Other

"HP:0002110 | Bronchiectasis | Very frequent (99-80%)"

Orphanet's HPO annotation independently supports bronchiectasis as a very frequent cystic fibrosis phenotype.

Hemoptysis FREQUENT HP:0002105

Minor hemoptysis is common; massive hemoptysis occurs in 4-5% of patients.

Show evidence (2 references)

PMID:16100161 SUPPORT Human clinical

"Massive hemoptysis occurred with an average annual incidence of 0.87% and in 4.1% of patients overall."

US registry cohort of 28,858 patients, supporting the frequency of massive hemoptysis in the notes. It does not measure minor hemoptysis, which the FREQUENT frequency rests on.

PMID:16100161 SUPPORT Human clinical

"Massive hemoptysis is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease."

Supports massive hemoptysis as a serious complication tied to advanced lung disease.

Pneumothorax VERY_RARE HP:0002107

Occurs in 3-4% of CF patients; recurrence rate is high.

Show evidence (2 references)

PMID:16100160 SUPPORT Human clinical

"Pneumothorax occurred with an average annual incidence of 0.64% and in 3.4% of patients overall."

US registry cohort of 28,858 patients supporting the 3-4% figure in the notes and the VERY_RARE (<5%) frequency.

PMID:16100160 SUPPORT Human clinical

"Pneumothorax is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease."

Supports the link to advanced lung disease; the same study reports FEV1 below 30% predicted as a risk factor.

Growth 2

Failure to Thrive VERY_FREQUENT HP:0001508

A classic presenting feature, especially before newborn screening era. Nutritional status strongly correlates with lung function and survival.

Show evidence (1 reference)

PMID:33178516 SUPPORT Human clinical

"It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."

Review confirms failure to thrive as a classic presentation of cystic fibrosis.

Short Stature FREQUENT HP:0004322

Improved with optimized nutritional support and CFTR modulator therapy.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Malnutrition from pancreatic insufficiency contributes to growth failure and short stature.

Other 1

Allergic Bronchopulmonary Aspergillosis OCCASIONAL MONDO:0015243

Affects 2-15% of CF patients; requires high index of suspicion.

Show evidence (2 references)

PMID:41537324 SUPPORT Other

"Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus, commonly found in patients with cystic fibrosis and severe asthma"

Supports ABPA as a hypersensitivity reaction to A. fumigatus occurring in CF.

PMID:41537324 SUPPORT Other

"It leads to bronchial inflammation, excessive mucus secretion, and progressive lung function decline."

Supports the airway consequences in the description.

🧬

Genetic Associations

CFTR (Causative)

Gene: CFTR hgnc:1884 gene page

Show evidence (3 references)

PMID:31697873 SUPPORT Human clinical

"Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation."

Phase 3 trial confirms CFTR mutations cause CF and F508del is the most common mutation.

PMID:23974870 SUPPORT Human clinical

"Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis."

CFTR2 project establishes the scope of CFTR variant heterogeneity.

PMID:23974870 SUPPORT Human clinical

"we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe"

CFTR2 project provides the largest systematic analysis of CFTR variant-disease relationships.

Variants (6)

F508del (Phe508del)

Deletion of phenylalanine at position 508 in the CFTR protein. The most common CF-causing mutation, present on at least one allele in nearly 90% of CF patients. Causes misfolding of CFTR protein leading to endoplasmic reticulum retention, proteasomal degradation, and near-complete absence of CFTR at the cell surface (Class II defect). The small amount of protein reaching the surface also has reduced channel open probability (Class III) and reduced stability (Class VI).

Show evidence (1 reference)

PMID:31697873 SUPPORT Human clinical

"nearly 90% of patients have at least one copy of the Phe508del CFTR mutation"

Confirms F508del is present in nearly 90% of CF patients.

G551D (Gly551Asp)

Missense mutation causing glycine-to-aspartate substitution at position 551. CFTR protein reaches the cell surface normally but has severely reduced channel gating (Class III defect). The first CFTR mutation for which targeted modulator therapy (ivacaftor) was approved, producing dramatic clinical benefit.

Show evidence (1 reference)

PMID:22047557 SUPPORT Human clinical

"The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001)."

Landmark Phase 3 trial demonstrating ivacaftor efficacy in G551D patients.

G542X

Nonsense mutation creating a premature stop codon at position 542. No functional CFTR protein is produced (Class I defect). One of the most common severe mutations after F508del.

Show evidence (1 reference)

PMID:23974870 SUPPORT Human clinical

"These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."

CFTR2 project establishes disease liability of common CFTR variants including nonsense mutations.

W1282X

Nonsense mutation at position 1282 causing premature termination. Class I defect with no functional protein produced. Common in Ashkenazi Jewish populations.

Show evidence (1 reference)

PMID:23974870 SUPPORT Human clinical

"These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."

CFTR2 project classifies W1282X as a disease-causing variant.

N1303K

Missense mutation causing protein misfolding and degradation similar to F508del (Class II defect).

Show evidence (1 reference)

PMID:23974870 SUPPORT Human clinical

"These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."

CFTR2 project evaluates N1303K as a disease-causing variant.

R117H

Missense mutation producing CFTR with reduced chloride conductance (Class IV defect). Associated with variable phenotype depending on the polythymidine tract variant (5T, 7T, 9T) on the same allele. R117H-5T causes more severe disease; R117H-7T may cause CFTR-related disorder or be benign.

SLC26A9 (Modifier)

Gene: SLC26A9 relationship_type: MODIFIER

Show evidence (2 references)

PMID:30807572 SUPPORT Human clinical

"With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on..."

Genome-wide significant, replicated association of the SLC26A9 locus with meconium ileus in more than 6,500 people with cystic fibrosis. The trait is meconium ileus specifically, not cystic fibrosis susceptibility or lung disease severity.

PMID:30807572 SUPPORT Human clinical

"The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine."

Transcriptome integration assigns the regulatory effect of the SLC26A9 locus to the pancreas rather than the intestine, which is what makes the contributing tissue, and not just the contributing gene, part of the claim.

ATP12A (Modifier)

Gene: ATP12A relationship_type: MODIFIER

Show evidence (1 reference)

PMID:30807572 SUPPORT Human clinical

Reports ATP12A as a newly identified genome-wide significant modifier locus for meconium ileus in the consortium analysis.

SLC6A14 (Modifier)

Gene: SLC6A14 relationship_type: MODIFIER

Show evidence (2 references)

PMID:30807572 SUPPORT Human clinical

Reports the replicated genome-wide significant SLC6A14 locus for meconium ileus in the consortium analysis.

PMID:30807572 SUPPORT Human clinical

"Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4))."

Separates the lung-disease-severity signal from the meconium ileus signal and ties it to airway-specific regulation of SLC6A14 in cystic fibrosis nasal epithelium, supporting an organ-specific modifier effect.

🗃️

External Assertions

Orphanet Cystic fibrosis record

Orphanet structured disease record ORPHA:586

Orphanet structured record for cystic fibrosis, including synonyms, definition, inheritance, natural history, epidemiology, genes, HPO phenotypes, and cross-references.

Show evidence (2 references)

ORPHA:586 SUPPORT Other

"MONDO:0009061 | Exact"

Orphanet cross-references ORPHA:586 exactly to MONDO:0009061.

ORPHA:586 SUPPORT Other

"OMIM:219700 | Exact"

Orphanet cross-references ORPHA:586 exactly to OMIM:219700.

💊

Medical Actions

Elexacaftor-Tezacaftor-Ivacaftor (Trikafta/Kaftrio)

Action: Pharmacotherapy NCIT:C15986

Agent: elexacaftor NCIT:C169935 tezacaftor NCIT:C152581 ivacaftor CHEBI:66901

Triple combination CFTR modulator therapy containing two correctors (elexacaftor, tezacaftor) that improve F508del-CFTR folding and trafficking to the cell surface, plus a potentiator (ivacaftor) that increases channel open probability. Approved for patients aged 2+ years with at least one F508del allele, covering approximately 90% of CF patients. Produces dramatic improvements in lung function, nutritional status, and quality of life.

Show evidence (6 references)

PMID:31697873 SUPPORT Human clinical

"Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower"

Phase 3 RCT demonstrates significant improvement in lung function and 63% reduction in pulmonary exacerbations with Trikafta.

PMID:31697873 SUPPORT Human clinical

"a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised...that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower"

Trikafta also improves quality of life scores and reduces sweat chloride, a biomarker of CFTR function.

PMID:41702741 SUPPORT Other

"The introduction of CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) has significantly altered the nutritional trajectory of children with cystic fibrosis (cwCF)."

Consensus-based guidance recognizes elexacaftor/tezacaftor/ivacaftor as the CFTR modulator that has altered the clinical and nutritional trajectory of children with cystic fibrosis.

+ 3 more references

Ivacaftor (Kalydeco)

Action: Pharmacotherapy NCIT:C15986

Agent: ivacaftor CHEBI:66901

CFTR potentiator that increases the channel open probability of CFTR protein at the cell surface. First approved CFTR modulator, initially for G551D mutation and subsequently expanded to other gating mutations. As monotherapy, effective only for mutations where CFTR reaches the cell surface (Class III, IV, V mutations).

Show evidence (3 references)

PMID:22047557 SUPPORT Human clinical

"The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001)."

Landmark Phase 3 trial demonstrating sustained lung function improvement with ivacaftor in G551D patients.

PMID:22047557 SUPPORT Human clinical

"Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48"

Beyond lung function, the pivotal ivacaftor trial reduced the risk of pulmonary exacerbations by 55% through 48 weeks, a distinct clinical benefit of CFTR potentiation.

PMID:22047557 SUPPORT Human clinical

"By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo"

Ivacaftor also improved nutritional status (2.7 kg greater weight gain than placebo at 48 weeks), reflecting systemic CFTR restoration beyond the airway.

Airway Clearance Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Chest physiotherapy techniques to mobilize and clear airway secretions. Includes manual chest percussion and postural drainage, oscillating positive expiratory pressure devices (e.g., Flutter, Acapella), high-frequency chest wall oscillation vests, autogenic drainage, and regular exercise. Performed daily; no technique has been shown to be clearly superior to the others.

Show evidence (3 references)

PMID:30676656 SUPPORT Other

"To clear their lungs of mucus, people with cystic fibrosis perform airway clearance techniques daily."

States the purpose of airway clearance in CF and that it is a daily routine.

PMID:30676656 SUPPORT Other

"There are a variety of airway clearance techniques, including conventional chest physiotherapy, positive expiratory pressure (PEP) therapy, high-pressure PEP therapy, active cycle of breathing techniques, autogenic drainage, airway oscillating devices"

Supports the range of techniques listed in the description.

PMID:30676656 SUPPORT Other

"We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV1, except for reporting no difference between PEP therapy and oscillating devices after six months of treatment"

Overview of six Cochrane reviews finding no technique clearly superior to another, which is why technique choice is individualized.

Dornase Alfa (Pulmozyme)

Action: Pharmacotherapy NCIT:C15986

Agent: dornase alfa NCIT:C81664

Inhaled recombinant human DNase that cleaves extracellular DNA released from necrotic neutrophils in CF sputum, reducing mucus viscosity and improving airway clearance. Recommended for daily use in most CF patients.

Show evidence (1 reference)

PMID:8874241 SUPPORT Human clinical

"Dornase alfa improved the mean percent change in FEV1 from baseline by 9.4% compared with 2.1% for placebo (p < 0.001)."

Randomized controlled trial demonstrates significant improvement in lung function with dornase alfa.

Hypertonic Saline (7%)

Action: Pharmacotherapy NCIT:C15986

Agent: sodium chloride CHEBI:26710

Platform: Small molecule

Inhaled nebulized hypertonic saline that osmotically draws water onto the airway surface, rehydrating the periciliary layer and improving mucociliary clearance. Used as adjunctive therapy to improve mucus mobilization.

Show evidence (3 references)

PMID:16421365 SUPPORT Human clinical

"In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit."

Randomized trial in 24 patients linking the sustained increase in mucus clearance to osmotic hydration of the airway surface, which is the mechanism in the description.

PMID:16421364 SUPPORT Human clinical

"The hypertonic-saline group also had significantly fewer pulmonary exacerbations (relative reduction, 56 percent; P=0.02)"

48-week randomized trial in 164 patients showing clinical benefit of adjunctive 7% saline.

PMID:16421364 SUPPORT Human clinical

"Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis."

Supports use as adjunctive therapy.

Inhaled Antibiotics

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Chronic suppressive inhaled antibiotic therapy for patients with chronic Pseudomonas aeruginosa infection. Inhaled tobramycin (alternating months) and inhaled aztreonam lysine are most commonly used. Reduces bacterial density, decreases hospitalization, and improves lung function.

Show evidence (1 reference)

PMID:9878641 SUPPORT Human clinical

"intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization."

Two placebo-controlled trials in 520 patients with P. aeruginosa infection, using four-weeks-on, four-weeks-off cycles, supporting the reduced bacterial density and the lung function benefit in the description.

Systemic Antibiotics

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Oral and intravenous antibiotics for acute pulmonary exacerbations and chronic suppressive therapy. Azithromycin is used chronically for its anti-inflammatory and anti-Pseudomonal properties. IV antibiotic courses (typically 14-21 days) target specific pathogens identified on sputum culture.

Show evidence (2 references)

PMID:14519709 SUPPORT Human clinical

"Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03)"

Placebo-controlled trial of chronic oral azithromycin in 185 patients chronically infected with P. aeruginosa, supporting chronic azithromycin use. It supports the azithromycin claim only; the intravenous exacerbation courses in the description are not covered by this item.

PMID:14519709 SUPPORT Human clinical

"The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group"

Supports the lung function benefit of chronic azithromycin.

Pancreatic Enzyme Replacement Therapy (PERT)

Action: Pharmacotherapy NCIT:C15986

Oral pancreatic enzyme supplements (lipase, protease, amylase) taken with all meals and snacks to replace deficient endogenous enzymes. Dosing is individualized based on fat intake and symptoms. Essential for maintaining adequate nutrition in pancreatic-insufficient patients.

Show evidence (1 reference)

PMID:32761612 SUPPORT Other

"Most people with cystic fibrosis (CF) (80% to 90%) need pancreatic enzyme replacement therapy (PERT) to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed."

Cochrane review background supporting PERT with all food, individualized dosing, and its role in preventing malnutrition.

Nutritional Support

Action: Nutritional Support NCIT:C15433

High-calorie, high-fat diet with fat-soluble vitamin supplementation (A, D, E, K) and sodium chloride supplementation. CF patients have increased caloric requirements (120-150% of normal) due to malabsorption, chronic infection, and increased work of breathing. Enteral tube feeding may be needed for patients unable to maintain adequate weight.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

"Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific..."

Evidence-based guidelines emphasize optimization of nutritional health for CF patients.

Insulin Therapy for CFRD

Action: Pharmacotherapy NCIT:C15986

Agent: insulin CHEBI:145810

Platform: Protein replacement

Insulin is the recommended treatment for CF-related diabetes. Oral hypoglycemic agents are not recommended outside research trials because they are less effective than insulin in improving nutritional and metabolic outcomes. Insulin improves nutritional status and lung function in addition to glycemic control.

Show evidence (3 references)

PMID:21115772 SUPPORT Other

"Patients with CFRD should be treated with insulin therapy."

ADA/CFF guideline recommendation supporting insulin as the recommended treatment.

PMID:21115772 SUPPORT Other

"Oral diabetes agents are not as effective as insulin in improving nutritional and metabolic outcomes in CFRD and are not recommended outside the context of clinical research trials."

Supports the statement that oral agents are not recommended. The guideline gives lower efficacy as the reason.

PMID:21115772 SUPPORT Other

"There is evidence that CF patients on insulin therapy who achieve glycemic control demonstrate improvement in weight, protein anabolism, pulmonary function, and survival."

Supports the nutritional and lung function benefits of insulin.

Ursodeoxycholic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: ursodeoxycholic acid CHEBI:9907

Hydrophilic bile acid used to improve bile flow and potentially slow progression of CF liver disease. Commonly prescribed for patients with elevated liver enzymes or evidence of focal biliary cirrhosis, though evidence for long-term clinical benefit is limited.

Show evidence (2 references)

PMID:28891588 SUPPORT Other

"There were no data available for analysis for long-term outcomes such as death or need for liver transplantation."

Cochrane review of randomized trials supporting the statement that long-term clinical benefit is unproven.

PMID:28891588 SUPPORT Other

"There is currently insufficient evidence to justify its routine use in cystic fibrosis."

Supports the limited evidence base for UDCA in CF liver disease.

Lung Transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

Bilateral lung transplantation is offered for end-stage CF lung disease when predicted survival without transplant is limited (typically FEV1 <30% predicted with rapid decline). Five-year survival after transplant is approximately 50-60%. CF lung disease does not recur in the transplanted lungs, but immunosuppression-related complications and chronic rejection (bronchiolitis obliterans syndrome) limit long-term outcomes.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."

Respiratory failure as the leading cause of death necessitates lung transplantation for end-stage disease.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for patients and families regarding autosomal recessive inheritance, carrier testing for at-risk relatives, prenatal diagnosis options, and reproductive planning. Carrier frequency is approximately 1 in 25 in European-descent populations.

🌍

Environmental Factors

Pseudomonas aeruginosa

Transition from non-mucoid to mucoid phenotype is a milestone event in CF.

The most important pathogen in CF lung disease. Initial acquisition of non-mucoid strains progresses to chronic infection with mucoid, alginate-producing phenotypes that form antibiotic-resistant biofilms. Chronic Pseudomonas infection is associated with accelerated decline in lung function and increased mortality. Early eradication protocols aim to delay chronic colonization.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Chronic endobronchial infection including Pseudomonas is a defining characteristic of CF.

Mechanism Target:

TRIGGERS Chronic Bacterial Infection — The node describes this species becoming the dominant pathogen in adolescence and adulthood and transitioning to a mucoid biofilm phenotype, so colonisation by it is the node's own content.

Show evidence (2 references)

PMID:42198683 SUPPORT Other

"Defective cystic fibrosis transmembrane conductance regulator (CFTR) function disrupts airway hydration and mucociliary clearance, creating a microenvironment that facilitates infection, particularly with Pseudomonas aeruginosa (P. aeruginosa)"

Names this organism as the one the CF airway microenvironment particularly facilitates infection by, and reaches it through the hydration and clearance defects this entry models upstream. A review, so tagged accordingly, but one about CF airway infection rather than a sentence borrowed from a paper on another subject.

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Names chronic endobronchial airway infection as a defining feature. It supports the node but does not name this organism, which is why the organism-specific sentence above is the primary support for the link.

Staphylococcus aureus

Most common respiratory pathogen in young CF children.

Often the first pathogen to colonize CF airways in infancy. Both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains are common. MRSA infection is associated with worse survival.

Show evidence (2 references)

PMID:34578208 SUPPORT REVIEW SYNTHESIS Other

"Staphylococcus aureus is one of the first pathogens detectable in the airways of young CF patients and the bacterium with the highest prevalence at an early age. Already among children younger than two years of age its prevalence exceeds 50%"

Supports early acquisition and the notes' claim that S. aureus is the most common pathogen in young children with CF.

PMID:20551409 SUPPORT Human clinical

"After adjustment for time-varying covariates associated with severity of illness, MRSA remained associated with a higher risk of death (1.27; 95% CI, 1.11-1.45)."

Registry cohort of 19,833 US patients in which respiratory MRSA was associated with higher mortality after adjustment for disease severity, supporting the MRSA outcome claim in the description.

Mechanism Target:

TRIGGERS Chronic Bacterial Infection — Staphylococcus aureus is one of the first organisms to colonise the CF airway and the most prevalent pathogen in early childhood, so its acquisition is one of the routes into the chronic infection this node describes.

Show evidence (1 reference)

PMID:34578208 SUPPORT REVIEW SYNTHESIS Other

"Staphylococcus aureus is next to Pseudomonas aeruginosa the most isolated pathogen from the airways of cystic fibrosis (CF) patients, who are often infected by a dominant S. aureus clone for extended periods."

States that CF airways are often infected by a dominant S. aureus clone for extended periods, which is persistent airway infection by this organism.

Burkholderia cepacia complex

Infection control and patient segregation are critical.

Highly virulent group of gram-negative bacteria associated with greater impairment of lung function than Pseudomonas aeruginosa and, in a minority of infected patients, with cepacia syndrome: an acute necrotizing pneumonia with rapid respiratory failure and high mortality. Burkholderia cenocepacia is the species most often reported in cepacia syndrome.

Show evidence (3 references)

PMID:36815622 SUPPORT Human clinical

"Cepacia syndrome (CS) is an acute, necrotizing pneumonia with a high mortality rate, occurring in patients with cystic fibrosis (CF) infected with Burkholderia cepacia complex (BCC)."

Defines cepacia syndrome as a complication of this infection in CF.

PMID:36815622 SUPPORT Human clinical

"Burkholderia cenocepacia was the most frequently reported causative agent."

In the 18 published cepacia syndrome cases reviewed, B. cenocepacia was the species most often reported.

PMID:6420530 SUPPORT Human clinical

"A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate has occurred in eight patients over the past 3 years, with a 62% fatality rate."

The original description of cepacia syndrome, supporting rapid and often fatal respiratory decline.

Mechanism Target:

TRIGGERS Chronic Bacterial Infection — Burkholderia cepacia complex is one of the pathogens this node names. Infection with it causes worse lung function than Pseudomonas aeruginosa infection, and in some patients progresses to cepacia syndrome.

Show evidence (1 reference)

PMID:6420530 SUPPORT Human clinical

"Patients infected with P. cepacia have greater impairment of pulmonary function than those with P. aeruginosa."

Clinic cohort of about 500 CF patients in which infection with this organism (then named Pseudomonas cepacia) was associated with worse pulmonary function than P. aeruginosa infection.

Non-tuberculous Mycobacteria

Screening sputum cultures recommended annually.

Mycobacterium abscessus complex and Mycobacterium avium complex are the species most often isolated in CF, and NTM-positive cultures have become more common. M. abscessus is associated with greater morbidity and mortality and faster lung function decline. NTM pulmonary disease must be assessed in lung transplant candidates.

Show evidence (4 references)

PMID:26666259 SUPPORT Other

"Non-tuberculous mycobacteria (NTM) are increasingly being isolated from the sputum of adults and children with cystic fibrosis (CF), both in North America and in Europe."

Supports rising recognition of NTM in CF.

PMID:26666259 SUPPORT Other

"individuals with MABSC-positive cultures are more likely to meet American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) criteria for diagnosing NTM pulmonary disease (NTM-PD, see Diagnosis of NTM-PD in CF section), and have worse morbidity and mortality associated with a..."

Supports the greater severity of M. abscessus complex infection stated in the description.

PMID:26666259 SUPPORT Other

"Recommendation 2: The CF Foundation and the ECFS recommend that cultures for NTM be performed annually in spontaneously expectorating individuals with a stable clinical course."

Supports the annual screening recommendation in the notes.

+ 1 more reference

Mechanism Target:

TRIGGERS Chronic Bacterial Infection — Non-tuberculous mycobacteria are environmental organisms that cause chronic pulmonary infection in CF, and are among the pathogens this node names.

Show evidence (1 reference)

PMID:26666259 SUPPORT Other

"Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF)."

Consensus statement naming chronic pulmonary infection by these environmental organisms in CF, which is this exposure acting on this node.

Aspergillus fumigatus

ABPA is treated with systemic corticosteroids and antifungal agents, with the monoclonal antibodies omalizumab or mepolizumab as further options.

Fungal colonization of CF airways that can trigger allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity response causing bronchial inflammation, mucus hypersecretion and progressive lung function decline.

Show evidence (3 references)

PMID:41537324 SUPPORT Other

"Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus, commonly found in patients with cystic fibrosis and severe asthma"

Supports this organism as the trigger of a hypersensitivity response (ABPA) that is common in CF.

PMID:41537324 SUPPORT Other

"It leads to bronchial inflammation, excessive mucus secretion, and progressive lung function decline."

Supports the consequences of ABPA stated in the description.

PMID:41537324 SUPPORT Other

"Treatments include systemic corticosteroids, antifungals, and monoclonal antibodies such as omalizumab and mepolizumab."

Supports the treatment statement in the notes.

Mechanism Target:

TRIGGERS Allergic Bronchopulmonary Aspergillosis — The only link in this entry that targets a phenotype rather than a pathophysiology node, which the schema and the target test both allow for an exposure acting directly on a manifestation. The phenotype is a hypersensitivity response to colonisation by this organism, so the exposure is named in the target's own description.

Show evidence (1 reference)

PMID:41537324 SUPPORT Other

"Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus, commonly found in patients with cystic fibrosis and severe asthma"

Defines the target as a hypersensitivity reaction to this organism and places it in this disease specifically. Exposure and target in one sentence.

Tobacco Smoke Exposure

Strict avoidance counseling is part of standard CF care. Bound to ECTO:6000029 (exposure to tobacco smoking) rather than ECTO:0100013 (exposure to tobacco), whose definition is "An exposure event involving nicotine tobacco consumption" and so fits the passive half of this entry even less well than the smoking term does. ECTO:7000059 (exposure to smoke) was not used because it drops tobacco entirely. ECTO has no secondhand-smoke term, so no available term covers both routes; the smoking term is the closest anchor, and the "both active and passive" scope is carried by the description and by preferred_term rather than by the binding.

Tobacco smoke exposure, studied mostly as secondhand exposure in children, is associated with lower lung function in CF. Ending the exposure is associated with fewer pulmonary exacerbations and better lung function, so it is a modifiable risk factor, especially in children.

Show evidence (3 references)

PMID:37142525 SUPPORT Human clinical

"Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV1 (estimated decrease: -5.11% predicted; 95% CI: -7.20, -3.47)."

Meta-analysis of six pediatric CF studies finding lower FEV1 with secondhand smoke exposure.

PMID:34281808 SUPPORT Human clinical

"Cessation of smoke exposure reduced the odds of a pulmonary exacerbation in 12 months by 17% (OR 0.83, p < 0.001) in the first year of cessation"

US registry analysis of 3,633 children and adolescents showing that ending smoke exposure is associated with fewer exacerbations, which is what makes the exposure modifiable.

PMID:34281808 SUPPORT Human clinical

"Both smoking cessation and exposure prevention should be prioritized in pediatric CF care."

Supports avoidance counseling as part of CF care, as stated in the notes.

Air Pollution

Epidemiologic association; exposure minimization recommended.

Ambient air pollution (fine and coarse particulate matter, ozone) is associated with increased pulmonary exacerbation rates and lower lung function in CF.

Show evidence (2 references)

PMID:14718248 SUPPORT Human clinical

"Annual average exposures to particulate air pollution was associated with an increased risk of pulmonary exacerbations and a decline in lung function, suggesting a role of environmental exposures on prognosis in CF."

US registry cohort linking residential air pollution to exacerbations and lung function.

PMID:14718248 SUPPORT Human clinical

"a 10-ppb rise in ozone was associated with a 10% (95% CI, 3-17%) increase in odds of two or more exacerbations"

Supports ozone as one of the pollutants in the description.

🔬

Biochemical Markers

Sweat Chloride (Elevated)

Context: Sweat chloride >=60 mmol/L is diagnostic of CF; 30-59 mmol/L is intermediate and requires further evaluation; <30 mmol/L makes CF unlikely.

Show evidence (3 references)

PMID:30986316 SUPPORT Human clinical

"Diagnosis of CF is confirmed by demonstration of elevated sweat chloride."

Elevated sweat chloride is the diagnostic hallmark of CF.

PMID:28129811 SUPPORT Human clinical

"It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test."

CF Foundation consensus guidelines recommend sweat chloride testing for all CFTR-related diagnoses.

ORPHA:586 SUPPORT Other

"HP:0012236 | Elevated sweat chloride | Very frequent (99-80%)"

Orphanet's HPO annotation independently supports elevated sweat chloride as a very frequent cystic fibrosis finding.

Immunoreactive Trypsinogen (IRT) (Elevated)

Context: Elevated in newborn dried blood spots; used as first-tier newborn screening test. Elevated IRT reflects pancreatic injury in utero.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Most cases of CF are identified through newborn screening (NBS)."

Newborn screening using IRT is the primary method of CF identification.

Fecal Elastase (Decreased)

Context: Fecal elastase-1 <200 mcg/g indicates pancreatic insufficiency; <100 mcg/g indicates severe insufficiency. Used to confirm exocrine pancreatic function status.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Pancreatic insufficiency is assessed using fecal elastase measurements.

Fat-Soluble Vitamins (A, D, E, K) (Decreased)

Context: Deficiencies common due to fat malabsorption in pancreatic-insufficient patients. Levels should be monitored annually.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Malabsorption from pancreatic insufficiency causes fat-soluble vitamin deficiencies.

Liver Enzymes (Variable)

Context: Elevated ALT, AST, and GGT may indicate CF liver disease. GGT is often the first to elevate.

Show evidence (1 reference)

PMID:33526571 SUPPORT Human clinical

Liver dysfunction in CF is monitored using liver enzyme measurements.

Blood Glucose / HbA1c (Variable)

Context: Annual oral glucose tolerance test recommended from age 10 for CFRD screening. HbA1c is unreliable in CF due to increased red cell turnover.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."

CF-related diabetes requires monitoring of glucose levels.

Sputum Microbiology (Variable)

Context: Routine sputum cultures guide antibiotic therapy. Typical organisms include Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, and non-tuberculous mycobacteria.

Show evidence (1 reference)

PMID:30986316 SUPPORT Human clinical

"Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."

Chronic endobronchial infection is monitored through sputum microbiology.

Forced Expiratory Volume in 1 Second (FEV1) (Reduced with progressive obstructive lung disease; improves or declines more slowly with effective CFTR modulator therapy.)

Context: Spirometric pulmonary function measure (percent of predicted FEV1) used to grade obstructive lung disease severity, monitor progression, and assess pharmacodynamic response to CFTR modulator therapy. FEV1 is recognized by the FDA as a validated surrogate endpoint supporting traditional approval of cystic fibrosis drugs.

Pathograph Readouts

Pharmacodynamic marker of Small-Airway Obstruction Negative Regulatory surrogate

Higher or less-declining percent-predicted FEV1 indicates reduced small-airway obstruction; treatment-induced improvement in FEV1 reports the pharmacodynamic response to CFTR potentiator therapy and underpins the FDA surrogate-endpoint basis for traditional approval of cystic fibrosis drugs.

FDA-SE-adult-noncancer-017 FDA

Forced expiratory volume in 1 second (FEV1)

Traditional Validated surrogate endpoint

Patients with cystic fibrosis

FDA-SE-pediatric-noncancer-011 FDA

Forced expiratory volume in 1 second (FEV1)

Traditional Validated surrogate endpoint

Patients with cystic fibrosis

Show evidence (2 references)

PMID:22047557 SUPPORT Human clinical

"The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1))."

The pivotal randomized trial of the CFTR potentiator ivacaftor used percent-predicted FEV1 as its primary endpoint, establishing FEV1 as the pharmacodynamic readout for CFTR-modulator efficacy.

PMID:22047557 SUPPORT Human clinical

"The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group"

FEV1 improved measurably with CFTR potentiator therapy versus placebo, confirming FEV1 as a treatment-responsive pharmacodynamic marker of small-airway obstruction.

Show evidence (1 reference)

PMID:22047557 SUPPORT Human clinical

"Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks."

Spirometric lung function (FEV1) tracks treatment response in cystic fibrosis, supporting its use as a monitoring and pharmacodynamic biomarker.

Blood DNA methylation epigenetic age acceleration (Variable)

Context: Epigenetic age estimated from blood DNA methylation (Illumina EPIC v2 array) with an epigenetic clock and compared with chronological age. In an adult cohort of 52 people with CF starting elexacaftor/tezacaftor/ivacaftor (ETI), half had an epigenetic age above their chronological age at baseline and the other half below it; the accelerated half had lower FEV1. Research measure only, with no clinical decision threshold.

Pathograph Readouts

Correlates with Small-Airway Obstruction Positive Monitoring

Greater epigenetic age acceleration tracks lower percent-predicted FEV1, that is, more obstructive lung disease, before and after one year of ETI. Whether the clock adds information beyond spirometry is not established.

Show evidence (1 reference)

PMID:40724864 SUPPORT PRIMARY RESULT Human clinical

"we found that ER was negatively related to FEV1 both at T0 (slope = -0.348; p = 0.014) and T1 (slope = -0.423; p = 0.002)"

In 52 adults with CF, the epigenetic age ratio fell as FEV1 rose, at baseline and after one year of ETI, linking epigenetic age acceleration to the severity of obstructive lung disease.

Show evidence (5 references)

PMID:40724864 SUPPORT PRIMARY RESULT Human clinical

"In the remaining 26 (50%) the ratio was positive, with the epigenetic age being significantly higher than the chronological one."

Half of the 52-patient adult cohort had accelerated blood epigenetic age before starting ETI.

PMID:40724864 SUPPORT PRIMARY RESULT Human clinical

"The second group of CF subjects had an epigenetic age lower than the chronological one at T0 and lung function was better maintained."

The other half of the cohort was epigenetically younger than its chronological age, which is why presence is recorded as variable rather than increased.

PMID:40724864 SUPPORT PRIMARY RESULT Human clinical

"Half of the subjects had a significantly accelerated epigenetic age and a worse lung function. The therapy with ETI impacted on both the two parameters"

After one year of ETI, both the epigenetic age ratio and FEV1 improved in the accelerated group (Table 1: median ratio 8.1 at baseline, 3.2 at one year, p = 0.001). This is a single-arm before/after comparison.

+ 2 more references

🔬

Diagnosis

Sweat Chloride Test (Quantitative Pilocarpine Iontophoresis)

Gold standard diagnostic test for CF. Pilocarpine iontophoresis stimulates localized sweating; sweat is collected and chloride concentration measured. Chloride >=60 mmol/L is diagnostic, 30-59 mmol/L is intermediate, <30 mmol/L is CF-unlikely.

sweat electrolyte test NCIT:C18020

sweat chloride LOINC:2077-6

Reference Ranges

Chloride [Moles/volume] in Sweat (CF Foundation 2017 consensus diagnostic decision limits, all ages)

CF unlikely (< 30.0 mmol/L) Intermediate (30.0–60.0 mmol/L) Diagnostic of CF (≥ 60.0 mmol/L) → Elevated sweat chloride

CF unlikely: Below the intermediate threshold; CF is unlikely on sweat chloride alone.

Intermediate: Inconclusive; the consensus directs further evaluation of CFTR function and genotype, which the nasal potential difference and intestinal current measurement rows describe.

Diagnostic of CF: Supportive of the diagnosis of CF; in a screen-positive infant this result confirms it.

Two of the three boundaries come from the consensus itself and one from a guideline that adopts it: the 2017 CF Foundation nonscreened-population paper states that the intermediate threshold was lowered from 40 mmol/L to 30 mmol/L, and the 2025 Australasian sweat-testing guideline, written to align with the international consensus, states the intermediate result as values between 30 and 59 mmol/L for all ages and 60 mmol/L or more as supportive of a diagnosis of CF. The 2017 De Boeck and Vermeulen review words the confirmatory value as "above 60mmol/L", one point off the consensus "60 or more"; the band keeps the consensus boundary and the discrepancy is disclosed here rather than shifted. The half-open bands put exactly 30 in the intermediate band and exactly 60 in the diagnostic band, which agrees with both guideline statements.

Show evidence (4 references)

PMID:28129813 SUPPORT REVIEW SYNTHESIS Other

"On the basis of the large number of patients with bona fide CF currently followed in registries with sweat chloride levels between 30 and 40 mmol/L, the threshold considered "intermediate" was lowered from 40 mmol/L in the prior diagnostic guidelines to 30 mmol/L."

The CF Foundation 2017 consensus decision that sets the lower boundary of the intermediate band at 30 mmol/L.

PMID:40476459 SUPPORT REVIEW SYNTHESIS Other

"International consensus guidelines now recommend a standard set of clinical decision limits for sweat chloride, with values between 30 and 59 mmol/L, as the intermediate result for all ages."

States the intermediate band as the international consensus limits this range reproduces.

PMID:40476459 SUPPORT REVIEW SYNTHESIS Other

"Sweat chloride concentrations of ≥60 mmol/L are supportive of a diagnosis of CF."

States the lower boundary of the diagnostic band.

+ 1 more reference

Must be performed at a CF Foundation-accredited laboratory. Minimum sweat volume required for reliable results. Should be performed on two separate occasions. The measurement is bound at the method-less quantitative sweat chloride code (LOINC:2077-6), which is also the loinc_term of the Sweat Chloride biochemical marker; the screen-method codes (LOINC:56448-4, LOINC:105200-0) and the chloride-and-sodium panel (LOINC:74993-7) exist in the Monarch KG and are deliberately not bound, as the quantitative pilocarpine iontophoresis measurement is the one the decision limits apply to.

Show evidence (3 references)

PMID:28576637 SUPPORT Human clinical

"Even in 2016, the most reliable and widely available diagnostic test for CF is the measurement of chloride concentration in sweat."

Review emphasizes sweat chloride as the most reliable and widely available diagnostic test.

PMID:28576637 SUPPORT Human clinical

"The method of choice is sweat induction by pilocarpine iontophoresis, followed by sweat collection on a gauze or filter paper or in a Macroduct coil."

Supports quantitative pilocarpine iontophoresis as the preferred sweat testing approach.

PMID:28129811 SUPPORT Human clinical

"It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test."

CF Foundation consensus guidelines establish sweat chloride as the recommended diagnostic test.

CFTR Genetic Testing

Identification of two disease-causing CFTR mutations confirms the diagnosis. Panel testing covers the most common mutations; expanded sequencing and deletion/duplication analysis can identify rare variants. The CFTR2 database provides clinical classification of variants.

molecular genetic testing NCIT:C19770

Genetic testing alone is insufficient for diagnosis if sweat chloride is normal, as some variants have variable penetrance.

Show evidence (2 references)

PMID:28855057 SUPPORT Human clinical

"Cystic fibrosis is caused by a gene mutation leading to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein."

Supports the role of identifying disease-causing CFTR mutations within a multimodal diagnostic framework.

PMID:23974870 SUPPORT Human clinical

"These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."

CFTR2 project provides systematic classification of CFTR variants for diagnostic interpretation.

Newborn Screening

Population-based screening using immunoreactive trypsinogen (IRT) measured in dried blood spots collected at 24-48 hours of life. Elevated IRT is followed by either CFTR mutation panel or second IRT measurement. Positive screens require confirmatory sweat chloride testing.

disease screening NCIT:C15419

immunoreactive trypsinogen (IRT), DBS LOINC:48633-2 CFTR mutation panel, DBS (second tier in IRT/DNA protocols) LOINC:54083-1

Reference Ranges

Trypsinogen I Free [Mass/volume] in DBS (newborn screening, Denmark national programme (IRT/DNA, from May 2016))

Screen negative (< 50 ng/mL) Elevated IRT, CFTR F508del analysis (50–145 ng/mL) Very high IRT, CFTR sequencing (≥ 145 ng/mL)

Elevated IRT, CFTR F508del analysis: IRT at or above the 50 ng/mL cut-off triggered F508del analysis on the same dried blood spot; a single F508del allele led on to CFTR sequencing.

Very high IRT, CFTR sequencing: IRT above the very-high cut-off led directly to next-generation sequencing of CFTR regardless of F508del status.

Source wording: IRT "followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present" and, for "a very high IRT value above 145 ng/mL", CFTR sequencing. Two decision levels, so three bands. The source says "above 145", so a value exactly at 145 ng/mL fell in the middle tier; the half-open band convention places it in the top tier, a one-point discrepancy recorded here. Screening cut-offs differ by programme; this is Denmark's.

Show evidence (1 reference)

PMID:31682332 SUPPORT Human clinical

"The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane..."

States both IRT decision levels of the Danish programme and what each triggered.

Trypsinogen I Free [Mass/volume] in DBS (newborn screening, Balearic Islands (Spain) regional programme, after protocol revisions over 14 years)

Screen negative (< 60 ng/mL) Screen positive (≥ 60 ng/mL)

Screen positive: IRT at or above the programme cut-off proceeded to the programme's second-tier mutation analysis and sweat testing.

Source wording: "After different changes in the protocol, an IRT cut-off value of 60 ng/mL was established." Recorded as a second programme's cut-off to make the between-programme spread visible.

Show evidence (1 reference)

PMID:25680858 SUPPORT Human clinical

"After different changes in the protocol, an IRT cut-off value of 60 ng/mL was established."

States the IRT cut-off the Balearic Islands programme settled on.

Enables early diagnosis and treatment, improving outcomes. False negatives can occur with meconium ileus. LOINC codes and labels were read from the Monarch KG and seeded into cache/loinc/terms.csv by scripts/seed_loinc_cache.sh. IRT is bound to the method-less quantitative DBS code. The CFTR second tier is bound to LOINC's dried-blood-spot mutation-panel result code; every LOINC molecular genetics code carries a "by Molecular genetics method" clause, so no method-less alternative exists, and the DBS code was preferred over the blood-or-tissue targeted-panel code (LOINC:38404-0) because the screening panel is run on the screening card. It is bound at panel level; LOINC's per-variant codes (for example CFTR gene.p.Phe508del, LOINC:21655-6) are deliberately not bound.

Show evidence (4 references)

PMID:28576637 SUPPORT Human clinical

"In screen positive babies, the diagnosis of CF must be confirmed by a sweat test demonstrating a sweat chloride concentration above 60mmol/L."

Supports newborn screening as an entry point that requires confirmatory sweat chloride testing.

PMID:30986316 SUPPORT Human clinical

"Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF."

Clinical review confirms newborn screening as primary route to CF diagnosis and notes inconclusive cases.

PMID:7680526 SUPPORT Human clinical

"The second uses the IRT assay with a 100 ng/ml cutoff in conjunction with direct analysis for the delta F508 CF transmembrane conductance regulator (CFTR) mutation in a two-tiered (i.e., IRT/DNA) protocol, followed by a sweat test."

The Wisconsin programme's IRT/DNA protocol: dried-blood-spot IRT as first tier and CFTR mutation analysis as second tier, the two measurements bound above.

+ 1 more reference

Nasal Potential Difference

Measurement of transepithelial voltage across nasal mucosa before and after perfusion with chloride-free solution and isoproterenol. Abnormal pattern (hyperpolarized baseline, absent chloride-free response) supports CFTR dysfunction. Used as ancillary diagnostic test in borderline cases.

transepithelial nasal potential difference measurement

Available only at specialized centers. Technically demanding.

Show evidence (2 references)

PMID:28576637 SUPPORT Human clinical

"These patients should be referred to expert centers where bioassays of CFTR function like nasal potential difference measurement or intestinal current measurement can be done."

Supports nasal potential difference as a specialized test for diagnostically inconclusive cases.

PMID:35163362 SUPPORT Human clinical

"Ex vivo and in vivo assays similarly evaluate current (intestinal current measurement) and membrane potential differences (nasal potential difference), on tissues from individual patients."

Confirms NPD as a recognized CFTR functional assay used in diagnostic evaluation.

Intestinal Current Measurement

Ex vivo measurement of CFTR-mediated chloride transport in rectal biopsy tissue. Provides direct assessment of CFTR function. Used in research settings and for diagnosis in cases with inconclusive sweat chloride.

rectal biopsy-based intestinal current measurement NCIT:C51693

Primarily available in European centers. Highly sensitive and specific.

Show evidence (2 references)

PMID:40943780 SUPPORT Human clinical

"Intestinal Current Measurement (ICM) is a novel diagnostic technique that may document the abnormal function of the cystic fibrosis transmembrane conductance regulator."

Directly supports ICM as a CFTR-function diagnostic technique.

PMID:40943780 SUPPORT Human clinical

"The conducted study suggests that ICM may offer diagnostic value, especially in cases where sweat test results are equivocal."

Supports using ICM as an adjunctive test when sweat chloride results are borderline.

📈

Progression

Age of onset

Age: All ages

Show evidence (1 reference)

ORPHA:586 SUPPORT Other

"Age of onset: All ages"

Orphanet's natural-history section records cystic fibrosis onset as occurring across all ages.

📊

Prevalence

European descent

Prevalence at birth 28.571429–40.0 per 100,000 1–9 per 10,000 (births)

Show evidence (2 references)

PMID:27140670 SUPPORT Human clinical

"Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia."

Lancet seminar confirms highest CF prevalence in populations of European descent.

PMID:9506637 SUPPORT Human clinical

"Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States."

Gives about 1 in 3,200 white live births in the United States, within the stated range.

African American

Prevalence at birth 6.666667 per 100,000 1–9 per 100,000 (births)

Approximately 1 in 15,000 Black live births in the United States, from US CF Foundation registry data.

Show evidence (1 reference)

PMID:9506637 SUPPORT Human clinical

"Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States."

US registry comparison of 601 Black and 17,755 white patients giving the birth incidence among Black infants.

Japan

Prevalence at birth 0.285714 per 100,000 1–9 per 1,000,000 (births)

About 1 in 350,000 live births, estimated from published Japanese case reports and national live-birth counts after 1980.

Show evidence (1 reference)

PMID:9161949 SUPPORT Human clinical

"A simple calculation based on the number of reported CF cases and of live births after 1980 suggested that the incidence of CF is about 1 in 350,000 in the Japanese population."

Case-ascertainment estimate for Japan; a likely underestimate because it relies on published case reports.

China

Unknown 0.77861 per 100,000 1–9 per 1,000,000

About 1 in 128,434, a genetic estimate from CFTR pathogenic-variant carrier frequencies in Chinese exome data rather than a count of diagnosed cases, so the measure type is left as UNKNOWN.

Show evidence (1 reference)

PMID:35313924 SUPPORT Computational

"we excluded individuals identified or suspected with CF and their parents in our cohorts and estimated the Chinese CF prevalence is approximately 1/128,434."

Prevalence estimated computationally from curated CFTR variant frequencies in 30,951 exome samples.

Europe

Point prevalence 10.0–50.0 per 100,000 1–9 per 10,000

Show evidence (1 reference)

ORPHA:586 SUPPORT Other

"1-5 / 10 000 | Europe | Point prevalence | ORPHANET"

Orphanet reports the European point prevalence class for cystic fibrosis.

Europe

Prevalence at birth 10.0–50.0 per 100,000 1–9 per 10,000 (births)

Show evidence (1 reference)

ORPHA:586 SUPPORT Other

"1-5 / 10 000 | Europe | Prevalence at birth | ORPHANET"

Orphanet reports the European prevalence-at-birth class for cystic fibrosis.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Cystic Fibrosis:

Primary ciliary dyskinesia MONDO:0016575

Overlapping Features Primary ciliary dyskinesia can closely resemble cystic fibrosis with chronic sinopulmonary symptoms driven by impaired mucociliary clearance.

Distinguishing Features

CF is caused by CFTR dysfunction, whereas primary ciliary dyskinesia is caused by structural/functional ciliary defects.
PCD is generally less prevalent than CF and requires a different specialist diagnostic work-up and management strategy.

Show evidence (1 reference)

PMID:36828173 SUPPORT Human clinical

"Cystic fibrosis (CF) and Primary ciliary dyskinesia (PCD) are both rare chronic diseases, inherited disorders associated with multiple complications, namely respiratory complications, due to impaired mucociliary clearance that affect severely patients' lives."

Supports major clinical overlap in respiratory presentations that necessitates differential diagnosis.

Asthma MONDO:0004979

Overlapping Features Asthma may overlap with CF pulmonary symptoms, especially wheeze and dyspnea, and can complicate interpretation of obstructive respiratory findings.

Distinguishing Features

CF diagnosis requires evidence of CFTR dysfunction (e.g., sweat chloride and/or genotype), while isolated asthma does not.
CF-asthma overlap remains debated, so objective CFTR-focused testing is needed when symptoms overlap.

Show evidence (1 reference)

PMID:33560464 SUPPORT Human clinical

"Respiratory symptoms for both CF and asthma include cough, wheezing, and dyspnea."

Confirms direct symptom overlap between CF and asthma, supporting asthma as an important differential diagnosis.

Non-cystic fibrosis bronchiectasis MONDO:0004822

Overlapping Features Non-CF bronchiectasis can phenocopy CF-related chronic productive cough and recurrent respiratory exacerbations but arises from heterogeneous non-CF etiologies.

Distinguishing Features

Etiologic evaluation in non-CF bronchiectasis emphasizes alternative causes (e.g., prior infection, immunodeficiency, autoimmune disease, PCD) rather than CFTR-confirmed disease.
Non-CF bronchiectasis prevalence increases strongly with age, whereas CF is usually identified earlier in life through newborn screening or pediatric symptoms.

Show evidence (1 reference)

PMID:40293759 SUPPORT Human clinical

"Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations."

Supports overlapping chronic respiratory presentation with CF and the need to differentiate CF from non-CF bronchiectatic disease.

📊

Related Datasets

Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition geo:GSE150674

Single-cell sequencing dataset of human airway epithelium from normal and cystic fibrosis lungs, including donor airway samples used to define altered epithelial cell-state composition in CF.

human SINGLE CELL RNA SEQ n=38

proximal airway epithelium UBERON:0001005

Conditions: cystic fibrosis healthy control

Findings

CF proximal airways show shifted epithelial-state composition with increased transitioning ciliated/secretory programs

Show evidence (1 reference)

PMID:33958799 SUPPORT Human clinical

"Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells."

Single-cell airway profiling identifies disease-dependent epithelial state shifts in CF.

PMID:33958799

Donor-cohort count from the linked Nat Med study (19 CF + 19 healthy proximal-airway donors); GEO may include additional technical records not counted as biological samples.

ScRNA-seq Expression of APOC2 and IFI27 Identifies Four Alveolar Macrophage Superclusters in Cystic Fibrosis and Healthy BALF geo:GSE193782

Single-cell RNA sequencing dataset of bronchoalveolar lavage cells from healthy controls and uninflamed cystic fibrosis subjects used to define alveolar macrophage superclusters and immune-cell heterogeneity.

human SINGLE CELL RNA SEQ n=7

lung (bronchoalveolar lavage cells) UBERON:0002048

Conditions: cystic fibrosis healthy control

Findings

BAL single-cell profiling identifies conserved alveolar macrophage superclusters across healthy and uninflamed CF subjects

Show evidence (1 reference)

PMID:35820705 SUPPORT Human clinical

"We performed single-cell RNA sequencing on 113,213 bronchoalveolar lavage cells from four healthy and three uninflamed cystic fibrosis subjects and identified two MARCKS+LGMN+IMs, FOLR2+SELENOP+ and SPP1+PLA2G7+ IMs, monocyte subtypes, DC1, DC2, migDCs, plasmacytoid DCs, lymphocytes, epithelial..."

The study reports core BAL immune-cell architecture including four alveolar macrophage superclusters in CF-context samples.

PMID:35820705

Provides CF-relevant BAL immune-cell state reference for airway inflammation mechanisms.

Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity [scRNAseq-hPSC] geo:GSE266789

Early human fetal lung single-cell atlas dataset profiling over 150,000 cells from gestational weeks 10-19, with trajectories of CFTR-expressing progenitor populations and comparison to hPSC-derived fetal lung models.

human SINGLE CELL RNA SEQ n=19

fetal lung tissue UBERON:0002048

Conditions: normal fetal development

Findings

Fetal lung development includes CFTR-high progenitor trajectories that inform developmental context for CFTR biology

Show evidence (1 reference)

PMID:39003323 SUPPORT Human clinical

"We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR)."

Establishes developmental CFTR-expressing progenitor trajectories relevant to CFTR biology.

PMID:39003323

Developmental fetal-lung atlas with explicit CFTR-expressing progenitor characterization.

Cystic Fibrosis and healthy control biopsy cellxgene:54004c5c-af08-4693-a606-73871b6ef989

Single-cell transcriptomic profiling of cystic fibrosis and healthy control biopsies available on CZI CELLxGENE Discover. Provides disease-specific cell state annotations for CF airway pathology.

human SINGLE CELL RNA SEQ

airway biopsy UBERON:0002048

Conditions: cystic fibrosis healthy control

DOI:10.1016/j.jcf.2025.01.016

CZI CELLxGENE collection.

Single‐cell <scp>RNA</scp> sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation doi:10.1111/liv.15963

Single-cell RNA sequencing of four CF liver disease explant livers identifying differential endothelial characteristics including a distinct population of liver sinusoidal endothelial cells upregulating complement cascade genes.

human SINGLE CELL RNA SEQ n=4

liver explant UBERON:0002107

Conditions: cystic fibrosis liver disease

Findings

CF liver explants contain a distinct population of sinusoidal endothelial cells with upregulated complement and coagulation genes

Show evidence (1 reference)

PMID:38847551 SUPPORT Human clinical

"we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease"

First scRNA-seq characterization of endothelial involvement in CF liver disease.

PMID:38847551

First comprehensive single-cell analysis of CF hepatic complications; supports endothelial involvement in CFLD.

Theratyping cystic fibrosis<i>in vitro</i>in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells doi:10.1183/13993003.00908-2021

Patient-derived nasal epithelial stem cells expanded via conditional reprogramming and used to generate 3D airway organoids and ALI cultures for personalized CFTR modulator efficacy testing (theratyping).

human MULTI OMICS PERTURBATION

nasal epithelial organoid UBERON:0001005

Conditions: cystic fibrosis

Findings

Conditionally reprogrammed nasal epithelial stem cells generate organoids suitable for personalized CFTR modulator testing

Show evidence (1 reference)

PMID:34413153 SUPPORT In vitro / ex vivo

"We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients."

Demonstrates non-invasive patient-specific organoid model for personalized drug screening.

PMID:34413153

Experimental model enabling theratyping for patients with rare CFTR genotypes not eligible for standard modulator therapy.

Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia doi:10.26508/lsa.202101320

Novel method for generating nasal-brushing-derived airway organoids from 2D air-liquid interface cultures, enabling consistent detection of CFTR modulator responses via forskolin-induced swelling assay.

human MULTI OMICS PERTURBATION

nasal epithelial organoid UBERON:0001005

Conditions: cystic fibrosis

Findings

2D-to-3D transition culture method enables consistent CFTR modulator response detection in nasal airway organoids

Show evidence (1 reference)

PMID:35922154 SUPPORT In vitro / ex vivo

"we therefore describe an alternative method of culturing nasal-brushing-derived airway organoids, which are created from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture"

Combines advantages of ALI differentiation with 3D organoid FIS assay for improved scalability.

PMID:35922154

Improved organoid culture protocol with neuregulin-1β and interleukin-1β for consistent CFTR functional readouts.

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis doi:10.26508/lsa.202201857

Validation of 2D human intestinal organoid monolayers as a preclinical drug testing tool, demonstrating comparable CFTR functional responses across 2D HIO, 3D HIO, and HNE methods with good correlation to clinical outcome markers.

human MULTI OMICS PERTURBATION

intestinal organoid monolayer UBERON:0000160

Conditions: cystic fibrosis

Findings

2D intestinal organoid monolayers show comparable CFTR functional responses to 3D organoids and HNE cultures with good clinical correlation

Show evidence (1 reference)

PMID:37024122 SUPPORT In vitro / ex vivo

"This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE."

Expands utility of intestinal monolayers as scalable preclinical drug testing tool for CF.

PMID:37024122

Demonstrates larger measurable CFTR functional range and apical membrane access advantages of 2D HIO over HNE and 3D HIO.

Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology doi:10.1007/s00018-025-05627-7

Endometrial organoid models from CF patients and CF mice revealing molecular and pathway differences in hormone responses, with single-cell RNA sequencing of CF mouse uterus confirming similar molecular traits to human CF endometrium.

human SINGLE CELL RNA SEQ

endometrial organoid UBERON:0001295

Conditions: cystic fibrosis healthy control

Findings

CF endometrial organoids recapitulate disease characteristics and reveal cycle-dependent molecular aberrations correctable by CFTR modulators

Show evidence (1 reference)

PMID:40074868 SUPPORT In vitro / ex vivo

"we developed organoid models from CF patient endometrium. The organoids recapitulated CF characteristics and revealed molecular and pathway differences in cycle-recapitulating hormone responses compared to healthy endometrial organoids."

Expands CF model systems beyond respiratory and GI to reproductive tissue pathobiology.

PMID:40074868

Includes scRNA-seq of CF mouse uterus; relevant to CF fertility challenges and reproductive pathobiology.

Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip doi:10.1016/j.jcf.2021.10.004

Microfluidic organ-on-a-chip device lined by primary human CF bronchial epithelial cells at air-liquid interface with pulmonary microvascular endothelial cells, recapitulating CF airway pathophysiology including mucus accumulation, inflammation, and Pseudomonas aeruginosa infection.

human MULTI OMICS PERTURBATION

bronchial epithelium on microfluidic chip UBERON:0002031

Conditions: cystic fibrosis healthy control

Findings

CF airway-on-a-chip recapitulates enhanced mucus accumulation, increased cilia density, higher IL-8 secretion, and enhanced Pseudomonas aeruginosa growth

Show evidence (1 reference)

PMID:34799298 SUPPORT In vitro / ex vivo

"The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells."

Organ-on-chip platform enabling physiological CF modeling with infection and inflammation readouts.

PMID:34799298

Organ-on-a-chip model from Wyss Institute; supports drug testing and personalized medicine applications.

Development of cystic fibrosis and noncystic fibrosis airway cell lines doi:10.1152/ajplung.00355.2002

Immortalized human airway epithelial cell lines derived from normal (NuLi-1) and CF (CuFi-1, CuFi-3, CuFi-4) genotypes using hTERT and HPV-16 E6/E7, capable of forming polarized differentiated epithelia at air-liquid interface.

human MULTI OMICS PERTURBATION

airway epithelial cell line UBERON:0001005

Conditions: cystic fibrosis healthy control

Findings

NuLi and CuFi cell lines maintain genotype-specific ion channel physiology and NF-kB innate immune responses at ALI

Show evidence (1 reference)

PMID:12676769 SUPPORT In vitro / ex vivo

"When grown at the air-liquid interface, the cell lines were capable of forming polarized differentiated epithelia that exhibited transepithelial resistance and maintained the ion channel physiology expected for the genotypes."

Immortalized CF cell lines supporting reproducible ion physiology and innate immunity studies.

PMID:12676769

Immortalized CF cell line resource; CuFi lines are correctable by adenoviral CFTR vectors.

🔬

Clinical Trials

NCT03525444 PHASE_III COMPLETED

Phase 3, randomized, double-blind, placebo-controlled trial evaluating elexacaftor-tezacaftor-ivacaftor in patients aged 12+ with cystic fibrosis heterozygous for F508del and a minimal-function CFTR mutation. This landmark trial led to FDA approval of Trikafta.

Target Phenotypes: Bronchiectasis HP:0002110 Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:31697873 SUPPORT Human clinical

"Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective."

This Phase 3 trial established efficacy of Trikafta for CF patients with one F508del allele plus a minimal-function mutation.

🧫

Experimental Models

Patient-derived airway organoid theratyping model ORGANOID namo:Organoid

Patient-derived nasal epithelial stem cells expanded from nasal brushings and differentiated into airway organoids for personalized CFTR modulator response testing.

Organism

human NCBITaxon:9606

Tissue

respiratory airway UBERON:0001005

Cell source

Patient-derived nasal epithelial stem cells obtained by nasal brushing

Culture

3D airway organoids linked to differentiated air-liquid interface cultures

Publication

PMID:34413153

Pathograph links

CFTR Dysfunction Measures genotype-specific epithelial CFTR dysfunction and rescue by modulators in patient-derived airway tissue.

Findings

Patient-derived airway organoids enable genotype-specific CFTR modulator response testing, including rare genotypes

Show evidence (2 references)

PMID:34413153 SUPPORT In vitro / ex vivo

Supports use of patient-derived airway organoids for CFTR theratyping in a genotype-specific epithelial system.

PMID:35922154 SUPPORT In vitro / ex vivo

Supports reproducible CFTR functional readouts from nasal-brushing-derived airway organoid cultures.

Show evidence (1 reference)

PMID:34413153 SUPPORT In vitro / ex vivo

Supports this as a disease-relevant patient-derived organoid model system for CF.

CF airway-on-chip microphysiological model ORGAN_ON_CHIP namo:OrganOnChip

Human microfluidic airway chip lined by primary CF bronchial epithelial cells and pulmonary microvascular endothelial cells, recapitulating mucus, inflammation, and infection phenotypes under air-liquid interface culture.

Organism

human NCBITaxon:9606

Tissue

bronchial epithelium UBERON:0002031

Cell source

Primary human CF bronchial epithelial cells with pulmonary microvascular endothelial coculture

Culture

Microfluidic organ-on-chip with air-liquid interface airway compartment

Publication

PMID:34799298

Pathograph links

Airway Surface Liquid Depletion Recapitulates dehydrated mucus-layer phenotypes downstream of epithelial ion-transport failure.

Impaired Mucociliary Clearance Captures ciliary and mucus-transport abnormalities in differentiated CF airway epithelium.

Chronic Bacterial Infection Provides a controllable airway context for infection and bacterial overgrowth phenotypes in CF epithelium.

Findings

CF airway chips recapitulate mucus accumulation, ciliary abnormalities, inflammatory signaling, and bacterial overgrowth

Show evidence (1 reference)

PMID:34799298 SUPPORT In vitro / ex vivo

Establishes the chip as a physiologically relevant CF airway model.

Show evidence (1 reference)

PMID:34799298 SUPPORT In vitro / ex vivo

Supports inclusion of this organ-on-chip system as a CF-relevant experimental model.

NuLi/CuFi airway epithelial cell-line model CELL_LINE namo:CellLineModel

Immortalized human airway epithelial cell lines representing normal and CF genotypes, differentiated at air-liquid interface to study ion transport and innate immune phenotypes.

Organism

human NCBITaxon:9606

Tissue

respiratory airway UBERON:0001005

Cell source

Immortalized human airway epithelial cell lines (NuLi-1, CuFi-1, CuFi-3, CuFi-4)

Culture

Polarized differentiated air-liquid interface epithelial culture

Publication

PMID:12676769

Pathograph links

CFTR Dysfunction Preserves genotype-specific CFTR-dependent ion-transport defects in a reusable airway epithelial system.

ENaC Hyperactivity and Sodium Hyperabsorption Supports mechanistic readouts of abnormal epithelial sodium transport downstream of CFTR loss.

Findings

NuLi and CuFi lines retain genotype-specific ion-transport and epithelial differentiation phenotypes in vitro

Show evidence (1 reference)

PMID:12676769 SUPPORT In vitro / ex vivo

Confirms durable genotype-relevant airway epithelial physiology in a reusable CF cell-line model.

Show evidence (1 reference)

PMID:12676769 SUPPORT In vitro / ex vivo

Supports inclusion of this cell-line system as a CF experimental model.

🧮

Computational Models

O'Donoghue quantitative model of human nasal epithelial ion transport ODE equations and parameters in the article and supplemental material KINETIC

Coupled nonlinear ODE model of sodium, chloride, potassium, and water transport across human nasal epithelial cells. Parameter estimation and Monte Carlo filtering compare non-CF and CF potential-difference responses to amiloride and low-chloride challenges.

PMID:23732645

Variable	Model ID	Unit
Apical CFTR chloride permeability Apical chloride-channel permeability attributed to CFTR	`P_Cl_a`	m/s
Apical ENaC sodium permeability Apical sodium permeability attributed to ENaC	`P_Na_a`	m/s
Transepithelial potential difference Modeled nasal epithelial voltage relative to the serosal compartment	`Vt`	mV
Amiloride-sensitive potential difference Change in transepithelial voltage after apical ENaC blockade	`delta_Vt_amiloride`	mV

Pathograph links

CFTR Dysfunction perturbs fidelity: moderate Reduces apical CFTR chloride permeability and calculates the resulting transepithelial and membrane-potential responses.

Limitations: The model represents a flooded nasal epithelial monolayer and omits bicarbonate transport, airway geometry, mucus, cilia, inflammation, and regional lung heterogeneity.

ENaC Hyperactivity and Sodium Hyperabsorption measures fidelity: moderate Infers the ENaC permeability change needed to reproduce CF basal and amiloride-sensitive nasal potential differences.

Limitations: ENaC permeability is inferred from epithelial electrical recordings and the result depends on assumptions about the represented transporters and paracellular pathway.

Findings

Loss of CFTR permeability alone could not reproduce the magnitude of CF epithelial bioelectric changes; increased ENaC permeability was also required.

Show evidence (1 reference)

PMID:23732645 SUPPORT Computational

"We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed..."

Directly states the model comparison supporting coupled CFTR loss and ENaC increase.

Curated from the paper and supplemental equations; no exact deposited code implementation was identified. Calibration used primary cultured nasal epithelium rather than patient-specific longitudinal data.

Show evidence (1 reference)

PMID:23732645 SUPPORT Computational

"To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport."

Directly identifies the quantitative model and its tissue scope.

Sandefur purinergic model of airway-surface-liquid homeostasis ODE equations and parameters in the article and supplemental material MATLAB ode15s KINETIC

Systems model coupling epithelial ion and water transport to extracellular ATP and adenosine signaling. Fifteen ODEs represent baseline ASL homeostasis; a 23-equation extension simulates prolonged low-dose P2Y2-agonist delivery.

PMID:28808008

Variable	Model ID	Unit
Airway surface liquid height Depth of the airway surface liquid compartment	`ASL_height`	micrometer
Extracellular ATP concentration Purinergic signal regulating epithelial ion-channel permeability	`ATP`	nM
Extracellular adenosine concentration Purinergic metabolite regulating epithelial ion transport	`ADO`	nM
CFTR chloride permeability Apical chloride permeability through CFTR channels	`pCFTR`
ENaC sodium permeability Apical sodium permeability through ENaC channels	`pENaC`

Pathograph links

CFTR Dysfunction perturbs fidelity: moderate Reduces CFTR-mediated chloride secretion within a calibrated model of cultured human airway epithelium.

Limitations: CF required simultaneous parameter changes in chloride, sodium, and potassium transport; CFTR loss is therefore not an isolated disease arm.

ENaC Hyperactivity and Sodium Hyperabsorption partially recapitulates fidelity: moderate Increased sodium absorption is required with reduced chloride secretion to reproduce the CF epithelial state.

Limitations: Transport parameters were fitted to cultured epithelia and do not encode patient genotype, airway anatomy, immune responses, or infection.

Airway Surface Liquid Depletion recapitulates fidelity: moderate Predicts the lower resting ASL height in CF and its dependence on chloride secretion, sodium absorption, and extracellular nucleotide metabolism.

Limitations: ASL height is modeled in cultured epithelium; extrapolation to spatially heterogeneous intact airways and clinical response is unvalidated.

Findings

Reproducing the CF state required reduced chloride secretion, increased potassium secretion, and increased sodium absorption.

Show evidence (1 reference)

PMID:28808008 SUPPORT Computational

"To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required."

Directly reports the fitted transport changes required for the CF condition.

The model predicted basal ASL height and dehydration caused by accelerated nucleotide metabolism, and proposed prolonged low-dose agonist delivery as a rehydration strategy.

Show evidence (1 reference)

PMID:28808008 SUPPORT Computational

"The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to..."

Reports both the ASL-height validation target and the simulated intervention.

The prolonged low-dose Denufosol strategy is a model prediction, not clinical evidence. The paper notes that prior short, high-dose Denufosol failed to show sufficient phase-III benefit; the proposed schedule requires testing.

Show evidence (1 reference)

PMID:28808008 SUPPORT Computational

"Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling."

Directly states the model's coupled transport-signaling scope.

Kurbatova physiologically based model of mucociliary clearance Physiological equations and parameters in the publication PHYSIOLOGICAL

Regional lung model of mucociliary transport with separate periciliary-liquid and mucus layers. It compares normal and CF clearance and simulates how dornase-alfa-induced mucus-viscosity reduction interacts with central versus peripheral aerosol deposition.

PMID:25746843

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Periciliary liquid layer Hydrated layer surrounding airway cilia	`PCL`
Mucus layer Transported viscoelastic airway secretion layer	`mucus_layer`
Mucus viscosity Rheological property reduced by simulated dornase alfa	`mucus_viscosity`
Aerosol deposition region Relative deposition of inhaled drug in central or peripheral airways	`deposition_location`
Mucus clearance Regional transport of airway mucus	`mucus_clearance`

Pathograph links

Airway Surface Liquid Depletion partially recapitulates fidelity: moderate Represents the depleted periciliary-liquid layer that changes mucus transport in CF airways.

Limitations: Hydration is reduced to a layered physiological representation rather than coupled explicitly to CFTR, ENaC, purinergic signaling, or epithelial cells.

Impaired Mucociliary Clearance recapitulates fidelity: moderate Simulates impaired regional mucus transport and its response to reduced mucus viscosity after inhaled dornase alfa.

Limitations: The model prediction about deposition location was not validated as a patient-specific dosing rule and omits infection, inflammation, and heterogeneous mucus plugging.

Findings

Simulated dornase alfa increased mucus clearance more when drug deposition was concentrated in peripheral small airways.

Show evidence (1 reference)

PMID:25746843 SUPPORT Computational

"Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways."

Directly states the model's regional-deposition result.

Curated directly from the paper; no exact deposited implementation was identified. The deposition result is hypothesis-generating and should not be treated as an established clinical aerosol-delivery recommendation.

Show evidence (1 reference)

PMID:25746843 SUPPORT Computational

"We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer."

Directly identifies the physiological model and its two-layer structure.

{ }

Source YAML

click to show

name: Cystic Fibrosis
creation_date: '2025-12-19T14:27:56Z'
description: >-
  Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder
  caused by mutations in the CFTR gene encoding the cystic fibrosis transmembrane
  conductance regulator, a chloride and bicarbonate channel expressed in epithelial
  cells. CFTR dysfunction leads to dehydrated, viscous secretions in multiple organ
  systems, most critically the airways and pancreas. Nearly 2,000 CFTR variants have
  been identified, with the Phe508del (F508del) mutation present in nearly 90% of
  patients. The disease is characterized by progressive bronchiectasis, chronic
  bacterial lung infection, exocrine pancreatic insufficiency, male infertility due
  to congenital bilateral absence of the vas deferens, and elevated sweat chloride.
  Multidisciplinary care and CFTR modulator therapies have extended median survival
  beyond 40 years, with the advent of elexacaftor-tezacaftor-ivacaftor (Trikafta)
  representing a transformational advance for the majority of patients.
category: Genetic
parents:
- Respiratory Disease
- Inborn Error of Metabolism
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009061
      label: cystic fibrosis
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:586
    mapping_justification: Orphanet ORPHA:586 cross-reference table lists MONDO:0009061 as an exact match.
external_assertions:
- name: Orphanet Cystic fibrosis record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:586
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=586
  description: >-
    Orphanet structured record for cystic fibrosis, including synonyms,
    definition, inheritance, natural history, epidemiology, genes, HPO
    phenotypes, and cross-references.
  evidence:
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009061 | Exact"
    explanation: Orphanet cross-references ORPHA:586 exactly to MONDO:0009061.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:219700 | Exact"
    explanation: Orphanet cross-references ORPHA:586 exactly to OMIM:219700.
prevalence:
- population: European descent
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 28.571429
  rate_high: 40.0
  percentage: 1 in 2,500 to 3,500 live births
  evidence:
  - reference: PMID:27140670
    reference_title: "Cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia."
    explanation: Lancet seminar confirms highest CF prevalence in populations of European descent.
  - reference: PMID:9506637
    reference_title: "Comparison of the clinical manifestations of cystic fibrosis in black and white patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States."
    explanation: >-
      Gives about 1 in 3,200 white live births in the United States, within
      the stated range.
- population: African American
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 6.666667
  notes: Approximately 1 in 15,000 Black live births in the United States, from US CF Foundation registry data.
  evidence:
  - reference: PMID:9506637
    reference_title: "Comparison of the clinical manifestations of cystic fibrosis in black and white patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States."
    explanation: >-
      US registry comparison of 601 Black and 17,755 white patients giving
      the birth incidence among Black infants.
- population: Japan
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.285714
  notes: About 1 in 350,000 live births, estimated from published Japanese case reports and national live-birth counts after 1980.
  evidence:
  - reference: PMID:9161949
    reference_title: "The estimated incidence of cystic fibrosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A simple calculation based on the number of reported CF cases and of live births after 1980 suggested that the incidence of CF is about 1 in 350,000 in the Japanese population."
    explanation: >-
      Case-ascertainment estimate for Japan; a likely underestimate because it
      relies on published case reports.
- population: China
  measure_type: UNKNOWN
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.778610
  notes: >-
    About 1 in 128,434, a genetic estimate from CFTR pathogenic-variant carrier
    frequencies in Chinese exome data rather than a count of diagnosed cases,
    so the measure type is left as UNKNOWN.
  evidence:
  - reference: PMID:35313924
    reference_title: "Systematic estimation of cystic fibrosis prevalence in Chinese and genetic spectrum comparison to Caucasians."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "we excluded individuals identified or suspected with CF and their parents in our cohorts and estimated the Chinese CF prevalence is approximately 1/128,434."
    explanation: >-
      Prevalence estimated computationally from curated CFTR variant
      frequencies in 30,951 exome samples.
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 10.0
  rate_high: 50.0
  percentage: 1-5 / 10 000 point prevalence
  evidence:
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet reports the European point prevalence class for cystic fibrosis.
- population: Europe
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 10.0
  rate_high: 50.0
  percentage: 1-5 / 10 000 prevalence at birth
  evidence:
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Prevalence at birth | ORPHANET"
    explanation: Orphanet reports the European prevalence-at-birth class for cystic fibrosis.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Clinical review confirms autosomal recessive inheritance pattern.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet lists cystic fibrosis inheritance as autosomal recessive.
progression:
- phase: Age of onset
  age_range: All ages
  evidence:
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet's natural-history section records cystic fibrosis onset as occurring across all ages.
definitions:
- name: CF Foundation Diagnostic Criteria (2017)
  definition_type: CASE_DEFINITION
  description: >-
    Consensus guidelines from the Cystic Fibrosis Foundation for establishing a
    diagnosis of CF in individuals from newborn to adult, requiring evidence of
    CFTR dysfunction via sweat chloride testing combined with clinical features
    or two disease-causing CFTR mutations.
  scope: Diagnosis of cystic fibrosis in all age groups
  criteria_sets:
  - name: Diagnostic criteria for cystic fibrosis
    description: >-
      CF diagnosis requires clinical features consistent with CF in at least one
      organ system OR positive newborn screen, PLUS evidence of CFTR dysfunction
      demonstrated by elevated sweat chloride (>=60 mmol/L) or identification of
      two CF-causing CFTR mutations.
    core_clinical_characteristics:
    - preferred_term: Elevated sweat chloride
      term:
        id: HP:0012236
        label: Elevated sweat chloride
    - preferred_term: Recurrent respiratory infections
      term:
        id: HP:0002205
        label: Recurrent respiratory infections
    - preferred_term: Exocrine pancreatic insufficiency
      term:
        id: HP:0001738
        label: Exocrine pancreatic insufficiency
    - preferred_term: Male infertility
      term:
        id: HP:0003251
        label: Male infertility
    - preferred_term: Meconium ileus
      term:
        id: HP:0004401
        label: Meconium ileus
  evidence:
  - reference: PMID:28129811
    reference_title: "Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test."
    explanation: CF Foundation consensus guidelines establish sweat chloride testing as the cornerstone of CF diagnosis.
- name: Newborn Screening Algorithm
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    Most CF cases in the US and many other countries are identified through newborn
    screening (NBS) programs that measure immunoreactive trypsinogen (IRT) in dried
    blood spots, followed by CFTR mutation panel or a second IRT measurement. Positive
    screens require diagnostic confirmation with sweat chloride testing.
  scope: Newborn screening for cystic fibrosis
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of CF are identified through newborn screening (NBS)."
    explanation: Clinical review confirms newborn screening as the primary route to CF diagnosis.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_cftr_loss_of_function_model
  hypothesis_label: Canonical CFTR Loss-of-Function Model
  status: CANONICAL
  description: >-
    Biallelic CFTR pathogenic variants impair the cyclic-AMP-regulated
    apical anion channel that exports chloride and bicarbonate at
    epithelial surfaces. Loss of CFTR-mediated anion secretion (and
    secondary hyperabsorption of sodium and water) produces dehydrated,
    acidic, viscous airway surface liquid and pancreatic/biliary
    secretions. The resulting impaired mucociliary clearance, chronic
    bacterial airway infection, and obstructive secretions drive the
    progressive bronchiectatic lung disease, exocrine pancreatic
    insufficiency, hepatobiliary disease, elevated sweat chloride, and
    male infertility (CBAVD) characteristic of cystic fibrosis. CFTR
    modulator therapies (correctors/potentiators, exemplified by
    elexacaftor/tezacaftor/ivacaftor) that restore residual CFTR activity
    provide direct interventional validation of this canonical pathway.
  notes: >-
    Retained as CANONICAL following independent assessment of the 2026
    OpenScientist hypothesis-search report (see
    kb/hypotheses/Cystic_Fibrosis/canonical_cftr_loss_of_function_model/assessments/openscientist-assessment-by-codex.md;
    reconciliation tracked in issue #7325). The core mechanism is well
    supported by convergent evidence: newborn CF-pig airway-surface-liquid
    acidification impairs bacterial killing before infection or
    inflammation, and randomized/registry CFTR-modulator trials (ETI:
    ppFEV1 +9.9 across 11,151 registry patients) provide direct human
    interventional validation. Several report-level claims required
    narrowing rather than verbatim promotion: (1) as of the 2013 CFTR2
    analysis, few of the nearly 2,000 then-reported CFTR variants had
    empirical evidence of disease causation, so an unqualified ">2,000
    disease-causing variants" count conflates reported with clinically
    classified variants; CFTR2 has interpreted substantially more variants
    since, so any exact count must be dated to its source snapshot rather
    than asserted in the present tense; (2) bicarbonate
    secretion has been shown to be rate-limiting for host defense in mixed
    porcine airway epithelia and cell-culture systems, but this does not
    establish bicarbonate as the universal rate-limiting determinant over
    chloride across all human tissues and genotypes; (3) human
    monocyte-derived macrophages show direct CFTR-dependent defects, but a
    cited CFTR-depleted zebrafish neutrophil-recruitment finding traced the
    effect to epithelial oxidative signaling rather than
    immune-cell-autonomous CFTR dysfunction, so the two should not be
    conflated as one parallel immune mechanism; (4) residual airway
    inflammation and
    molecular abnormalities persisting after highly effective modulator
    therapy reflect incomplete correction of CFTR function rather than
    proof that inflammation becomes independent of ongoing CFTR
    dysfunction; and (5) next-generation vanzacaftor evidence of
    differential response in two previously unresponsive genotypes is from
    intestinal organoids, not yet a demonstrated clinical rescue.
  evidence:
  - reference: PMID:27140670
    reference_title: "Cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs."
    explanation: >
      Elborn 2016 Lancet seminar identifies CFTR functional failure as
      the central mechanism producing mucus retention, chronic infection,
      and progressive airway inflammation — the canonical pathogenic
      chain for cystic fibrosis lung disease.
  - reference: PMID:23974870
    reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis."
    explanation: >
      Corrects an OpenScientist report claim that treated all ~2,000
      reported CFTR variants as disease-causing. The snippet's point is
      that most reported variants have never been empirically evaluated,
      not that they were evaluated and failed: of the 159 variants common
      enough to assess in this 39,696-person cohort, 127 (80%) did meet
      both clinical and functional criteria consistent with disease. The
      unsupported step is therefore the slide from ~2,000 reported to
      ~2,000 disease-causing, per issue #7325. Figures are the 2013 CFTR2
      snapshot.
  - reference: PMID:22763554
    reference_title: "Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs."
    explanation: >-
      Bidirectional perturbation of airway surface liquid pH in newborn pigs
      is the strongest single perturbational support for the canonical model:
      lowering pH reproduces the host-defence defect in wild-type animals and
      raising pH rescues it in CF animals, at an age when the lungs are still
      free of infection and inflammation. It establishes causal primacy for the
      CFTR-dependent step in that model, not every downstream human
      manifestation.
  - reference: PMID:41738096
    reference_title: "Elexacaftor/tezacaftor/ivacaftor for cystic fibrosis and rare CFTR variants: in vitro translation to a phase 3, double-blind, randomized, placebo-controlled trial, and real-world study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95% CI: 7.2, 11.3; P < .0001]), and secondary endpoints of sweat chloride (-28.3 mmol/L [95% CI: -32.1, -24.5 mmol/L; P < .0001])"
    explanation: >-
      Randomized, placebo-controlled restoration of variant CFTR function moves
      both a direct CFTR biomarker (sweat chloride) and lung function in the
      predicted directions, in participants carrying rare non-F508del variants.
      This is interventional validation of the canonical pathway that does not
      depend on the F508del genotype.
pathophysiology:
- name: CFTR Dysfunction
  description: >-
    Mutations in the CFTR gene reduce or eliminate CFTR channel function at
    epithelial surfaces. Defective CFTR impairs epithelial anion and water
    handling, creating dehydrated secretions that initiate respiratory,
    gastrointestinal, hepatobiliary, sweat-gland, and reproductive disease.
  cell_types:
  - preferred_term: Epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  molecular_functions:
  - preferred_term: chloride channel activity
    term:
      id: GO:0005254
      label: chloride channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: Chloride Transport
    modifier: DECREASED
    term:
      id: GO:0006821
      label: chloride transport
  - preferred_term: bicarbonate transport
    modifier: DECREASED
    term:
      id: GO:0015701
      label: bicarbonate transport
  evidence:
  - reference: PMID:9922375
    reference_title: "Structure and function of the CFTR chloride channel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl- channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis."
    explanation: Comprehensive review establishes CFTR as chloride channel whose dysfunction causes cystic fibrosis.
  - reference: PMID:9922375
    reference_title: "Structure and function of the CFTR chloride channel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain."
    explanation: Describes the five-domain architecture of CFTR critical to understanding mutation effects.
  downstream:
  - target: Airway Surface Liquid Depletion
    description: Loss of epithelial chloride and bicarbonate secretion dehydrates airway surface liquid.
    evidence:
    - reference: PMID:23878362
      reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption."
      explanation: CFTR loss with reduced Cl-/HCO3- secretion is linked to airway dehydration.
  - target: Airway Surface Liquid Acidification
    description: >-
      Loss of CFTR-mediated bicarbonate secretion lowers the pH of the airway
      surface liquid, a step separable from depletion of its volume.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22763554
      reference_title: "Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport."
      explanation: >-
        Attributes the acidified airway surface liquid of newborn CF pigs to the
        bicarbonate-transport function of CFTR specifically, making this a direct
        consequence of the upstream channel defect.
  - target: Macrophage CFTR Dysfunction
    description: >-
      CFTR is expressed and functional in monocyte-derived macrophages, so the
      same genetic defect acts on innate immune cells in parallel with
      epithelium rather than only through them.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36265882
      reference_title: "Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane."
      explanation: >-
        Macrophage CFTR expression, function and membrane localisation are
        measurable and modulator-responsive in cells from people with cystic
        fibrosis, establishing that the CFTR defect is present in this lineage
        and not merely inferred from the epithelial phenotype.
  - target: ENaC Hyperactivity and Sodium Hyperabsorption
    description: Loss of CFTR-mediated inhibition increases ENaC-dependent sodium and water absorption.
    evidence:
    - reference: PMID:23878362
      reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption."
      explanation: Supports CFTR loss as an upstream cause of ENaC hyperactivity.
  - target: Impaired Pancreatic Organogenesis
    description: CFTR dysfunction during fetal pancreatic development may reduce pancreatic mass and islet number, establishing a developmental foundation for pancreatic disease.
    evidence:
    - reference: PMID:42262528
      reference_title: "Unravelling the developmental origins of cystic fibrosis-related diabetes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "people with CF present with pancreatic pathology and glucose abnormalities as early as in utero. This therefore suggests that the CF transmembrane conductance regulator (CFTR) gene mutations that cause CF may impair pancreatic organogenesis, thus leading to CFRD."
      explanation: Clinical review evidence supports CFTR's role in fetal pancreatic organogenesis.
  - target: Pancreatic Duct Obstruction
    description: Viscid epithelial secretions obstruct pancreatic ducts and initiate pancreatic injury.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports pancreatic dysfunction as a core epithelial consequence of CF.
  - target: Intestinal Obstruction
    description: Dehydrated intestinal secretions cause bowel obstruction.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
      explanation: Supports bowel obstruction as a downstream complication of CFTR dysfunction.
  - target: Sweat Gland Dysfunction
    description: Failure of sweat-duct chloride reabsorption raises sweat chloride.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnosis of CF is confirmed by demonstration of elevated sweat chloride."
      explanation: Elevated sweat chloride supports sweat-duct ion-transport dysfunction downstream of CFTR loss.
  - target: Vas Deferens Agenesis
    description: CFTR dysfunction contributes to male reproductive tract abnormalities and infertility.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports male infertility as a canonical downstream manifestation of CF.
  - target: Hepatobiliary Obstruction
    description: Viscid bile causes biliary obstruction and hepatobiliary disease.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
      explanation: Supports hepatobiliary disease as a downstream complication of CF.
  - target: Sinonasal Disease
    description: Impaired epithelial ion and fluid transport promotes chronic sinonasal disease.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
      explanation: Supports sinusitis as a downstream clinical consequence.
  - target: Reduced Female Fertility
    description: Thick cervical mucus and impaired epithelial fluid transport reduce female fertility.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: ENaC Hyperactivity and Sodium Hyperabsorption
  description: >-
    In CF airways, reduced CFTR function disinhibits ENaC, increasing epithelial
    sodium and water absorption and worsening airway dehydration.
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: sodium ion transport
    modifier: INCREASED
    term:
      id: GO:0006814
      label: sodium ion transport
  evidence:
  - reference: PMID:23878362
    reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption."
    explanation: Supports ENaC hyperactivity and increased Na+/water absorption in CF airway epithelium.
  downstream:
  - target: Airway Surface Liquid Depletion
    description: Increased Na+/H2O absorption further depletes airway surface liquid.
    evidence:
    - reference: PMID:23878362
      reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption."
      explanation: Supports direct contribution of ENaC hyperabsorption to airway dehydration.
- name: Airway Surface Liquid Depletion
  description: >-
    Reduced epithelial anion secretion together with increased sodium absorption
    depletes the periciliary liquid layer and airway surface liquid.
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: mucus secretion
    modifier: ABNORMAL
    term:
      id: GO:0070254
      label: mucus secretion
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:23878362
    reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption."
    explanation: Review describes ENaC hyperactivity and dehydration mechanism in CF airways.
  downstream:
  - target: Impaired Mucociliary Clearance
    description: Airway liquid depletion causes ineffective mucus transport and mucus stasis.
    evidence:
    - reference: PMID:23878362
      reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus."
      explanation: Supports the mechanistic link between airway dehydration and defective mucus clearance.
- name: Airway Surface Liquid Acidification
  biological_scale: TISSUE
  description: >-
    Loss of CFTR-mediated bicarbonate secretion lowers the pH of the thin airway
    surface liquid layer. Acidic airway surface liquid inhibits the antimicrobial
    activity of the secreted host-defence proteins it carries, so bacteria landing
    on the surface are killed less efficiently. This arm is separable from volume
    depletion and from mucus stasis: in newborn cystic fibrosis pigs it is present
    at birth, before any infection or inflammation. The amount of CFTR is
    rate-limiting for bicarbonate secretion over its whole range, unlike chloride
    secretion, which plateaus once a minority of cells express CFTR; that dose
    relationship has been established in mixed porcine airway epithelia and in
    cultured human bronchial epithelium rather than across human tissues,
    genotypes and disease stages, so it should not be read as a universal
    bicarbonate-over-chloride hierarchy.
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: bicarbonate transport
    modifier: DECREASED
    term:
      id: GO:0015701
      label: bicarbonate transport
  - preferred_term: Antibacterial activity of airway surface liquid
    modifier: DECREASED
    term:
      id: GO:0042742
      label: defense response to bacterium
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:22763554
    reference_title: "Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL."
    explanation: >-
      Measures the acidification directly in newborn CF pigs and shows that pH
      itself, rather than any downstream consequence of infection, suppresses the
      antimicrobial activity of the airway surface liquid.
  - reference: PMID:27114540
    reference_title: "Relationships among CFTR expression, HCO3- secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Thus, in contrast to Cl(-) secretion, the amount of CFTR is rate-limiting for HCO3 (-) secretion and for correcting host defense abnormalities."
    explanation: >-
      Porcine airway epithelia with graded proportions of CFTR-expressing cells
      show that bicarbonate secretion, airway surface liquid pH and antimicrobial
      activity scale with CFTR abundance, whereas chloride secretion saturates
      early. This supports bicarbonate as a dose-limiting arm in this system; it
      does not establish the same hierarchy across human tissues and genotypes.
  - reference: PMID:38573173
    reference_title: "Pulmonary Ionocytes Regulate Airway Surface Liquid pH in Primary Human Bronchial Epithelial Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cAMP-stimulated non-CF ionocytes do not secrete Na+ or Cl- into the ASL, but rather modulate its pH by secreting bicarbonate via CFTR-linked Cl-/bicarbonate exchange."
    explanation: >-
      Single-cell ion-transport measurements in primary human bronchial
      epithelium assign the pH-setting function to pulmonary ionocytes acting
      through CFTR-linked bicarbonate exchange, and the bulk fluid-secretion
      function to club cells. This separates the pH arm from the volume arm in
      human cells and identifies which cell type carries it.
  downstream:
  - target: Chronic Bacterial Infection
    description: >-
      Acidic airway surface liquid kills inhaled bacteria less efficiently,
      permitting colonization independently of mucus stasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22763554
      reference_title: "Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung."
      explanation: >-
        States the edge from acidified airway surface liquid to failed bacterial
        killing in the newborn CF pig lung. The step from impaired killing to
        established chronic human infection is inferred rather than measured in
        this model.
- name: Impaired Mucociliary Clearance
  description: >-
    Dehydrated airway surfaces reduce effective mucus transport, allowing mucus to
    remain adherent on airway epithelium.
  biological_processes:
  - preferred_term: mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  evidence:
  - reference: PMID:23878362
    reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus."
    explanation: Supports impaired mucociliary clearance as a discrete downstream step after airway dehydration.
  downstream:
  - target: Mucus Plugging
    description: Failed mucus transport promotes adherent mucus plugging.
    evidence:
    - reference: PMID:27140670
      reference_title: "Cystic fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs."
      explanation: Human clinical review supports airway mucus retention as a direct downstream step toward mucus plugging.
  - target: Chronic Productive Cough
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Mucus Plugging
  description: >-
    Impaired mucus transport generates concentrated, adherent mucus plugs that
    persist in the airway lumen.
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: mucus secretion
    modifier: ABNORMAL
    term:
      id: GO:0070254
      label: mucus secretion
  evidence:
  - reference: PMID:22711878
    reference_title: "Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice."
    explanation: Study demonstrates the mechanistic link between CFTR dysfunction and abnormal mucus properties.
  downstream:
  - target: Small-Airway Obstruction
    description: Luminal mucus plugs narrow and obstruct small airways.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports progressive obstructive airway physiology as a downstream consequence of CF airway disease.
  - target: Chronic Bacterial Infection
    description: Retained mucus supports persistent bacterial colonization and chronic endobronchial infection.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
      explanation: Supports progression from mucus retention to chronic airway infection.
  - target: Allergic Bronchopulmonary Aspergillosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Small-Airway Obstruction
  description: >-
    Progressive luminal obstruction and air trapping in small airways emerges from
    persistent mucus plugging.
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Supports small-airway obstruction as a central respiratory disease feature.
  downstream:
  - target: Bronchiectasis
    description: Persistent obstruction contributes to irreversible airway structural damage.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
      explanation: Supports progression from chronic airway disease to bronchiectasis.
- name: Chronic Bacterial Infection
  description: >-
    The CF airway is chronically colonized by characteristic pathogens.
    Staphylococcus aureus typically predominates in early childhood, followed by
    Pseudomonas aeruginosa which becomes the dominant pathogen in adolescence and
    adulthood. P. aeruginosa transitions to a mucoid phenotype with alginate
    biofilm production, making eradication extremely difficult. Other important
    pathogens include Burkholderia cepacia complex, Stenotrophomonas maltophilia,
    Achromobacter xylosoxidans, and non-tuberculous mycobacteria.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Clinical review identifies chronic endobronchial infection as a defining characteristic of CF.
  biological_processes:
  - preferred_term: Defense response to bacterium
    modifier: DYSREGULATED
    term:
      id: GO:0042742
      label: defense response to bacterium
  downstream:
  - target: Neutrophilic Airway Inflammation
    description: Chronic infection drives persistent neutrophil-predominant airway inflammation.
    evidence:
    - reference: PMID:23878362
      reference_title: "Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption."
      explanation: Supports infection-associated persistent neutrophilia in CF lungs.
  - target: Bronchiectasis
    description: Recurrent endobronchial infection contributes to progressive bronchiectatic damage.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
      explanation: Supports chronic airway infection as an upstream driver of bronchiectasis.
  - target: Recurrent Respiratory Infections
    causal_link_type: DIRECT
- name: Macrophage CFTR Dysfunction
  biological_scale: CELLULAR
  description: >-
    CFTR is expressed and functional in monocyte-derived macrophages, and
    macrophages from people with cystic fibrosis show reduced phagocytosis,
    reduced intracellular killing of cystic fibrosis pathogens, and reduced
    efferocytosis of apoptotic neutrophils. Elexacaftor/tezacaftor/ivacaftor
    partially restores these effector functions while leaving inflammatory
    cytokine production unchanged, which places the defect at least partly
    within the immune cell rather than entirely downstream of the epithelial
    surface. The evidence is ex vivo, from blood-derived macrophages, so the
    independent contribution of this arm to airway disease in vivo is not
    quantified and it should not be generalized to every immune lineage.
  cell_types:
  - preferred_term: Monocyte-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: phagocytosis
    modifier: DECREASED
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:36265882
    reference_title: "Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged."
    explanation: >-
      Blood-derived macrophages from 56 people with cystic fibrosis, assayed
      before and during modulator therapy, show CFTR-dependent effector
      deficits. That correction is partial and does not extend to cytokine
      production is the reason this node is curated as a parallel arm of
      uncertain weight rather than a fully corrected one.
  downstream:
  - target: Chronic Bacterial Infection
    description: >-
      Reduced macrophage phagocytosis and intracellular killing of cystic
      fibrosis pathogens is expected to contribute to bacterial persistence
      alongside the epithelial surface defect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36265882
      reference_title: "Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "However, MDM CFTR function correlated with clinical outcomes better than sweat chloride."
      explanation: >-
        Macrophage CFTR function tracked clinical outcome more closely than the
        standard epithelial biomarker in this cohort, which is consistent with an
        immune-cell contribution to infection burden. It is a correlation in an
        uncontrolled observational design, so the edge is recorded with unknown
        intermediates rather than as a measured causal step.
- name: Neutrophilic Airway Inflammation
  description: >-
    The CF airway shows persistent neutrophil-predominant inflammation, with a
    protease-rich inflammatory milieu that amplifies local tissue injury.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: neutrophil chemotaxis
    modifier: INCREASED
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
  evidence:
  - reference: PMID:29258516
    reference_title: "Neutrophil elastase in bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF."
    explanation: Review confirms neutrophil elastase as a key marker of inflammation in CF and bronchiectasis.
  downstream:
  - target: Neutrophil Elastase-Mediated Tissue Injury
    description: Protease-dominant neutrophilic inflammation drives extracellular airway tissue damage.
    evidence:
    - reference: PMID:29258516
      reference_title: "Neutrophil elastase in bronchiectasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF."
      explanation: Supports neutrophil elastase as a mechanistically relevant injury effector derived from CF-related neutrophilic inflammation.
- name: Neutrophil Elastase-Mediated Tissue Injury
  description: >-
    Neutrophil elastase burden and protease-antiprotease imbalance contribute to
    structural airway tissue damage.
  biological_processes:
  - preferred_term: proteolysis
    modifier: INCREASED
    term:
      id: GO:0006508
      label: proteolysis
  evidence:
  - reference: PMID:29258516
    reference_title: "Neutrophil elastase in bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment."
    explanation: Supports persistent NE activity as a biologically relevant marker in chronic suppurative airway disease with CF-based mechanistic context.
  downstream:
  - target: Airway Remodeling
    description: Persistent proteolytic injury promotes abnormal airway wall remodeling.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
      explanation: Supports progression from chronic airway injury to irreversible structural disease.
- name: Airway Remodeling
  description: >-
    Repeated infection-inflammation injury cycles alter airway wall architecture,
    producing thickening, scarring, and loss of normal elastic structure.
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
    explanation: Supports progressive structural airway deterioration in CF lung disease.
  downstream:
  - target: Bronchiectasis
    description: Structural remodeling culminates in irreversible bronchial dilation.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
      explanation: Supports bronchiectasis as an endpoint of progressive airway remodeling.
- name: Bronchiectasis
  description: >-
    Progressive, irreversible bronchial dilation develops from chronic obstruction,
    infection, and inflammatory injury.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
    explanation: Clinical review confirms progressive bronchiectasis leading to respiratory failure as the primary cause of mortality.
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Respiratory Failure
    description: End-stage bronchiectasis leads to hypoxemic and hypercapnic respiratory failure.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
      explanation: Supports direct progression from advanced bronchiectasis to respiratory failure.
  - target: Hemoptysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pneumothorax
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Respiratory Failure
  description: >-
    End-stage CF lung disease results in progressive respiratory failure with
    hypoxemia, hypercapnia, and cor pulmonale. Respiratory failure is the leading
    cause of death in CF patients and the primary indication for lung
    transplantation.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
    explanation: Respiratory failure is confirmed as the leading cause of CF mortality.
  downstream:
  - target: Digital Clubbing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Pancreatic Organogenesis
  description: >-
    CFTR dysfunction during fetal pancreatic development impairs the organogenesis
    of both endocrine and exocrine pancreatic tissue. Clinical evidence demonstrates
    that CF patients present with pancreatic pathology and glucose abnormalities as
    early as in utero. CFTR's role during pancreatic development may reduce
    pancreatic mass and islet cell number from birth, establishing a developmental
    foundation that predisposes to CF-related diabetes (CFRD) and exocrine
    insufficiency, distinct from post-natal destruction mechanisms.
  cell_types:
  - preferred_term: Pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  - preferred_term: Pancreatic acinar cell
    term:
      id: CL:0002064
      label: pancreatic acinar cell
  - preferred_term: Pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  biological_processes:
  - preferred_term: pancreas development
    modifier: DECREASED
    term:
      id: GO:0031016
      label: pancreas development
  locations:
  - preferred_term: Pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  evidence:
  - reference: PMID:42262528
    reference_title: "Unravelling the developmental origins of cystic fibrosis-related diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An emerging body of evidence supports that CFRD may have developmental origins, as people with CF present with pancreatic pathology and glucose abnormalities as early as in utero. This therefore suggests that the CF transmembrane conductance regulator (CFTR) gene mutations that cause CF may impair pancreatic organogenesis, thus leading to CFRD."
    explanation: Primary literature establishes developmental origins of CF pancreatic pathology, with evidence of pancreatic dysfunction in utero.
  downstream:
  - target: CF-Related Diabetes
    description: Reduced islet mass and number from impaired organogenesis contribute to insulin insufficiency.
    evidence:
    - reference: PMID:42262528
      reference_title: "Unravelling the developmental origins of cystic fibrosis-related diabetes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An emerging body of evidence supports that CFRD may have developmental origins, as people with CF present with pancreatic pathology and glucose abnormalities as early as in utero."
      explanation: Developmental islet dysfunction is proposed as a foundational mechanism for CF-related diabetes.
- name: Pancreatic Duct Obstruction
  description: >-
    CFTR dysfunction in pancreatic ductal epithelium impairs bicarbonate and fluid
    secretion, leading to viscid secretions that obstruct pancreatic ducts.
  cell_types:
  - preferred_term: Pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  biological_processes:
  - preferred_term: bicarbonate transport
    modifier: DECREASED
    term:
      id: GO:0015701
      label: bicarbonate transport
  locations:
  - preferred_term: Pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Pediatric review confirms pancreatic insufficiency and dysfunction as core CF manifestations.
  downstream:
  - target: Exocrine Pancreatic Tissue Destruction
    description: Persistent ductal obstruction promotes acinar injury and fibrosis.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports progression from pancreatic dysfunction to destructive exocrine pancreatic disease.
  - target: Exocrine Pancreatic Insufficiency
    description: Ductal disease progresses to insufficient exocrine enzyme output.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
      explanation: Supports pancreatic insufficiency as a major downstream endpoint of pancreatic duct disease.
- name: Exocrine Pancreatic Tissue Destruction
  description: >-
    Ongoing duct obstruction and intrapancreatic injury damage exocrine tissue and
    promote fibrosis.
  cell_types:
  - preferred_term: Pancreatic acinar cell
    term:
      id: CL:0002064
      label: pancreatic acinar cell
  biological_processes:
  - preferred_term: proteolysis
    modifier: INCREASED
    term:
      id: GO:0006508
      label: proteolysis
  locations:
  - preferred_term: Pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Supports destructive pancreatic dysfunction as part of the CF multiorgan phenotype.
  downstream:
  - target: Exocrine Pancreatic Insufficiency
    description: Loss of acinar tissue lowers digestive enzyme delivery to the gut.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
      explanation: Supports exocrine insufficiency as a direct pancreatic outcome.
  - target: CF-Related Diabetes
    description: Progressive pancreatic destruction contributes to insulin deficiency.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
      explanation: Supports diabetes mellitus as a downstream pancreatic complication in CF.
- name: Exocrine Pancreatic Insufficiency
  description: >-
    Destruction of exocrine pancreatic tissue causes insufficient production of
    digestive enzymes including lipase, amylase, and proteases. Present in 85-90%
    of CF patients, pancreatic insufficiency causes fat and protein malabsorption
    leading to steatorrhea, failure to thrive, and fat-soluble vitamin deficiency
    (vitamins A, D, E, K). Pancreatic sufficiency is more common in patients with
    at least one mild (class IV-V) CFTR mutation.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Clinical review identifies pancreatic insufficiency as a defining characteristic of cystic fibrosis.
  downstream:
  - target: Fat Malabsorption
    description: Low pancreatic lipase causes fat malabsorption with steatorrhea.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports direct progression from exocrine pancreatic insufficiency to malabsorption.
  - target: Fat-Soluble Vitamin Deficiency
    description: Malabsorption of vitamins A, D, E, K causes deficiency states.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports vitamin deficiency risk as part of exocrine insufficiency-driven malabsorption.
  - target: Protein-Calorie Malnutrition
    description: Impaired digestion and absorption lead to failure to thrive.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports malnutrition as a direct nutritional consequence of exocrine insufficiency.
- name: Fat Malabsorption
  description: >-
    Insufficient pancreatic lipase causes malabsorption of dietary fat, resulting
    in
    steatorrhea (fatty, bulky, foul-smelling stools), caloric loss, and deficiency
    of fat-soluble vitamins. Fat malabsorption is a major contributor to
    malnutrition and failure to thrive in CF.
  biological_processes:
  - preferred_term: lipid digestion
    modifier: DECREASED
    term:
      id: GO:0044241
      label: lipid digestion
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Pediatric review confirms malabsorption as a clinical characteristic of CF.
  downstream:
  - target: Fat-Soluble Vitamin Deficiency
    description: Impaired intestinal fat absorption reduces uptake of vitamins A, D, E, and K.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports vitamin deficiency risk downstream of CF malabsorption.
  - target: Protein-Calorie Malnutrition
    description: Chronic caloric and nutrient loss worsens growth and nutritional status.
    evidence:
    - reference: PMID:33178516
      reference_title: "Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."
      explanation: Supports progression from malabsorption to failure-to-thrive malnutrition phenotype.
  - target: Steatorrhea
    causal_link_type: DIRECT
- name: Fat-Soluble Vitamin Deficiency
  description: >-
    Malabsorption of fat-soluble vitamins A, D, E, and K leads to specific
    deficiency states. Vitamin A deficiency can cause night blindness, vitamin D
    deficiency contributes to CF bone disease, vitamin E deficiency may cause
    neurological symptoms, and vitamin K deficiency increases bleeding risk.
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Malabsorption leads to vitamin deficiencies as part of the CF nutritional phenotype.
  downstream:
  - target: CF Bone Disease
    description: Chronic vitamin D and K deficiency contributes to low bone mass and skeletal fragility.
    evidence:
    - reference: PMID:15613415
      reference_title: "Guide to bone health and disease in cystic fibrosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency"
      explanation: >-
        CF Foundation consensus summary naming poor fat-soluble vitamin
        absorption as a risk factor for CF-related bone disease, which is this
        edge. It does not separate vitamin D from vitamin K.
- name: Protein-Calorie Malnutrition
  description: >-
    Combined effects of pancreatic insufficiency, increased metabolic demands from
    chronic infection and inflammation, and poor appetite lead to protein-calorie
    malnutrition, failure to thrive in children, and poor weight maintenance in
    adults. Nutritional status is strongly correlated with lung function and survival.
  evidence:
  - reference: PMID:33178516
    reference_title: "Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."
    explanation: Case report review confirms malabsorption and failure to thrive as classic CF presentations.
  downstream:
  - target: CF Bone Disease
    description: Sustained undernutrition worsens bone accrual and skeletal strength.
    evidence:
    - reference: PMID:33526571
      reference_title: "Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
      explanation: Supports chronic malnutrition as a plausible upstream contributor to CF bone disease.
  - target: Rectal Prolapse
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gastroesophageal Reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed Puberty
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Failure to Thrive
    causal_link_type: DIRECT
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: CF-Related Diabetes
  description: >-
    Progressive fibrosis and fatty infiltration of the pancreas destroys
    islets of Langerhans, reducing insulin secretion capacity. CF-related diabetes
    (CFRD) is distinct from type 1 and type 2 diabetes, characterized primarily by
    insulin insufficiency with variable insulin resistance, especially during
    pulmonary exacerbations. CFRD affects up to 50% of adult CF patients and is
    associated with accelerated decline in lung function and increased mortality
    if untreated.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists diabetes mellitus among established complications of CF.
  cell_types:
  - preferred_term: Pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  locations:
  - preferred_term: Pancreas
    term:
      id: UBERON:0001264
      label: pancreas
- name: Intestinal Obstruction
  description: >-
    Dehydrated intestinal secretions cause bowel obstruction at different ages.
    Meconium ileus occurs in 15-20% of CF neonates due to inspissated meconium
    in the distal ileum. In older children and adults, distal intestinal
    obstruction syndrome (DIOS) presents with similar pathophysiology in the
    ileocecal region. Constipation is also common due to dehydrated intestinal
    contents.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists bowel obstruction among established complications of CF.
  downstream:
  - target: Meconium Ileus
    causal_link_type: DIRECT
  - target: Distal Intestinal Obstruction Syndrome
    causal_link_type: DIRECT
- name: Hepatobiliary Obstruction
  description: >-
    CFTR dysfunction in cholangiocytes causes viscid bile secretions that obstruct
    intrahepatic bile ductules. This leads to focal biliary cirrhosis, which can
    progress to multilobular cirrhosis with portal hypertension in 5-10% of CF
    patients. CF liver disease is the third leading cause of death after
    respiratory failure and transplant complications.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists hepatobiliary disease among established complications of CF.
  cell_types:
  - preferred_term: Cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  locations:
  - preferred_term: Liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Focal Biliary Cirrhosis
    causal_link_type: DIRECT
  - target: Portal Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Sweat Gland Dysfunction
  description: >-
    In sweat glands, CFTR is required for chloride reabsorption in the sweat duct.
    Loss of CFTR function results in failure to reabsorb chloride from primary sweat,
    producing sweat with elevated chloride concentration. This is the basis of the
    diagnostic sweat chloride test. Excessive salt loss can cause hyponatremic
    dehydration, especially in hot weather or during exercise.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis of CF is confirmed by demonstration of elevated sweat chloride."
    explanation: Elevated sweat chloride reflects defective CFTR-mediated chloride reabsorption in sweat ducts.
  biological_processes:
  - preferred_term: Chloride Transport
    modifier: DECREASED
    term:
      id: GO:0006821
      label: chloride transport
  downstream:
  - target: Hyponatremic Dehydration
    description: Chronic sweat salt loss predisposes to hyponatremic volume depletion.
    evidence:
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
      explanation: Supports hyponatremic dehydration as a direct downstream consequence of sweat-gland salt-loss physiology.
- name: Hyponatremic Dehydration
  description: >-
    Excessive sweat sodium and chloride loss can produce clinically significant
    hyponatremic dehydration, especially with heat stress or inadequate salt intake.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists hyponatremic dehydration among established cystic fibrosis complications.
- name: Vas Deferens Agenesis
  description: >-
    CFTR is required for normal development of the Wolffian duct derivatives.
    Congenital bilateral absence of the vas deferens (CBAVD) occurs in approximately
    97-98% of males with CF due to inspissation and atresia of the vas deferens
    during fetal development. CBAVD causes obstructive azoospermia and male
    infertility. Notably, CBAVD can occur as an isolated finding in males who
    carry one or two CFTR mutations with residual function, representing a
    CFTR-related disorder.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review confirms infertility as an established complication of CF.
  downstream:
  - target: Male Infertility
    causal_link_type: DIRECT
- name: Sinonasal Disease
  description: >-
    CFTR dysfunction in the sinonasal epithelium causes mucus retention and chronic
    inflammation in the paranasal sinuses. Chronic rhinosinusitis affects nearly all
    CF patients. Nasal polyposis occurs in 10-32% of CF patients and is unusual in
    children without CF, making it an important diagnostic clue.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists sinusitis among established complications of CF.
  downstream:
  - target: Nasal Polyposis
    causal_link_type: DIRECT
  - target: Chronic Sinusitis
    causal_link_type: DIRECT
- name: CF Bone Disease
  description: >-
    CF-related bone disease results from multiple converging mechanisms including
    vitamin D deficiency from fat malabsorption, chronic systemic inflammation
    with elevated cytokines (IL-6, TNF-alpha) that promote osteoclast activity,
    reduced physical activity, delayed puberty with reduced sex steroids,
    glucocorticoid use, and possibly direct CFTR effects on osteoblast function.
    Osteopenia and osteoporosis are common in adults with CF.
  evidence:
  - reference: PMID:15613415
    reference_title: "Guide to bone health and disease in cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy) for poor bone health."
    explanation: >-
      Consensus summary listing the converging risk factors in this node. It
      names bone-active cytokines without specifying IL-6 or TNF-alpha, and
      does not discuss a direct CFTR effect on osteoblasts, which the
      description marks as possible.
  - reference: PMID:15613415
    reference_title: "Guide to bone health and disease in cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures."
    explanation: >-
      Supports the statement that low bone density is common in adults with
      CF.
  downstream:
  - target: Osteoporosis
    causal_link_type: DIRECT
phenotypes:
# Respiratory phenotypes
- category: Respiratory
  name: Chronic Productive Cough
  description: Persistent cough with purulent sputum production, often the earliest respiratory symptom of CF.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: One of the classic presenting symptoms of CF along with steatorrhea and failure to thrive.
  phenotype_term:
    preferred_term: Chronic Productive Cough
    term:
      id: HP:0031245
      label: Productive cough
  evidence:
  - reference: PMID:33178516
    reference_title: "Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."
    explanation: Review confirms chronic productive cough as a classic presentation of cystic fibrosis.
- category: Respiratory
  name: Recurrent Respiratory Infections
  description: Chronic and recurrent lower respiratory tract infections with characteristic CF pathogens including Pseudomonas aeruginosa and Staphylococcus aureus.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Chronic Pseudomonas aeruginosa and Staphylococcus aureus infections are hallmarks of CF lung disease.
  phenotype_term:
    preferred_term: Recurrent Respiratory Infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Clinical review identifies chronic airway infection as a defining characteristic of cystic fibrosis.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
    explanation: Orphanet's HPO annotation independently supports recurrent respiratory infections as a very frequent cystic fibrosis phenotype.
- category: Respiratory
  name: Bronchiectasis
  description: Progressive airway damage from chronic infection and inflammation leading to permanent bronchial dilation.
  frequency: VERY_FREQUENT
  notes: Progressive and eventually universal in CF patients; the primary driver of morbidity and mortality.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
    explanation: Clinical review confirms progressive bronchiectasis as a consequence of chronic airway infection in CF.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002110 | Bronchiectasis | Very frequent (99-80%)"
    explanation: Orphanet's HPO annotation independently supports bronchiectasis as a very frequent cystic fibrosis phenotype.
- category: Respiratory
  name: Hemoptysis
  description: Coughing up blood due to erosion of bronchial arteries by chronic inflammation and bronchiectasis. Massive hemoptysis is a serious complication of advanced lung disease, with increased morbidity and mortality.
  frequency: FREQUENT
  notes: Minor hemoptysis is common; massive hemoptysis occurs in 4-5% of patients.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:16100161
    reference_title: "Massive hemoptysis in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Massive hemoptysis occurred with an average annual incidence of 0.87% and in 4.1% of patients overall."
    explanation: >-
      US registry cohort of 28,858 patients, supporting the frequency of
      massive hemoptysis in the notes. It does not measure minor hemoptysis,
      which the FREQUENT frequency rests on.
  - reference: PMID:16100161
    reference_title: "Massive hemoptysis in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Massive hemoptysis is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease."
    explanation: >-
      Supports massive hemoptysis as a serious complication tied to advanced
      lung disease.
- category: Respiratory
  name: Pneumothorax
  description: Spontaneous pneumothorax, occurring mainly in patients with advanced lung disease. Risk increases with severity of airflow obstruction.
  frequency: VERY_RARE
  notes: Occurs in 3-4% of CF patients; recurrence rate is high.
  phenotype_term:
    preferred_term: Pneumothorax
    term:
      id: HP:0002107
      label: Pneumothorax
  evidence:
  - reference: PMID:16100160
    reference_title: "Pneumothorax in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pneumothorax occurred with an average annual incidence of 0.64% and in 3.4% of patients overall."
    explanation: >-
      US registry cohort of 28,858 patients supporting the 3-4% figure in
      the notes and the VERY_RARE (<5%) frequency.
  - reference: PMID:16100160
    reference_title: "Pneumothorax in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pneumothorax is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease."
    explanation: >-
      Supports the link to advanced lung disease; the same study reports
      FEV1 below 30% predicted as a risk factor.
- category: Respiratory
  name: Allergic Bronchopulmonary Aspergillosis
  phenotype_term:
    preferred_term: Allergic Bronchopulmonary Aspergillosis
    term:
      id: MONDO:0015243
      label: allergic bronchopulmonary aspergillosis
  description: Hypersensitivity response to Aspergillus fumigatus colonization of CF airways, causing bronchial inflammation, mucus hypersecretion and progressive lung function decline.
  frequency: OCCASIONAL
  notes: Affects 2-15% of CF patients; requires high index of suspicion.
  evidence:
  - reference: PMID:41537324
    reference_title: "[How do I treat : allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus, commonly found in patients with cystic fibrosis and severe asthma"
    explanation: >-
      Supports ABPA as a hypersensitivity reaction to A. fumigatus occurring
      in CF.
  - reference: PMID:41537324
    reference_title: "[How do I treat : allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It leads to bronchial inflammation, excessive mucus secretion, and progressive lung function decline."
    explanation: >-
      Supports the airway consequences in the description.
- category: Respiratory
  name: Digital Clubbing
  description: Enlargement and rounding of the fingertips and nail beds due to chronic hypoxemia from progressive lung disease.
  frequency: FREQUENT
  notes: Develops with progression of lung disease; correlates with severity.
  phenotype_term:
    preferred_term: Digital Clubbing
    term:
      id: HP:0001217
      label: Clubbing
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Progressive obstructive lung disease leads to chronic hypoxemia and clubbing.
# ENT phenotypes
- category: ENT
  name: Nasal Polyposis
  description: Benign mucosal growths in the nasal passages and paranasal sinuses. Nasal polyposis in children is highly suggestive of CF and should prompt diagnostic evaluation.
  frequency: FREQUENT
  notes: Present in 10-32% of CF patients. In children, nasal polyps are uncommon outside of CF and should trigger sweat testing.
  phenotype_term:
    preferred_term: Nasal Polyposis
    term:
      id: HP:0100582
      label: Nasal polyposis
- category: ENT
  name: Chronic Sinusitis
  description: Near-universal chronic rhinosinusitis in CF patients due to mucus retention and inflammation in the paranasal sinuses. Often causes nasal obstruction, facial pain, and anosmia.
  frequency: VERY_FREQUENT
  notes: Radiographic sinusitis is nearly universal; symptomatic disease varies.
  phenotype_term:
    preferred_term: Chronic Sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists sinusitis among established complications of CF.
# Gastrointestinal phenotypes
- category: Gastrointestinal
  name: Exocrine Pancreatic Insufficiency
  description: Insufficient production of pancreatic digestive enzymes causing malabsorption of fats, proteins, and fat-soluble vitamins.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Present in 85-90% of CF patients, typically those with two severe CFTR mutations. Patients with at least one mild mutation may retain pancreatic sufficiency.
  phenotype_term:
    preferred_term: Pancreatic Insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Clinical review identifies pancreatic insufficiency as a defining characteristic of cystic fibrosis.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001738 | Exocrine pancreatic insufficiency | Very frequent (99-80%)"
    explanation: Orphanet's HPO annotation independently supports exocrine pancreatic insufficiency as a very frequent cystic fibrosis phenotype.
- category: Gastrointestinal
  name: Steatorrhea
  description: Fatty, bulky, foul-smelling stools resulting from fat malabsorption due to pancreatic lipase deficiency.
  frequency: VERY_FREQUENT
  notes: A classic presenting symptom of CF in infancy and early childhood.
  phenotype_term:
    preferred_term: Steatorrhea
    term:
      id: HP:0002570
      label: Steatorrhea
  evidence:
  - reference: PMID:33178516
    reference_title: "Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."
    explanation: Review confirms steatorrhea as a classic presentation of cystic fibrosis due to malabsorption.
- category: Gastrointestinal
  name: Meconium Ileus
  description: Neonatal bowel obstruction caused by inspissated meconium in the distal ileum, often the first clinical manifestation of CF.
  frequency: OCCASIONAL
  diagnostic: true
  notes: Present in 15-20% of CF newborns. May be complicated by volvulus, atresia, or perforation. Meconium ileus in a neonate is highly suggestive of CF.
  phenotype_term:
    preferred_term: Meconium Ileus
    term:
      id: HP:0004401
      label: Meconium ileus
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists bowel obstruction (including meconium ileus) among established complications of CF.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004401 | Meconium ileus | Occasional (29-5%)"
    explanation: Orphanet's HPO annotation independently supports meconium ileus as an occasional cystic fibrosis phenotype.
- category: Gastrointestinal
  name: Distal Intestinal Obstruction Syndrome
  description: Partial or complete intestinal obstruction in the ileocecal region due to accumulation of viscid intestinal contents. Analogous to meconium ileus but occurring in older children and adults.
  frequency: OCCASIONAL
  notes: Occurs in approximately 10-15% of CF patients. Risk factors include pancreatic insufficiency, dehydration, and inadequate enzyme replacement.
  phenotype_term:
    preferred_term: Intestinal Obstruction
    term:
      id: HP:0005214
      label: Intestinal obstruction
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Bowel obstruction including DIOS is an established complication in CF patients.
- category: Gastrointestinal
  name: Rectal Prolapse
  description: Protrusion of rectal mucosa through the anus, historically a common presenting feature of CF in undiagnosed children due to malnutrition and chronic cough-related straining.
  frequency: OCCASIONAL
  notes: Less common since advent of newborn screening and early treatment.
  phenotype_term:
    preferred_term: Rectal Prolapse
    term:
      id: HP:0002035
      label: Rectal prolapse
  evidence:
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002035 | Rectal prolapse | Occasional (29-5%)"
    explanation: Orphanet's HPO annotation independently supports rectal prolapse as an occasional cystic fibrosis phenotype.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  description: Increased gastroesophageal reflux in CF patients, potentially exacerbated by cough, chest physiotherapy, and increased abdominal pressure. May worsen lung disease through aspiration.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal Reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:33202431
    reference_title: "Gastroesophageal Reflux Disease and Need for Antireflux Surgery in Children with Cystic Fibrosis: A Systematic Review on Incidence, Surgical Complications, and Postoperative Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall incidence of GERD was 46% (range, 19-81%), derived from seven studies (n = 212 patients)."
    explanation: >-
      Systematic review supporting the FREQUENT frequency in children with
      CF.
  - reference: PMID:33202431
    reference_title: "Gastroesophageal Reflux Disease and Need for Antireflux Surgery in Children with Cystic Fibrosis: A Systematic Review on Incidence, Surgical Complications, and Postoperative Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastroesophageal reflux disease (GERD) is associated with accelerated decline in lung health in children with cystic fibrosis (CF)."
    explanation: >-
      Supports the statement that reflux may worsen lung disease.
# Hepatobiliary phenotypes
- category: Hepatobiliary
  name: Focal Biliary Cirrhosis
  description: Obstruction of intrahepatic bile ductules by viscid secretions causes focal biliary fibrosis, which may progress to multilobular cirrhosis with portal hypertension in 5-10% of patients.
  frequency: OCCASIONAL
  notes: CF liver disease is the third leading cause of CF mortality. Ursodeoxycholic acid may slow progression.
  phenotype_term:
    preferred_term: Biliary Cirrhosis
    term:
      id: HP:0002613
      label: Biliary cirrhosis
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists hepatobiliary disease among established complications of CF.
- category: Hepatobiliary
  name: Portal Hypertension
  description: Increased portal venous pressure from multilobular biliary cirrhosis, which may cause variceal bleeding, splenomegaly, and ascites.
  frequency: OCCASIONAL
  notes: Occurs in patients who progress to multilobular cirrhosis. May require portosystemic shunting or liver transplantation.
  phenotype_term:
    preferred_term: Portal Hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Liver and pancreatic dysfunction in CF includes cirrhosis leading to portal hypertension.
# Endocrine phenotypes
- category: Endocrine
  name: CF-Related Diabetes
  description: Diabetes caused by progressive destruction of pancreatic islets, characterized by insulin insufficiency with variable insulin resistance. Distinct from type 1 and type 2 diabetes. Associated with accelerated decline in lung function and increased mortality if untreated.
  frequency: FREQUENT
  notes: Prevalence increases with age, affecting up to 20% of adolescents and 50% of adults with CF. Annual screening with oral glucose tolerance test recommended from age 10.
  phenotype_term:
    preferred_term: Diabetes Mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists diabetes mellitus among established complications of CF.
- category: Endocrine
  name: Delayed Puberty
  description: Delayed onset of puberty due to chronic illness, malnutrition, and possibly direct effects of CFTR dysfunction on gonadal function.
  frequency: FREQUENT
  notes: More common when nutritional status is poor.
  phenotype_term:
    preferred_term: Delayed Puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Malnutrition from pancreatic insufficiency contributes to delayed puberty in CF patients.
# Growth phenotypes
- category: Growth
  name: Failure to Thrive
  description: Poor weight gain and growth failure due to pancreatic insufficiency, malabsorption, increased caloric requirements from chronic lung infection, and poor appetite.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: A classic presenting feature, especially before newborn screening era. Nutritional status strongly correlates with lung function and survival.
  phenotype_term:
    preferred_term: Failure to Thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33178516
    reference_title: "Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It classically presents in childhood with chronic productive cough, malabsorption causing steatorrhea, and failure to thrive."
    explanation: Review confirms failure to thrive as a classic presentation of cystic fibrosis.
- category: Growth
  name: Short Stature
  description: Reduced height for age resulting from chronic malnutrition, systemic inflammation, and delayed puberty.
  frequency: FREQUENT
  notes: Improved with optimized nutritional support and CFTR modulator therapy.
  phenotype_term:
    preferred_term: Short Stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Malnutrition from pancreatic insufficiency contributes to growth failure and short stature.
# Reproductive phenotypes
- category: Reproductive
  name: Male Infertility
  description: Obstructive azoospermia due to congenital bilateral absence of the vas deferens (CBAVD) in 97-98% of males with CF. Spermatogenesis is usually normal, and assisted reproduction is possible via sperm extraction techniques.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: CBAVD can also occur as an isolated finding in males carrying one or two CFTR mutations, representing a CFTR-related disorder.
  phenotype_term:
    preferred_term: Male Infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists infertility among the established complications of cystic fibrosis.
- category: Reproductive
  name: Reduced Female Fertility
  description: Reduced fertility in females with CF due to altered cervical mucus, ovulatory dysfunction and impaired uterine pH. Pregnancy rates have risen with CFTR modulator therapy.
  frequency: FREQUENT
  notes: Not absolute infertility; many CF women conceive, especially with improved health status on modulator therapy.
  phenotype_term:
    preferred_term: Reduced Female Fertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:42167573
    reference_title: "Reproductive Considerations in Females With Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Infertility has historically affected approximately 37% of females with CF (FwCF) who attempt conception-more than twice the general population rate-driven by mechanisms including altered cervical mucus, ovulatory dysfunction, and impaired uterine pH."
    explanation: >-
      Supports the frequency and the mechanisms in the description.
  - reference: PMID:42167573
    reference_title: "Reproductive Considerations in Females With Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since FDA approval of elexacaftor/tezacaftor/ivacaftor in 2019, pregnancy rates among FwCF have more than doubled."
    explanation: >-
      Supports improved fertility with CFTR modulator therapy.
# Metabolic phenotypes
- category: Metabolic
  name: Hyponatremic Dehydration
  description: Excessive sodium and chloride loss in sweat predisposes CF patients to salt-depletion dehydration, especially in hot weather, during exercise, or with gastroenteritis.
  frequency: OCCASIONAL
  notes: Can be a presenting feature in infancy. Salt supplementation is recommended.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: Clinical review lists hyponatremic dehydration among established complications of CF.
- category: Metabolic
  name: Fat-Soluble Vitamin Deficiency
  description: Deficiency of vitamins A, D, E, and K due to fat malabsorption from pancreatic insufficiency. Vitamin D deficiency contributes to bone disease; vitamin K deficiency increases bleeding risk.
  frequency: VERY_FREQUENT
  notes: Routine supplementation of fat-soluble vitamins is standard of care.
  phenotype_term:
    preferred_term: Intestinal malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Malabsorption from pancreatic insufficiency causes vitamin deficiencies.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002024 | Malabsorption | Very frequent (99-80%)"
    explanation: Orphanet's HPO annotation independently supports malabsorption as a very frequent cystic fibrosis phenotype.
# Musculoskeletal phenotypes
- category: Musculoskeletal
  name: Osteoporosis
  description: Reduced bone mineral density resulting from vitamin D deficiency, chronic inflammation, reduced physical activity, delayed puberty, and glucocorticoid exposure. Fracture risk is increased, particularly vertebral fractures.
  frequency: OCCASIONAL
  notes: Bone density screening with DXA recommended for adults with CF.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:19949942
    reference_title: "The prevalence of osteoporosis, osteopenia, and fractures among adults with cystic fibrosis: a systematic literature review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled prevalence of osteoporosis in adults with cystic fibrosis was 23.5% (95% CI, 16.6-31.0)."
    explanation: >-
      Meta-analysis of 12 adult cohorts (1,055 patients); 23.5% places
      osteoporosis in the OCCASIONAL (5-29%) band.
  - reference: PMID:19949942
    reference_title: "The prevalence of osteoporosis, osteopenia, and fractures among adults with cystic fibrosis: a systematic literature review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled prevalences of radiological vertebral fractures and nonvertebral fractures were 14% (95% CI, 7.8-21.7) and 19.7% (95% CI, 6.0-38.8), respectively."
    explanation: >-
      Supports increased fracture risk, including vertebral fractures. Rib
      fractures are not reported separately.
  - reference: PMID:15613415
    reference_title: "Guide to bone health and disease in cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy"
    explanation: >-
      CF Foundation consensus summary listing the risk factors named in the
      description.
biochemical:
- name: Sweat Chloride
  loinc_term:
    id: LOINC:2077-6
    label: Chloride [Moles/volume] in Sweat
  presence: Elevated
  context: Sweat chloride >=60 mmol/L is diagnostic of CF; 30-59 mmol/L is intermediate and requires further evaluation; <30 mmol/L makes CF unlikely.
  notes: >-
    The LOINC code is the method-less quantitative sweat chloride measurement; the CF Foundation
    decision limits summarised in context are carried as interpretation_bands on the Sweat
    Chloride Test diagnosis row, keyed on the same code.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis of CF is confirmed by demonstration of elevated sweat chloride."
    explanation: Elevated sweat chloride is the diagnostic hallmark of CF.
  - reference: PMID:28129811
    reference_title: "Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test."
    explanation: CF Foundation consensus guidelines recommend sweat chloride testing for all CFTR-related diagnoses.
  - reference: ORPHA:586
    reference_title: "Cystic fibrosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012236 | Elevated sweat chloride | Very frequent (99-80%)"
    explanation: Orphanet's HPO annotation independently supports elevated sweat chloride as a very frequent cystic fibrosis finding.
- name: Immunoreactive Trypsinogen (IRT)
  presence: Elevated
  context: Elevated in newborn dried blood spots; used as first-tier newborn screening test. Elevated IRT reflects pancreatic injury in utero.
  loinc_term:
    id: LOINC:48633-2
    label: Trypsinogen I Free [Mass/volume] in DBS
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of CF are identified through newborn screening (NBS)."
    explanation: Newborn screening using IRT is the primary method of CF identification.
- name: Fecal Elastase
  presence: Decreased
  context: Fecal elastase-1 <200 mcg/g indicates pancreatic insufficiency; <100 mcg/g indicates severe insufficiency. Used to confirm exocrine pancreatic function status.
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Pancreatic insufficiency is assessed using fecal elastase measurements.
- name: Fat-Soluble Vitamins (A, D, E, K)
  presence: Decreased
  context: Deficiencies common due to fat malabsorption in pancreatic-insufficient patients. Levels should be monitored annually.
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Malabsorption from pancreatic insufficiency causes fat-soluble vitamin deficiencies.
- name: Liver Enzymes
  presence: Variable
  context: Elevated ALT, AST, and GGT may indicate CF liver disease. GGT is often the first to elevate.
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility."
    explanation: Liver dysfunction in CF is monitored using liver enzyme measurements.
- name: Blood Glucose / HbA1c
  presence: Variable
  context: Annual oral glucose tolerance test recommended from age 10 for CFRD screening. HbA1c is unreliable in CF due to increased red cell turnover.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility."
    explanation: CF-related diabetes requires monitoring of glucose levels.
- name: Sputum Microbiology
  presence: Variable
  context: Routine sputum cultures guide antibiotic therapy. Typical organisms include Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, and non-tuberculous mycobacteria.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Chronic endobronchial infection is monitored through sputum microbiology.
- name: Forced Expiratory Volume in 1 Second (FEV1)
  presence: Reduced with progressive obstructive lung disease; improves or declines more slowly with effective CFTR modulator therapy.
  context: >-
    Spirometric pulmonary function measure (percent of predicted FEV1) used to
    grade obstructive lung disease severity, monitor progression, and assess
    pharmacodynamic response to CFTR modulator therapy. FEV1 is recognized by
    the FDA as a validated surrogate endpoint supporting traditional approval of
    cystic fibrosis drugs.
  biomarker_term:
    preferred_term: Forced Expiratory Volume in 1 Second (FEV1)
    term:
      id: NCIT:C38084
      label: Forced Expiratory Volume in 1 Second
  synonyms:
  - FEV1
  - percent predicted FEV1
  readouts:
  - target: Small-Airway Obstruction
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: NEGATIVE
    endpoint_context: REGULATORY_SURROGATE
    regulatory_endpoint_refs:
    - FDA-SE-adult-noncancer-017
    - FDA-SE-pediatric-noncancer-011
    interpretation: >-
      Higher or less-declining percent-predicted FEV1 indicates reduced
      small-airway obstruction; treatment-induced improvement in FEV1 reports
      the pharmacodynamic response to CFTR potentiator therapy and underpins the
      FDA surrogate-endpoint basis for traditional approval of cystic fibrosis
      drugs.
    evidence:
    - reference: PMID:22047557
      reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1))."
      explanation: >-
        The pivotal randomized trial of the CFTR potentiator ivacaftor used
        percent-predicted FEV1 as its primary endpoint, establishing FEV1 as the
        pharmacodynamic readout for CFTR-modulator efficacy.
    - reference: PMID:22047557
      reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group"
      explanation: >-
        FEV1 improved measurably with CFTR potentiator therapy versus placebo,
        confirming FEV1 as a treatment-responsive pharmacodynamic marker of
        small-airway obstruction.
  evidence:
  - reference: PMID:22047557
    reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks."
    explanation: >-
      Spirometric lung function (FEV1) tracks treatment response in cystic
      fibrosis, supporting its use as a monitoring and pharmacodynamic biomarker.
- name: Blood DNA methylation epigenetic age acceleration
  presence: Variable
  context: >-
    Epigenetic age estimated from blood DNA methylation (Illumina EPIC v2 array)
    with an epigenetic clock and compared with chronological age. In an adult
    cohort of 52 people with CF starting elexacaftor/tezacaftor/ivacaftor (ETI),
    half had an epigenetic age above their chronological age at baseline and the
    other half below it; the accelerated half had lower FEV1. Research measure
    only, with no clinical decision threshold.
  biomarker_term:
    preferred_term: Blood DNA methylation epigenetic clock estimate
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  synonyms:
  - epigenetic age acceleration
  - DNA methylation age
  notes: >-
    NCIT has no term for an epigenetic clock or for biological age, so the assay
    is bound and the clock carried in preferred_term, as in the
    epigenetic_alterations module (design decisions section 12). The two cohorts
    used different clocks and are not numerically comparable: the 52-patient
    Naples cohort used the Horvath Skin & Blood clock and an epigenetic age ratio,
    and the 8-patient Vancouver pilot used DNAmGrimAge2 residuals adjusted for
    blood-cell composition. Acceleration is not uniform in CF: half of the Naples
    cohort was epigenetically younger than its chronological age at baseline, and
    the age ratio did not correlate with sweat chloride there. The decrease in
    age acceleration after one year of ETI is an observational before/after
    change without an untreated comparator, and the inflammatory-marker
    association comes only from the not-yet-peer-reviewed pilot, so no causal
    link from CFTR restoration to epigenetic aging is curated here.
  readouts:
  - target: Small-Airway Obstruction
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Greater epigenetic age acceleration tracks lower percent-predicted FEV1,
      that is, more obstructive lung disease, before and after one year of ETI.
      Whether the clock adds information beyond spirometry is not established.
    evidence:
    - reference: PMID:40724864
      reference_title: "Pulmonary Function Modulates Epigenetic Age in Subjects with Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "we found that ER was negatively related to FEV1 both at T0 (slope = -0.348; p = 0.014) and T1 (slope = -0.423; p = 0.002)"
      explanation: >-
        In 52 adults with CF, the epigenetic age ratio fell as FEV1 rose, at
        baseline and after one year of ETI, linking epigenetic age acceleration
        to the severity of obstructive lung disease.
  evidence:
  - reference: PMID:40724864
    reference_title: "Pulmonary Function Modulates Epigenetic Age in Subjects with Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In the remaining 26 (50%) the ratio was positive, with the epigenetic age being significantly higher than the chronological one."
    explanation: >-
      Half of the 52-patient adult cohort had accelerated blood epigenetic age
      before starting ETI.
  - reference: PMID:40724864
    reference_title: "Pulmonary Function Modulates Epigenetic Age in Subjects with Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The second group of CF subjects had an epigenetic age lower than the chronological one at T0 and lung function was better maintained."
    explanation: >-
      The other half of the cohort was epigenetically younger than its
      chronological age, which is why presence is recorded as variable rather
      than increased.
  - reference: PMID:40724864
    reference_title: "Pulmonary Function Modulates Epigenetic Age in Subjects with Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Half of the subjects had a significantly accelerated epigenetic age and a worse lung function. The therapy with ETI impacted on both the two parameters"
    explanation: >-
      After one year of ETI, both the epigenetic age ratio and FEV1 improved in
      the accelerated group (Table 1: median ratio 8.1 at baseline, 3.2 at one
      year, p = 0.001). This is a single-arm before/after comparison.
  - reference: PPR:PPR1322615
    reference_title: "Elexacaftor/tezacaftor/ivacaftor treatment is associated with epigenetic age deceleration in cystic fibrosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "DNAmGrimAge2 age acceleration decreased following ETI initiation and was associated with markers of innate and neutrophilic inflammation and CF disease activity."
    explanation: >-
      Not peer reviewed. An independent 8-patient pilot using a different clock
      (DNAmGrimAge2) found the same direction of change after one year of ETI;
      it corroborates the peer-reviewed cohort above and is not the sole support
      for any claim here.
  - reference: PPR:PPR1322615
    reference_title: "Elexacaftor/tezacaftor/ivacaftor treatment is associated with epigenetic age deceleration in cystic fibrosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Greater age acceleration was associated with higher IL-6, IL-1β, and calprotectin concentrations."
    explanation: >-
      Not peer reviewed. Within-participant correlation in eight patients; it
      reports an association with circulating inflammatory markers and is not
      used to wire the marker to the Neutrophilic Airway Inflammation node.
genetic:
- name: CFTR
  gene_term:
    preferred_term: CFTR
    term:
      id: hgnc:1884
      label: CFTR
  association: Causative
  notes: >-
    The CFTR gene (7q31.2) encodes the cystic fibrosis transmembrane conductance
    regulator, a 1480-amino acid chloride and bicarbonate channel. Nearly 2,000
    CFTR variants have been identified. The Clinical and Functional Translation of
    CFTR (CFTR2) project has systematically characterized disease liability of the
    most common variants, with 159 variants at allele frequency >=0.01%, of which
    127 met both clinical and functional criteria for disease causation.
  evidence:
  - reference: PMID:31697873
    reference_title: "Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation."
    explanation: Phase 3 trial confirms CFTR mutations cause CF and F508del is the most common mutation.
  - reference: PMID:23974870
    reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis."
    explanation: CFTR2 project establishes the scope of CFTR variant heterogeneity.
  - reference: PMID:23974870
    reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe"
    explanation: CFTR2 project provides the largest systematic analysis of CFTR variant-disease relationships.
  variants:
  - name: F508del (Phe508del)
    description: >-
      Deletion of phenylalanine at position 508 in the CFTR protein. The most common
      CF-causing mutation, present on at least one allele in nearly 90% of CF
      patients. Causes misfolding of CFTR protein leading to endoplasmic reticulum
      retention, proteasomal degradation, and near-complete absence of CFTR at the
      cell surface (Class II defect). The small amount of protein reaching the
      surface also has reduced channel open probability (Class III) and reduced
      stability (Class VI).
    evidence:
    - reference: PMID:31697873
      reference_title: "Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "nearly 90% of patients have at least one copy of the Phe508del CFTR mutation"
      explanation: Confirms F508del is present in nearly 90% of CF patients.
  - name: G551D (Gly551Asp)
    description: >-
      Missense mutation causing glycine-to-aspartate substitution at position 551.
      CFTR protein reaches the cell surface normally but has severely reduced channel
      gating (Class III defect). The first CFTR mutation for which targeted modulator
      therapy (ivacaftor) was approved, producing dramatic clinical benefit.
    evidence:
    - reference: PMID:22047557
      reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001)."
      explanation: Landmark Phase 3 trial demonstrating ivacaftor efficacy in G551D patients.
  - name: G542X
    description: >-
      Nonsense mutation creating a premature stop codon at position 542. No functional
      CFTR protein is produced (Class I defect). One of the most common severe
      mutations after F508del.
    evidence:
    - reference: PMID:23974870
      reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."
      explanation: CFTR2 project establishes disease liability of common CFTR variants including nonsense mutations.
  - name: W1282X
    description: >-
      Nonsense mutation at position 1282 causing premature termination. Class I defect
      with no functional protein produced. Common in Ashkenazi Jewish populations.
    evidence:
    - reference: PMID:23974870
      reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."
      explanation: CFTR2 project classifies W1282X as a disease-causing variant.
  - name: N1303K
    description: >-
      Missense mutation causing protein misfolding and degradation similar to F508del
      (Class II defect).
    evidence:
    - reference: PMID:23974870
      reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."
      explanation: CFTR2 project evaluates N1303K as a disease-causing variant.
  - name: R117H
    description: >-
      Missense mutation producing CFTR with reduced chloride conductance (Class IV
      defect). Associated with variable phenotype depending on the polythymidine
      tract variant (5T, 7T, 9T) on the same allele. R117H-5T causes more severe
      disease; R117H-7T may cause CFTR-related disorder or be benign.
- name: SLC26A9
  gene_term:
    preferred_term: SLC26A9
  association: Modifier
  relationship_type: MODIFIER
  notes: >-
    Chloride channel/anion transporter at a chromosome 1 locus replicated as a
    modifier of meconium ileus in the International CF Gene Modifier Consortium.
    The locus colocalizes with pancreatic expression of the gene even though the
    phenotype manifests in the intestine. No HGNC binding is recorded here
    because the identifier is not present in this repository's term caches; add
    the binding when it is.
  evidence:
  - reference: PMID:30807572
    reference_title: "Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively)"
    explanation: >-
      Genome-wide significant, replicated association of the SLC26A9 locus with
      meconium ileus in more than 6,500 people with cystic fibrosis. The trait is
      meconium ileus specifically, not cystic fibrosis susceptibility or lung
      disease severity.
  - reference: PMID:30807572
    reference_title: "Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine."
    explanation: >-
      Transcriptome integration assigns the regulatory effect of the SLC26A9
      locus to the pancreas rather than the intestine, which is what makes the
      contributing tissue, and not just the contributing gene, part of the claim.
- name: ATP12A
  gene_term:
    preferred_term: ATP12A
  association: Modifier
  relationship_type: MODIFIER
  notes: >-
    Non-gastric proton pump at a chromosome 13 locus newly identified as a
    modifier of meconium ileus. It secretes protons into the airway lumen and is
    of interest as a CFTR-independent route to correcting airway surface liquid
    pH. No HGNC binding is recorded here because the identifier is not present in
    this repository's term caches.
  evidence:
  - reference: PMID:30807572
    reference_title: "Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively)"
    explanation: >-
      Reports ATP12A as a newly identified genome-wide significant modifier locus
      for meconium ileus in the consortium analysis.
- name: SLC6A14
  gene_term:
    preferred_term: SLC6A14
  association: Modifier
  relationship_type: MODIFIER
  notes: >-
    Amino-acid transporter at an X-chromosome locus replicated as a modifier of
    meconium ileus, with a separate and differently located signal for lung
    disease severity that colocalizes with airway-specific regulation of the same
    gene in cystic fibrosis nasal epithelium. No HGNC binding is recorded here
    because the identifier is not present in this repository's term caches.
  evidence:
  - reference: PMID:30807572
    reference_title: "Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively)"
    explanation: >-
      Reports the replicated genome-wide significant SLC6A14 locus for meconium
      ileus in the consortium analysis.
  - reference: PMID:30807572
    reference_title: "Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4))."
    explanation: >-
      Separates the lung-disease-severity signal from the meconium ileus signal
      and ties it to airway-specific regulation of SLC6A14 in cystic fibrosis
      nasal epithelium, supporting an organ-specific modifier effect.
diagnosis:
- name: Sweat Chloride Test (Quantitative Pilocarpine Iontophoresis)
  description: >-
    Gold standard diagnostic test for CF. Pilocarpine iontophoresis stimulates
    localized sweating; sweat is collected and chloride concentration measured.
    Chloride >=60 mmol/L is diagnostic, 30-59 mmol/L is intermediate, <30 mmol/L
    is CF-unlikely.
  diagnosis_term:
    preferred_term: sweat electrolyte test
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  measurements:
  - preferred_term: sweat chloride
    term:
      id: LOINC:2077-6
      label: Chloride [Moles/volume] in Sweat
  reference_ranges:
  - loinc_term:
      id: LOINC:2077-6
      label: Chloride [Moles/volume] in Sweat
    unit: mmol/L
    population: CF Foundation 2017 consensus diagnostic decision limits, all ages
    notes: >-
      Two of the three boundaries come from the consensus itself and one from a
      guideline that adopts it: the 2017 CF Foundation nonscreened-population
      paper states that the intermediate threshold was lowered from 40 mmol/L to
      30 mmol/L, and the 2025 Australasian sweat-testing guideline, written to
      align with the international consensus, states the intermediate result as
      values between 30 and 59 mmol/L for all ages and 60 mmol/L or more as
      supportive of a diagnosis of CF. The 2017 De Boeck and Vermeulen review
      words the confirmatory value as "above 60mmol/L", one point off the
      consensus "60 or more"; the band keeps the consensus boundary and the
      discrepancy is disclosed here rather than shifted. The half-open bands put
      exactly 30 in the intermediate band and exactly 60 in the diagnostic band,
      which agrees with both guideline statements.
    evidence:
    - reference: PMID:28129813
      reference_title: "Diagnosis of Cystic Fibrosis in Nonscreened Populations."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "On the basis of the large number of patients with bona fide CF currently followed in registries with sweat chloride levels between 30 and 40 mmol/L, the threshold considered \"intermediate\" was lowered from 40 mmol/L in the prior diagnostic guidelines to 30 mmol/L."
      explanation: The CF Foundation 2017 consensus decision that sets the lower boundary of the intermediate band at 30 mmol/L.
    - reference: PMID:40476459
      reference_title: "Australasian guideline for the performance of sweat chloride testing 3rd edition: to support cystic fibrosis screening, diagnosis and monitoring."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "International consensus guidelines now recommend a standard set of clinical decision limits for sweat chloride, with values between 30 and 59 mmol/L, as the intermediate result for all ages."
      explanation: States the intermediate band as the international consensus limits this range reproduces.
    - reference: PMID:40476459
      reference_title: "Australasian guideline for the performance of sweat chloride testing 3rd edition: to support cystic fibrosis screening, diagnosis and monitoring."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Sweat chloride concentrations of ≥60 mmol/L are supportive of a diagnosis of CF."
      explanation: States the lower boundary of the diagnostic band.
    - reference: PMID:28576637
      reference_title: "The diagnosis of cystic fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "In screen positive babies, the diagnosis of CF must be confirmed by a sweat test demonstrating a sweat chloride concentration above 60mmol/L."
      explanation: The confirmatory role of the diagnostic band in screen-positive infants; this review's "above 60" wording is the one-point discrepancy disclosed in the range notes.
    interpretation_bands:
    - name: CF unlikely
      upper_bound: 30.0
      unit: mmol/L
      abnormal_flag: NORMAL
      interpretation: >-
        Below the intermediate threshold; CF is unlikely on sweat chloride alone.
    - name: Intermediate
      lower_bound: 30.0
      upper_bound: 60.0
      unit: mmol/L
      abnormal_flag: HIGH
      interpretation: >-
        Inconclusive; the consensus directs further evaluation of CFTR function and
        genotype, which the nasal potential difference and intestinal current
        measurement rows describe.
    - name: Diagnostic of CF
      lower_bound: 60.0
      unit: mmol/L
      abnormal_flag: CRITICAL_HIGH
      phenotype_term:
        preferred_term: Elevated sweat chloride
        term:
          id: HP:0012236
          label: Elevated sweat chloride
      interpretation: >-
        Supportive of the diagnosis of CF; in a screen-positive infant this result
        confirms it.
  notes: >-
    Must be performed at a CF Foundation-accredited laboratory. Minimum sweat volume required for reliable results. Should be performed on two separate occasions.
    The measurement is bound at the method-less quantitative sweat chloride code (LOINC:2077-6),
    which is also the loinc_term of the Sweat Chloride biochemical marker; the screen-method
    codes (LOINC:56448-4, LOINC:105200-0) and the chloride-and-sodium panel (LOINC:74993-7)
    exist in the Monarch KG and are deliberately not bound, as the quantitative pilocarpine
    iontophoresis measurement is the one the decision limits apply to.
  evidence:
  - reference: PMID:28576637
    reference_title: "The diagnosis of cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even in 2016, the most reliable and widely available diagnostic test for CF is the measurement of chloride concentration in sweat."
    explanation: Review emphasizes sweat chloride as the most reliable and widely available diagnostic test.
  - reference: PMID:28576637
    reference_title: "The diagnosis of cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The method of choice is sweat induction by pilocarpine iontophoresis, followed by sweat collection on a gauze or filter paper or in a Macroduct coil."
    explanation: Supports quantitative pilocarpine iontophoresis as the preferred sweat testing approach.
  - reference: PMID:28129811
    reference_title: "Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test."
    explanation: CF Foundation consensus guidelines establish sweat chloride as the recommended diagnostic test.
- name: CFTR Genetic Testing
  description: >-
    Identification of two disease-causing CFTR mutations confirms the diagnosis.
    Panel testing covers the most common mutations; expanded sequencing and
    deletion/duplication analysis can identify rare variants. The CFTR2 database
    provides clinical classification of variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  notes: Genetic testing alone is insufficient for diagnosis if sweat chloride is normal, as some variants have variable penetrance.
  evidence:
  - reference: PMID:28855057
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis is caused by a gene mutation leading to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein."
    explanation: Supports the role of identifying disease-causing CFTR mutations within a multimodal diagnostic framework.
  - reference: PMID:23974870
    reference_title: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease."
    explanation: CFTR2 project provides systematic classification of CFTR variants for diagnostic interpretation.
- name: Newborn Screening
  description: >-
    Population-based screening using immunoreactive trypsinogen (IRT) measured in
    dried blood spots collected at 24-48 hours of life. Elevated IRT is followed by
    either CFTR mutation panel or second IRT measurement. Positive screens require
    confirmatory sweat chloride testing.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  measurements:
  - preferred_term: immunoreactive trypsinogen (IRT), DBS
    term:
      id: LOINC:48633-2
      label: Trypsinogen I Free [Mass/volume] in DBS
  - preferred_term: CFTR mutation panel, DBS (second tier in IRT/DNA protocols)
    term:
      id: LOINC:54083-1
      label: CFTR gene mutations found [Identifier] in DBS by Molecular genetics method Nominal
  reference_ranges:
  - loinc_term:
      id: LOINC:48633-2
      label: Trypsinogen I Free [Mass/volume] in DBS
    unit: ng/mL
    population: newborn screening, Denmark national programme (IRT/DNA, from May 2016)
    notes: >-
      Source wording: IRT "followed by evaluation for the F508del mutation when a value
      at or above the 50 ng/mL cutoff was present" and, for "a very high IRT value above
      145 ng/mL", CFTR sequencing. Two decision levels, so three bands. The source says
      "above 145", so a value exactly at 145 ng/mL fell in the middle tier; the half-open
      band convention places it in the top tier, a one-point discrepancy recorded here.
      Screening cut-offs differ by programme; this is Denmark's.
    interpretation_bands:
    - name: Screen negative
      upper_bound: 50
      unit: ng/mL
      abnormal_flag: NORMAL
    - name: Elevated IRT, CFTR F508del analysis
      lower_bound: 50
      upper_bound: 145
      unit: ng/mL
      abnormal_flag: HIGH
      interpretation: >-
        IRT at or above the 50 ng/mL cut-off triggered F508del analysis on the same
        dried blood spot; a single F508del allele led on to CFTR sequencing.
    - name: Very high IRT, CFTR sequencing
      lower_bound: 145
      unit: ng/mL
      abnormal_flag: HIGH
      interpretation: >-
        IRT above the very-high cut-off led directly to next-generation sequencing of
        CFTR regardless of F508del status.
    evidence:
    - reference: PMID:31682332
      reference_title: "Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed."
      explanation: >-
        States both IRT decision levels of the Danish programme and what each
        triggered.
  - loinc_term:
      id: LOINC:48633-2
      label: Trypsinogen I Free [Mass/volume] in DBS
    unit: ng/mL
    population: newborn screening, Balearic Islands (Spain) regional programme, after protocol revisions over 14 years
    notes: >-
      Source wording: "After different changes in the protocol, an IRT cut-off value of
      60 ng/mL was established." Recorded as a second programme's cut-off to make the
      between-programme spread visible.
    interpretation_bands:
    - name: Screen negative
      upper_bound: 60
      unit: ng/mL
      abnormal_flag: NORMAL
    - name: Screen positive
      lower_bound: 60
      unit: ng/mL
      abnormal_flag: HIGH
      interpretation: >-
        IRT at or above the programme cut-off proceeded to the programme's second-tier
        mutation analysis and sweat testing.
    evidence:
    - reference: PMID:25680858
      reference_title: "Assessing the improvements in the newborn screening strategy for cystic fibrosis in the Balearic Islands."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After different changes in the protocol, an IRT cut-off value of 60 ng/mL was established."
      explanation: >-
        States the IRT cut-off the Balearic Islands programme settled on.
  notes: >-
    Enables early diagnosis and treatment, improving outcomes. False negatives can
    occur with meconium ileus. LOINC codes and labels were read from the Monarch KG
    and seeded into cache/loinc/terms.csv by scripts/seed_loinc_cache.sh. IRT is
    bound to the method-less quantitative DBS code. The CFTR second tier is bound to
    LOINC's dried-blood-spot mutation-panel result code; every LOINC molecular
    genetics code carries a "by Molecular genetics method" clause, so no method-less
    alternative exists, and the DBS code was preferred over the blood-or-tissue
    targeted-panel code (LOINC:38404-0) because the screening panel is run on the
    screening card. It is bound at panel level; LOINC's per-variant codes (for
    example CFTR gene.p.Phe508del, LOINC:21655-6) are deliberately not bound.
  evidence:
  - reference: PMID:28576637
    reference_title: "The diagnosis of cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In screen positive babies, the diagnosis of CF must be confirmed by a sweat test demonstrating a sweat chloride concentration above 60mmol/L."
    explanation: Supports newborn screening as an entry point that requires confirmatory sweat chloride testing.
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF."
    explanation: Clinical review confirms newborn screening as primary route to CF diagnosis and notes inconclusive cases.
  - reference: PMID:7680526
    reference_title: "Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second uses the IRT assay with a 100 ng/ml cutoff in conjunction with direct analysis for the delta F508 CF transmembrane conductance regulator (CFTR) mutation in a two-tiered (i.e., IRT/DNA) protocol, followed by a sweat test."
    explanation: >-
      The Wisconsin programme's IRT/DNA protocol: dried-blood-spot IRT as first tier
      and CFTR mutation analysis as second tier, the two measurements bound above.
  - reference: PMID:31682332
    reference_title: "Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the first 2 years of NBS CF screening in Denmark, we identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis."
    explanation: >-
      A national programme whose algorithm reads IRT and CFTR mutation status from the
      screening specimen.
- name: Nasal Potential Difference
  description: >-
    Measurement of transepithelial voltage across nasal mucosa before and after
    perfusion with chloride-free solution and isoproterenol. Abnormal pattern
    (hyperpolarized baseline, absent chloride-free response) supports CFTR
    dysfunction. Used as ancillary diagnostic test in borderline cases.
  diagnosis_term:
    preferred_term: transepithelial nasal potential difference measurement
  notes: Available only at specialized centers. Technically demanding.
  evidence:
  - reference: PMID:28576637
    reference_title: "The diagnosis of cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients should be referred to expert centers where bioassays of CFTR function like nasal potential difference measurement or intestinal current measurement can be done."
    explanation: Supports nasal potential difference as a specialized test for diagnostically inconclusive cases.
  - reference: PMID:35163362
    reference_title: "Assays of CFTR Function In Vitro, Ex Vivo and In Vivo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ex vivo and in vivo assays similarly evaluate current (intestinal current measurement) and membrane potential differences (nasal potential difference), on tissues from individual patients."
    explanation: Confirms NPD as a recognized CFTR functional assay used in diagnostic evaluation.
- name: Intestinal Current Measurement
  description: >-
    Ex vivo measurement of CFTR-mediated chloride transport in rectal biopsy tissue.
    Provides direct assessment of CFTR function. Used in research settings and for
    diagnosis in cases with inconclusive sweat chloride.
  diagnosis_term:
    preferred_term: rectal biopsy-based intestinal current measurement
    term:
      id: NCIT:C51693
      label: Rectal Biopsy
  notes: Primarily available in European centers. Highly sensitive and specific.
  evidence:
  - reference: PMID:40943780
    reference_title: "Pilot Evaluation of Intestinal Current Measurement in Cystic Fibrosis and CRMS/CFSPID Patients in Poland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intestinal Current Measurement (ICM) is a novel diagnostic technique that may document the abnormal function of the cystic fibrosis transmembrane conductance regulator."
    explanation: Directly supports ICM as a CFTR-function diagnostic technique.
  - reference: PMID:40943780
    reference_title: "Pilot Evaluation of Intestinal Current Measurement in Cystic Fibrosis and CRMS/CFSPID Patients in Poland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The conducted study suggests that ICM may offer diagnostic value, especially in cases where sweat test results are equivocal."
    explanation: Supports using ICM as an adjunctive test when sweat chloride results are borderline.
differential_diagnoses:
- name: Primary ciliary dyskinesia
  disease_term:
    preferred_term: primary ciliary dyskinesia
    term:
      id: MONDO:0016575
      label: primary ciliary dyskinesia
  description: >-
    Primary ciliary dyskinesia can closely resemble cystic fibrosis with chronic
    sinopulmonary symptoms driven by impaired mucociliary clearance.
  distinguishing_features:
  - CF is caused by CFTR dysfunction, whereas primary ciliary dyskinesia is caused by structural/functional ciliary defects.
  - PCD is generally less prevalent than CF and requires a different specialist diagnostic work-up and management strategy.
  evidence:
  - reference: PMID:36828173
    reference_title: "Cystic fibrosis and primary ciliary dyskinesia: Similarities and differences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) and Primary ciliary dyskinesia (PCD) are both rare chronic diseases, inherited disorders associated with multiple complications, namely respiratory complications, due to impaired mucociliary clearance that affect severely patients' lives."
    explanation: Supports major clinical overlap in respiratory presentations that necessitates differential diagnosis.
- name: Asthma
  disease_term:
    preferred_term: asthma
    term:
      id: MONDO:0004979
      label: asthma
  description: >-
    Asthma may overlap with CF pulmonary symptoms, especially wheeze and dyspnea,
    and can complicate interpretation of obstructive respiratory findings.
  distinguishing_features:
  - CF diagnosis requires evidence of CFTR dysfunction (e.g., sweat chloride and/or genotype), while isolated asthma does not.
  - CF-asthma overlap remains debated, so objective CFTR-focused testing is needed when symptoms overlap.
  evidence:
  - reference: PMID:33560464
    reference_title: "Asthma in Cystic Fibrosis: Definitions and Implications of This Overlap Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory symptoms for both CF and asthma include cough, wheezing, and dyspnea."
    explanation: Confirms direct symptom overlap between CF and asthma, supporting asthma as an important differential diagnosis.
- name: Non-cystic fibrosis bronchiectasis
  disease_term:
    preferred_term: non-cystic fibrosis bronchiectasis
    term:
      id: MONDO:0004822
      label: bronchiectasis
  description: >-
    Non-CF bronchiectasis can phenocopy CF-related chronic productive cough and
    recurrent respiratory exacerbations but arises from heterogeneous non-CF
    etiologies.
  distinguishing_features:
  - Etiologic evaluation in non-CF bronchiectasis emphasizes alternative causes (e.g., prior infection, immunodeficiency, autoimmune disease, PCD) rather than CFTR-confirmed disease.
  - Non-CF bronchiectasis prevalence increases strongly with age, whereas CF is usually identified earlier in life through newborn screening or pediatric symptoms.
  evidence:
  - reference: PMID:40293759
    reference_title: "Non-Cystic Fibrosis Bronchiectasis in Adults: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations."
    explanation: Supports overlapping chronic respiratory presentation with CF and the need to differentiate CF from non-CF bronchiectatic disease.
- name: CFTR-related metabolic syndrome (CRMS/CFSPID)
  disease_term:
    preferred_term: CFTR-related metabolic syndrome
    term:
      id: MONDO:0100627
      label: CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis
  description: >-
    CRMS/CFSPID is a diagnostic boundary condition identified after positive newborn
    screening when available testing does not yet establish definitive cystic
    fibrosis.
  distinguishing_features:
  - Patients with CRMS/CFSPID have inconclusive findings rather than definitive CF diagnosis at initial evaluation.
  - Follow-up and additional functional testing are often required to determine whether patients evolve toward CF, CFTR-related disorder, or non-CF classification.
  evidence:
  - reference: PMID:40943780
    reference_title: "Pilot Evaluation of Intestinal Current Measurement in Cystic Fibrosis and CRMS/CFSPID Patients in Poland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The term 'cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID)' refers to patients with positive screening tests but without a final diagnosis of Cystic Fibrosis (CF)."
    explanation: Directly supports CRMS/CFSPID as a key differential category when CF diagnosis remains unresolved after positive screening.
computational_models:
- name: O'Donoghue quantitative model of human nasal epithelial ion transport
  description: >-
    Coupled nonlinear ODE model of sodium, chloride, potassium, and water
    transport across human nasal epithelial cells. Parameter estimation and
    Monte Carlo filtering compare non-CF and CF potential-difference responses
    to amiloride and low-chloride challenges.
  model_type: KINETIC
  model_id: ODonoghue-HNE-ion-transport-2013
  model_format: ODE equations and parameters in the article and supplemental material
  publication: PMID:23732645
  modeled_mechanisms:
  - target: CFTR Dysfunction
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Reduces apical CFTR chloride permeability and calculates the resulting
      transepithelial and membrane-potential responses.
    limitations: >-
      The model represents a flooded nasal epithelial monolayer and omits
      bicarbonate transport, airway geometry, mucus, cilia, inflammation, and
      regional lung heterogeneity.
  - target: ENaC Hyperactivity and Sodium Hyperabsorption
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Infers the ENaC permeability change needed to reproduce CF basal and
      amiloride-sensitive nasal potential differences.
    limitations: >-
      ENaC permeability is inferred from epithelial electrical recordings and
      the result depends on assumptions about the represented transporters and
      paracellular pathway.
  variables:
  - name: Apical CFTR chloride permeability
    dataset_identifier: P_Cl_a
    description: Apical chloride-channel permeability attributed to CFTR
    unit: m/s
  - name: Apical ENaC sodium permeability
    dataset_identifier: P_Na_a
    description: Apical sodium permeability attributed to ENaC
    unit: m/s
  - name: Transepithelial potential difference
    dataset_identifier: Vt
    description: Modeled nasal epithelial voltage relative to the serosal compartment
    unit: mV
  - name: Amiloride-sensitive potential difference
    dataset_identifier: delta_Vt_amiloride
    description: Change in transepithelial voltage after apical ENaC blockade
    unit: mV
  evidence:
  - reference: PMID:23732645
    reference_title: "Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport."
    explanation: Directly identifies the quantitative model and its tissue scope.
  findings:
  - statement: >-
      Loss of CFTR permeability alone could not reproduce the magnitude of CF
      epithelial bioelectric changes; increased ENaC permeability was also
      required.
    evidence:
    - reference: PMID:23732645
      reference_title: "Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data."
      explanation: Directly states the model comparison supporting coupled CFTR loss and ENaC increase.
  notes: >-
    Curated from the paper and supplemental equations; no exact deposited code
    implementation was identified. Calibration used primary cultured nasal
    epithelium rather than patient-specific longitudinal data.
- name: Sandefur purinergic model of airway-surface-liquid homeostasis
  description: >-
    Systems model coupling epithelial ion and water transport to extracellular
    ATP and adenosine signaling. Fifteen ODEs represent baseline ASL homeostasis;
    a 23-equation extension simulates prolonged low-dose P2Y2-agonist delivery.
  model_type: KINETIC
  model_id: Sandefur-ASL-homeostasis-2017
  model_software: MATLAB ode15s
  model_format: ODE equations and parameters in the article and supplemental material
  publication: PMID:28808008
  modeled_mechanisms:
  - target: CFTR Dysfunction
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Reduces CFTR-mediated chloride secretion within a calibrated model of
      cultured human airway epithelium.
    limitations: >-
      CF required simultaneous parameter changes in chloride, sodium, and
      potassium transport; CFTR loss is therefore not an isolated disease arm.
  - target: ENaC Hyperactivity and Sodium Hyperabsorption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Increased sodium absorption is required with reduced chloride secretion
      to reproduce the CF epithelial state.
    limitations: >-
      Transport parameters were fitted to cultured epithelia and do not encode
      patient genotype, airway anatomy, immune responses, or infection.
  - target: Airway Surface Liquid Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Predicts the lower resting ASL height in CF and its dependence on chloride
      secretion, sodium absorption, and extracellular nucleotide metabolism.
    limitations: >-
      ASL height is modeled in cultured epithelium; extrapolation to spatially
      heterogeneous intact airways and clinical response is unvalidated.
  variables:
  - name: Airway surface liquid height
    dataset_identifier: ASL_height
    description: Depth of the airway surface liquid compartment
    unit: micrometer
  - name: Extracellular ATP concentration
    dataset_identifier: ATP
    description: Purinergic signal regulating epithelial ion-channel permeability
    unit: nM
  - name: Extracellular adenosine concentration
    dataset_identifier: ADO
    description: Purinergic metabolite regulating epithelial ion transport
    unit: nM
  - name: CFTR chloride permeability
    dataset_identifier: pCFTR
    description: Apical chloride permeability through CFTR channels
  - name: ENaC sodium permeability
    dataset_identifier: pENaC
    description: Apical sodium permeability through ENaC channels
  evidence:
  - reference: PMID:28808008
    reference_title: "Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling."
    explanation: Directly states the model's coupled transport-signaling scope.
  findings:
  - statement: >-
      Reproducing the CF state required reduced chloride secretion, increased
      potassium secretion, and increased sodium absorption.
    evidence:
    - reference: PMID:28808008
      reference_title: "Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required."
      explanation: Directly reports the fitted transport changes required for the CF condition.
  - statement: >-
      The model predicted basal ASL height and dehydration caused by accelerated
      nucleotide metabolism, and proposed prolonged low-dose agonist delivery as
      a rehydration strategy.
    evidence:
    - reference: PMID:28808008
      reference_title: "Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways."
      explanation: Reports both the ASL-height validation target and the simulated intervention.
  notes: >-
    The prolonged low-dose Denufosol strategy is a model prediction, not clinical
    evidence. The paper notes that prior short, high-dose Denufosol failed to
    show sufficient phase-III benefit; the proposed schedule requires testing.
- name: Kurbatova physiologically based model of mucociliary clearance
  description: >-
    Regional lung model of mucociliary transport with separate periciliary-liquid
    and mucus layers. It compares normal and CF clearance and simulates how
    dornase-alfa-induced mucus-viscosity reduction interacts with central versus
    peripheral aerosol deposition.
  model_type: PHYSIOLOGICAL
  model_id: Kurbatova-CF-MCC-2015
  model_format: Physiological equations and parameters in the publication
  publication: PMID:25746843
  modeled_mechanisms:
  - target: Airway Surface Liquid Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Represents the depleted periciliary-liquid layer that changes mucus
      transport in CF airways.
    limitations: >-
      Hydration is reduced to a layered physiological representation rather than
      coupled explicitly to CFTR, ENaC, purinergic signaling, or epithelial cells.
  - target: Impaired Mucociliary Clearance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Simulates impaired regional mucus transport and its response to reduced
      mucus viscosity after inhaled dornase alfa.
    limitations: >-
      The model prediction about deposition location was not validated as a
      patient-specific dosing rule and omits infection, inflammation, and
      heterogeneous mucus plugging.
  variables:
  - name: Periciliary liquid layer
    dataset_identifier: PCL
    description: Hydrated layer surrounding airway cilia
  - name: Mucus layer
    dataset_identifier: mucus_layer
    description: Transported viscoelastic airway secretion layer
  - name: Mucus viscosity
    dataset_identifier: mucus_viscosity
    description: Rheological property reduced by simulated dornase alfa
  - name: Aerosol deposition region
    dataset_identifier: deposition_location
    description: Relative deposition of inhaled drug in central or peripheral airways
  - name: Mucus clearance
    dataset_identifier: mucus_clearance
    description: Regional transport of airway mucus
  evidence:
  - reference: PMID:25746843
    reference_title: "Model of mucociliary clearance in cystic fibrosis lungs."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer."
    explanation: Directly identifies the physiological model and its two-layer structure.
  findings:
  - statement: >-
      Simulated dornase alfa increased mucus clearance more when drug deposition
      was concentrated in peripheral small airways.
    evidence:
    - reference: PMID:25746843
      reference_title: "Model of mucociliary clearance in cystic fibrosis lungs."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways."
      explanation: Directly states the model's regional-deposition result.
  notes: >-
    Curated directly from the paper; no exact deposited implementation was
    identified. The deposition result is hypothesis-generating and should not
    be treated as an established clinical aerosol-delivery recommendation.
environmental:
- name: Pseudomonas aeruginosa
  influences_mechanisms:
  - target: Chronic Bacterial Infection
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The node describes this species becoming the dominant pathogen in
      adolescence and adulthood and transitioning to a mucoid biofilm
      phenotype, so colonisation by it is the node's own content.
    evidence:
    - reference: PMID:42198683
      reference_title: "Host-Pathogen Interactions in Cystic Fibrosis Lung Disease: Adaptation, Persistence, and Clinical Implications of Pseudomonas aeruginosa."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Defective cystic fibrosis transmembrane conductance regulator (CFTR) function disrupts airway hydration and mucociliary clearance, creating a microenvironment that facilitates infection, particularly with Pseudomonas aeruginosa (P. aeruginosa)"
      explanation: >-
        Names this organism as the one the CF airway microenvironment
        particularly facilitates infection by, and reaches it through the
        hydration and clearance defects this entry models upstream. A review,
        so tagged accordingly, but one about CF airway infection rather than a
        sentence borrowed from a paper on another subject.
    - reference: PMID:30986316
      reference_title: "Review of Cystic Fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
      explanation: >-
        Names chronic endobronchial airway infection as a defining feature. It
        supports the node but does not name this organism, which is why the
        organism-specific sentence above is the primary support for the link.
  description: >-
    The most important pathogen in CF lung disease. Initial acquisition of
    non-mucoid strains progresses to chronic infection with mucoid, alginate-producing
    phenotypes that form antibiotic-resistant biofilms. Chronic Pseudomonas infection
    is associated with accelerated decline in lung function and increased mortality.
    Early eradication protocols aim to delay chronic colonization.
  notes: Transition from non-mucoid to mucoid phenotype is a milestone event in CF.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Chronic endobronchial infection including Pseudomonas is a defining characteristic of CF.
- name: Staphylococcus aureus
  influences_mechanisms:
  - target: Chronic Bacterial Infection
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Staphylococcus aureus is one of the first organisms to colonise the CF
      airway and the most prevalent pathogen in early childhood, so its
      acquisition is one of the routes into the chronic infection this node
      describes.
    evidence:
    - reference: PMID:34578208
      reference_title: "Staphylococcus aureus and Cystic Fibrosis-A Close Relationship. What Can We Learn from Sequencing Studies?"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Staphylococcus aureus is next to Pseudomonas aeruginosa the most isolated pathogen from the airways of cystic fibrosis (CF) patients, who are often infected by a dominant S. aureus clone for extended periods."
      explanation: >-
        States that CF airways are often infected by a dominant S. aureus
        clone for extended periods, which is persistent airway infection by
        this organism.
  description: >-
    Often the first pathogen to colonize CF airways in infancy. Both
    methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains are
    common. MRSA infection is associated with worse survival.
  notes: Most common respiratory pathogen in young CF children.
  evidence:
  - reference: PMID:34578208
    reference_title: "Staphylococcus aureus and Cystic Fibrosis-A Close Relationship. What Can We Learn from Sequencing Studies?"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Staphylococcus aureus is one of the first pathogens detectable in the airways of young CF patients and the bacterium with the highest prevalence at an early age. Already among children younger than two years of age its prevalence exceeds 50%"
    explanation: >-
      Supports early acquisition and the notes' claim that S. aureus is the
      most common pathogen in young children with CF.
  - reference: PMID:20551409
    reference_title: "Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After adjustment for time-varying covariates associated with severity of illness, MRSA remained associated with a higher risk of death (1.27; 95% CI, 1.11-1.45)."
    explanation: >-
      Registry cohort of 19,833 US patients in which respiratory MRSA was
      associated with higher mortality after adjustment for disease severity,
      supporting the MRSA outcome claim in the description.
- name: Burkholderia cepacia complex
  influences_mechanisms:
  - target: Chronic Bacterial Infection
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Burkholderia cepacia complex is one of the pathogens this node names.
      Infection with it causes worse lung function than Pseudomonas
      aeruginosa infection, and in some patients progresses to cepacia
      syndrome.
    evidence:
    - reference: PMID:6420530
      reference_title: "Pseudomonas cepacia infection in cystic fibrosis: an emerging problem."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients infected with P. cepacia have greater impairment of pulmonary function than those with P. aeruginosa."
      explanation: >-
        Clinic cohort of about 500 CF patients in which infection with this
        organism (then named Pseudomonas cepacia) was associated with worse
        pulmonary function than P. aeruginosa infection.
  description: >-
    Highly virulent group of gram-negative bacteria associated with greater
    impairment of lung function than Pseudomonas aeruginosa and, in a minority
    of infected patients, with cepacia syndrome: an acute necrotizing pneumonia
    with rapid respiratory failure and high mortality. Burkholderia cenocepacia
    is the species most often reported in cepacia syndrome.
  notes: Infection control and patient segregation are critical.
  evidence:
  - reference: PMID:36815622
    reference_title: "Cepacia syndrome in cystic fibrosis: A systematic review of the literature and possible new perspectives in treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cepacia syndrome (CS) is an acute, necrotizing pneumonia with a high mortality rate, occurring in patients with cystic fibrosis (CF) infected with Burkholderia cepacia complex (BCC)."
    explanation: Defines cepacia syndrome as a complication of this infection in CF.
  - reference: PMID:36815622
    reference_title: "Cepacia syndrome in cystic fibrosis: A systematic review of the literature and possible new perspectives in treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burkholderia cenocepacia was the most frequently reported causative agent."
    explanation: >-
      In the 18 published cepacia syndrome cases reviewed, B. cenocepacia was
      the species most often reported.
  - reference: PMID:6420530
    reference_title: "Pseudomonas cepacia infection in cystic fibrosis: an emerging problem."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate has occurred in eight patients over the past 3 years, with a 62% fatality rate."
    explanation: >-
      The original description of cepacia syndrome, supporting rapid and
      often fatal respiratory decline.
- name: Non-tuberculous Mycobacteria
  influences_mechanisms:
  - target: Chronic Bacterial Infection
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Non-tuberculous mycobacteria are environmental organisms that cause
      chronic pulmonary infection in CF, and are among the pathogens this
      node names.
    evidence:
    - reference: PMID:26666259
      reference_title: "US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF)."
      explanation: >-
        Consensus statement naming chronic pulmonary infection by these
        environmental organisms in CF, which is this exposure acting on this
        node.
  description: >-
    Mycobacterium abscessus complex and Mycobacterium avium complex are the
    species most often isolated in CF, and NTM-positive cultures have become
    more common. M. abscessus is associated with greater morbidity and
    mortality and faster lung function decline. NTM pulmonary disease must be
    assessed in lung transplant candidates.
  notes: Screening sputum cultures recommended annually.
  evidence:
  - reference: PMID:26666259
    reference_title: "US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-tuberculous mycobacteria (NTM) are increasingly being isolated from the sputum of adults and children with cystic fibrosis (CF), both in North America and in Europe."
    explanation: Supports rising recognition of NTM in CF.
  - reference: PMID:26666259
    reference_title: "US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "individuals with MABSC-positive cultures are more likely to meet American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) criteria for diagnosing NTM pulmonary disease (NTM-PD, see Diagnosis of NTM-PD in CF section), and have worse morbidity and mortality associated with a more rapid decline in lung function."
    explanation: >-
      Supports the greater severity of M. abscessus complex infection stated
      in the description.
  - reference: PMID:26666259
    reference_title: "US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recommendation 2: The CF Foundation and the ECFS recommend that cultures for NTM be performed annually in spontaneously expectorating individuals with a stable clinical course."
    explanation: Supports the annual screening recommendation in the notes.
  - reference: PMID:26666259
    reference_title: "US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recommendation 45: The CF Foundation and the ECFS recommend that all individuals with CF being considered for lung transplantation should be evaluated for NTM-PD."
    explanation: Supports the transplant-assessment statement in the description.
- name: Aspergillus fumigatus
  influences_mechanisms:
  - target: Allergic Bronchopulmonary Aspergillosis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The only link in this entry that targets a phenotype rather than a
      pathophysiology node, which the schema and the target test both allow
      for an exposure acting directly on a manifestation. The phenotype is a
      hypersensitivity response to colonisation by this organism, so the
      exposure is named in the target's own description.
    evidence:
    - reference: PMID:41537324
      reference_title: "[How do I treat : allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus, commonly found in patients with cystic fibrosis and severe asthma"
      explanation: >-
        Defines the target as a hypersensitivity reaction to this organism and
        places it in this disease specifically. Exposure and target in one
        sentence.
  description: >-
    Fungal colonization of CF airways that can trigger allergic bronchopulmonary
    aspergillosis (ABPA), a hypersensitivity response causing bronchial
    inflammation, mucus hypersecretion and progressive lung function decline.
  notes: ABPA is treated with systemic corticosteroids and antifungal agents, with the monoclonal antibodies omalizumab or mepolizumab as further options.
  evidence:
  - reference: PMID:41537324
    reference_title: "[How do I treat : allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus, commonly found in patients with cystic fibrosis and severe asthma"
    explanation: >-
      Supports this organism as the trigger of a hypersensitivity response
      (ABPA) that is common in CF.
  - reference: PMID:41537324
    reference_title: "[How do I treat : allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It leads to bronchial inflammation, excessive mucus secretion, and progressive lung function decline."
    explanation: Supports the consequences of ABPA stated in the description.
  - reference: PMID:41537324
    reference_title: "[How do I treat : allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatments include systemic corticosteroids, antifungals, and monoclonal antibodies such as omalizumab and mepolizumab."
    explanation: Supports the treatment statement in the notes.
- name: Tobacco Smoke Exposure
  exposure_term:
    preferred_term: tobacco smoke exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  description: >-
    Tobacco smoke exposure, studied mostly as secondhand exposure in children,
    is associated with lower lung function in CF. Ending the exposure is
    associated with fewer pulmonary exacerbations and better lung function, so
    it is a modifiable risk factor, especially in children.
  notes: >-
    Strict avoidance counseling is part of standard CF care. Bound to
    ECTO:6000029 (exposure to tobacco smoking) rather than ECTO:0100013
    (exposure to tobacco), whose definition is "An exposure event involving
    nicotine tobacco consumption" and so fits the passive half of this entry
    even less well than the smoking term does. ECTO:7000059 (exposure to smoke)
    was not used because it drops tobacco entirely. ECTO has no secondhand-smoke
    term, so no available term covers both routes; the smoking term is the
    closest anchor, and the "both active and passive" scope is carried by the
    description and by preferred_term rather than by the binding.
  evidence:
  - reference: PMID:37142525
    reference_title: "Lung function and secondhand smoke exposure among children with cystic fibrosis: A Bayesian meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV1 (estimated decrease: -5.11% predicted; 95% CI: -7.20, -3.47)."
    explanation: >-
      Meta-analysis of six pediatric CF studies finding lower FEV1 with
      secondhand smoke exposure.
  - reference: PMID:34281808
    reference_title: "Cessation of smoke exposure improves pediatric CF outcomes: Longitudinal analysis of CF Foundation Patient Registry data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cessation of smoke exposure reduced the odds of a pulmonary exacerbation in 12 months by 17% (OR 0.83, p < 0.001) in the first year of cessation"
    explanation: >-
      US registry analysis of 3,633 children and adolescents showing that
      ending smoke exposure is associated with fewer exacerbations, which is
      what makes the exposure modifiable.
  - reference: PMID:34281808
    reference_title: "Cessation of smoke exposure improves pediatric CF outcomes: Longitudinal analysis of CF Foundation Patient Registry data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both smoking cessation and exposure prevention should be prioritized in pediatric CF care."
    explanation: Supports avoidance counseling as part of CF care, as stated in the notes.
- name: Air Pollution
  exposure_term:
    preferred_term: air pollution exposure
    term:
      id: ECTO:8000036
      label: exposure to air pollution
  description: >-
    Ambient air pollution (fine and coarse particulate matter, ozone) is
    associated with increased pulmonary exacerbation rates and lower lung
    function in CF.
  notes: Epidemiologic association; exposure minimization recommended.
  evidence:
  - reference: PMID:14718248
    reference_title: "Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual average exposures to particulate air pollution was associated with an increased risk of pulmonary exacerbations and a decline in lung function, suggesting a role of environmental exposures on prognosis in CF."
    explanation: >-
      US registry cohort linking residential air pollution to exacerbations
      and lung function.
  - reference: PMID:14718248
    reference_title: "Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 10-ppb rise in ozone was associated with a 10% (95% CI, 3-17%) increase in odds of two or more exacerbations"
    explanation: Supports ozone as one of the pollutants in the description.
treatments:
- name: Elexacaftor-Tezacaftor-Ivacaftor (Trikafta/Kaftrio)
  description: >-
    Triple combination CFTR modulator therapy containing two correctors
    (elexacaftor, tezacaftor) that improve F508del-CFTR folding and trafficking
    to the cell surface, plus a potentiator (ivacaftor) that increases channel
    open probability. Approved for patients aged 2+ years with at least one
    F508del allele, covering approximately 90% of CF patients. Produces dramatic
    improvements in lung function, nutritional status, and quality of life.
  evidence:
  - reference: PMID:31697873
    reference_title: "Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower"
    explanation: Phase 3 RCT demonstrates significant improvement in lung function and 63% reduction in pulmonary exacerbations with Trikafta.
  - reference: PMID:31697873
    reference_title: "Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised...that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower"
    explanation: Trikafta also improves quality of life scores and reduces sweat chloride, a biomarker of CFTR function.
  - reference: PMID:41702741
    reference_title: Consensus-based guidance for the nutritional management of children with cystic fibrosis on ELEXACAFTOR/TEZACAFTOR/IVACAFTOR.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The introduction of CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) has significantly altered the nutritional trajectory of children with cystic fibrosis (cwCF)."
    explanation: Consensus-based guidance recognizes elexacaftor/tezacaftor/ivacaftor as the CFTR modulator that has altered the clinical and nutritional trajectory of children with cystic fibrosis.
  - reference: PMID:42033769
    reference_title: "Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) in People with Cystic Fibrosis in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 11,151 PwCF included in the ppFEV1 analysis, we found a mean ppFEV1 increase of 9.9 (95% CI 9.6-10.2) between the pre- and post-ETI initiation periods over three years."
    explanation: >-
      Registry effectiveness analysis showing that the lung-function benefit seen
      in the randomized trials is sustained for three years at population scale.
      The design is observational, so secular trend and selection are not
      excluded.
  - reference: PMID:42033769
    reference_title: "Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) in People with Cystic Fibrosis in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 32% had an improvement in both FEV1 and BMI, indicating that not all PwCF respond uniformly to ETI therapy."
    explanation: >-
      Qualifies the population-level result: fewer than a third of participants
      with both measurements improved on both, so the mean effect should not be
      read as a uniform individual response.
  - reference: PMID:41738096
    reference_title: "Elexacaftor/tezacaftor/ivacaftor for cystic fibrosis and rare CFTR variants: in vitro translation to a phase 3, double-blind, randomized, placebo-controlled trial, and real-world study."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor."
    explanation: >-
      Theratyping of rare exonic CFTR variants expressed in Fischer rat thyroid
      cells is the in vitro basis for extending this therapy beyond F508del
      genotypes; the accompanying trial provides the clinical arm of that claim.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: elexacaftor
      term:
        id: NCIT:C169935
        label: Elexacaftor
    - preferred_term: tezacaftor
      term:
        id: NCIT:C152581
        label: Tezacaftor
    - preferred_term: ivacaftor
      term:
        id: CHEBI:66901
        label: ivacaftor
- name: Ivacaftor (Kalydeco)
  description: >-
    CFTR potentiator that increases the channel open probability of CFTR protein
    at the cell surface. First approved CFTR modulator, initially for G551D
    mutation and subsequently expanded to other gating mutations. As monotherapy,
    effective only for mutations where CFTR reaches the cell surface
    (Class III, IV, V mutations).
  evidence:
  - reference: PMID:22047557
    reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001)."
    explanation: Landmark Phase 3 trial demonstrating sustained lung function improvement with ivacaftor in G551D patients.
  - reference: PMID:22047557
    reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48"
    explanation: Beyond lung function, the pivotal ivacaftor trial reduced the risk of pulmonary exacerbations by 55% through 48 weeks, a distinct clinical benefit of CFTR potentiation.
  - reference: PMID:22047557
    reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo"
    explanation: Ivacaftor also improved nutritional status (2.7 kg greater weight gain than placebo at 48 weeks), reflecting systemic CFTR restoration beyond the airway.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ivacaftor
      term:
        id: CHEBI:66901
        label: ivacaftor
- name: Airway Clearance Therapy
  description: >-
    Chest physiotherapy techniques to mobilize and clear airway secretions.
    Includes manual chest percussion and postural drainage, oscillating positive
    expiratory pressure devices (e.g., Flutter, Acapella), high-frequency chest
    wall oscillation vests, autogenic drainage, and regular exercise. Performed
    daily; no technique has been shown to be clearly superior to the others.
  evidence:
  - reference: PMID:30676656
    reference_title: "Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To clear their lungs of mucus, people with cystic fibrosis perform airway clearance techniques daily."
    explanation: >-
      States the purpose of airway clearance in CF and that it is a daily
      routine.
  - reference: PMID:30676656
    reference_title: "Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are a variety of airway clearance techniques, including conventional chest physiotherapy, positive expiratory pressure (PEP) therapy, high-pressure PEP therapy, active cycle of breathing techniques, autogenic drainage, airway oscillating devices"
    explanation: >-
      Supports the range of techniques listed in the description.
  - reference: PMID:30676656
    reference_title: "Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV1, except for reporting no difference between PEP therapy and oscillating devices after six months of treatment"
    explanation: >-
      Overview of six Cochrane reviews finding no technique clearly superior
      to another, which is why technique choice is individualized.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Dornase Alfa (Pulmozyme)
  description: >-
    Inhaled recombinant human DNase that cleaves extracellular DNA released from
    necrotic neutrophils in CF sputum, reducing mucus viscosity and improving
    airway clearance. Recommended for daily use in most CF patients.
  evidence:
  - reference: PMID:8874241
    reference_title: "Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dornase alfa improved the mean percent change in FEV1 from baseline by 9.4% compared with 2.1% for placebo (p < 0.001)."
    explanation: Randomized controlled trial demonstrates significant improvement in lung function with dornase alfa.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dornase alfa
      term:
        id: NCIT:C81664
        label: Dornase Alfa
- name: Hypertonic Saline (7%)
  description: >-
    Inhaled nebulized hypertonic saline that osmotically draws water onto the
    airway surface, rehydrating the periciliary layer and improving mucociliary
    clearance. Used as adjunctive therapy to improve mucus mobilization.
  evidence:
  - reference: PMID:16421365
    reference_title: "Mucus clearance and lung function in cystic fibrosis with hypertonic saline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit."
    explanation: >-
      Randomized trial in 24 patients linking the sustained increase in
      mucus clearance to osmotic hydration of the airway surface, which is
      the mechanism in the description.
  - reference: PMID:16421364
    reference_title: "A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hypertonic-saline group also had significantly fewer pulmonary exacerbations (relative reduction, 56 percent; P=0.02)"
    explanation: >-
      48-week randomized trial in 164 patients showing clinical benefit of
      adjunctive 7% saline.
  - reference: PMID:16421364
    reference_title: "A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis."
    explanation: >-
      Supports use as adjunctive therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium chloride
      term:
        id: CHEBI:26710
        label: sodium chloride
- name: Inhaled Antibiotics
  description: >-
    Chronic suppressive inhaled antibiotic therapy for patients with chronic
    Pseudomonas aeruginosa infection. Inhaled tobramycin (alternating months)
    and inhaled aztreonam lysine are most commonly used. Reduces bacterial
    density, decreases hospitalization, and improves lung function.
  evidence:
  - reference: PMID:9878641
    reference_title: "Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization."
    explanation: >-
      Two placebo-controlled trials in 520 patients with P. aeruginosa
      infection, using four-weeks-on, four-weeks-off cycles, supporting the
      reduced bacterial density and the lung function benefit in the
      description.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Systemic Antibiotics
  description: >-
    Oral and intravenous antibiotics for acute pulmonary exacerbations and
    chronic suppressive therapy. Azithromycin is used chronically for its
    anti-inflammatory and anti-Pseudomonal properties. IV antibiotic courses
    (typically 14-21 days) target specific pathogens identified on sputum culture.
  evidence:
  - reference: PMID:14519709
    reference_title: "Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03)"
    explanation: >-
      Placebo-controlled trial of chronic oral azithromycin in 185 patients
      chronically infected with P. aeruginosa, supporting chronic
      azithromycin use. It supports the azithromycin claim only; the
      intravenous exacerbation courses in the description are not covered by
      this item.
  - reference: PMID:14519709
    reference_title: "Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group"
    explanation: >-
      Supports the lung function benefit of chronic azithromycin.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Pancreatic Enzyme Replacement Therapy (PERT)
  description: >-
    Oral pancreatic enzyme supplements (lipase, protease, amylase) taken with
    all meals and snacks to replace deficient endogenous enzymes. Dosing is
    individualized based on fat intake and symptoms. Essential for maintaining
    adequate nutrition in pancreatic-insufficient patients.
  evidence:
  - reference: PMID:32761612
    reference_title: "Pancreatic enzyme replacement therapy for people with cystic fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most people with cystic fibrosis (CF) (80% to 90%) need pancreatic enzyme replacement therapy (PERT) to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed."
    explanation: >-
      Cochrane review background supporting PERT with all food,
      individualized dosing, and its role in preventing malnutrition.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Nutritional Support
  description: >-
    High-calorie, high-fat diet with fat-soluble vitamin supplementation (A, D, E,
    K)
    and sodium chloride supplementation. CF patients have increased caloric
    requirements (120-150% of normal) due to malabsorption, chronic infection,
    and increased work of breathing. Enteral tube feeding may be needed for
    patients unable to maintain adequate weight.
  evidence:
  - reference: PMID:33526571
    reference_title: "Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers."
    explanation: Evidence-based guidelines emphasize optimization of nutritional health for CF patients.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: Insulin Therapy for CFRD
  description: >-
    Insulin is the recommended treatment for CF-related diabetes. Oral
    hypoglycemic agents are not recommended outside research trials because they
    are less effective than insulin in improving nutritional and metabolic
    outcomes. Insulin improves nutritional status and lung function in addition
    to glycemic control.
  evidence:
  - reference: PMID:21115772
    reference_title: "Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with CFRD should be treated with insulin therapy."
    explanation: >-
      ADA/CFF guideline recommendation supporting insulin as the recommended
      treatment.
  - reference: PMID:21115772
    reference_title: "Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Oral diabetes agents are not as effective as insulin in improving nutritional and metabolic outcomes in CFRD and are not recommended outside the context of clinical research trials."
    explanation: >-
      Supports the statement that oral agents are not recommended. The
      guideline gives lower efficacy as the reason.
  - reference: PMID:21115772
    reference_title: "Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There is evidence that CF patients on insulin therapy who achieve glycemic control demonstrate improvement in weight, protein anabolism, pulmonary function, and survival."
    explanation: >-
      Supports the nutritional and lung function benefits of insulin.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: insulin
      term:
        id: CHEBI:145810
        label: insulin
- name: Ursodeoxycholic Acid
  description: >-
    Hydrophilic bile acid used to improve bile flow and potentially slow
    progression of CF liver disease. Commonly prescribed for patients with
    elevated liver enzymes or evidence of focal biliary cirrhosis, though
    evidence for long-term clinical benefit is limited.
  evidence:
  - reference: PMID:28891588
    reference_title: "Ursodeoxycholic acid for cystic fibrosis-related liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There were no data available for analysis for long-term outcomes such as death or need for liver transplantation."
    explanation: >-
      Cochrane review of randomized trials supporting the statement that
      long-term clinical benefit is unproven.
  - reference: PMID:28891588
    reference_title: "Ursodeoxycholic acid for cystic fibrosis-related liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There is currently insufficient evidence to justify its routine use in cystic fibrosis."
    explanation: >-
      Supports the limited evidence base for UDCA in CF liver disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
- name: Lung Transplantation
  description: >-
    Bilateral lung transplantation is offered for end-stage CF lung disease
    when predicted survival without transplant is limited (typically FEV1 <30%
    predicted with rapid decline). Five-year survival after transplant is
    approximately 50-60%. CF lung disease does not recur in the transplanted lungs,
    but immunosuppression-related complications and chronic rejection (bronchiolitis
    obliterans syndrome) limit long-term outcomes.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF."
    explanation: Respiratory failure as the leading cause of death necessitates lung transplantation for end-stage disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
- name: Genetic Counseling
  description: >-
    Counseling for patients and families regarding autosomal recessive
    inheritance, carrier testing for at-risk relatives, prenatal diagnosis
    options, and reproductive planning. Carrier frequency is approximately
    1 in 25 in European-descent populations.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
clinical_trials:
- name: NCT03525444
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase 3, randomized, double-blind, placebo-controlled trial evaluating
    elexacaftor-tezacaftor-ivacaftor in patients aged 12+ with cystic fibrosis
    heterozygous for F508del and a minimal-function CFTR mutation. This landmark
    trial led to FDA approval of Trikafta.
  target_phenotypes:
  - preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:31697873
    reference_title: "Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective."
    explanation: This Phase 3 trial established efficacy of Trikafta for CF patients with one F508del allele plus a minimal-function mutation.
has_subtypes:
# CFTR mutation class subtypes
- name: Class I - No Protein Production
  classification: mutation_class
  description: >-
    Nonsense mutations, frameshift mutations, and canonical splice site mutations
    that result in premature termination codons and no functional CFTR protein
    production due to mRNA degradation via nonsense-mediated decay. Examples include
    G542X, W1282X, R553X, and 621+1G>T. Class I mutations cause severe disease
    with pancreatic insufficiency.
  children:
  - G542X
  - W1282X
  - R553X
  evidence:
  - reference: PMID:26823392
    reference_title: "From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Class I encompasses frameshift, splicing, or nonsense mutations that introduce premature termination codons (PTC), resulting in severely reduced or absent CFTR expression."
    explanation: >-
      Defines class I as premature-termination mutations with severely
      reduced or absent CFTR expression.
  - reference: PMID:26823392
    reference_title: "From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "First, the level of the W1282X transcript is reduced by nonsense-mediated RNA decay"
    explanation: >-
      Supports nonsense-mediated decay as the mechanism, for the class I
      example W1282X.
  - reference: PMID:1376016
    reference_title: "Genetic determination of exocrine pancreatic function in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T"
    explanation: >-
      Places the class I examples G542X, R553X, W1282X and 621+1G>T among
      the severe alleles associated with pancreatic insufficiency.
- name: Class II - Processing/Trafficking Defect
  classification: mutation_class
  description: >-
    Mutations causing CFTR protein misfolding, endoplasmic reticulum retention, and
    proteasomal degradation. The most important example is F508del, present in nearly
    90% of CF patients. Misfolded protein is recognized by ER quality control and
    targeted for ubiquitin-proteasome degradation, resulting in minimal CFTR at the
    cell surface. Corrector drugs (lumacaftor, tezacaftor, elexacaftor) partially
    rescue F508del trafficking.
  children:
  - F508del
  - N1303K
  - I507del
  evidence:
  - reference: PMID:31697873
    reference_title: "Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nearly 90% of patients have at least one copy of the Phe508del CFTR mutation"
    explanation: Confirms the high prevalence of the prototypical Class II mutation F508del.
- name: Class III - Gating Defect
  classification: mutation_class
  description: >-
    CFTR protein reaches the cell surface normally but channel gating is severely
    impaired, resulting in very low open probability. The prototypical example is
    G551D. Potentiator drugs (ivacaftor) increase channel open probability and
    produce dramatic clinical benefit.
  children:
  - G551D
  - S549N
  - G1244E
  evidence:
  - reference: PMID:22047557
    reference_title: "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001)."
    explanation: Ivacaftor trial in G551D patients demonstrates therapeutic targeting of gating mutations.
- name: Class IV - Conductance Defect
  classification: mutation_class
  description: >-
    CFTR reaches the cell surface and channel opens, but chloride conductance
    through the channel pore is reduced. Typically associated with milder phenotype
    and pancreatic sufficiency. Examples include R117H, R334W, and R347P.
  children:
  - R117H
  - R334W
  - R347P
  evidence:
  - reference: PMID:26823392
    reference_title: "From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Class IV mutations alter the channel conductance by impeding the ion conduction pore, leading to a reduced unitary conductance"
    explanation: >-
      Defines class IV as a conductance defect of the channel pore.
  - reference: PMID:1376016
    reference_title: "Genetic determination of exocrine pancreatic function in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T"
    explanation: >-
      Places the class IV examples R117H, R334W and R347P among the mild
      alleles associated with pancreatic sufficiency, supporting the milder
      phenotype.
- name: Class V - Reduced Quantity
  classification: mutation_class
  description: >-
    Mutations that reduce the amount of normal CFTR protein produced, such as
    alternative splice site mutations that produce some normal transcript alongside
    aberrant transcript. Typically associated with milder phenotype and pancreatic
    sufficiency. Examples include 3849+10kbC>T and A455E.
  children:
  - 3849+10kbC>T
  - A455E
  evidence:
  - reference: PMID:26823392
    reference_title: "From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Class V mutations do not change the conformation of the protein but alter its abundance by introducing promoter or splicing abnormalities"
    explanation: >-
      Defines class V as reduced abundance of normal CFTR through promoter
      or splicing abnormalities.
  - reference: PMID:1376016
    reference_title: "Genetic determination of exocrine pancreatic function in cystic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T"
    explanation: >-
      Places the class V example A455E among the mild alleles associated
      with pancreatic sufficiency. The study did not test 3849+10kbC>T.
- name: Class VI - Decreased Stability
  classification: mutation_class
  description: >-
    CFTR protein reaches the cell surface and functions but has accelerated
    turnover and reduced plasma membrane stability. Rescued F508del protein
    (after corrector therapy) exhibits this additional defect, necessitating
    combination therapy with correctors and potentiators.
  evidence:
  - reference: PMID:26823392
    reference_title: "From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Class VI mutations destabilize the channel in post-ER compartments and/or at the plasma membrane (PM), by reducing its conformational stability"
    explanation: >-
      Defines class VI as reduced stability of CFTR after it leaves the ER.
  - reference: PMID:26823392
    reference_title: "From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unless the folding and conformational dynamics of the rescued ΔF508-CFTR are fully restored to that of the wild-type protein by pharmacological treatment, this mutation remains partially defective and requires correction of its gating and/or peripheral stability defect."
    explanation: >-
      Supports the statement that corrector-rescued F508del keeps a
      stability defect and needs combined correction.
- name: Classic Cystic Fibrosis
  classification: clinical_phenotype
  description: >-
    Severe disease phenotype with two severe CFTR mutations, pancreatic insufficiency,
    progressive bronchiectasis, elevated sweat chloride (>=60 mmol/L), and male
    infertility due to CBAVD. Represents the majority of CF patients.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection."
    explanation: Clinical review describes the classic CF phenotype of pancreatic insufficiency and chronic airway infection.
- name: Atypical (Non-Classic) Cystic Fibrosis
  classification: clinical_phenotype
  description: >-
    Milder disease phenotype, often with at least one CFTR mutation conferring
    residual function (Class IV, V). May present with pancreatic sufficiency,
    milder lung disease, borderline or normal sweat chloride, and later age of
    diagnosis. Some patients are not diagnosed until adulthood.
  evidence:
  - reference: PMID:33178516
    reference_title: "Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "There exists another clinically diverse group of individuals with cystic fibrosis who usually have onset in adulthood with minimal symptoms involving only a single organ, or more, and a negative sweat chloride test called atypical CF."
    explanation: >-
      Introduction of a case report describing atypical CF as adult-onset,
      milder disease that can have a normal sweat chloride, supporting the
      milder phenotype and late diagnosis in the description. The case itself,
      diagnosed at 57, illustrates adult diagnosis.
- name: CFTR-Related Metabolic Syndrome (CRMS) / CF Screen Positive Inconclusive Diagnosis (CFSPID)
  classification: clinical_phenotype
  description: >-
    Designation for infants identified by newborn screening who do not meet
    diagnostic criteria for CF but have some evidence of CFTR dysfunction.
    Defined as either intermediate sweat chloride (30-59 mmol/L) with fewer than
    two CF-causing CFTR mutations, or normal sweat chloride (<30 mmol/L) with
    two CFTR mutations of which at least one has unclear clinical significance.
    A small proportion may evolve to a CF diagnosis over time. Requires longitudinal
    monitoring.
  evidence:
  - reference: PMID:30986316
    reference_title: "Review of Cystic Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF."
    explanation: Clinical review describes the scenario of inconclusive CF diagnosis after positive newborn screening.
  - reference: PMID:28129811
    reference_title: "Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent"
    explanation: >-
      CF Foundation consensus guideline defining the merged CRMS/CFSPID
      designation for screen-positive newborns with inconclusive testing. The
      sweat chloride thresholds in the description come from the full
      guideline and are not in this abstract sentence.
# CFTR-related disorders
- name: Congenital Bilateral Absence of the Vas Deferens (CBAVD)
  classification: CFTR_related_disorder
  description: >-
    Isolated congenital bilateral absence of the vas deferens causing obstructive
    azoospermia and male infertility, without other features of classic CF. Found
    in approximately 1-2% of infertile males. Most affected men carry at least
    one CFTR mutation, often including the 5T poly-T variant or R117H. Sweat
    chloride is typically normal or borderline. Lung and pancreatic function
    are preserved.
- name: CFTR-Related Pancreatitis
  classification: CFTR_related_disorder
  description: >-
    Recurrent acute or chronic pancreatitis in individuals carrying one or two
    CFTR mutations with residual function, without meeting diagnostic criteria
    for CF. CFTR dysfunction impairs bicarbonate secretion in pancreatic ducts,
    predisposing to ductal obstruction and pancreatitis. Sweat chloride is
    typically normal or borderline.
- name: CFTR-Related Disseminated Bronchiectasis
  classification: CFTR_related_disorder
  description: >-
    Diffuse bronchiectasis in individuals carrying CFTR mutations who do not
    meet diagnostic criteria for CF. Sweat chloride may be normal or borderline.
    Represents the milder end of the CFTR dysfunction spectrum affecting
    the airways.
discussions:
- discussion_id: hemt_era_residual_disease
  prompt: >-
    Why does airway inflammation persist after highly effective CFTR modulator
    therapy, and is any part of it genuinely independent of ongoing CFTR
    dysfunction?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Neutrophilic Airway Inflammation
  - treatments#Elexacaftor-Tezacaftor-Ivacaftor (Trikafta/Kaftrio)
  rationale: >-
    Sputum proteomes and cytokine profiles improve substantially on
    elexacaftor/tezacaftor/ivacaftor but remain distinct from healthy controls,
    and residual oxidative stress and infection persist at levels comparable to
    non-cystic-fibrosis bronchiectasis. In vitro, restoring roughly 60% of CFTR
    function does not normalize the lipid imbalance or the basal inflammatory
    cytokine profile of cystic fibrosis bronchial epithelium. What these
    observations establish is incomplete normalization, not independence from
    CFTR. Partial target restoration, irreversible structural injury, persistent
    infection and microbiome disruption, late treatment initiation, and
    cell-type-specific drug exposure are all still viable explanations, and the
    published data do not separate them. The distinction matters for therapy: a
    self-sustaining cascade would justify adjunct anti-inflammatory treatment on
    top of modulators, whereas incomplete correction argues for deeper or earlier
    CFTR restoration.
  proposed_experiments:
  - experiment_id: exp_cf_infant_vs_late_eti_multiomics
    name: Longitudinal airway multi-omics in infant-initiated versus late-initiated modulator therapy
    description: >-
      Follow two prospective cohorts starting elexacaftor/tezacaftor/ivacaftor,
      one before six months of age and one after established structural lung
      disease, with serial airway proteomics, cytokines, microbiome sequencing
      and imaging, against matched controls without cystic fibrosis.
    decision_criterion: >-
      Convergence of the infant-initiated cohort on the control airway proteome
      and microbiome would attribute the residual signature to accumulated injury
      and timing; persistence of an inflammatory signature in that cohort despite
      equivalent restored CFTR function would support a component that no longer
      depends on ongoing CFTR dysfunction.
    would_support:
    - pathophysiology#Neutrophilic Airway Inflammation
    supporting_outcome:
    - >-
        A residual inflammatory and proteomic signature that persists in children
        treated from infancy, at the same restored CFTR function as later-treated
        patients, would show the inflammatory arm running partly independently of
        current CFTR activity.
    refuting_outcome:
    - >-
        Normalization of the airway proteome, cytokines and microbiome in the
        infant-initiated cohort would attribute the residual disease of
        later-treated patients to prior structural and microbial injury rather than
        to a CFTR-independent inflammatory program.
  evidence:
  - reference: PMID:42128740
    reference_title: "CFTR modulator therapy reshapes airway inflammation in cystic fibrosis: Insights from proteomics and machine learning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite these improvements, proteomic and cytokine profiles remained distinct from healthy controls."
    explanation: >-
      Longitudinal sputum proteomics and cytokines in 30 people with cystic
      fibrosis before and during modulator therapy, compared with seven healthy
      controls, document that normalization is incomplete. Seven controls is a
      small comparison group, and the study does not test why the difference
      remains.
  - reference: PMID:33613309
    reference_title: "CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress."
    explanation: >-
      Shows residual lipid and oxidative-stress abnormalities in cystic fibrosis
      bronchial epithelium after short-term modulator treatment. Because the
      correction reached only about 60% of non-cystic-fibrosis function over 72
      hours, this is equally compatible with incomplete correction and with a
      CFTR-independent component.
  - reference: PMID:40227282
    reference_title: "How Effectively Can Oxidative Stress and Inflammation Be Reversed When CFTR Function Is Pharmacologically Improved?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, despite these advancements, residual airway infection, oxidative stress and inflammation persist, with levels similar to other chronic lung conditions, like non-CF bronchiectasis."
    explanation: >-
      Review framing the residual burden and the reason it is clinically
      consequential. It synthesizes published series rather than reporting new
      data, so it supports the existence of the gap and not any particular
      mechanism for it.
- discussion_id: immune_cell_cftr_contribution
  prompt: >-
    How much of cystic fibrosis lung disease is attributable to
    immune-cell-autonomous CFTR dysfunction, independently of the epithelial
    surface defect?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Macrophage CFTR Dysfunction
  rationale: >-
    Macrophage CFTR is measurable, modulator-responsive, and associated with
    reduced phagocytosis, intracellular killing and efferocytosis, and ENaC is
    overexpressed in cystic fibrosis immune cells in a way that CFTR inhibition
    reproduces in non-cystic-fibrosis cells. All of this is ex vivo work on
    blood-derived cells. No study separates the immune contribution from the
    epithelial one in vivo, so the weight of this arm in human airway disease is
    unknown, and it cannot be assumed to hold for every immune lineage. A
    frequently cited zebrafish result does not close the gap either: those larvae
    were globally CFTR-depleted, and the excess neutrophil recruitment was traced
    to an epithelial oxidative response rather than to an immune-cell-autonomous
    defect. Resolving this determines whether immune-directed therapy, such as
    ENaC modulation in macrophages, is worth pursuing alongside CFTR modulators.
  proposed_experiments:
  - experiment_id: exp_cf_bone_marrow_chimera
    name: Reciprocal bone-marrow chimeras between CFTR-null and wild-type animals
    description: >-
      Transplant wild-type marrow into CFTR-null recipients and CFTR-null marrow
      into wild-type recipients in an animal model that develops airway disease,
      then compare bacterial burden, neutrophilic inflammation and airway
      histopathology against the two unmanipulated genotypes.
    decision_criterion: >-
      An intermediate phenotype in both chimera directions would quantify a real
      immune-cell-autonomous contribution; a phenotype that tracks recipient
      airway genotype alone would place the mechanism entirely in the epithelium.
    would_support:
    - pathophysiology#Macrophage CFTR Dysfunction
    supporting_outcome:
    - >-
        Wild-type marrow reducing disease in CFTR-null recipients, and CFTR-null
        marrow producing inflammation in wild-type recipients, would establish an
        immune-cell-autonomous contribution and give its approximate size.
    refuting_outcome:
    - >-
        Disease severity determined solely by the recipient airway genotype, with
        no effect of donor marrow genotype, would show the macrophage defect to be
        a downstream marker rather than an independent driver.
  evidence:
  - reference: PMID:39574739
    reference_title: "ENaC contributes to macrophage dysfunction in cystic fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Baseline expression of ENaC in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF controls and persisted after exposure to bacteria."
    explanation: >-
      Reports ENaC overexpression across cystic fibrosis immune lineages, which
      the same work reproduces by inhibiting CFTR in non-cystic-fibrosis
      macrophages, making the ion-channel abnormality a candidate
      immune-cell-autonomous mechanism. This source is a bioRxiv preprint and has
      not been peer reviewed, and the assays are ex vivo, so it marks out the
      question rather than answering it.
notes: >-
  Cystic fibrosis care has been transformed by CFTR modulator therapy, particularly
  elexacaftor-tezacaftor-ivacaftor (Trikafta), which provides substantial clinical
  benefit for approximately 90% of CF patients. Median survival has increased from
  early childhood death to beyond 40 years, with further improvements expected.
  Multidisciplinary care at specialized CF centers remains essential, encompassing
  pulmonary, nutritional, endocrine, hepatic, and psychosocial aspects. The CF
  Foundation accredits specialized care centers and maintains registries that drive
  quality improvement. Remaining therapeutic challenges include patients with
  nonsense mutations (Class I) not responsive to current modulators, established
  lung damage in older patients, and long-term effects of CFTR modulator therapy.
  Gene therapy and mRNA-based approaches are under active investigation for patients
  with mutations not amenable to small molecule modulation.
disease_term:
  preferred_term: cystic fibrosis
  term:
    id: MONDO:0009061
    label: cystic fibrosis
classifications:
  channelopathy_category:
    classification_value: epithelial channelopathy
  harrisons_chapter:
  - classification_value: RESPIRATORY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
experimental_models:
- name: Patient-derived airway organoid theratyping model
  description: >-
    Patient-derived nasal epithelial stem cells expanded from nasal brushings
    and differentiated into airway organoids for personalized CFTR modulator
    response testing.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory airway
    term:
      id: UBERON:0001005
      label: respiratory airway
  conditions:
  - cystic fibrosis
  - CFTR modulator theratyping
  cell_source: Patient-derived nasal epithelial stem cells obtained by nasal brushing
  culture_system: 3D airway organoids linked to differentiated air-liquid interface cultures
  publication: PMID:34413153
  modeled_mechanisms:
  - target: CFTR Dysfunction
    description: Measures genotype-specific epithelial CFTR dysfunction and rescue by modulators in patient-derived airway tissue.
  findings:
  - statement: Patient-derived airway organoids enable genotype-specific CFTR modulator response testing, including rare genotypes
    evidence:
    - reference: PMID:34413153
      reference_title: "Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients."
      explanation: Supports use of patient-derived airway organoids for CFTR theratyping in a genotype-specific epithelial system.
    - reference: PMID:35922154
      reference_title: "Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we therefore describe an alternative method of culturing nasal-brushing-derived airway organoids, which are created from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture"
      explanation: Supports reproducible CFTR functional readouts from nasal-brushing-derived airway organoid cultures.
  evidence:
  - reference: PMID:34413153
    reference_title: "Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients."
    explanation: Supports this as a disease-relevant patient-derived organoid model system for CF.
- name: CF airway-on-chip microphysiological model
  description: >-
    Human microfluidic airway chip lined by primary CF bronchial epithelial
    cells and pulmonary microvascular endothelial cells, recapitulating mucus,
    inflammation, and infection phenotypes under air-liquid interface culture.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: bronchial epithelium
    term:
      id: UBERON:0002031
      label: epithelium of bronchus
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  conditions:
  - cystic fibrosis
  - healthy control
  - Pseudomonas aeruginosa infection modeling
  cell_source: Primary human CF bronchial epithelial cells with pulmonary microvascular endothelial coculture
  culture_system: Microfluidic organ-on-chip with air-liquid interface airway compartment
  publication: PMID:34799298
  modeled_mechanisms:
  - target: Airway Surface Liquid Depletion
    description: Recapitulates dehydrated mucus-layer phenotypes downstream of epithelial ion-transport failure.
  - target: Impaired Mucociliary Clearance
    description: Captures ciliary and mucus-transport abnormalities in differentiated CF airway epithelium.
  - target: Chronic Bacterial Infection
    description: Provides a controllable airway context for infection and bacterial overgrowth phenotypes in CF epithelium.
  findings:
  - statement: CF airway chips recapitulate mucus accumulation, ciliary abnormalities, inflammatory signaling, and bacterial overgrowth
    evidence:
    - reference: PMID:34799298
      reference_title: "Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells."
      explanation: Establishes the chip as a physiologically relevant CF airway model.
  evidence:
  - reference: PMID:34799298
    reference_title: "Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells."
    explanation: Supports inclusion of this organ-on-chip system as a CF-relevant experimental model.
- name: NuLi/CuFi airway epithelial cell-line model
  description: >-
    Immortalized human airway epithelial cell lines representing normal and CF
    genotypes, differentiated at air-liquid interface to study ion transport
    and innate immune phenotypes.
  experimental_model_type: CELL_LINE
  namo_type: namo:CellLineModel
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory airway
    term:
      id: UBERON:0001005
      label: respiratory airway
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  conditions:
  - cystic fibrosis
  - healthy control
  cell_source: Immortalized human airway epithelial cell lines (NuLi-1, CuFi-1, CuFi-3, CuFi-4)
  culture_system: Polarized differentiated air-liquid interface epithelial culture
  publication: PMID:12676769
  modeled_mechanisms:
  - target: CFTR Dysfunction
    description: Preserves genotype-specific CFTR-dependent ion-transport defects in a reusable airway epithelial system.
  - target: ENaC Hyperactivity and Sodium Hyperabsorption
    description: Supports mechanistic readouts of abnormal epithelial sodium transport downstream of CFTR loss.
  findings:
  - statement: NuLi and CuFi lines retain genotype-specific ion-transport and epithelial differentiation phenotypes in vitro
    evidence:
    - reference: PMID:12676769
      reference_title: "Development of cystic fibrosis and noncystic fibrosis airway cell lines."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "When grown at the air-liquid interface, the cell lines were capable of forming polarized differentiated epithelia that exhibited transepithelial resistance and maintained the ion channel physiology expected for the genotypes."
      explanation: Confirms durable genotype-relevant airway epithelial physiology in a reusable CF cell-line model.
  evidence:
  - reference: PMID:12676769
    reference_title: "Development of cystic fibrosis and noncystic fibrosis airway cell lines."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When grown at the air-liquid interface, the cell lines were capable of forming polarized differentiated epithelia that exhibited transepithelial resistance and maintained the ion channel physiology expected for the genotypes."
    explanation: Supports inclusion of this cell-line system as a CF experimental model.
datasets:
- accession: geo:GSE150674
  title: Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition
  description: >-
    Single-cell sequencing dataset of human airway epithelium from normal and
    cystic fibrosis lungs, including donor airway samples used to define altered
    epithelial cell-state composition in CF.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: proximal airway epithelium
    term:
      id: UBERON:0001005
      label: respiratory airway
    tissue_term:
      preferred_term: respiratory airway
      term:
        id: UBERON:0001005
        label: respiratory airway
  sample_count: 38
  conditions:
  - cystic fibrosis
  - healthy control
  publication: PMID:33958799
  findings:
  - statement: CF proximal airways show shifted epithelial-state composition with increased transitioning ciliated/secretory programs
    evidence:
    - reference: PMID:33958799
      reference_title: "Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells."
      explanation: Single-cell airway profiling identifies disease-dependent epithelial state shifts in CF.
  notes: Donor-cohort count from the linked Nat Med study (19 CF + 19 healthy proximal-airway donors); GEO may include additional technical records not counted as biological samples.
- accession: geo:GSE193782
  title: ScRNA-seq Expression of APOC2 and IFI27 Identifies Four Alveolar Macrophage Superclusters in Cystic Fibrosis and Healthy BALF
  description: >-
    Single-cell RNA sequencing dataset of bronchoalveolar lavage cells from
    healthy controls and uninflamed cystic fibrosis subjects used to define
    alveolar macrophage superclusters and immune-cell heterogeneity.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: lung (bronchoalveolar lavage cells)
    term:
      id: UBERON:0002048
      label: lung
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  sample_count: 7
  conditions:
  - cystic fibrosis
  - healthy control
  publication: PMID:35820705
  findings:
  - statement: BAL single-cell profiling identifies conserved alveolar macrophage superclusters across healthy and uninflamed CF subjects
    evidence:
    - reference: PMID:35820705
      reference_title: "ScRNA-seq expression of IFI27 and APOC2 identifies four alveolar macrophage superclusters in healthy BALF."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We performed single-cell RNA sequencing on 113,213 bronchoalveolar lavage cells from four healthy and three uninflamed cystic fibrosis subjects and identified two MARCKS+LGMN+IMs, FOLR2+SELENOP+ and SPP1+PLA2G7+ IMs, monocyte subtypes, DC1, DC2, migDCs, plasmacytoid DCs, lymphocytes, epithelial cells, and four AM superclusters (families) based on the gene expression of IFI27 and APOC2"
      explanation: The study reports core BAL immune-cell architecture including four alveolar macrophage superclusters in CF-context samples.
  notes: Provides CF-relevant BAL immune-cell state reference for airway inflammation mechanisms.
- accession: geo:GSE266789
  title: "Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity [scRNAseq-hPSC]"
  description: >-
    Early human fetal lung single-cell atlas dataset profiling over 150,000
    cells from gestational weeks 10-19, with trajectories of CFTR-expressing
    progenitor populations and comparison to hPSC-derived fetal lung models.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: fetal lung tissue
    term:
      id: UBERON:0002048
      label: lung
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  sample_count: 19
  conditions:
  - normal fetal development
  publication: PMID:39003323
  findings:
  - statement: Fetal lung development includes CFTR-high progenitor trajectories that inform developmental context for CFTR biology
    evidence:
    - reference: PMID:39003323
      reference_title: "Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR)."
      explanation: Establishes developmental CFTR-expressing progenitor trajectories relevant to CFTR biology.
  notes: Developmental fetal-lung atlas with explicit CFTR-expressing progenitor characterization.
  # CELLxGENE - CF and healthy control biopsy
- accession: "cellxgene:54004c5c-af08-4693-a606-73871b6ef989"
  title: Cystic Fibrosis and healthy control biopsy
  description: >-
    Single-cell transcriptomic profiling of cystic fibrosis and healthy control
    biopsies available on CZI CELLxGENE Discover. Provides disease-specific
    cell state annotations for CF airway pathology.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: airway biopsy
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  conditions:
  - cystic fibrosis
  - healthy control
  publication: DOI:10.1016/j.jcf.2025.01.016
  notes: CZI CELLxGENE collection.
  # --- Experimental / Organoid / Physiological Model Datasets (Issue  # 302) ---
- accession: doi:10.1111/liv.15963
  title: "Single‐cell <scp>RNA</scp> sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation"
  description: >-
    Single-cell RNA sequencing of four CF liver disease explant livers identifying
    differential endothelial characteristics including a distinct population of
    liver sinusoidal endothelial cells upregulating complement cascade genes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: liver explant
    term:
      id: UBERON:0002107
      label: liver
    tissue_term:
      preferred_term: liver
      term:
        id: UBERON:0002107
        label: liver
  sample_count: 4
  conditions:
  - cystic fibrosis liver disease
  publication: PMID:38847551
  findings:
  - statement: CF liver explants contain a distinct population of sinusoidal endothelial cells with upregulated complement and coagulation genes
    evidence:
    - reference: PMID:38847551
      reference_title: "Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease"
      explanation: First scRNA-seq characterization of endothelial involvement in CF liver disease.
  notes: First comprehensive single-cell analysis of CF hepatic complications; supports endothelial involvement in CFLD.
- accession: doi:10.1183/13993003.00908-2021
  title: "Theratyping cystic fibrosis<i>in vitro</i>in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells"
  description: >-
    Patient-derived nasal epithelial stem cells expanded via conditional reprogramming
    and used to generate 3D airway organoids and ALI cultures for personalized CFTR
    modulator efficacy testing (theratyping).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: nasal epithelial organoid
    term:
      id: UBERON:0001005
      label: respiratory airway
    tissue_term:
      preferred_term: nasal epithelium
      term:
        id: UBERON:0001005
        label: respiratory airway
  conditions:
  - cystic fibrosis
  publication: PMID:34413153
  findings:
  - statement: Conditionally reprogrammed nasal epithelial stem cells generate organoids suitable for personalized CFTR modulator testing
    evidence:
    - reference: PMID:34413153
      reference_title: "Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients."
      explanation: Demonstrates non-invasive patient-specific organoid model for personalized drug screening.
  notes: Experimental model enabling theratyping for patients with rare CFTR genotypes not eligible for standard modulator therapy.
- accession: doi:10.26508/lsa.202101320
  title: Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia
  description: >-
    Novel method for generating nasal-brushing-derived airway organoids from 2D
    air-liquid interface cultures, enabling consistent detection of CFTR modulator
    responses via forskolin-induced swelling assay.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: nasal epithelial organoid
    term:
      id: UBERON:0001005
      label: respiratory airway
    tissue_term:
      preferred_term: nasal epithelium
      term:
        id: UBERON:0001005
        label: respiratory airway
  conditions:
  - cystic fibrosis
  publication: PMID:35922154
  findings:
  - statement: 2D-to-3D transition culture method enables consistent CFTR modulator response detection in nasal airway organoids
    evidence:
    - reference: PMID:35922154
      reference_title: "Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we therefore describe an alternative method of culturing nasal-brushing-derived airway organoids, which are created from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture"
      explanation: Combines advantages of ALI differentiation with 3D organoid FIS assay for improved scalability.
  notes: Improved organoid culture protocol with neuregulin-1β and interleukin-1β for consistent CFTR functional readouts.
- accession: doi:10.26508/lsa.202201857
  title: Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis
  description: >-
    Validation of 2D human intestinal organoid monolayers as a preclinical drug
    testing tool, demonstrating comparable CFTR functional responses across 2D HIO,
    3D HIO, and HNE methods with good correlation to clinical outcome markers.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: intestinal organoid monolayer
    term:
      id: UBERON:0000160
      label: intestine
    tissue_term:
      preferred_term: intestine
      term:
        id: UBERON:0000160
        label: intestine
  conditions:
  - cystic fibrosis
  publication: PMID:37024122
  findings:
  - statement: 2D intestinal organoid monolayers show comparable CFTR functional responses to 3D organoids and HNE cultures with good clinical correlation
    evidence:
    - reference: PMID:37024122
      reference_title: "Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE."
      explanation: Expands utility of intestinal monolayers as scalable preclinical drug testing tool for CF.
  notes: Demonstrates larger measurable CFTR functional range and apical membrane access advantages of 2D HIO over HNE and 3D HIO.
- accession: doi:10.1007/s00018-025-05627-7
  title: Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology
  description: >-
    Endometrial organoid models from CF patients and CF mice revealing molecular
    and pathway differences in hormone responses, with single-cell RNA sequencing
    of CF mouse uterus confirming similar molecular traits to human CF endometrium.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: endometrial organoid
    term:
      id: UBERON:0001295
      label: endometrium
    tissue_term:
      preferred_term: endometrium
      term:
        id: UBERON:0001295
        label: endometrium
  conditions:
  - cystic fibrosis
  - healthy control
  publication: PMID:40074868
  findings:
  - statement: CF endometrial organoids recapitulate disease characteristics and reveal cycle-dependent molecular aberrations correctable by CFTR modulators
    evidence:
    - reference: PMID:40074868
      reference_title: "Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we developed organoid models from CF patient endometrium. The organoids recapitulated CF characteristics and revealed molecular and pathway differences in cycle-recapitulating hormone responses compared to healthy endometrial organoids."
      explanation: Expands CF model systems beyond respiratory and GI to reproductive tissue pathobiology.
  notes: Includes scRNA-seq of CF mouse uterus; relevant to CF fertility challenges and reproductive pathobiology.
- accession: doi:10.1016/j.jcf.2021.10.004
  title: Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip
  description: >-
    Microfluidic organ-on-a-chip device lined by primary human CF bronchial
    epithelial cells at air-liquid interface with pulmonary microvascular
    endothelial cells, recapitulating CF airway pathophysiology including mucus
    accumulation, inflammation, and Pseudomonas aeruginosa infection.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: bronchial epithelium on microfluidic chip
    term:
      id: UBERON:0002031
      label: epithelium of bronchus
    tissue_term:
      preferred_term: bronchial epithelium
      term:
        id: UBERON:0002031
        label: epithelium of bronchus
  conditions:
  - cystic fibrosis
  - healthy control
  publication: PMID:34799298
  findings:
  - statement: CF airway-on-a-chip recapitulates enhanced mucus accumulation, increased cilia density, higher IL-8 secretion, and enhanced Pseudomonas aeruginosa growth
    evidence:
    - reference: PMID:34799298
      reference_title: "Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells."
      explanation: Organ-on-chip platform enabling physiological CF modeling with infection and inflammation readouts.
  notes: Organ-on-a-chip model from Wyss Institute; supports drug testing and personalized medicine applications.
- accession: doi:10.1152/ajplung.00355.2002
  title: "Development of cystic fibrosis and noncystic fibrosis airway cell lines"
  description: >-
    Immortalized human airway epithelial cell lines derived from normal (NuLi-1)
    and CF (CuFi-1, CuFi-3, CuFi-4) genotypes using hTERT and HPV-16 E6/E7,
    capable of forming polarized differentiated epithelia at air-liquid interface.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: airway epithelial cell line
    term:
      id: UBERON:0001005
      label: respiratory airway
    tissue_term:
      preferred_term: respiratory airway
      term:
        id: UBERON:0001005
        label: respiratory airway
  conditions:
  - cystic fibrosis
  - healthy control
  publication: PMID:12676769
  findings:
  - statement: NuLi and CuFi cell lines maintain genotype-specific ion channel physiology and NF-kB innate immune responses at ALI
    evidence:
    - reference: PMID:12676769
      reference_title: "Development of cystic fibrosis and noncystic fibrosis airway cell lines."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "When grown at the air-liquid interface, the cell lines were capable of forming polarized differentiated epithelia that exhibited transepithelial resistance and maintained the ion channel physiology expected for the genotypes."
      explanation: Immortalized CF cell lines supporting reproducible ion physiology and innate immunity studies.
  notes: Immortalized CF cell line resource; CuFi lines are correctable by adenoviral CFTR vectors.

📚

References & Deep Research

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

Name: Cystic Fibrosis
Category: Genetic
Existing deep-research providers: openai
Existing evidence reference count in YAML: 105

Key Pathophysiology Nodes

CFTR Dysfunction
Airway Surface Liquid Depletion
Mucus Plugging and Airway Obstruction
Chronic Bacterial Infection
Neutrophilic Airway Inflammation
Bronchiectasis and Airway Remodeling
Respiratory Failure
Pancreatic Duct Obstruction
Exocrine Pancreatic Insufficiency
Fat Malabsorption
Fat-Soluble Vitamin Deficiency
Protein-Calorie Malnutrition

Citation Inventory (for evidence mapping)

DOI:10.1186/s12931-017-0691-x
PMID:37699417

OpenAI ▸

1. Core Pathophysiology

o3-deep-research-2025-06-26 115 citations 2026-02-11T12:07:04.516914

1. Core Pathophysiology

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene, which encodes the cystic fibrosis transmembrane conductance regulator. The CFTR protein is an ATP-binding cassette (ABC) transporter-class ion channel that normally functions as a cAMP-regulated epithelial chloride channel (www.ncbi.nlm.nih.gov). It also regulates bicarbonate transport and influences other ion channels. In healthy epithelia, CFTR-mediated chloride and bicarbonate secretion balances sodium absorption to maintain hydration of mucosal surfaces (pmc.ncbi.nlm.nih.gov). In CF, CFTR dysfunction is the primary defect: mutations render the chloride/bicarbonate channel absent or defective at the cell surface (pmc.ncbi.nlm.nih.gov). As a result, epithelial ion transport is dysregulated – chloride and bicarbonate secretion is impaired while unchecked sodium absorption through the epithelial sodium channel (ENaC) leads to excessive water reabsorption (pmc.ncbi.nlm.nih.gov). The airway surface liquid becomes depleted and secretions thicken, causing viscous mucus that the cilia cannot clear (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). One review summarizes that in CF airways, “CFTR is diminished, and ENaC is upregulated, leading to mucus dehydration and increased chance of infection” (pmc.ncbi.nlm.nih.gov) (PMID: 23878362). This dehydrated, hyperviscous mucus is a hallmark of CF pathophysiology across multiple organs (pmc.ncbi.nlm.nih.gov). CFTR is expressed in the epithelial cells of the airways, submucosal glands, pancreas, intestines, biliary tract, sweat glands, and reproductive ducts, so CFTR dysfunction causes a complex multi-organ disease (www.nature.com). However, most morbidity and mortality in CF stems from the progressive lung disease resulting from mucus obstruction and its consequences (www.nature.com).

In the bronchopulmonary system, the loss of CFTR leads to abnormal ion and fluid transport on airway surfaces, producing thick, sticky mucus that clogs small airways (pmc.ncbi.nlm.nih.gov). Mucociliary clearance is impaired, and bacteria become trapped, leading to persistent airway infection. The lungs of CF patients often become colonized in early childhood with organisms like Staphylococcus aureus and Haemophilus influenzae, and later Pseudomonas aeruginosa and other gram-negative bacteria, resulting in chronic suppurative infection (news.unchealthcare.org) (news.unchealthcare.org). The stagnant mucus and microbes trigger a robust inflammatory response. Neutrophils are recruited excessively to CF airways (even in early life before overt infection) (respiratory-research.biomedcentral.com). These neutrophils release proteases and oxidants that cause tissue damage. Notably, neutrophil elastase (NE), a serine protease, is abundant in CF airway fluids and plays a central role in driving lung pathology (respiratory-research.biomedcentral.com). Studies have found high NE activity and IL-8 levels in bronchoalveolar lavage (BAL) fluid of infants with CF, correlating with the early development of bronchiectasis (respiratory-research.biomedcentral.com) (PMID: 29258516). NE and other proteases create a self-perpetuating cycle of inflammation: NE cleaves and inactivates important host defense molecules (like lactoferrin and complement components) (respiratory-research.biomedcentral.com), stimulates further chemokine release (IL-8) attracting more neutrophils (respiratory-research.biomedcentral.com), and directly impairs ciliary function while inducing goblet cell hyperplasia and mucin overproduction (respiratory-research.biomedcentral.com). As one review describes, “NE impairs ciliary beating and promotes expression of respiratory mucins (MUC5AC and MUC5B), resulting in muco-ciliary clearance failure.” (respiratory-research.biomedcentral.com). NE and other neutrophil proteases also degrade structural proteins (e.g. elastin in airway walls), leading to irreversible bronchiectasis (permanent airway dilation and remodeling) (respiratory-research.biomedcentral.com). Thus, CF lung disease is characterized by a vicious cycle of mucus obstruction → infection → neutrophilic inflammation → tissue damage, which perpetuates further obstruction and infection. Over years, this cycle causes progressive airway destruction, fibrosis, and loss of pulmonary function. The end-stage of CF lung disease is respiratory failure due to diffuse bronchiectasis and fibrotic lung changes.

Beyond the lungs, CFTR dysfunction affects other systems in parallel. In the pancreas, CFTR is crucial for bicarbonate and chloride secretion in pancreatic ducts. CFTR loss leads to thick, protein-rich secretions that obstruct the small pancreatic ducts (pmc.ncbi.nlm.nih.gov). This causes exocrine pancreatic insufficiency in ~85% of patients: digestive enzymes cannot reach the intestines, resulting in malabsorption of fats and protein, nutrient deficiencies, and steatorrhea (fatty stools) (pmc.ncbi.nlm.nih.gov). Pancreatic obstruction at birth can cause pancreatic damage (fibrosis) and explains why many CF infants have meconium ileus (intestinal blockage by thick meconium) shortly after birth. Recurrent obstruction and inflammation can also lead to pancreatitis in some CF individuals, and eventually CF-related diabetes (CFRD) due to islet cell destruction in later life (pmc.ncbi.nlm.nih.gov). In the intestines, thick secretions and abnormal ion/water transport lead to viscid meconium in neonates (meconium ileus, a neonatal intestinal obstruction pathognomonic for CF) and contribute to distal intestinal obstruction syndrome in older patients (pmc.ncbi.nlm.nih.gov). In the hepatobiliary system, thick bile and mucus can clog bile ducts, leading to focal biliary cirrhosis and gallstones; about 5–10% of CF patients develop multilobular cirrhosis or portal hypertension from bile duct obstruction and chronic inflammation in the liver. In the sinuses, CFTR mutations cause chronic rhinosinusitis and nasal polyps due to similar mucus stasis in sinus epithelia. Almost all CF patients have sinus radiographic abnormalities, and nasal polyps occur in ~10–20% (pmc.ncbi.nlm.nih.gov). The reproductive tract is also affected: >95% of males with CF have obstructive azoospermia due to congenital bilateral absence of the vas deferens (CBAVD), which results from CFTR’s role in embryonic development of the wolffian duct or early obstruction of the vas deferens (pmc.ncbi.nlm.nih.gov). Females with CF have generally normal anatomy but may have reduced fertility from thick cervical mucus and malnutrition. Finally, in the sweat glands, CFTR normally facilitates chloride (and sodium) reabsorption in sweat duct epithelia. CFTR loss renders sweat ducts unable to reclaim salt, leading to excessive salt loss in sweat – the classic “salty skin” of CF patients (pmc.ncbi.nlm.nih.gov). This was one of the earliest clues to CF’s nature: infants with CF were noted to taste salty, and in 1959 Gibson and Cooke introduced the pilocarpine sweat test as a diagnostic, which remains a standard test (sweat chloride ≥60 mM is strongly indicative of CF) (pmc.ncbi.nlm.nih.gov). Thus, the core pathophysiological feature of CF across organs is dehydrated, thick secretions due to defective epithelial ion transport, leading to obstruction, tissue damage, and dysfunction of affected organs.

Molecularly, thousands of different CFTR gene variants can cause CF, and these are grouped by their effect on the CFTR protein. Common mutations include F508del (deletion of phenylalanine at position 508), present on at least one allele in ~85–90% of CF patients worldwide (pmc.ncbi.nlm.nih.gov). The F508del mutation produces a misfolded CFTR protein that is tagged for degradation and fails to reach the cell surface (a Class II trafficking mutation) (pmc.ncbi.nlm.nih.gov). Other mutations produce no protein at all (Class I, nonsense or frameshift mutations), defective channel gating (Class III, e.g. G551D), decreased channel conductance (Class IV), reduced mRNA/protein production (Class V), or unstable surface expression (Class VI) (pmc.ncbi.nlm.nih.gov). Despite this genetic heterogeneity, the final common pathway is insufficient functional CFTR at the apical membrane of epithelial cells. The severity of ion transport dysfunction (and thus disease severity) can vary with mutation class and the amount of residual CFTR function (pmc.ncbi.nlm.nih.gov). For instance, “gating” mutations like G551D result in CFTR at the surface but non-functional, whereas milder mutations that allow some CFTR function may lead to atypical or less severe CF phenotypes (e.g. isolated CBAVD or pancreatic-sufficient CF). Environmental and modifier genes (involving inflammation, infection susceptibility, etc.) also contribute to the wide variability in disease severity among CF patients (www.nature.com) (www.nature.com).

2. Key Molecular Players

Genes/Proteins: The key gene in CF is CFTR (HGNC:1884), located on chromosome 7q31.2, which encodes the CFTR protein (UniProt P13569). CFTR is a 1480-amino-acid glycoprotein that functions as a regulated chloride/bicarbonate channel in the apical membrane of epithelial cells (www.ncbi.nlm.nih.gov). CFTR’s activity is regulated by cAMP/PKA phosphorylation and ATP binding/hydrolysis at its nucleotide-binding domains. Mutations in CFTR (>2,000 variants identified) are causally responsible for CF (pmc.ncbi.nlm.nih.gov). The most prevalent pathogenic variant is F508del (p.Phe508del), which accounts for two defective alleles in ~44% of CF patients and one allele in another ~40% (pmc.ncbi.nlm.nih.gov). Other notable CFTR mutations include G551D (a gating defect), G542X (a premature stop codon), N1303K, W1282X, etc. All patients have biallelic CFTR mutations; the combination of mutations influences the phenotype (e.g. pancreatic-sufficient vs insufficient CF is often related to “milder” mutations that retain partial function (pmc.ncbi.nlm.nih.gov)). Aside from CFTR itself, no other single gene causes CF, but many modifier genes can modulate CF severity. For example, variants in genes encoding muco-inflammatory regulators (like MUC5B, TGFB1, TNF, EDNRA, etc.) and immune response genes (IL-8, MSRA) have been associated with differences in lung function or infection severity in CF (www.nature.com) (www.nature.com). These are not causal of CF, but they can exacerbate or ameliorate aspects of disease (so-called modifier gene effects). In the CF airways, ENaC (epithelial sodium channel) is a critical interacting protein (though not mutated in CF). ENaC is a heterotrimeric sodium channel (subunits α/β/γ encoded by SCNN1A, SCNN1B, SCNN1G) on the apical membrane of the same cells that express CFTR. CFTR normally downregulates ENaC activity; hence in CF, ENaC becomes overactive, driving increased Na⁺ absorption and airway surface liquid depletion (pmc.ncbi.nlm.nih.gov). This makes ENaC a key contributor to the airway surface dehydration in CF pathophysiology. As a result, ENaC is being explored as a therapeutic target (e.g. inhaled ENaC inhibitors) to complement CFTR modulator therapy (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Other proteins involved in CF pathology include mucins like MUC5AC and MUC5B (the major gel-forming mucins in airway mucus). Their genes are not mutated in CF, but their expression and properties are altered secondary to CFTR dysfunction and chronic inflammation (respiratory-research.biomedcentral.com). In CF, mucins tend to be overly concentrated and improperly unfolded due to lack of bicarbonate; this contributes to the dense mucus plaques that obstruct airways (news.unchealthcare.org). Neutrophil elastase (ELANE gene) is another key protein in CF lung disease: it is a protease released by neutrophils that damages tissues and mucus clearance mechanisms, as discussed above. Elevated elastase activity is a biomarker of CF airway disease severity (respiratory-research.biomedcentral.com) (respiratory-research.biomedcentral.com). Other inflammatory mediators are also abundant in CF airways – for instance, IL-8 (CXCL8) is a neutrophil chemoattractant often found at high levels in CF sputum and BAL fluid, perpetuating neutrophil influx (respiratory-research.biomedcentral.com). TNF-α and IL-1β from immune cells contribute to the inflammatory milieu, and oxidative enzymes like myeloperoxidase (from neutrophils) generate oxidants that injure airway cells. Additionally, persistent bacteria in CF airways (such as Pseudomonas aeruginosa) produce virulence factors (e.g. alginate in mucoid Pseudomonas) that further thicken mucus and evade host defenses, though bacteria are not “molecular players” in the human sense, their presence is integral to disease mechanisms. In the gastrointestinal tract, digestive enzymes (pancreatic proteases, lipases) and bicarbonate transporters are downstream players affected by CFTR loss – for instance, the pancreatic ductal Cl⁻/HCO₃⁻ exchanger (SLC26A6) works in concert with CFTR, and without CFTR function, bicarbonate secretion is inadequate, leading to enzyme precipitation and duct blockage (pmc.ncbi.nlm.nih.gov).

It should also be noted that a revolution in therapy has introduced CFTR modulator drugs – small molecules that target the CFTR protein defects. These include ivacaftor (VX-770), a CFTR potentiator that increases channel opening for certain gating mutants (like G551D) (www.nature.com), and correctors like lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445) that help misfolded F508del CFTR fold and traffic to the membrane (www.nature.com). The latest approved combination, elexacaftor/tezacaftor/ivacaftor (brand name Trikafta), can restore significant CFTR function in cells with the F508del mutation and others (www.nature.com). While these drugs are therapeutic (see section on real-world implementation), they are also important molecular tools that validate CFTR as the central player in CF pathogenesis – partial restoration of CFTR activity by modulators dramatically improves the cellular ion transport and thus the disease manifestations (www.nature.com). This underscores CFTR’s key role in all downstream pathological processes.

Chemical Entities: Several ions and small molecules are directly involved in CF pathophysiology. The most fundamental are chloride (Cl⁻) and sodium (Na⁺) ions. Chloride is the primary ion whose transport is disrupted by CFTR mutations – normally, CFTR allows Cl⁻ to exit epithelial cells into secretions (airway surface liquid, pancreatic fluid, sweat, etc.). In CF, chloride is trapped inside cells, leading to low chloride and water content in secretions and high sweat chloride on the skin surface (since sweat ducts cannot reabsorb Cl⁻) (pmc.ncbi.nlm.nih.gov). Sodium absorption through ENaC is the counterpoint: CFTR dysfunction leads to hyperactive Na⁺ uptake, which drags water out of mucus. The imbalance of Cl⁻ and Na⁺ movement causes hyperconcentrated mucus with high salt concentration but low water content (pmc.ncbi.nlm.nih.gov). Bicarbonate (HCO₃⁻) is another critical ion: CFTR conducts bicarbonate or regulates its secretion via other channels. Bicarbonate helps maintain an alkaline pH and proper unfolding of mucins. In CF, bicarbonate transport is reduced, leading to more acidic secretions. This impairs mucin expansion – mucins secreted by goblet cells are densely packed granules that require bicarbonate-rich fluid to swell and form a normal gel. Without sufficient HCO₃⁻, mucus remains dense and sticky (pmc.ncbi.nlm.nih.gov). A landmark experiment showed that in CF mice, intestinal mucus remained attached and impermeable, but adding a high concentration of bicarbonate restored mucus properties to normal (pmc.ncbi.nlm.nih.gov). In other words, “CF is caused by a nonfunctional chloride and bicarbonate ion channel (CFTR),” and loss of bicarbonate secretion is a key link to the “stagnant mucus” phenotype of the disease (pmc.ncbi.nlm.nih.gov) (PMID: 22711878). Thus, bicarbonate deficiency in CF secretions contributes to mucus pathology and perhaps to a more acidic airway surface that impairs antibacterial defenses (airway surface liquid pH is often lower in CF, reducing the activity of antimicrobial peptides). Water (H₂O) is indirectly the key molecule being mis-regulated; CFTR dysfunction results in dehydration of airway surface liquid. Hydration status of mucus is essentially the outcome of ion movement, so water is crucial for the rheology of secretions. ATP is another molecule of note: CFTR is an ATP-gated channel, and CFTR mutations like F508del affect ATP binding and hydrolysis cycle of the channel. cAMP (cyclic AMP) is the second messenger that activates PKA to open CFTR; thus cAMP levels and signaling (e.g. via β₂-adrenergic receptors) play a role in modulating CFTR activity. Pharmacologically, several small-molecule drugs interact with these pathways: e.g., Ivacaftor (CHEBI:64288) increases the probability of the CFTR channel being open (especially effective for Class III gating mutants) (www.nature.com). Corrector drugs (lumacaftor, tezacaftor, elexacaftor) are chemical chaperones that bind CFTR during folding. Other chemical entities relevant to CF include antibiotics (like tobramycin, aztreonam, etc., used to suppress airway infections) and mucolytics (e.g. dornase alfa, a DNAse enzyme that digests extracellular DNA in sputum). While these therapeutic agents are not part of the pathophysiology per se, their development was informed by understanding CF’s molecular mechanisms. Additionally, ions in sweat (Cl⁻ and Na⁺) serve as diagnostic chemicals: CF patients classically have sweat chloride concentrations >60 mmol/L (normal <30), often accompanied by high sodium, which can lead to salt depletion episodes in hot climates if not managed.

Cell Types: CF pathophysiology involves several cell types, chiefly epithelial cells of various organs. In the lungs, the critical cells are the ciliated respiratory epithelial cells (airway lining cells) that express CFTR on their apical surface. These include bronchiolar and bronchial epithelial cells (CL:0000066) that have motile cilia and interspersed goblet cells (mucus-secreting cells). CFTR is also highly expressed in the submucosal gland cells of the airways (submucosal glands produce a significant portion of airway mucus, especially in larger airways). Dysfunction of CFTR in these cell types leads to dehydrated periciliary fluid and mucus, and the glands produce mucus that is too concentrated. In the pancreas, the relevant cells are pancreatic duct epithelial cells (which normally secrete bicarbonate-rich fluid via CFTR) and acinar cells (which secrete digestive enzymes). Acinar cells themselves don’t express much CFTR, but their enzyme secretions cannot be flushed out without ductal fluid; thus, duct obstruction secondarily damages acinar cells. In the intestine, enterocytes and goblet cells of the intestinal mucosa (especially in the distal ileum and proximal colon) are affected – goblet cells produce abnormal mucus and enterocytes struggle with salt/fluid transport, causing thick stool. In the biliary tract, cholangiocytes (bile duct epithelial cells) rely on CFTR for bile fluid secretion; loss of CFTR causes bile precipitates and damage to these cells. In sweat glands, ductal epithelial cells fail to reabsorb salt. In the reproductive tract, the epididymal and vas deferens epithelial cells require CFTR for normal duct development and fluid balance; CFTR loss leads to atrophy or agenesis of the vas deferens in male fetuses.

Beyond epithelial cells, immune and inflammatory cells play a major role in CF lung pathology. Neutrophils (PMNs) are the dominant inflammatory cells in CF airways – they migrate into the bronchi in huge numbers in response to infection and CFTR-related dysregulation of inflammation. Neutrophils in CF may be functionally altered; for example, CFTR is expressed in leukocytes at low levels, and intrinsic CFTR dysfunction in immune cells might contribute to an overly aggressive but ineffective inflammatory response (some studies suggest CF neutrophils have impaired bacterial killing but excessive release of proteases and extracellular traps). Macrophages are also present in CF lungs and can ingest bacteria, but in CF they show impaired phagocytosis and altered cytokine profiles (possibly due to the chronic inflammatory environment). T-lymphocytes and other immune cells are involved to a lesser extent, with a biased Th17 and Th2 response noted in CF airways chronically. In CF-related diabetes, pancreatic islet β-cells are eventually destroyed by autoimmunity and fibrotic damage. In CF liver disease, hepatic stellate cells may be activated by bile duct injury to produce fibrosis. However, the primary cell-type focus of CF pathogenesis is the polarized epithelial cell in various organs, as that is where CFTR resides and its loss initiates downstream pathology.

Anatomical Locations: CF is a multi-organ disease, but certain anatomic sites are particularly impacted:
- Lungs (UBERON:0002048) – especially the bronchi and bronchioles of the respiratory tract. The entire airway tree from the trachea to small bronchioles is affected by thick mucus. Bronchioles are often the earliest sites of obstruction (leading to air trapping and collapse of distal alveoli). Over time, major airways develop bronchiectasis (dilated, damaged airways). The upper respiratory tract (nasal passages and paranasal sinuses) is also affected, with chronic sinusitis and nasal polyposis common.
- Pancreas (UBERON:0001264) – mainly the exocrine pancreas. The pancreatic ducts (which normally carry digestive enzymes and bicarbonate) are obstructed by viscid secretions, leading to pancreatic tissue destruction. The endocrine pancreas can also be affected secondarily, leading to CF-related diabetes.
- Gastrointestinal tract – particularly the small intestine (UBERON:0002108) at the ileum and the colon. Newborns with CF may have meconium ileus (obstruction at the distal ileum/ileocecal region). Throughout life, CF patients can suffer distal intestinal obstruction syndrome (DIOS) in the ileocecal area due to thick stool. The intestinal mucosa in CF also exhibits abnormal ion transport, which can cause constipation or obstruction if not managed.
- Hepatobiliary system – the bile ducts in the liver (intrahepatic bile ducts and extrahepatic ducts) can become clogged by thick secretions. This can cause focal biliary fibrosis and cirrhosis in the liver (UBERON:0002107). The gallbladder and gallstones are also more frequent in CF due to altered bile composition.
- Sweat glands – specifically the eccrine sweat glands in the skin. The sweat gland ducts are unable to reabsorb salt in CF, which anatomically results in high salt content on the skin surface (clinically tested at the forearm sweat glands).
- Reproductive tract – in males, the vas deferens (UBERON:0003889) and epididymis do not develop properly or are obliterated early (CBAVD). The testes themselves are usually normal and produce sperm, but sperm have no exit due to the missing vas deferens. In females, the cervix may have thick mucus, and there may be reduced fertility, but the anatomy (uterus, ovaries) is preserved.
- Other organs: The lungs and pancreas are considered the principal affected organs with life-threatening manifestations, but CF can also affect the upper GI tract (e.g. GERD is common in CF, and CFTR is expressed in salivary glands and esophagus to some extent). The ears (middle ear) can have chronic otitis media, especially in children, partly due to Eustachian tube dysfunction from thick secretions. Bones are indirectly affected (CF patients often have low bone density due to malabsorption and chronic inflammation, leading to higher risk of fractures).

Overall, CF pathophysiology centers on epithelial dysfunction in specific anatomic sites leading to organ-specific disease: chronic lung disease, pancreatic insufficiency, hepatobiliary disease, etc., all unified by the common thread of CFTR mutation and abnormal mucus/secretions.

3. Disrupted Biological Processes (GO Terms)

Cystic fibrosis perturbs numerous biological processes. Key Gene Ontology (GO) categories relevant to CF include:

Ion Transport and Homeostasis: The primary process affected is chloride transmembrane transport (GO:1902476) across epithelial cell membranes. CFTR normally mediates chloride ion export; in CF this process is defective (pmc.ncbi.nlm.nih.gov). Sodium ion transport (GO:0006814) is secondarily increased via ENaC hyperactivity (pmc.ncbi.nlm.nih.gov). Together, these disrupt epithelial fluid transport and ion homeostasis on airway surfaces and in ducts. Bicarbonate transport (part of GO:0015701 bicarbonate transport) is also impaired, contributing to altered pH of secretions (pmc.ncbi.nlm.nih.gov).
Water Transport and Secretion: Linked to ion movement, CF causes failure of water transport and fluid secretion in glands. Though water transport is passive, the GO process fluid secretion (GO:0007589) is broadly disrupted – e.g., pancreatic fluid and airway surface liquid are diminished. The result is dehydration of the mucus layer (no specific GO term for “airway surface liquid homeostasis”, but this involves processes of ion transport and water homeostasis GO:0055082).
Mucociliary Clearance: CF fundamentally deranges mucociliary transport (GO:0120195, the process by which cilia move mucus). Due to dehydrated mucus and ciliary dysfunction, the process of clearing inhaled particles and pathogens is defective. Ciliary beat frequency is reduced by factors like neutrophil elastase and the thick mucus environment (respiratory-research.biomedcentral.com). Thus, epithelial cilium movement involved in mucociliary clearance (GO:0003351) is adversely affected in CF.
Mucin Production and Secretion: CF triggers abnormal mucin metabolic processes. Goblet cell differentiation and mucin secretion (GO:0070254 secretion by goblet cells) can be increased as a reactive process, leading to goblet cell hyperplasia. CF airway epithelial cells often show an upregulation of mucin genes (like MUC5B, MUC5AC) and produce mucus that is hyperconcentrated (respiratory-research.biomedcentral.com). Mucin packing/unfolding is disrupted due to lack of bicarbonate, meaning the process of mucin expansion upon secretion is incomplete (pmc.ncbi.nlm.nih.gov). This is a critical and unique biological process bridging cellular secretion to extracellular mucus gel formation.
Protein Folding and Degradation: On a cellular level, mutations like F508del cause defects in protein folding (GO:0006457) and result in CFTR being retained in the endoplasmic reticulum and targeted for ER-associated degradation (ERAD). The misfolded CFTR is ubiquitinated and destroyed by the proteasome (related to GO:0006515, protein quality control for misfolded proteins). Therefore, CF epithelia experience an augmented activity of the unfolded protein response (GO:0030968) and proteostasis mechanisms as they attempt to handle mutant CFTR. These processes are part of the molecular pathogenesis (Class II mutations cause a trafficking block (pmc.ncbi.nlm.nih.gov)).
Signal Transduction: CFTR dysfunction can perturb signaling pathways. For instance, CFTR has been implicated in regulating lung inflammation signaling. NF-κB signaling (GO:0051092) in CF cells may be heightened due to persistent infection and intrinsic stress, leading to increased cytokine production (IL-8, etc.). The lack of CFTR has been suggested to alter Toll-like receptor signaling in airway cells, possibly making them hyper-responsive to bacterial components. Additionally, cAMP-mediated signaling (GO:0019933) is central to CFTR regulation; in CF, even if cAMP is present, the effector (CFTR channel opening) is ineffective.
Immune and Inflammatory Response: CF lung disease involves chronic activation of innate immune response (GO:0045087). Neutrophil chemotaxis (GO:0030593) to the lungs is a prominent process – CF airways produce high levels of chemokines (like IL-8) recruiting neutrophils (respiratory-research.biomedcentral.com). The inflammatory response (GO:0006954) becomes dysregulated: neutrophils release excessive proteases and ROS, causing tissue damage. The normal resolution of inflammation is impaired, partly because neutrophils in CF undergo NETosis (releasing neutrophil extracellular traps) and die, spilling DNA and proteases that further clog airways. So processes like neutrophil degranulation (GO:0043312) and NET formation are upregulated. Oxidative stress processes are also in play: neutrophils and other cells generate reactive oxygen species (hydrogen peroxide, hypochlorous acid via myeloperoxidase) in excess, leading to oxidative damage to proteins and DNA in the lung.
Developmental Processes: CFTR is involved in certain developmental processes – notably development of the vas deferens. In CF males, the development of the Wolffian duct-derived structures (GO:0008584) is perturbed, leading to absent vas deferens (this is a developmental anomaly rather than a postnatal process). CFTR may also have roles in bone development and salt taste transduction, but those are less understood.
Metabolic Processes: Malabsorption from pancreatic insufficiency leads to altered nutrient metabolism. For instance, fat malabsorption causes deficiencies in fat-soluble vitamins (A, D, E, K) – affecting processes like vitamin K metabolic process (GO:0042373) and others, which manifests in coagulopathy or bone disease if not supplemented. CF-related diabetes involves the process of glucose homeostasis (GO:0042593) being disrupted due to insulin deficiency.

In summary, CF disrupts a broad network of biological processes: ion and fluid transport, mucociliary clearance, proteostasis, and immune responses are at the core of its pathophysiology. As Graeber & Mall (2023) note, understanding CF requires linking the molecular defect in CFTR to downstream processes like “mucus dysfunction, impaired host defenses, airway infection, and chronic inflammation” (pubmed.ncbi.nlm.nih.gov). Each of these processes corresponds to groups of GO terms that are highly relevant to CF and are prime targets for therapeutic intervention and research.

4. Key Cellular Components (Subcellular Localization)

The pathological processes of CF can be mapped to specific cellular and subcellular locations (corresponding to GO Cellular Component terms):

Apical Plasma Membrane (GO:0016324): This is where the CFTR protein normally resides and functions. In epithelial cells lining ducts and airways, CFTR is localized to the apical membrane – the surface facing the lumen. CFTR’s role here is to transport chloride and bicarbonate out of the cell. In CF, the apical membrane has either no CFTR or a non-functional CFTR, so it fails to secrete chloride into the lumen (pmc.ncbi.nlm.nih.gov). The epithelial sodium channel (ENaC) is also on the apical membrane; in CF, ENaC activity becomes unrestrained at this location (pmc.ncbi.nlm.nih.gov). The cystic fibrosis defect is fundamentally at the apical membrane domain of epithelial cells, and many downstream issues (like thick mucus) manifest just beyond this membrane at the cell surface.
Airway Surface Liquid (Extracellular Fluid Layer): Just above the apical membrane of airway epithelial cells lies the thin layer of periciliary fluid and mucus – collectively the airway surface liquid (ASL), which is part of the extracellular region (GO:0005576). This is not a membrane-bound compartment but is crucial in CF. Normally ~7–10 μm thick, this liquid layer keeps mucus hydrated and allows cilia to beat. In CF, the ASL is depleted and hyperconcentrated (pmc.ncbi.nlm.nih.gov), leading to adherent mucus. The mucus itself (composed of secreted mucins, DNA, cell debris) accumulates in the airway lumen forming plaques and plugs (news.unchealthcare.org). These obstruct the bronchial lumen (anatomically) and functionally represent a pathological extracellular component in CF lungs. Mucus plugs often localize initially in small airways (bronchioles), which correspond to tiny luminal spaces that are easily occluded.
Secretory Granules (Golgi and Exocytic Pathway): Within goblet cells and submucosal gland cells, mucin granules are stored in secretory vesicles prior to exocytosis (GO:0030141, secretory granule lumen). In CF, the content of these granules (mucins) may be secreted normally, but due to acidic/low-volume extracellular environment, the mucins cannot expand properly and remain aggregated (pmc.ncbi.nlm.nih.gov). Additionally, the production of these granules can be upregulated due to chronic irritation. The CFTR protein itself during its biogenesis travels through the endoplasmic reticulum (GO:0005783) and Golgi apparatus (GO:0005794) in epithelial cells. For Class II mutations like F508del, CFTR is misfolded in the ER and targeted for degradation rather than reaching the Golgi. The proteasome (GO:0000502) in the cytosol is thus an important location in CF cells – it degrades mutant CFTR that fail quality control. CFTR that does fold correctly gets processed in the Golgi and delivered to the apical membrane via vesicles (GO:0030133, transport vesicle), but in CF patients with trafficking mutants, this delivery is inefficient or absent (pmc.ncbi.nlm.nih.gov).
Cell Surface and Tight Junctions: CFTR also interacts with other proteins at the cell surface, including components of tight junctions (GO:0005923). There is evidence CFTR may modulate tight junction permeability and that in CF, epithelial tight junctions could be abnormally tight or leaky influencing ion movement paracellularly. However, this is a minor aspect; the main issue at the cell surface is the absence of functional CFTR channel pores.
Lysosomes and Autophagosomes: Some studies suggest that CFTR dysfunction (particularly F508del) can lead to abnormalities in autophagy (GO:0006914) and lysosomal function in cells. F508del CFTR misfolding has been linked to accumulation of protein aggregates that may stress the cell’s clearing systems, and dysfunctional autophagy has been observed in CF cell models, contributing to exaggerated inflammation. For instance, beyond the proteasomal degradation, some mutant CFTR may be routed to lysosomes (GO:0005764) for destruction. Restoring autophagy in CF cells (e.g., by some small molecules) has been shown to improve CFTR trafficking in experimental systems. Thus, cytosolic compartments like the aggresome and autophagosome could be considered relevant in CF cellular pathology, although these are more on the research frontier.
Extracellular Space (Airway lumen and sputum): The extracellular space in CF airways is essentially the mucus layer and bronchoalveolar lining fluid. This space in CF becomes enriched with DNA from neutrophils (due to NETs and cell lysis), actin, filamentous polymers, and it is where bacteria reside as biofilms. DNA and filamentous actin significantly increase sputum viscosity. Clinically, the DNA in this extracellular space is targeted by the drug dornase alfa (recombinant DNase) to improve mucus rheology. Also, extracellular DNA and proteins (like neutrophil elastase) in CF sputum bind to protease inhibitors and reduce their effectiveness (respiratory-research.biomedcentral.com), essentially making the extracellular milieu highly proteolytic and pro-inflammatory.
Specific organ structures: In the pancreas, thick secretions accumulate within the pancreatic ducts (small interlobular ducts) – effectively an extracellular (duct lumen) issue, leading to intraductal precipitates and eventual fibrotic replacement of exocrine tissue. In the sweat gland ducts, the cellular component of interest is the ductal lumen where chloride reabsorption fails – high salt remains in the duct lumen and is excreted. In the vas deferens, the lumen either never forms or is obliterated by secretions in utero; anatomically, the vas deferens is usually absent or fibrosed in CF (so technically the cellular component is lost entirely in that case).

In summary, CF pathophysiology can be visualized at the cellular level as a defect at the apical membrane of epithelial cells leading to downstream changes in the extracellular environment (thick mucus in lumens). Key subcellular sites include the ER (where mutant CFTR misfolds), Golgi (trafficking), proteasomes (degradation of CFTR), and the airway surface liquid layer (which becomes dehydrated). By considering these cellular components, researchers design targeted interventions – for example, CFTR modulators aim to get CFTR to the apical membrane, osmolyte therapies (hypertonic saline, Mannitol) aim to rehydrate the airway surface liquid, and DNase targets the extracellular DNA in mucus. Each of these therapies corresponds to a cellular/extracellular compartment involved in CF disease.

5. Disease Progression

Initiation and Early Pathogenesis: Cystic fibrosis begins in utero with the expression of mutant CFTR; by birth, certain manifestations can appear (e.g. meconium ileus in 15–20% of newborns with CF). The disease process is ongoing even in asymptomatic newborns. With universal newborn screening in many countries, most infants are now diagnosed within the first month of life (often before signs appear) (pmc.ncbi.nlm.nih.gov). However, studies of infants diagnosed via screening have shown that lung disease is present early. For instance, bronchoalveolar lavage studies in young infants (ages ~3 months) have found neutrophilic inflammation and elevated neutrophil elastase even in those without prior infections (respiratory-research.biomedcentral.com). Sly et al. (2009) observed that some infants with CF have detectable airway changes (air trapping, inflammation) on CT scans at a few months old (respiratory-research.biomedcentral.com). These findings indicate that CF lung disease often starts in the first months of life with a sterile neutrophilic inflammation (possibly due to an inherently abnormal airway environment) (respiratory-research.biomedcentral.com). Thus, the initial trigger of disease is the intrinsic ion transport defect leading to mucus stasis, which can provoke an inflammatory response even in the absence of infection (so-called “primary inflammation” of CF airways (www.nature.com)).

Early childhood: As infants grow into toddlers, they begin to experience respiratory symptoms. By age 1–2, many CF children develop a chronic cough. Early airway colonization occurs – Staphylococcus aureus is often found in CF infants’ airways, and other microbes follow. With each viral cold or bacterial infection, a pulmonary exacerbation can occur (worsening cough, increased sputum, difficulty breathing). These acute events accelerate damage. The pancreatic insufficiency, if present, manifests in infancy as malabsorption: frequent, oily stools, failure to thrive, and abdominal distension. With pancreatic enzyme replacement therapy, nutrition can be supported, but if untreated, malnutrition and vitamin deficiencies would progress. The hepatic manifestations are usually silent in infancy (liver disease tends to occur later, though some infants might have elevated liver enzymes). Sinus disease may begin early but is harder to detect (chronic nasal congestion). During early childhood, if aggressive therapy is given (airway clearance techniques, antibiotics, enzymes), lung function can be maintained near normal. However, airway remodeling may already be underway: by a few years old, some children show bronchiectasis on CT scans (respiratory-research.biomedcentral.com). This indicates that the window for preventing permanent lung damage is very early – reinforcing why early intervention is crucial.

Late childhood to adolescence: By school age (5–10 years), most CF patients historically acquired persistent colonization with Pseudomonas aeruginosa, a milestone that often marks an acceleration in lung decline. Chronic Pseudomonas infection is associated with biofilm formation in airways and a more intense neutrophilic inflammation. Clinically, children might start needing daily respiratory therapies (chest physiotherapy, nebulized antibiotics, mucolytics). Lung function (FEV₁) may start to decline measurably in late childhood, especially if chronic infections are established. Exacerbations (episodes of increased cough, sputum, and lung function drop) tend to become more frequent with age. Each exacerbation can cause a step-wise loss in lung function that might not fully recover post-treatment. By the teen years, many CF patients have moderate lung disease with bronchiectasis evident on imaging and FEV₁ trending down. Adolescence also brings CF-related diabetes onset in some patients (as pancreatic islets suffer damage); glucose intolerance often emerges by late teens or early adulthood in CF patients, especially those with pancreatic insufficiency and longer survival. Puberty can be delayed in CF due to chronic illness and malnutrition, and growth spurts might be blunted – many teens with CF have lower BMI percentiles despite enzyme supplementation, due to the high caloric needs and chronic inflammation.

Adulthood and Late-stage disease: Historically, many CF patients did not survive to adulthood, but with modern care, over 50% of CF individuals in developed countries are adults (pmc.ncbi.nlm.nih.gov). The adult phase of CF is often dominated by progressive lung decline. By early adulthood (20s to 30s), patients without highly effective therapy often have significant bronchiectasis in all lobes, chronic hypoxemia, and frequent exacerbations requiring intravenous antibiotics (tune-ups). Many develop complications like hemoptysis (coughing up blood) due to inflamed bronchial arteries in dilated airways, or pneumothorax (lung collapse) due to ruptured cystic airspaces. The endocrine manifestations like CF-related diabetes become more common (~40–50% of adults over 30 with CF have CFRD). Osteoporosis may occur prematurely due to malabsorption and steroid use for inflammation. In a subset, liver cirrhosis progresses to cause portal hypertension, varices, and risk of liver failure in late teens or adulthood. Male infertility is typically an issue when adult CF patients consider having children – since nearly all males have azoospermia, many pursue assisted reproductive techniques with sperm aspiration if they wish to father children. Psychosocially, adults with CF deal with managing a chronic illness – frequent hospitalizations for lung infections, and possibly lung transplant evaluation when lung function falls below ~30% predicted. Terminal stage CF lung disease is characterized by respiratory failure, often in the 3rd or 4th decade of life in classic cases: patients become dependent on oxygen and have hypercapnia due to inadequate ventilation from destroyed airways. Without intervention, this results in death from respiratory failure or cor pulmonale. Lung transplantation is a life-extending option at this stage, and CF is one of the most common indications for lung transplant in young adults.

Distinct Phases: One can describe CF progression in clinical stages: an early stage (often asymptomatic newborn identified by screening), a mild symptomatic stage in early childhood (where interventions can maintain near-normal lung function), a moderate stage in adolescence (chronic infection is established, lung function decline begins), and a severe stage in adulthood (advanced lung disease with complications and consideration of transplant). Another perspective is organ-specific staging: for lungs, clinicians sometimes use lung function (FEV₁ % predicted) to stage disease (mild if >70%, moderate 40–69%, severe <40%). For example, a child might be in a “mild lung disease stage” and later progress to “severe lung disease stage.” CF progression is also sometimes discussed as pre- and post-CFTR modulator eras, which we address below.

Impact of New Therapies: It is critical to note that recent developments (2019–2024) have dramatically altered the typical disease trajectory for many patients. The advent of CFTR modulator therapies, especially the triple-combination modulator (elexacaftor/tezacaftor/ivacaftor) approved in 2019, has changed the progression for those eligible (roughly 85–90% of CF patients with at least one F508del allele) (www.nature.com). These modulators partially restore CFTR function at the cellular level, thereby improving ion transport and hydrating secretions. Clinically, patients on highly effective modulators have shown rapid improvements: for example, a mean increase of 10-14 percentage points in FEV₁, weight gain, reduced sweat chloride, and ~60% fewer pulmonary exacerbations in trials (www.nature.com) (www.nature.com). Real-world data in 2021–2023 confirm fewer hospitalizations and dramatic improvements in quality of life for modulator-treated patients. As a result, many patients who, prior to modulators, would be in a downward spiral of lung function in their 20s are now experiencing stabilization or even improvement of lung function. Some adults with advanced disease have been able to avoid or delay lung transplant due to modulator therapy. The long-term disease progression on modulators is still being studied, but current evidence shows slower FEV₁ decline and possible amelioration of some organ damage if started early. For instance, children starting modulators before significant lung damage may potentially never develop severe bronchiectasis. It is conceivable that CF could become a much more benign disease for most patients, with survival extending further. Indeed, “the introduction of a highly effective triple combination CFTR modulator therapy that has unprecedented clinical benefits in ~90% of eligible people with CF has fundamentally changed the therapeutic landscape and improved prognosis” (www.nature.com). However, challenges remain: ~10% of CF patients (those with rare CFTR mutations not responsive to current modulators or with end-stage complications) still face a high burden of disease and need alternative therapies (www.nature.com). Additionally, any established lung damage (fibrosis, bronchiectasis) cannot be fully reversed by modulators, so early intervention is key.

Life Expectancy Trends: As a measure of disease progression at the population level, life expectancy in CF has steadily improved over decades. In 1938 when CF was first described, it was invariably fatal in infancy or early childhood (pmc.ncbi.nlm.nih.gov). By the 1980s, median survival was into the teens. By the 2000s, median predicted survival was late 30s. Currently, in the US and many developed countries, median survival is estimated to be around 44–50 years (pmc.ncbi.nlm.nih.gov), and children born today with CF are expected to live into mid-adulthood and beyond, especially if they have access to modulators. For example, the Cystic Fibrosis Foundation patient registry (USA) reported a median life expectancy of ~50 years for those born in recent years, a number that will likely be revised upward as the full impact of modulator therapy is realized (pmc.ncbi.nlm.nih.gov). It’s worth noting that progression and outcomes still vary individually: factors like genotype, adherence to therapy, access to specialized CF care, and social determinants can accelerate or slow disease progression (www.nature.com) (www.nature.com). For instance, individuals with residual CFTR function mutations (milder genotypes) might have a slower progression and later diagnosis (some not diagnosed until adulthood if they primarily have pancreatic-sufficient CF or atypical CF symptoms). On the other hand, patients with classic severe mutations who acquire aggressive infections early can still have a rapid decline if not effectively treated.

In summary, CF disease progression traditionally followed a relentless decline, especially in lung function, over 2–4 decades, with well-defined complications at various stages (infections in childhood, complications like CFRD and liver disease in adolescence, respiratory failure in adulthood). Now, with modern treatment, the trajectory is improving – early-life interventions (newborn screening, prophylactic care) aim to delay or prevent the establishment of chronic lung disease, and CFTR modulators aim to correct the basic defect and alter the natural history. The goal is that future CF patients might not experience the classic severe “late stage” at all, effectively transforming CF into a chronic manageable condition with normal or near-normal lifespan (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Ongoing research in gene therapy and gene editing holds the hope of an eventual cure that could halt disease progression at the causal level for all patients (pubmed.ncbi.nlm.nih.gov).

6. Phenotypic Manifestations and Clinical Correlation

Cystic fibrosis has a well-defined clinical phenotype with multisystem involvement. Many of the hallmark clinical features of CF are direct consequences of the underlying molecular and cellular defects described above. Key phenotypic manifestations include:

Chronic Pulmonary Disease: Virtually all CF patients develop progressive lung disease. Clinically, this presents as chronic cough (often productive of thick sputum), wheezing, and recurrent respiratory infections (bronchitis or pneumonia). Over time, these recurrent infections lead to chronic colonization of the lungs with bacteria (e.g. Pseudomonas aeruginosa, Burkholderia cepacia complex, Staphylococcus aureus), and patients experience intermittent pulmonary exacerbations characterized by increased cough, sputum, shortness of breath, and often fevers. One distinctive manifestation is bronchiectasis – pathological dilation of bronchi – which on high-resolution CT scans appears in most CF patients by adolescence. Bronchiectasis is responsible for persistent moist crackles on lung exam and contributes to further mucus pooling. Digital clubbing (enlargement of fingertips) is commonly observed in CF (HP:0001217), believed to result from chronic hypoxia and inflammation in the lungs. As lung disease advances, patients can develop hypoxemia (low blood oxygen) requiring supplemental oxygen, and signs of respiratory failure or cor pulmonale (right heart failure due to lung disease) in late stages. The connection to pathophysiology: these respiratory phenotypes arise because CFTR dysfunction led to thick mucus that causes infection/inflammation, which in turn yields the symptoms of cough, sputum, and lung damage. Importantly, muco-obstructive exacerbations are a key phenotype; they often require intravenous antibiotics and intensified therapy. The severity of lung involvement is often quantified by FEV₁ (forced expiratory volume in 1s) – a phenotype measurable by spirometry. CF patients typically show obstructive lung physiology on PFTs, with reduced FEV₁ that declines with age (absent intervention). For example, without modulators, the median FEV₁ in CF might decline by ~1-3% predicted per year in young adulthood. With modulators, this decline is attenuated. Clinical scoring systems like the Bhalla score on CT or the Shwachman-Kulczycki score historically summarized the pulmonary phenotype severity.
Exocrine Pancreatic Insufficiency: ~85% of CF patients have pancreatic insufficiency (HP:0001738) from infancy or early childhood. This manifests as steatorrhea (bulky, greasy, foul-smelling stools due to fat malabsorption), failure to thrive or poor weight gain in infancy (HP:0001508), protuberant abdomen, and deficiency of fat-soluble vitamins (leading to e.g. vitamin K deficiency coagulopathy or vitamin D deficiency rickets if untreated). Parents may notice infants with CF have frequent, oily diarrhea and voracious appetites but poor growth. Pancreatic insufficiency is due to the blockage and autolysis of pancreatic tissue in utero/early life, as described in pathophysiology. It is effectively managed by pancreatic enzyme replacement capsules and high-calorie diets, which has greatly improved nutritional phenotypes. Still, even with enzyme supplements, many CF patients struggle to maintain normal body mass; the phenotype of malnutrition (low BMI) correlates with worse lung outcomes. A small subset (~15%) of CF patients have milder CFTR mutations allowing some pancreatic function – they are pancreatic-sufficient and may have near-normal digestion (sometimes not diagnosed until later in life due to lack of malabsorption symptoms). However, even pancreatic-sufficient CF patients can develop pancreatitis as an episodic phenotype (recurrent acute pancreatitis occurs in some CFTR mutations, especially those associated with CFTR-related disorders).
Meconium Ileus and Gastrointestinal Obstruction: In neonates, meconium ileus (HP:0005109) is a classic CF phenotype – about 15% of CF newborns present within the first 48 hours of life with intestinal obstruction by abnormally thick meconium in the ileum (pmc.ncbi.nlm.nih.gov). This often requires contrast enema or even surgery (it can lead to perforation if untreated). Its presence at birth is highly suggestive of CF. Later in life, older children and adults can experience a similar blockage called Distal Intestinal Obstruction Syndrome (DIOS), where thick stool causes obstruction at the ileocecal junction. Symptoms include abdominal pain, distension, and absence of stool passage. CF patients also have a higher incidence of intussusception in childhood (telescoping of the bowel) likely related to thick stool acting as a lead point. GERD (acid reflux) is more common in CF, possibly due to increased abdominal pressure from coughing and anatomic changes; reflux can in turn exacerbate lung issues by microaspiration. Over years, some CF patients develop gastrointestinal manifestations like CF-related liver disease – often first noted as hepatomegaly or abnormal liver enzymes in childhood. About 5-7% develop cirrhosis with portal hypertension (esophageal varices, splenomegaly) typically in adolescence. This “CF liver disease” phenotype can lead to complications requiring interventions (endoscopy for varices, even liver transplant in ~1-2% of patients). Gallbladder involvement (like gallstones or microgallbladder) is also noted as a phenotype in some CF adults.
Sweat Abnormalities: CF patients have salty sweat, which is usually noticed by parents (“kissing the baby tastes salty”). The sweat test is a formal measurement of this phenotype: nearly all individuals with classic CF have sweat chloride >60 mM on a pilocarpine iontophoresis test (normal is <30) (pmc.ncbi.nlm.nih.gov). This is not just diagnostic; it can have clinical consequences – CF infants can develop hyponatremic dehydration in hot weather if salt intake isn’t increased, a phenomenon first described in the 1940s (pmc.ncbi.nlm.nih.gov). Some CF patients (especially those with milder mutations) have intermediate sweat chloride levels (30–60 mM) and may be diagnosed after newborn screening or later in life with atypical CF; sweat test remains a key phenotype bridging the molecular defect (CFTR in sweat ducts) to a clinical sign.
ENT Manifestations: Chronic sinusitis is present in most CF patients (HP:0000246 for chronic sinusitis). They often have nasal congestion, sinus headaches, and about 10-20% develop nasal polyps (HP:0100574) at a young age that may require surgical removal (pmc.ncbi.nlm.nih.gov). The presence of nasal polyps in a child is a clinical red flag for CF. Middle ear infections (otitis media) are also more frequent in CF children.
Male Infertility: More than 95% of males with CF are infertile due to azoospermia (absence of sperm in ejaculate) caused by the congenital absence of the vas deferens (HP:0000037). This phenotype is often how CFTR mutations are discovered in men with otherwise mild or no lung disease (CBAVD can be an isolated manifestation of CFTR-related disorder). In CF patients, this is typically known from adolescence. Females with CF have normal fertility potential, though reduced if ill; however, in the era of better health, many women with CF conceive successfully (with higher-risk pregnancies due to cardiorespiratory strain).
CF-Related Diabetes (CFRD): By adulthood ~30-50% of CF patients develop a unique form of diabetes (HP:0004904) caused by insulin insufficiency from pancreatic damage, often compounded by peripheral insulin resistance from infection and steroid use. CFRD clinically resembles type1 & type2 hybrid – patients may have polyuria, polydipsia, weight loss, or just declining lung function as a clue. This phenotype typically appears in late adolescence or adulthood and requires insulin therapy.
Musculoskeletal: Many CF patients, especially older, have low bone density (osteopenia/osteoporosis) due to malabsorption of vitamin D and chronic inflammation. This can lead to fractures or kyphosis (spinal curvature) in advanced disease. Also, muscle mass may be low due to catabolic illness. Clubbing of fingers (a musculoskeletal change of the nail beds) has been mentioned and is very common in CF lung disease (often evident by childhood).
Other systemic manifestations: Some CF patients develop allergic bronchopulmonary aspergillosis (ABPA) – an allergic immune response to Aspergillus fungus in the lungs, causing wheezing and pulmonary infiltrates; this is a complicating phenotype in ~10% of CF individuals. Another complication is amyloidosis (rarely) from chronic inflammation. Depression and anxiety are noted at higher rates in CF populations as comorbid mental health phenotypes due to the stress of chronic disease.

To succinctly connect to mechanisms: “CF is characterized by pulmonary manifestations (chronic obstructive lung disease with infection and bronchiectasis), sinusitis, malabsorption due to pancreatic exocrine insufficiency, liver disease (biliary cirrhosis), CF-related diabetes, and male infertility” (pmc.ncbi.nlm.nih.gov) (PMID: 33526571). Each of these clinical phenotypes is a direct consequence of CFTR dysfunction in the respective organ: lung disease from mucus obstruction and infection, digestive malabsorption from pancreatic blockage, etc. The severity of phenotypes can vary: for example, patients with “mild” CFTR mutations might present with only infertility and mild lung issues in late adulthood (atypical CF), whereas classic CF with no functional CFTR causes the full spectrum early in life.

Relevant Statistics: Before modulator therapies, lung disease caused 80-95% of CF mortality. The median age of survival in CF has improved to ~44 years in recent reports (pmc.ncbi.nlm.nih.gov), and it is projected to continue rising with widespread modulator use. Over 90% of CF patients have at least one copy of F508del mutation, which explains why triple modulator therapy can benefit about 90% of the CF population (www.nature.com). The introduction of these modulators has led to a 63% reduction in annualized pulmonary exacerbation rate in clinical trials for elexacaftor/tezacaftor/ivacaftor (www.nature.com) and significant improvements in BMI and quality of life scores. Newborn screening (NBS) has led to early diagnosis (median age of diagnosis in screened regions is <1 month). Thanks to NBS and proactive care, many CF children now have normal growth and only mild lung function decrement by age 6–10 (e.g., an Australian study showed mean FEV₁ ~100% at age 7 in screened cohorts) . However, disparities exist: CF patients of minority backgrounds may have rarer CFTR mutations not detectable by standard screens and may be diagnosed late (www.nature.com), and access to modulators is uneven globally. These factors can influence phenotype expression and outcomes.

In conclusion, the phenotypic spectrum of cystic fibrosis spans respiratory, gastrointestinal, endocrine, and reproductive systems, with chronic progressive lung disease being the most prominent feature linking to mortality. The classic clinical picture includes a child with chronic cough and lung infections, malabsorption with poor growth, and salty-tasting skin, and later complications like diabetes and infertility. This clinical phenotype is directly traceable to the underlying pathophysiology at the molecular level, and ongoing advancements in therapy are dramatically improving these manifestations. As one 2023 review noted, CF has transformed “from a fatal disease to a treatable one” due to therapies addressing the root cause (pubmed.ncbi.nlm.nih.gov), giving hope that future phenotypes will be far milder than the historical description. Each clinical sign and complication of CF, when mapped back, underscores the importance of CFTR in diverse organs and the wide-ranging impact of its dysfunction on human physiology.

Evidence and References: (Key sources supporting the above information include primary literature and authoritative reviews. Citations are provided in text for specific claims: e.g., Dickinson & Collaco 2021, PMID: 33526571 for multi-organ manifestations (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov); Mall et al. 2024, PMID: 34385510 for CFTR function and lung disease emphasis (www.nature.com); Grasemann & Ratjen 2023, PMID: 37913507 for updated pathophysiology; Graeber & Mall 2023, PMID: 37699417 for advances since 2018 (pubmed.ncbi.nlm.nih.gov); Boucher 2019, PMID: 31067370 for muco-obstructive pathology (news.unchealthcare.org); Hobbs et al. 2013, PMID: 23878362 for ENaC hyperactivity (pmc.ncbi.nlm.nih.gov); Gustafsson et al. 2012, PMID: 22711878 for bicarbonate’s role in mucin release (pmc.ncbi.nlm.nih.gov); and a 2017 study by Gramegna et al., PMID: 29258516 highlighting neutrophil elastase-driven inflammation in CF lungs (respiratory-research.biomedcentral.com) (respiratory-research.biomedcentral.com).)

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