Idiopathic Interstitial Pneumonia

Respiratory Disease MONDO:0002429 Pathograph 13 Show in embeddings browser Respiratory Disease Lung Disease

A classification family of diffuse parenchymal lung diseases of unknown cause, defined by the ATS/ERS international multidisciplinary classification. Injury to the alveolar-interstitial compartment in the absence of an identified cause is resolved into one of a small number of stereotyped histopathologic patterns — usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, respiratory bronchiolitis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia — and it is the pattern, reached by multidisciplinary discussion rather than histology alone, that assigns the clinicopathologic entity, its prognosis, and its treatment. This entry models what the entities share (the injury-response pivot and the progressive-fibrosis outcome common to their fibrosing members) and delegates entity-specific mechanism to the individual subtype entries; the full pathograph of idiopathic pulmonary fibrosis is curated separately in `Idiopathic_Pulmonary_Fibrosis.yaml` and is deliberately not duplicated here.

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8
Pathophys.
10
Phenotypes
2
Gaps
13
Pathograph
6
Medical Actions
8
Subtypes
1
Deep Research
◆

Subtypes

8
Idiopathic Pulmonary Fibrosis (UIP pattern) MONDO:0800504
Chronic fibrosing IIP defined by the usual interstitial pneumonia (UIP) pattern — patchy subpleural fibrosis with fibroblast foci and honeycombing — and the worst prognosis of the group. Curated in full as its own dismech entry (`Idiopathic_Pulmonary_Fibrosis.yaml`); it is referenced here rather than duplicated.
Show evidence (1 reference)
PMID:39761948 SUPPORT Human Clinical
"Prognosis is generally more favorable for iNSIP than for idiopathic pulmonary fibrosis, with many studies reporting a 5-year survival rate above 70%."
Establishes that IPF is the worse-prognosis member of the family relative to its nearest chronic fibrosing sibling, which is why the two are kept as separate entities rather than lumped.
Idiopathic Nonspecific Interstitial Pneumonia MONDO:0019622
Chronic fibrosing IIP defined by the temporally uniform NSIP pattern (cellular or fibrotic), diagnosed only once connective tissue disease, hypersensitivity pneumonitis, drug toxicity, and other secondary causes are excluded. Prognosis is better than IPF, and a subset nonetheless behaves as progressive pulmonary fibrosis.
Show evidence (2 references)
PMID:39761948 SUPPORT Human Clinical
"It is identified histologically by the nonspecific interstitial pneumonia pattern. A diagnosis of iNSIP is feasible once secondary causes or underlying diseases are ruled out."
States both defining features of the entity — the histologic pattern and the exclusion of secondary causes that makes it idiopathic.
PMID:24032382 SUPPORT Other
"Nonspecific interstitial pneumonia is now better defined."
The 2013 ATS/ERS update records that iNSIP was consolidated as a defined entity rather than a provisional diagnosis.
Cryptogenic Organizing Pneumonia MONDO:0015264
approximately 5% to 10% of IIPs
Acute/subacute IIP defined by the organizing pneumonia pattern — polypoid intra-alveolar granulation tissue (Masson bodies) with preserved lung architecture. Formerly called idiopathic bronchiolitis obliterans organizing pneumonia (BOOP). Characteristically steroid-responsive, which sets it apart from the chronic fibrosing entities.
Show evidence (1 reference)
PMID:40078018 SUPPORT Human Clinical
"COP accounts for approximately 5% to 10% of IIPs, with the average age of diagnosis ranging from 50 to 60 years."
Source for the subtype frequency within the IIP family and the typical age at diagnosis.
Acute Interstitial Pneumonia (Hamman-Rich syndrome) MONDO:0019203
Fulminant IIP defined by diffuse alveolar damage occurring without an identified cause. Clinically indistinguishable from ARDS, so the diagnosis requires histologic DAD plus exclusion of known ARDS triggers.
Show evidence (1 reference)
PMID:23001802 SUPPORT Other
"The main differences between AIP and ARDS are that AIP requires a histologic diagnosis of DAD and exclusion of known etiologies."
States the two criteria that make AIP an idiopathic interstitial pneumonia rather than ARDS.
Respiratory Bronchiolitis-Interstitial Lung Disease MONDO:0019204
Smoking-related IIP in which pigmented macrophages accumulate in and around respiratory bronchioles. Distinguished from the other entities by having an identified and removable driver — tobacco smoke — so smoking cessation is first-line therapy.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Respiratory bronchiolitis-associated ILD mainly affects smokers, showing ground-glass opacities on chest computed tomography (CT) scans and pigmented macrophages in the bronchoalveolar lavage fluid."
Establishes the smoking association and the macrophage-centred lesion that define this entity.
Desquamative Interstitial Pneumonia MONDO:0009887
The second smoking-related IIP, in which the same pigmented-macrophage accumulation becomes diffuse and fills the alveolar spaces rather than remaining bronchiolocentric, producing restrictive physiology and widespread ground-glass opacity.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Desquamative interstitial pneumonia, also related to smoking, is characterized by exertional dyspnea, dry cough, restrictive lung function, and ground-glass opacities on high-resolution CT."
Establishes the smoking association and the clinical-physiologic profile that distinguish DIP from its bronchiolocentric sibling RB-ILD.
Lymphoid Interstitial Pneumonia MONDO:0009537
Rare IIP in which diffuse lymphocytic infiltration expands the interstitium. Genuinely idiopathic LIP is uncommon; most cases are associated with an autoimmune disease (notably Sjogren syndrome) or an infection, which must be sought before the idiopathic label is applied.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Lymphoid interstitial pneumonia involves lymphocytic proliferation and is associated with autoimmune diseases or infections, treated with corticosteroids."
States the lymphoproliferative lesion, the secondary associations that must be excluded, and the treatment that follows from the lesion.
Idiopathic Pleuroparenchymal Fibroelastosis MONDO:0044633
Rare IIP added to the family in the 2013 ATS/ERS update, characterized by upper-lobe pleural and subpleural fibroelastosis in predominantly non-smokers. Included here because the 2013 classification explicitly widened the family beyond the six major entities.
Show evidence (2 references)
PMID:24032382 SUPPORT Other
"A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced."
The 2013 ATS/ERS update is the document that admits IPPFE to the IIP classification as a rare entity.
PMID:40081337 SUPPORT Human Clinical
"Idiopathic pleuroparenchymal fibroelastosis results in fibrosis in the upper lobes, primarily in nonsmokers, and is diagnosed through clinical and imaging findings, with no effective treatment to improve survival."
Gives the distribution, the smoking profile, and the absence of effective therapy that differentiate IPPFE from the other fibrosing entities.
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Discussions and Knowledge Gaps

2
A substantial minority of patients cannot be assigned to any of the defined IIP entities because their lungs show mixed patterns of injury. Are these genuinely distinct disease processes awaiting definition, or does the pattern-based classification impose discrete boundaries on what is really a continuum of injury responses?
KNOWLEDGE GAP OPEN disc_iip_unclassifiable_mixed_patterns
Attached to
pathophysiology#Resolution of injury into a stereotyped histopathologic pattern
The entire classification rests on the premise that the injured lung adopts one of a small number of discrete patterns. The 2013 ATS/ERS update records that a substantial percentage of patients defeat that premise, usually because more than one pattern is present in the same lung. This matters for a knowledge base: if the mixed cases are a continuum rather than a set of undiscovered entities, then the pattern nodes modelled here are convenient landmarks on a spectrum rather than mutually exclusive states, and a curated entry should not imply that a patient occupies exactly one of them.
Show evidence (1 reference)
PMID:24032382 SUPPORT Other
"A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury."
The classification's own authors record the limitation this gap is about.
Should an idiopathic interstitial pneumonia be classified by its histopathologic pattern or by its observed disease behaviour? The two axes disagree for the entities whose clinical course is heterogeneous, and antifibrotic therapy is now indicated on the behaviour axis while the entity name still comes from the pattern axis.
KNOWLEDGE GAP OPEN disc_iip_behaviour_vs_pattern_classification
Attached to
pathophysiology#Progressive pulmonary fibrosis pathophysiology#Resolution of injury into a stereotyped histopathologic pattern
The 2013 update proposed a behaviour-based classification precisely for the patients and entities the pattern-based scheme handles badly, and the 2022 guideline then defined progressive pulmonary fibrosis as a behaviour that cuts across entities and carries its own treatment recommendation. The result is a family whose members are named on one axis and treated on another. Which axis a mechanism knowledge base should treat as primary is unresolved, and the answer determines whether progressive pulmonary fibrosis is modelled as a shared outcome node (as here) or as a separate cross-cutting entity.
Show evidence (2 references)
PMID:24032382 SUPPORT Other
"A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course."
The behaviour-based alternative is proposed in the classification statement itself, which is what makes this a live tension rather than a settled question.
PMID:24032382 SUPPORT Other
"The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous."
Names the heterogeneity within single entities that makes the pattern label an incomplete predictor of course.
⚙

Pathophysiology

8
Injury to the alveolar-interstitial compartment of unknown cause
The shared initiating step of the family. Injury reaches the alveolar epithelium and the surrounding interstitium, and the search for a cause — connective tissue disease, inhaled antigen, drug, infection, occupational exposure — returns nothing. What makes an interstitial pneumonia idiopathic is therefore not a distinct kind of injury but the exhaustion of the differential, which is why every entity in this family is defined partly by exclusion.
alveolar type II pneumocyte CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alveolar type II pneumocyte, annotated with pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology.
wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↕ DYSREGULATED
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology. pulmonary alveolus UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary alveolus, annotated with alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Resolution of injury into a stereotyped histopathologic pattern
Show evidence (2 references)
PMID:41513514 SUPPORT Human Clinical
"Organizing pneumonia (OP) is a nonspecific lung parenchymal response to any form of injury, with its idiopathic variant coined as cryptogenic organizing pneumonia (COP)."
Directly states the logic this node encodes for one member of the family — the lesion is a stereotyped, cause-agnostic parenchymal response to injury, and the idiopathic entity is what remains once a cause cannot be found. Recorded as PARTIAL because the source argues it for organizing pneumonia rather than for the whole IIP family.
PMID:40967604 SUPPORT Human Clinical
"Diagnostic evaluation relies on excluding secondary causes of organizing pneumonia and includes a thorough history including medications, exposures, and signs or symptoms of underlying rheumatologic disease."
Documents the diagnosis-by-exclusion step this node asserts, naming the specific alternative causes that must be ruled out before an interstitial pneumonia is called idiopathic.
Resolution of injury into a stereotyped histopathologic pattern
The pivot of the whole family, and the reason it is a classification rather than a single disease. The injured lung has only a small repertoire of histopathologic responses — usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, respiratory bronchiolitis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia — and which one it adopts, not the (absent) cause, assigns the clinicopathologic entity together with its natural history and its treatment. Since 2002 that assignment has been made by multidisciplinary discussion integrating clinical, radiologic, and pathologic data rather than by histology alone.
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Organizing pneumonia pattern with intra-alveolar granulation tissue
Diffuse alveolar damage
Bronchiolocentric pigmented macrophage accumulation
Lymphocytic expansion of the interstitium
Myofibroblast activation in the fibrosing entities The chronic fibrosing arm of the classification (UIP in IPF, and the fibrotic NSIP pattern) enters the fibrotic response directly rather than through an intervening acute or inflammatory lesion.
Show evidence (2 references)
PMID:24032382 SUPPORT Other
"In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical "gold standard" of histologic..."
Both halves of this node come from one sentence pair — that the family resolves into a fixed, small set of defined entities, and that the entity is assigned by multidisciplinary discussion rather than by histology alone.
PMID:39761948 SUPPORT Human Clinical
"It is identified histologically by the nonspecific interstitial pneumonia pattern."
A worked instance of the pattern-assigns-entity rule this node states, for the idiopathic NSIP member of the family.
Organizing pneumonia pattern with intra-alveolar granulation tissue
The lesion of cryptogenic organizing pneumonia. Polypoid plugs of fibroblastic granulation tissue (Masson bodies) fill alveolar spaces, alveolar ducts, and distal bronchioles while the underlying alveolar architecture is preserved. Because the scaffold survives, the lesion is reversible — this is the mechanistic basis for the steroid responsiveness that separates COP from the chronic fibrosing entities.
wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↑ INCREASED
pulmonary alveolus UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary alveolus, annotated with alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:41513514 SUPPORT Human Clinical
"The hallmark pathological features are presence of polypoid granulation tissue, or Masson bodies, in the alveolar spaces, with lung architecture preserved in most patients with good clinical outcomes poststeroid treatment."
Supplies the lesion, its location, the preservation of architecture, and the good steroid-treated outcome that follows from it.
Diffuse alveolar damage
The lesion of acute interstitial pneumonia. Alveolar-capillary barrier disruption with hyaline membrane formation produces fulminant respiratory failure clinically indistinguishable from ARDS; survivors pass into an organizing phase that can leave fibrosis. AIP is the idiopathic form, so its diagnosis requires DAD on histology plus exclusion of every recognised ARDS trigger.
pulmonary alveolus UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary alveolus, annotated with alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Myofibroblast activation in the fibrosing entities The organizing phase that follows acute diffuse alveolar damage feeds the same fibroblast-driven remodelling as the chronic fibrosing entities.
Show evidence (1 reference)
PMID:23001802 SUPPORT Other
"Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of acute lung injury characterized clinically by acute respiratory failure with bilateral lung infiltrates and histologically by diffuse alveolar damage (DAD), a combination of findings previously known as the Hamman-Rich syndrome."
States the lesion, its clinical expression, and that the entity is the idiopathic member of the acute lung injury family.
Bronchiolocentric pigmented macrophage accumulation
The lesion shared by the two smoking-related IIPs. Pigmented ("smoker's") macrophages accumulate in respiratory bronchioles and the surrounding alveoli. Confined to the bronchiolar region the lesion is respiratory bronchiolitis-interstitial lung disease; when the same accumulation becomes diffuse and fills alveolar spaces it is desquamative interstitial pneumonia. This is the one arm of the classification with an identified and removable driver, which is why its first-line therapy is an exposure intervention rather than a drug.
alveolar macrophage CL:0000583 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alveolar macrophage (CL:0000583). CL:0000583 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
respiratory bronchiole UBERON:0002188 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in respiratory bronchiole (UBERON:0002188). UBERON:0002188 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:40081337 SUPPORT Human Clinical
"Respiratory bronchiolitis-associated ILD mainly affects smokers, showing ground-glass opacities on chest computed tomography (CT) scans and pigmented macrophages in the bronchoalveolar lavage fluid."
Names the cell, the pigment, and the smoking association that together define this arm of the classification.
PMID:40081337 SUPPORT Human Clinical
"Desquamative interstitial pneumonia, also related to smoking, is characterized by exertional dyspnea, dry cough, restrictive lung function, and ground-glass opacities on high-resolution CT."
Establishes that the second smoking-related entity shares the same driver, supporting their treatment as one lesion at two extents.
Lymphocytic expansion of the interstitium
The lesion of lymphoid interstitial pneumonia. Polyclonal lymphocytes and plasma cells diffusely infiltrate and widen the alveolar septa. Truly idiopathic LIP is rare; most cases sit downstream of an autoimmune disease (classically Sjogren syndrome) or an infection, so the same caveat that governs the whole family — idiopathic means the search failed — is at its most demanding here.
lymphocyte CL:0000542 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphocyte (CL:0000542). CL:0000542 is a cell type from the Cell Ontology.
lymphocyte proliferation GO:0046651 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lymphocyte proliferation (GO:0046651). GO:0046651 is a biological process from the Gene Ontology. ↑ INCREASED
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Lymphoid interstitial pneumonia involves lymphocytic proliferation and is associated with autoimmune diseases or infections, treated with corticosteroids."
Gives the cellular lesion, the secondary associations that must be excluded before calling it idiopathic, and the therapy that follows from it.
Myofibroblast activation in the fibrosing entities
Where the fibrosing members of the family converge on the conserved fibrotic response. Injured alveolar epithelium fails to re-epithelialise and instead releases profibrotic signals that drive fibroblasts into collagen-secreting myofibroblasts. This node is deliberately generic: the disease-specific upstream biology that feeds it in idiopathic pulmonary fibrosis — telomere attrition, AT2 senescence, aberrant basaloid cells, MUC5B — is curated on the IPF entry and is not re-derived here.
myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology. alveolar type II pneumocyte CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alveolar type II pneumocyte, annotated with pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology.
fibroblast proliferation GO:0048144 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased fibroblast proliferation (GO:0048144). GO:0048144 is a biological process from the Gene Ontology. ↑ INCREASED extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive pulmonary fibrosis
Show evidence (1 reference)
PMID:34084786 SUPPORT Human Clinical
"Key cells in the pathogenesis involve alveolar type 2 (AT2) cells, club cells and myofibroblasts; however, to what extent these cells are affected by telomere shortening and DNA damage is not yet known."
Identifies the epithelial and myofibroblast cell types this node asserts as the effectors of fibrogenesis across different types of progressive fibrosing interstitial lung disease, not only in IPF. Recorded as PARTIAL because the study measures telomere and DNA-damage biology in those cells rather than testing the activation step itself.
Progressive pulmonary fibrosis
The shared adverse outcome of the family and the reason its members are managed together despite their different lesions. Accumulating matrix destroys alveolar architecture, and a subset of every fibrosing entity — including entities with an otherwise favourable prognosis — declines on symptoms, physiology, and imaging in the way IPF does. The 2022 ATS/ERS/JRS/ALAT guideline made this a defined, treatable behaviour rather than a descriptive impression, and it is behaviour, not the original histopathologic label, that then governs antifibrotic therapy.
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:35486072 SUPPORT Other
"PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF."
The operational definition of the shared progressive behaviour this node models, and the explicit statement that it is recognised in interstitial lung diseases other than IPF.
PMID:39761948 SUPPORT Human Clinical
"Antifibrotic agents should be considered in a condition, termed progressive pulmonary fibrosis, where pulmonary fibrosis progressively worsens."
Shows the behaviour-based rule being applied to a non-IPF member of the family, which is the practical consequence of modelling this outcome at the root rather than per entity.
PMID:35431170 SUPPORT Other
"The definition of PF-ILD includes symptom progression, PFT decline, and extension of chest high-resolution computed tomography (HRCT) findings."
Independently states the three-domain composite that operationalises progression, corroborating the guideline definition.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Idiopathic Interstitial Pneumonia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Respiratory 5
Exertional dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39761948 SUPPORT Human Clinical
"Usually presenting with respiratory symptoms such as shortness of breath and cough, iNSIP has a subacute or chronic course."
Documents dyspnea as the presenting symptom of the chronic fibrosing arm of the family.
PMID:40078018 SUPPORT Human Clinical
"Patients primarily present with dry cough and dyspnea."
Shows the same presenting symptom in the acute/subacute arm, supporting dyspnea as a family-level rather than entity-level phenotype.
Chronic dry cough Nonproductive cough HP:0031246 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonproductive cough (HP:0031246). HP:0031246 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40078018 SUPPORT Human Clinical
"Patients primarily present with dry cough and dyspnea."
Names the cough as nonproductive and as one of the two dominant presenting symptoms.
Restrictive ventilatory defect HP:0002091 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive ventilatory defect (HP:0002091). HP:0002091 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Desquamative interstitial pneumonia, also related to smoking, is characterized by exertional dyspnea, dry cough, restrictive lung function, and ground-glass opacities on high-resolution CT."
Records restrictive physiology as a defining functional feature, here for the desquamative entity.
Pulmonary fibrosis HP:0002206 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary fibrosis (HP:0002206). HP:0002206 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39761948 SUPPORT Human Clinical
"Antifibrotic agents should be considered in a condition, termed progressive pulmonary fibrosis, where pulmonary fibrosis progressively worsens."
Documents pulmonary fibrosis as an outcome of a non-IPF member of the family and as the target of therapy.
Acute respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23001802 SUPPORT Other
"Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of acute lung injury characterized clinically by acute respiratory failure with bilateral lung infiltrates and histologically by diffuse alveolar damage (DAD), a combination of findings previously known as the Hamman-Rich syndrome."
States acute respiratory failure as the defining clinical presentation of the acute member of the family.
Other 5
Ground-glass opacification on HRCT HP:0025179 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ground-glass opacification (HP:0025179). HP:0025179 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39761948 SUPPORT Human Clinical
"Key imaging findings on chest high-resolution computed tomography include bilateral reticular opacities in lower lungs, traction bronchiectasis, reduced lung volumes and, ground-glass opacities."
Lists the HRCT findings, including ground-glass opacity, that carry the radiologic half of the multidisciplinary diagnosis.
Interstitial pneumonitis HP:0006515 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial pneumonitis (HP:0006515). HP:0006515 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24032382 SUPPORT Other
"In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria."
Establishes that these are interstitial pneumonias defined as a bounded set of entities under standardized criteria.
Reduced diffusing capacity for carbon monoxide Decreased DLCO HP:0045051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased DLCO (HP:0045051). HP:0045051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29367408 SUPPORT Human Clinical
"In this article we review the profound alterations in lung mechanics (reduced lung compliance and lung volumes), pulmonary gas exchange (reduced diffusing capacity, increased dead space ventilation, chronic arterial hypoxaemia) and airway physiology (increased cough reflex and increased airway..."
Places reduced diffusing capacity among the characteristic gas-exchange alterations, alongside the reduced lung volumes already curated as restrictive physiology. Recorded as PARTIAL because the source characterises IPF specifically rather than the whole family, and because it is a narrative physiology review rather than a cohort measurement.
Bibasilar fine inspiratory crackles HP:0030830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Crackles (HP:0030830). HP:0030830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30853366 SUPPORT Human Clinical
"Crucial physical findings are scalene muscle hypertrophy, bibasilar fine crackles, and finger clubbing."
Names bibasilar fine crackles as a crucial physical finding. Recorded as PARTIAL because the source describes idiopathic pulmonary fibrosis rather than every member of the family; the sign is far less prominent in the acute and organizing entities.
Digital clubbing Clubbing of fingers HP:0100759 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clubbing of fingers (HP:0100759). HP:0100759 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30853366 SUPPORT Human Clinical
"Crucial physical findings are scalene muscle hypertrophy, bibasilar fine crackles, and finger clubbing."
Names finger clubbing as a crucial physical finding, which is why the more specific "Clubbing of fingers" term is used rather than the general Clubbing term. Recorded as PARTIAL because the source characterises idiopathic pulmonary fibrosis rather than the whole family. No frequency is asserted: the commonly quoted 25-50% figure does not appear in any source cached for this entry, and a frequency band needs its own evidence.
💊

Medical Actions

6
Systemic corticosteroid therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest.
First-line for the inflammatory and organizing entities — COP above all, and LIP — where the lesion is cellular and the alveolar scaffold is intact. Deliberately not a family-wide recommendation: the same therapy does not benefit the chronic fibrosing entities, which is one practical reason the IIP root cannot be treated as a single disease.
Mechanism Target:
INHIBITS Organizing pneumonia pattern with intra-alveolar granulation tissue — Corticosteroids suppress the fibroblastic organizing lesion while the alveolar architecture is still intact, allowing it to resolve.
Show evidence (1 reference)
PMID:41513514 SUPPORT Human Clinical
"The hallmark pathological features are presence of polypoid granulation tissue, or Masson bodies, in the alveolar spaces, with lung architecture preserved in most patients with good clinical outcomes poststeroid treatment."
Ties the good post-steroid outcome directly to the intra-alveolar granulation-tissue lesion this treatment targets.
Show evidence (2 references)
PMID:40967604 SUPPORT Human Clinical
"A defining feature of COP is steroid-responsiveness, and most experts recommend prolonged corticosteroid courses (6-12 months)."
Establishes steroid responsiveness as definitional for the organizing entity and gives the treatment duration.
PMID:40081337 SUPPORT Human Clinical
"Lymphoid interstitial pneumonia involves lymphocytic proliferation and is associated with autoimmune diseases or infections, treated with corticosteroids."
Extends the same therapy to the lymphoid entity, the other cellular member of the family.
Smoking cessation
First-line and potentially disease-modifying for RB-ILD and DIP. The only intervention in the family that removes a driver rather than modulating a response, and the reason the smoking-related entities are separated out. NCIT has no clinical-intervention term for smoking cessation — NCIT:C17427 is classified under Behavior, not under Clinical Intervention or Procedure — so the action is left as free text rather than bound to an unreachable term.
Mechanism Target:
INHIBITS Bronchiolocentric pigmented macrophage accumulation — Removing the exposure removes the stimulus for the pigmented-macrophage accumulation that constitutes the lesion.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Respiratory bronchiolitis-associated ILD mainly affects smokers, showing ground-glass opacities on chest computed tomography (CT) scans and pigmented macrophages in the bronchoalveolar lavage fluid."
Establishes the smoking-to-macrophage-lesion link that makes removing the exposure a mechanism-directed intervention on this node.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Smoking cessation is essential for treatment, with corticosteroids used for severe cases."
States smoking cessation as the essential treatment for the smoking-related arm, with steroids reserved for severe disease.
Nintedanib for progressive pulmonary fibrosis
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: nintedanib CHEBI:85164 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nintedanib (CHEBI:85164). CHEBI:85164 is a therapeutic agent from Chemical Entities of Biological Interest.
Antifibrotic tyrosine kinase inhibitor. Recommended for interstitial lung disease other than IPF that meets the progressive-pulmonary-fibrosis criteria, so the indication is keyed to observed disease behaviour rather than to the original histopathologic label.
Mechanism Target:
INHIBITS Progressive pulmonary fibrosis — Nintedanib slows the fibrotic progression that defines the PPF behaviour, without reversing established fibrosis.
Show evidence (1 reference)
PMID:35486072 SUPPORT Human Clinical
"A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended."
The recommendation is made for the progressive-pulmonary-fibrosis behaviour that this target node models.
Show evidence (1 reference)
PMID:35486072 SUPPORT Human Clinical
"A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended."
The guideline recommendation that attaches antifibrotic therapy to the progressive-fibrosis behaviour rather than to a single entity.
Supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
The mainstay for acute interstitial pneumonia, where no therapy has been shown to alter the course, and a component of care across the family (supplemental oxygen when hypoxemic, symptom-directed and palliative measures). Pulmonary rehabilitation, previously named only inside this description, is now curated as its own treatment.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Acute interstitial pneumonia resembles acute respiratory distress syndrome but occurs without a clear cause and is managed with supportive care."
States supportive care as the management of the acute entity, in the absence of a disease-modifying option.
Pulmonary rehabilitation
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Structured supervised exercise training and education. Applies across the family rather than to one entity, and is also the standard preparation for transplant candidates. The functional and quality-of-life benefit is established; a survival benefit is suggested at five years but is not settled, and the entry does not claim one.
Show evidence (2 references)
PMID:39805518 SUPPORT Human Clinical
"Pulmonary rehabilitation (PR) is a beneficial intervention for people with interstitial lung disease (ILD); however, the effect of PR on survival is unclear."
States both the established benefit and the explicit limit of the evidence, which is why this entry claims function and quality of life but not survival.
PMID:39805518 SUPPORT Human Clinical
"Participation in PR among people with ILD may impact survival at 5 years."
The hedged survival signal from a pooled analysis of two randomized trials. Recorded as PARTIAL because the unadjusted comparison was not significant and no difference remained at ten years.
Lung transplantation
Action: Organ TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. NCIT:C15289
The only intervention that replaces the fibrotic lung rather than slowing its remodelling, and the definitive therapy for advanced fibrotic disease across this family rather than for one entity. Curated here rather than delegated to the IPF entry for exactly that reason. Access is limited by donor supply and by late referral, so timing of referral is itself a management decision.
Mechanism Target:
BYPASSES Progressive pulmonary fibrosis — Transplantation does not act on the fibrotic mechanism at all; it removes the diseased organ, so the causal chain modelled here is bypassed rather than inhibited. BYPASSES is used deliberately in preference to INHIBITS, which would misstate the mechanism.
Show evidence (1 reference)
PMID:40365094 SUPPORT Human Clinical
"Interstitial lung diseases (ILDs) are now the most common indication for lung transplant internationally."
Establishes that transplantation is directed at this disease family as a whole, which is what justifies attaching it to the shared progressive-fibrosis node rather than to a single entity.
Show evidence (2 references)
PMID:40365094 SUPPORT Human Clinical
"Despite this increase many patients with ILD who would potentially benefit from lung transplant are either not referred or referred too late."
Documents late referral as the practical limiting factor, supporting the description's emphasis on referral timing as a management decision.
PMID:40365094 SUPPORT Human Clinical
"Unfortunately, the number of potential lung transplant recipients exceeds available donor organs and some patients will die without transplant."
Documents the donor-supply constraint that bounds this therapy's reach.
🌍

Environmental Factors

1
Cigarette smoking
exposure to cigarette smoking ECTO:0100003 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to cigarette smoking (ECTO:0100003). ECTO:0100003 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
The one exposure that is an accepted driver of specific members of this family rather than an exclusion criterion. RB-ILD and DIP occur almost exclusively in smokers, which is why they retain the "idiopathic" label only by historical convention and are managed with an exposure intervention.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Desquamative interstitial pneumonia, also related to smoking, is characterized by exertional dyspnea, dry cough, restrictive lung function, and ground-glass opacities on high-resolution CT."
Confirms that the exposure drives a second member of the family, not only respiratory bronchiolitis-interstitial lung disease.
Mechanism Target:
TRIGGERS Bronchiolocentric pigmented macrophage accumulation — Tobacco smoke is the proximate cause of the pigmented-macrophage lesion that defines the smoking-related arm of the classification.
Show evidence (1 reference)
PMID:40081337 SUPPORT Human Clinical
"Respiratory bronchiolitis-associated ILD mainly affects smokers, showing ground-glass opacities on chest computed tomography (CT) scans and pigmented macrophages in the bronchoalveolar lavage fluid."
Links the exposure directly to the macrophage lesion this edge targets.
🔬

Diagnosis

3
Multidisciplinary discussion
The diagnostic standard for the family since 2002. Pulmonology, radiology, and pathology (with rheumatology where autoimmunity is in question) integrate clinical history, HRCT, and — when obtained — tissue, and it is this integrated assignment, not histology alone, that names the entity.
NEEDS TERM (NTR candidate). NCIT has no clinical-action term for multidisciplinary discussion as a diagnostic procedure; the nearest concepts are organizational (multidisciplinary team, tumor board) rather than the diagnostic act itself. The free-text preferred_term is therefore deliberate, not an omission. The other two diagnosis entries here are bound (NCIT:C20644, NCIT:C51748).
Show evidence (1 reference)
PMID:24032382 SUPPORT Other
"In addition, the historical "gold standard" of histologic diagnosis was replaced by a multidisciplinary approach."
The statement that displaced histology as the sole arbiter in favour of multidisciplinary diagnosis.
High-resolution computed tomography of the chest
Carries the radiologic half of the diagnosis and, in the fibrosing entities, can establish a definite or probable UIP pattern without biopsy. Also supplies one of the three domains of the progressive-pulmonary-fibrosis definition.
High-resolution computed tomography of the chest NCIT:C20644 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39761948 SUPPORT Human Clinical
"Key imaging findings on chest high-resolution computed tomography include bilateral reticular opacities in lower lungs, traction bronchiectasis, reduced lung volumes and, ground-glass opacities."
Documents HRCT as the modality that supplies the pattern-defining findings.
Lung tissue sampling
Reserved for cases the clinical and radiologic picture leaves indeterminate. Surgical lung biopsy was the traditional route; transbronchial lung cryobiopsy is now an accepted alternative where the expertise exists.
Lung biopsy NCIT:C51748 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35486072 SUPPORT Human Clinical
"A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise."
The current guideline position on how tissue is obtained when it is needed.
{ }

Source YAML

click to show 
name: Idiopathic Interstitial Pneumonia
creation_date: "2026-08-20T00:00:00Z"
category: Respiratory Disease
parents:
- Respiratory Disease
- Lung Disease
disease_term:
  preferred_term: idiopathic interstitial pneumonia
  term:
    id: MONDO:0002429
    label: idiopathic interstitial pneumonia
description: >-
  A classification family of diffuse parenchymal lung diseases of unknown cause,
  defined by the ATS/ERS international multidisciplinary classification. Injury
  to the alveolar-interstitial compartment in the absence of an identified cause
  is resolved into one of a small number of stereotyped histopathologic patterns
  — usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing
  pneumonia, diffuse alveolar damage, respiratory bronchiolitis, desquamative
  interstitial pneumonia, lymphoid interstitial pneumonia — and it is the pattern,
  reached by multidisciplinary discussion rather than histology alone, that
  assigns the clinicopathologic entity, its prognosis, and its treatment. This
  entry models what the entities share (the injury-response pivot and the
  progressive-fibrosis outcome common to their fibrosing members) and delegates
  entity-specific mechanism to the individual subtype entries; the full
  pathograph of idiopathic pulmonary fibrosis is curated separately in
  `Idiopathic_Pulmonary_Fibrosis.yaml` and is deliberately not duplicated here.
synonyms:
- IIP
- idiopathic interstitial pneumonitis
notes: >-
  Scoping decision. This is curated as a root Disease entry with `has_subtypes`
  rather than as a `kb/groupings/` Grouping because a dismech Grouping is a
  curated union over already-distinct Disease entries, and only one of the eight
  ATS/ERS entities (idiopathic pulmonary fibrosis) currently exists as its own
  entry — a one-member union would carry no auditable boundary. The root graph
  is deliberately restricted to the shared injury-response pivot and the shared
  progressive-fibrosis outcome, with each entity's distinctive pattern kept as a
  separate parallel node, so this is not a blended umbrella pathograph. Once
  three or more of the remaining entities have standalone entries, converting
  this family to a Grouping (retaining this entry as the umbrella Disease, as was
  done for diabetes mellitus) becomes the right structure.

has_subtypes:
- name: IPF
  display_name: Idiopathic Pulmonary Fibrosis (UIP pattern)
  classification: histological
  subtype_term:
    preferred_term: idiopathic pulmonary fibrosis
    term:
      id: MONDO:0800504
      label: idiopathic pulmonary fibrosis
  description: >-
    Chronic fibrosing IIP defined by the usual interstitial pneumonia (UIP)
    pattern — patchy subpleural fibrosis with fibroblast foci and honeycombing —
    and the worst prognosis of the group. Curated in full as its own dismech
    entry (`Idiopathic_Pulmonary_Fibrosis.yaml`); it is referenced here rather
    than duplicated.
  evidence:
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prognosis is generally more favorable for iNSIP than for idiopathic
      pulmonary fibrosis, with many studies reporting a 5-year survival rate
      above 70%.
    explanation: >-
      Establishes that IPF is the worse-prognosis member of the family relative
      to its nearest chronic fibrosing sibling, which is why the two are kept as
      separate entities rather than lumped.

- name: iNSIP
  display_name: Idiopathic Nonspecific Interstitial Pneumonia
  classification: histological
  subtype_term:
    preferred_term: non-specific interstitial pneumonia
    term:
      id: MONDO:0019622
      label: non-specific interstitial pneumonia
  description: >-
    Chronic fibrosing IIP defined by the temporally uniform NSIP pattern
    (cellular or fibrotic), diagnosed only once connective tissue disease,
    hypersensitivity pneumonitis, drug toxicity, and other secondary causes are
    excluded. Prognosis is better than IPF, and a subset nonetheless behaves as
    progressive pulmonary fibrosis.
  evidence:
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is identified histologically by the nonspecific interstitial pneumonia
      pattern. A diagnosis of iNSIP is feasible once secondary causes or
      underlying diseases are ruled out.
    explanation: >-
      States both defining features of the entity — the histologic pattern and
      the exclusion of secondary causes that makes it idiopathic.
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nonspecific interstitial pneumonia is now better defined.
    explanation: >-
      The 2013 ATS/ERS update records that iNSIP was consolidated as a defined
      entity rather than a provisional diagnosis.

- name: COP
  display_name: Cryptogenic Organizing Pneumonia
  classification: histological
  subtype_frequency: "approximately 5% to 10% of IIPs"
  subtype_term:
    preferred_term: cryptogenic organizing pneumonia
    term:
      id: MONDO:0015264
      label: cryptogenic organizing pneumonia
  description: >-
    Acute/subacute IIP defined by the organizing pneumonia pattern — polypoid
    intra-alveolar granulation tissue (Masson bodies) with preserved lung
    architecture. Formerly called idiopathic bronchiolitis obliterans organizing
    pneumonia (BOOP). Characteristically steroid-responsive, which sets it apart
    from the chronic fibrosing entities.
  evidence:
  - reference: PMID:40078018
    reference_title: "Korean Guidelines for Diagnosis and Management of Interstitial Lung Disease: Cryptogenic Organizing Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      COP accounts for approximately 5% to 10% of IIPs, with the average age of
      diagnosis ranging from 50 to 60 years.
    explanation: >-
      Source for the subtype frequency within the IIP family and the typical age
      at diagnosis.

- name: AIP
  display_name: Acute Interstitial Pneumonia (Hamman-Rich syndrome)
  classification: histological
  subtype_term:
    preferred_term: acute interstitial pneumonia
    term:
      id: MONDO:0019203
      label: acute interstitial pneumonia
  description: >-
    Fulminant IIP defined by diffuse alveolar damage occurring without an
    identified cause. Clinically indistinguishable from ARDS, so the diagnosis
    requires histologic DAD plus exclusion of known ARDS triggers.
  evidence:
  - reference: PMID:23001802
    reference_title: "Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The main differences between AIP and ARDS are that AIP requires a
      histologic diagnosis of DAD and exclusion of known etiologies.
    explanation: >-
      States the two criteria that make AIP an idiopathic interstitial pneumonia
      rather than ARDS.

- name: RB-ILD
  display_name: Respiratory Bronchiolitis-Interstitial Lung Disease
  classification: histological
  subtype_term:
    preferred_term: respiratory bronchiolitis-interstitial lung disease syndrome
    term:
      id: MONDO:0019204
      label: respiratory bronchiolitis-interstitial lung disease syndrome
  description: >-
    Smoking-related IIP in which pigmented macrophages accumulate in and around
    respiratory bronchioles. Distinguished from the other entities by having an
    identified and removable driver — tobacco smoke — so smoking cessation is
    first-line therapy.
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory bronchiolitis-associated ILD mainly affects smokers, showing
      ground-glass opacities on chest computed tomography (CT) scans and
      pigmented macrophages in the bronchoalveolar lavage fluid.
    explanation: >-
      Establishes the smoking association and the macrophage-centred lesion that
      define this entity.

- name: DIP
  display_name: Desquamative Interstitial Pneumonia
  classification: histological
  subtype_term:
    preferred_term: desquamative interstitial pneumonia
    term:
      id: MONDO:0009887
      label: desquamative interstitial pneumonia
  description: >-
    The second smoking-related IIP, in which the same pigmented-macrophage
    accumulation becomes diffuse and fills the alveolar spaces rather than
    remaining bronchiolocentric, producing restrictive physiology and widespread
    ground-glass opacity.
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Desquamative interstitial pneumonia, also related to smoking, is
      characterized by exertional dyspnea, dry cough, restrictive lung function,
      and ground-glass opacities on high-resolution CT.
    explanation: >-
      Establishes the smoking association and the clinical-physiologic profile
      that distinguish DIP from its bronchiolocentric sibling RB-ILD.

- name: LIP
  display_name: Lymphoid Interstitial Pneumonia
  classification: histological
  subtype_term:
    preferred_term: lymphoid interstitial pneumonia
    term:
      id: MONDO:0009537
      label: lymphoid interstitial pneumonia
  description: >-
    Rare IIP in which diffuse lymphocytic infiltration expands the interstitium.
    Genuinely idiopathic LIP is uncommon; most cases are associated with an
    autoimmune disease (notably Sjogren syndrome) or an infection, which must be
    sought before the idiopathic label is applied.
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoid interstitial pneumonia involves lymphocytic proliferation and is
      associated with autoimmune diseases or infections, treated with
      corticosteroids.
    explanation: >-
      States the lymphoproliferative lesion, the secondary associations that must
      be excluded, and the treatment that follows from the lesion.

- name: IPPFE
  display_name: Idiopathic Pleuroparenchymal Fibroelastosis
  classification: histological
  subtype_term:
    preferred_term: idiopathic pleuroparenchymal fibroelastosis
    term:
      id: MONDO:0044633
      label: idiopathic pleuroparenchymal fibroelastosis
  description: >-
    Rare IIP added to the family in the 2013 ATS/ERS update, characterized by
    upper-lobe pleural and subpleural fibroelastosis in predominantly
    non-smokers. Included here because the 2013 classification explicitly widened
    the family beyond the six major entities.
  evidence:
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A group of rare entities, including pleuroparenchymal fibroelastosis and
      rare histologic patterns, is introduced.
    explanation: >-
      The 2013 ATS/ERS update is the document that admits IPPFE to the IIP
      classification as a rare entity.
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic pleuroparenchymal fibroelastosis results in fibrosis in the
      upper lobes, primarily in nonsmokers, and is diagnosed through clinical and
      imaging findings, with no effective treatment to improve survival.
    explanation: >-
      Gives the distribution, the smoking profile, and the absence of effective
      therapy that differentiate IPPFE from the other fibrosing entities.

pathophysiology:
- name: Injury to the alveolar-interstitial compartment of unknown cause
  biological_scale: TISSUE
  role: trigger
  conforms_to: "fibrotic_response#Tissue Injury"
  description: >-
    The shared initiating step of the family. Injury reaches the alveolar
    epithelium and the surrounding interstitium, and the search for a cause —
    connective tissue disease, inhaled antigen, drug, infection, occupational
    exposure — returns nothing. What makes an interstitial pneumonia idiopathic
    is therefore not a distinct kind of injury but the exhaustion of the
    differential, which is why every entity in this family is defined partly by
    exclusion.
  cell_types:
  - preferred_term: alveolar type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  - preferred_term: pulmonary alveolus
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DYSREGULATED
  downstream:
  - target: Resolution of injury into a stereotyped histopathologic pattern
  evidence:
  - reference: PMID:41513514
    reference_title: "Organizing Pneumonia Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Organizing pneumonia (OP) is a nonspecific lung parenchymal response to any
      form of injury, with its idiopathic variant coined as cryptogenic
      organizing pneumonia (COP).
    explanation: >-
      Directly states the logic this node encodes for one member of the family —
      the lesion is a stereotyped, cause-agnostic parenchymal response to injury,
      and the idiopathic entity is what remains once a cause cannot be found.
      Recorded as PARTIAL because the source argues it for organizing pneumonia
      rather than for the whole IIP family.
  - reference: PMID:40967604
    reference_title: "Cryptogenic Organizing Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic evaluation relies on excluding secondary causes of organizing
      pneumonia and includes a thorough history including medications, exposures,
      and signs or symptoms of underlying rheumatologic disease.
    explanation: >-
      Documents the diagnosis-by-exclusion step this node asserts, naming the
      specific alternative causes that must be ruled out before an interstitial
      pneumonia is called idiopathic.

- name: Resolution of injury into a stereotyped histopathologic pattern
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The pivot of the whole family, and the reason it is a classification rather
    than a single disease. The injured lung has only a small repertoire of
    histopathologic responses — usual interstitial pneumonia, nonspecific
    interstitial pneumonia, organizing pneumonia, diffuse alveolar damage,
    respiratory bronchiolitis, desquamative interstitial pneumonia, lymphoid
    interstitial pneumonia — and which one it adopts, not the (absent) cause,
    assigns the clinicopathologic entity together with its natural history and
    its treatment. Since 2002 that assignment has been made by multidisciplinary
    discussion integrating clinical, radiologic, and pathologic data rather than
    by histology alone.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Organizing pneumonia pattern with intra-alveolar granulation tissue
  - target: Diffuse alveolar damage
  - target: Bronchiolocentric pigmented macrophage accumulation
  - target: Lymphocytic expansion of the interstitium
  - target: Myofibroblast activation in the fibrosing entities
    description: >-
      The chronic fibrosing arm of the classification (UIP in IPF, and the
      fibrotic NSIP pattern) enters the fibrotic response directly rather than
      through an intervening acute or inflammatory lesion.
  evidence:
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In 2002 the American Thoracic Society/European Respiratory Society
      (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs)
      defined seven specific entities, and provided standardized terminology and
      diagnostic criteria. In addition, the historical "gold standard" of
      histologic diagnosis was replaced by a multidisciplinary approach.
    explanation: >-
      Both halves of this node come from one sentence pair — that the family
      resolves into a fixed, small set of defined entities, and that the entity
      is assigned by multidisciplinary discussion rather than by histology alone.
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is identified histologically by the nonspecific interstitial pneumonia
      pattern.
    explanation: >-
      A worked instance of the pattern-assigns-entity rule this node states, for
      the idiopathic NSIP member of the family.

- name: Organizing pneumonia pattern with intra-alveolar granulation tissue
  biological_scale: TISSUE
  role: effector
  description: >-
    The lesion of cryptogenic organizing pneumonia. Polypoid plugs of
    fibroblastic granulation tissue (Masson bodies) fill alveolar spaces,
    alveolar ducts, and distal bronchioles while the underlying alveolar
    architecture is preserved. Because the scaffold survives, the lesion is
    reversible — this is the mechanistic basis for the steroid responsiveness
    that separates COP from the chronic fibrosing entities.
  locations:
  - preferred_term: pulmonary alveolus
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: INCREASED
  evidence:
  - reference: PMID:41513514
    reference_title: "Organizing Pneumonia Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark pathological features are presence of polypoid granulation
      tissue, or Masson bodies, in the alveolar spaces, with lung architecture
      preserved in most patients with good clinical outcomes poststeroid
      treatment.
    explanation: >-
      Supplies the lesion, its location, the preservation of architecture, and
      the good steroid-treated outcome that follows from it.

- name: Diffuse alveolar damage
  biological_scale: TISSUE
  role: effector
  description: >-
    The lesion of acute interstitial pneumonia. Alveolar-capillary barrier
    disruption with hyaline membrane formation produces fulminant respiratory
    failure clinically indistinguishable from ARDS; survivors pass into an
    organizing phase that can leave fibrosis. AIP is the idiopathic form, so its
    diagnosis requires DAD on histology plus exclusion of every recognised ARDS
    trigger.
  locations:
  - preferred_term: pulmonary alveolus
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Myofibroblast activation in the fibrosing entities
    description: >-
      The organizing phase that follows acute diffuse alveolar damage feeds the
      same fibroblast-driven remodelling as the chronic fibrosing entities.
  evidence:
  - reference: PMID:23001802
    reference_title: "Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of
      acute lung injury characterized clinically by acute respiratory failure
      with bilateral lung infiltrates and histologically by diffuse alveolar
      damage (DAD), a combination of findings previously known as the Hamman-Rich
      syndrome.
    explanation: >-
      States the lesion, its clinical expression, and that the entity is the
      idiopathic member of the acute lung injury family.

- name: Bronchiolocentric pigmented macrophage accumulation
  biological_scale: CELLULAR
  role: effector
  description: >-
    The lesion shared by the two smoking-related IIPs. Pigmented ("smoker's")
    macrophages accumulate in respiratory bronchioles and the surrounding
    alveoli. Confined to the bronchiolar region the lesion is respiratory
    bronchiolitis-interstitial lung disease; when the same accumulation becomes
    diffuse and fills alveolar spaces it is desquamative interstitial pneumonia.
    This is the one arm of the classification with an identified and removable
    driver, which is why its first-line therapy is an exposure intervention
    rather than a drug.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: respiratory bronchiole
    term:
      id: UBERON:0002188
      label: respiratory bronchiole
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory bronchiolitis-associated ILD mainly affects smokers, showing
      ground-glass opacities on chest computed tomography (CT) scans and
      pigmented macrophages in the bronchoalveolar lavage fluid.
    explanation: >-
      Names the cell, the pigment, and the smoking association that together
      define this arm of the classification.
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Desquamative interstitial pneumonia, also related to smoking, is
      characterized by exertional dyspnea, dry cough, restrictive lung function,
      and ground-glass opacities on high-resolution CT.
    explanation: >-
      Establishes that the second smoking-related entity shares the same driver,
      supporting their treatment as one lesion at two extents.

- name: Lymphocytic expansion of the interstitium
  biological_scale: CELLULAR
  role: effector
  description: >-
    The lesion of lymphoid interstitial pneumonia. Polyclonal lymphocytes and
    plasma cells diffusely infiltrate and widen the alveolar septa. Truly
    idiopathic LIP is rare; most cases sit downstream of an autoimmune disease
    (classically Sjogren syndrome) or an infection, so the same caveat that
    governs the whole family — idiopathic means the search failed — is at its
    most demanding here.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: lymphocyte proliferation
    term:
      id: GO:0046651
      label: lymphocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoid interstitial pneumonia involves lymphocytic proliferation and is
      associated with autoimmune diseases or infections, treated with
      corticosteroids.
    explanation: >-
      Gives the cellular lesion, the secondary associations that must be excluded
      before calling it idiopathic, and the therapy that follows from it.

- name: Myofibroblast activation in the fibrosing entities
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  description: >-
    Where the fibrosing members of the family converge on the conserved fibrotic
    response. Injured alveolar epithelium fails to re-epithelialise and instead
    releases profibrotic signals that drive fibroblasts into collagen-secreting
    myofibroblasts. This node is deliberately generic: the disease-specific
    upstream biology that feeds it in idiopathic pulmonary fibrosis — telomere
    attrition, AT2 senescence, aberrant basaloid cells, MUC5B — is curated on the
    IPF entry and is not re-derived here.
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: alveolar type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: fibroblast proliferation
    term:
      id: GO:0048144
      label: fibroblast proliferation
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  downstream:
  - target: Progressive pulmonary fibrosis
  evidence:
  - reference: PMID:34084786
    reference_title: "Telomere shortening and DNA damage in culprit cells of different types of progressive fibrosing interstitial lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key cells in the pathogenesis involve alveolar type 2 (AT2) cells, club
      cells and myofibroblasts; however, to what extent these cells are affected
      by telomere shortening and DNA damage is not yet known.
    explanation: >-
      Identifies the epithelial and myofibroblast cell types this node asserts as
      the effectors of fibrogenesis across different types of progressive
      fibrosing interstitial lung disease, not only in IPF. Recorded as PARTIAL
      because the study measures telomere and DNA-damage biology in those cells
      rather than testing the activation step itself.

- name: Progressive pulmonary fibrosis
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
  description: >-
    The shared adverse outcome of the family and the reason its members are
    managed together despite their different lesions. Accumulating matrix
    destroys alveolar architecture, and a subset of every fibrosing entity —
    including entities with an otherwise favourable prognosis — declines on
    symptoms, physiology, and imaging in the way IPF does. The 2022
    ATS/ERS/JRS/ALAT guideline made this a defined, treatable behaviour rather
    than a descriptive impression, and it is behaviour, not the original
    histopathologic label, that then governs antifibrotic therapy.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:35486072
    reference_title: "Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PPF was defined as at least two of three criteria (worsening symptoms,
      radiological progression, and physiological progression) occurring within
      the past year with no alternative explanation in a patient with an ILD
      other than IPF.
    explanation: >-
      The operational definition of the shared progressive behaviour this node
      models, and the explicit statement that it is recognised in interstitial
      lung diseases other than IPF.
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antifibrotic agents should be considered in a condition, termed progressive
      pulmonary fibrosis, where pulmonary fibrosis progressively worsens.
    explanation: >-
      Shows the behaviour-based rule being applied to a non-IPF member of the
      family, which is the practical consequence of modelling this outcome at the
      root rather than per entity.
  - reference: PMID:35431170
    reference_title: "Current perspective of progressive-fibrosing interstitial lung disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The definition of PF-ILD includes symptom progression, PFT decline, and
      extension of chest high-resolution computed tomography (HRCT) findings.
    explanation: >-
      Independently states the three-domain composite that operationalises
      progression, corroborating the guideline definition.

phenotypes:
- category: Clinical
  name: Exertional dyspnea
  description: >-
    Breathlessness on exertion is the presenting symptom across the family,
    whether the course is acute (AIP), subacute (COP), or chronic (iNSIP, IPF,
    DIP).
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Usually presenting with respiratory symptoms such as shortness of breath
      and cough, iNSIP has a subacute or chronic course.
    explanation: >-
      Documents dyspnea as the presenting symptom of the chronic fibrosing arm of
      the family.
  - reference: PMID:40078018
    reference_title: "Korean Guidelines for Diagnosis and Management of Interstitial Lung Disease: Cryptogenic Organizing Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients primarily present with dry cough and dyspnea.
    explanation: >-
      Shows the same presenting symptom in the acute/subacute arm, supporting
      dyspnea as a family-level rather than entity-level phenotype.

- category: Clinical
  name: Chronic dry cough
  description: >-
    A persistent nonproductive cough accompanies the dyspnea in most entities and
    is a major contributor to symptom burden.
  phenotype_term:
    preferred_term: Nonproductive cough
    term:
      id: HP:0031246
      label: Nonproductive cough
  evidence:
  - reference: PMID:40078018
    reference_title: "Korean Guidelines for Diagnosis and Management of Interstitial Lung Disease: Cryptogenic Organizing Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients primarily present with dry cough and dyspnea.
    explanation: >-
      Names the cough as nonproductive and as one of the two dominant presenting
      symptoms.

- category: Physiological
  name: Restrictive ventilatory defect
  description: >-
    Loss of compliant, ventilated parenchyma produces restrictive physiology with
    reduced lung volumes, the shared functional signature of the family and the
    basis of the FVC endpoint used to define progression.
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Desquamative interstitial pneumonia, also related to smoking, is
      characterized by exertional dyspnea, dry cough, restrictive lung function,
      and ground-glass opacities on high-resolution CT.
    explanation: >-
      Records restrictive physiology as a defining functional feature, here for
      the desquamative entity.

- category: Radiological
  name: Ground-glass opacification on HRCT
  description: >-
    Hazy increased attenuation that does not obscure the underlying vasculature.
    Prominent in the cellular and smoking-related entities and in iNSIP; in the
    fibrosing entities it is accompanied by reticulation and traction
    bronchiectasis.
  phenotype_term:
    preferred_term: Ground-glass opacification
    term:
      id: HP:0025179
      label: Ground-glass opacification
  evidence:
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key imaging findings on chest high-resolution computed tomography include
      bilateral reticular opacities in lower lungs, traction bronchiectasis,
      reduced lung volumes and, ground-glass opacities.
    explanation: >-
      Lists the HRCT findings, including ground-glass opacity, that carry the
      radiologic half of the multidisciplinary diagnosis.

- category: Radiological
  name: Interstitial pneumonitis
  description: >-
    Diffuse abnormality of the pulmonary interstitium on imaging and histology —
    the finding that places a patient in this family before the specific pattern
    is assigned.
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
  evidence:
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In 2002 the American Thoracic Society/European Respiratory Society
      (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs)
      defined seven specific entities, and provided standardized terminology and
      diagnostic criteria.
    explanation: >-
      Establishes that these are interstitial pneumonias defined as a bounded set
      of entities under standardized criteria.

- category: Structural
  name: Pulmonary fibrosis
  description: >-
    Irreversible scarring of the lung parenchyma. Universal in the chronic
    fibrosing entities, reached by a subset of the others, and the outcome that
    antifibrotic therapy is directed at.
  phenotype_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  evidence:
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antifibrotic agents should be considered in a condition, termed progressive
      pulmonary fibrosis, where pulmonary fibrosis progressively worsens.
    explanation: >-
      Documents pulmonary fibrosis as an outcome of a non-IPF member of the
      family and as the target of therapy.

- category: Clinical
  name: Acute respiratory failure
  description: >-
    The presentation of acute interstitial pneumonia, and the endpoint of the
    chronic fibrosing entities. Distinguishing new respiratory failure that
    represents AIP from an acute exacerbation of an established fibrotic IIP is a
    routine clinical problem.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:23001802
    reference_title: "Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of
      acute lung injury characterized clinically by acute respiratory failure
      with bilateral lung infiltrates and histologically by diffuse alveolar
      damage (DAD), a combination of findings previously known as the Hamman-Rich
      syndrome.
    explanation: >-
      States acute respiratory failure as the defining clinical presentation of
      the acute member of the family.

- category: Physiological
  name: Reduced diffusing capacity for carbon monoxide
  description: >-
    Impaired gas transfer across the thickened, remodelled alveolar-capillary
    membrane. The most sensitive physiologic abnormality in the family and
    typically the earliest to fall; a DLCO decline is one of the physiological
    criteria by which progressive pulmonary fibrosis is recognised, so the
    entry's own progression definition is keyed to it.
  phenotype_term:
    preferred_term: Decreased DLCO
    term:
      id: HP:0045051
      label: Decreased DLCO
  evidence:
  - reference: PMID:29367408
    reference_title: "Physiology of the lung in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this article we review the profound alterations in lung mechanics
      (reduced lung compliance and lung volumes), pulmonary gas exchange (reduced
      diffusing capacity, increased dead space ventilation, chronic arterial
      hypoxaemia) and airway physiology (increased cough reflex and increased
      airway volume), as well as pulmonary haemodynamics related to IPF.
    explanation: >-
      Places reduced diffusing capacity among the characteristic gas-exchange
      alterations, alongside the reduced lung volumes already curated as
      restrictive physiology. Recorded as PARTIAL because the source characterises
      IPF specifically rather than the whole family, and because it is a narrative
      physiology review rather than a cohort measurement.

- category: Clinical
  name: Bibasilar fine inspiratory crackles
  description: >-
    Fine end-inspiratory crackles at the lung bases, classically likened to
    Velcro. The cardinal auscultatory sign of fibrotic interstitial lung disease
    and often the finding that prompts the first HRCT.
  phenotype_term:
    preferred_term: Crackles
    term:
      id: HP:0030830
      label: Crackles
  evidence:
  - reference: PMID:30853366
    reference_title: "Evaluation and management of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Crucial physical findings are scalene muscle hypertrophy, bibasilar fine
      crackles, and finger clubbing.
    explanation: >-
      Names bibasilar fine crackles as a crucial physical finding. Recorded as
      PARTIAL because the source describes idiopathic pulmonary fibrosis rather
      than every member of the family; the sign is far less prominent in the
      acute and organizing entities.

- category: Clinical
  name: Digital clubbing
  description: >-
    Bulbous enlargement of the distal phalanges with increased nail-bed
    fluctuance. Common in the chronic fibrosing entities and largely absent from
    the acute and organizing ones, so its presence is a weak pointer towards a
    fibrosing pattern rather than a family-wide sign.
  phenotype_term:
    preferred_term: Clubbing of fingers
    term:
      id: HP:0100759
      label: Clubbing of fingers
  evidence:
  - reference: PMID:30853366
    reference_title: "Evaluation and management of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Crucial physical findings are scalene muscle hypertrophy, bibasilar fine
      crackles, and finger clubbing.
    explanation: >-
      Names finger clubbing as a crucial physical finding, which is why the more
      specific "Clubbing of fingers" term is used rather than the general
      Clubbing term. Recorded as PARTIAL because the source characterises
      idiopathic pulmonary fibrosis rather than the whole family. No frequency is
      asserted: the commonly quoted 25-50% figure does not appear in any source
      cached for this entry, and a frequency band needs its own evidence.

environmental:
- name: Cigarette smoking
  description: >-
    The one exposure that is an accepted driver of specific members of this
    family rather than an exclusion criterion. RB-ILD and DIP occur almost
    exclusively in smokers, which is why they retain the "idiopathic" label only
    by historical convention and are managed with an exposure intervention.
  exposure_term:
    preferred_term: exposure to cigarette smoking
    term:
      id: ECTO:0100003
      label: exposure to cigarette smoking
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Desquamative interstitial pneumonia, also related to smoking, is
      characterized by exertional dyspnea, dry cough, restrictive lung function,
      and ground-glass opacities on high-resolution CT.
    explanation: >-
      Confirms that the exposure drives a second member of the family, not only
      respiratory bronchiolitis-interstitial lung disease.
  influences_mechanisms:
  - target: Bronchiolocentric pigmented macrophage accumulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Tobacco smoke is the proximate cause of the pigmented-macrophage lesion
      that defines the smoking-related arm of the classification.
    evidence:
    - reference: PMID:40081337
      reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Respiratory bronchiolitis-associated ILD mainly affects smokers, showing
        ground-glass opacities on chest computed tomography (CT) scans and
        pigmented macrophages in the bronchoalveolar lavage fluid.
      explanation: >-
        Links the exposure directly to the macrophage lesion this edge targets.

diagnosis:
- name: Multidisciplinary discussion
  description: >-
    The diagnostic standard for the family since 2002. Pulmonology, radiology,
    and pathology (with rheumatology where autoimmunity is in question) integrate
    clinical history, HRCT, and — when obtained — tissue, and it is this
    integrated assignment, not histology alone, that names the entity.
  evidence:
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, the historical "gold standard" of histologic diagnosis was
      replaced by a multidisciplinary approach.
    explanation: >-
      The statement that displaced histology as the sole arbiter in favour of
      multidisciplinary diagnosis.
  notes: >-
    NEEDS TERM (NTR candidate). NCIT has no clinical-action term for
    multidisciplinary discussion as a diagnostic procedure; the nearest concepts
    are organizational (multidisciplinary team, tumor board) rather than the
    diagnostic act itself. The free-text preferred_term is therefore deliberate,
    not an omission. The other two diagnosis entries here are bound
    (NCIT:C20644, NCIT:C51748).

- name: High-resolution computed tomography of the chest
  diagnosis_term:
    preferred_term: High-resolution computed tomography of the chest
    term:
      id: NCIT:C20644
      label: High Resolution Computed Tomography
  description: >-
    Carries the radiologic half of the diagnosis and, in the fibrosing entities,
    can establish a definite or probable UIP pattern without biopsy. Also
    supplies one of the three domains of the progressive-pulmonary-fibrosis
    definition.
  evidence:
  - reference: PMID:39761948
    reference_title: "Korean Guidelines for Diagnosis and Management of Idiopathic Nonspecific Interstitial Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key imaging findings on chest high-resolution computed tomography include
      bilateral reticular opacities in lower lungs, traction bronchiectasis,
      reduced lung volumes and, ground-glass opacities.
    explanation: >-
      Documents HRCT as the modality that supplies the pattern-defining findings.

- name: Lung tissue sampling
  diagnosis_term:
    preferred_term: Lung biopsy
    term:
      id: NCIT:C51748
      label: Lung Biopsy
  description: >-
    Reserved for cases the clinical and radiologic picture leaves indeterminate.
    Surgical lung biopsy was the traditional route; transbronchial lung
    cryobiopsy is now an accepted alternative where the expertise exists.
  evidence:
  - reference: PMID:35486072
    reference_title: "Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A conditional recommendation was made to regard transbronchial lung
      cryobiopsy as an acceptable alternative to surgical lung biopsy in centers
      with appropriate expertise.
    explanation: >-
      The current guideline position on how tissue is obtained when it is needed.

treatments:
- name: Systemic corticosteroid therapy
  description: >-
    First-line for the inflammatory and organizing entities — COP above all, and
    LIP — where the lesion is cellular and the alveolar scaffold is intact.
    Deliberately not a family-wide recommendation: the same therapy does not
    benefit the chronic fibrosing entities, which is one practical reason the IIP
    root cannot be treated as a single disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: Organizing pneumonia pattern with intra-alveolar granulation tissue
    treatment_effect: INHIBITS
    description: >-
      Corticosteroids suppress the fibroblastic organizing lesion while the
      alveolar architecture is still intact, allowing it to resolve.
    evidence:
    - reference: PMID:41513514
      reference_title: "Organizing Pneumonia Phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The hallmark pathological features are presence of polypoid granulation
        tissue, or Masson bodies, in the alveolar spaces, with lung architecture
        preserved in most patients with good clinical outcomes poststeroid
        treatment.
      explanation: >-
        Ties the good post-steroid outcome directly to the intra-alveolar
        granulation-tissue lesion this treatment targets.
  evidence:
  - reference: PMID:40967604
    reference_title: "Cryptogenic Organizing Pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A defining feature of COP is steroid-responsiveness, and most experts
      recommend prolonged corticosteroid courses (6-12 months).
    explanation: >-
      Establishes steroid responsiveness as definitional for the organizing
      entity and gives the treatment duration.
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoid interstitial pneumonia involves lymphocytic proliferation and is
      associated with autoimmune diseases or infections, treated with
      corticosteroids.
    explanation: >-
      Extends the same therapy to the lymphoid entity, the other cellular member
      of the family.

- name: Smoking cessation
  description: >-
    First-line and potentially disease-modifying for RB-ILD and DIP. The only
    intervention in the family that removes a driver rather than modulating a
    response, and the reason the smoking-related entities are separated out.
    NCIT has no clinical-intervention term for smoking cessation — NCIT:C17427 is
    classified under Behavior, not under Clinical Intervention or Procedure — so
    the action is left as free text rather than bound to an unreachable term.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: smoking cessation
  target_mechanisms:
  - target: Bronchiolocentric pigmented macrophage accumulation
    treatment_effect: INHIBITS
    description: >-
      Removing the exposure removes the stimulus for the pigmented-macrophage
      accumulation that constitutes the lesion.
    evidence:
    - reference: PMID:40081337
      reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Respiratory bronchiolitis-associated ILD mainly affects smokers, showing
        ground-glass opacities on chest computed tomography (CT) scans and
        pigmented macrophages in the bronchoalveolar lavage fluid.
      explanation: >-
        Establishes the smoking-to-macrophage-lesion link that makes removing the
        exposure a mechanism-directed intervention on this node.
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Smoking cessation is essential for treatment, with corticosteroids used for
      severe cases.
    explanation: >-
      States smoking cessation as the essential treatment for the smoking-related
      arm, with steroids reserved for severe disease.

- name: Nintedanib for progressive pulmonary fibrosis
  description: >-
    Antifibrotic tyrosine kinase inhibitor. Recommended for interstitial lung
    disease other than IPF that meets the progressive-pulmonary-fibrosis
    criteria, so the indication is keyed to observed disease behaviour rather
    than to the original histopathologic label.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: nintedanib
      term:
        id: CHEBI:85164
        label: nintedanib
  target_mechanisms:
  - target: Progressive pulmonary fibrosis
    treatment_effect: INHIBITS
    description: >-
      Nintedanib slows the fibrotic progression that defines the PPF behaviour,
      without reversing established fibrosis.
    evidence:
    - reference: PMID:35486072
      reference_title: "Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A conditional recommendation was made for nintedanib, and additional
        research into pirfenidone was recommended.
      explanation: >-
        The recommendation is made for the progressive-pulmonary-fibrosis
        behaviour that this target node models.
  evidence:
  - reference: PMID:35486072
    reference_title: "Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A conditional recommendation was made for nintedanib, and additional
      research into pirfenidone was recommended.
    explanation: >-
      The guideline recommendation that attaches antifibrotic therapy to the
      progressive-fibrosis behaviour rather than to a single entity.

- name: Supportive care
  description: >-
    The mainstay for acute interstitial pneumonia, where no therapy has been
    shown to alter the course, and a component of care across the family
    (supplemental oxygen when hypoxemic, symptom-directed and palliative
    measures). Pulmonary rehabilitation, previously named only inside this
    description, is now curated as its own treatment.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40081337
    reference_title: "Korean Guidelines for the Diagnosis and Management of Interstitial Lung Disease: Other Forms of Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute interstitial pneumonia resembles acute respiratory distress syndrome
      but occurs without a clear cause and is managed with supportive care.
    explanation: >-
      States supportive care as the management of the acute entity, in the
      absence of a disease-modifying option.

- name: Pulmonary rehabilitation
  description: >-
    Structured supervised exercise training and education. Applies across the
    family rather than to one entity, and is also the standard preparation for
    transplant candidates. The functional and quality-of-life benefit is
    established; a survival benefit is suggested at five years but is not
    settled, and the entry does not claim one.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:39805518
    reference_title: "Impact of Pulmonary Rehabilitation on Survival in People With Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary rehabilitation (PR) is a beneficial intervention for people with
      interstitial lung disease (ILD); however, the effect of PR on survival is
      unclear.
    explanation: >-
      States both the established benefit and the explicit limit of the evidence,
      which is why this entry claims function and quality of life but not
      survival.
  - reference: PMID:39805518
    reference_title: "Impact of Pulmonary Rehabilitation on Survival in People With Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participation in PR among people with ILD may impact survival at 5 years.
    explanation: >-
      The hedged survival signal from a pooled analysis of two randomized trials.
      Recorded as PARTIAL because the unadjusted comparison was not significant
      and no difference remained at ten years.

- name: Lung transplantation
  description: >-
    The only intervention that replaces the fibrotic lung rather than slowing its
    remodelling, and the definitive therapy for advanced fibrotic disease across
    this family rather than for one entity. Curated here rather than delegated to
    the IPF entry for exactly that reason. Access is limited by donor supply and
    by late referral, so timing of referral is itself a management decision.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Progressive pulmonary fibrosis
    treatment_effect: BYPASSES
    description: >-
      Transplantation does not act on the fibrotic mechanism at all; it removes
      the diseased organ, so the causal chain modelled here is bypassed rather
      than inhibited. BYPASSES is used deliberately in preference to INHIBITS,
      which would misstate the mechanism.
    evidence:
    - reference: PMID:40365094
      reference_title: "Lung transplantation for interstitial lung disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Interstitial lung diseases (ILDs) are now the most common indication for
        lung transplant internationally.
      explanation: >-
        Establishes that transplantation is directed at this disease family as a
        whole, which is what justifies attaching it to the shared
        progressive-fibrosis node rather than to a single entity.
  evidence:
  - reference: PMID:40365094
    reference_title: "Lung transplantation for interstitial lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite this increase many patients with ILD who would potentially benefit
      from lung transplant are either not referred or referred too late.
    explanation: >-
      Documents late referral as the practical limiting factor, supporting the
      description's emphasis on referral timing as a management decision.
  - reference: PMID:40365094
    reference_title: "Lung transplantation for interstitial lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unfortunately, the number of potential lung transplant recipients exceeds
      available donor organs and some patients will die without transplant.
    explanation: >-
      Documents the donor-supply constraint that bounds this therapy's reach.

discussions:
- discussion_id: disc_iip_unclassifiable_mixed_patterns
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    A substantial minority of patients cannot be assigned to any of the defined
    IIP entities because their lungs show mixed patterns of injury. Are these
    genuinely distinct disease processes awaiting definition, or does the
    pattern-based classification impose discrete boundaries on what is really a
    continuum of injury responses?
  attaches_to:
  - pathophysiology#Resolution of injury into a stereotyped histopathologic pattern
  rationale: >-
    The entire classification rests on the premise that the injured lung adopts
    one of a small number of discrete patterns. The 2013 ATS/ERS update records
    that a substantial percentage of patients defeat that premise, usually
    because more than one pattern is present in the same lung. This matters for
    a knowledge base: if the mixed cases are a continuum rather than a set of
    undiscovered entities, then the pattern nodes modelled here are convenient
    landmarks on a spectrum rather than mutually exclusive states, and a curated
    entry should not imply that a patient occupies exactly one of them.
  evidence:
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A substantial percentage of patients with IIP are difficult to classify,
      often due to mixed patterns of lung injury.
    explanation: >-
      The classification's own authors record the limitation this gap is about.

- discussion_id: disc_iip_behaviour_vs_pattern_classification
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Should an idiopathic interstitial pneumonia be classified by its
    histopathologic pattern or by its observed disease behaviour? The two axes
    disagree for the entities whose clinical course is heterogeneous, and
    antifibrotic therapy is now indicated on the behaviour axis while the entity
    name still comes from the pattern axis.
  attaches_to:
  - pathophysiology#Progressive pulmonary fibrosis
  - pathophysiology#Resolution of injury into a stereotyped histopathologic pattern
  rationale: >-
    The 2013 update proposed a behaviour-based classification precisely for the
    patients and entities the pattern-based scheme handles badly, and the 2022
    guideline then defined progressive pulmonary fibrosis as a behaviour that
    cuts across entities and carries its own treatment recommendation. The result
    is a family whose members are named on one axis and treated on another. Which
    axis a mechanism knowledge base should treat as primary is unresolved, and
    the answer determines whether progressive pulmonary fibrosis is modelled as a
    shared outcome node (as here) or as a separate cross-cutting entity.
  evidence:
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A classification based on observed disease behavior is proposed for
      patients who are difficult to classify or for entities with heterogeneity
      in clinical course.
    explanation: >-
      The behaviour-based alternative is proposed in the classification statement
      itself, which is what makes this a live tension rather than a settled
      question.
  - reference: PMID:24032382
    reference_title: "An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical course of idiopathic pulmonary fibrosis and nonspecific
      interstitial pneumonia is recognized to be heterogeneous.
    explanation: >-
      Names the heterogeneity within single entities that makes the pattern label
      an incomplete predictor of course.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Idiopathic Interstitial Pneumonia: Disease-Characteristics Research Report
Edison Scientific Literature 48 citations 2026-08-20T07:25:45.791095

Idiopathic Interstitial Pneumonia: Disease-Characteristics Research Report

Scope note. Idiopathic interstitial pneumonia (IIP) is a family of diffuse parenchymal lung diseases, not a synonym for idiopathic pulmonary fibrosis (IPF). IPF is the best-studied, usually most severe chronic fibrotic IIP; consequently, most quantitative genetics, epidemiology, prognosis, and treatment evidence below is IPF-specific and is labeled accordingly.

Executive summary

IIPs are defined by combinations of clinical presentation, high-resolution CT (HRCT), and histopathologic patterns after exclusion of connective-tissue disease, inhalational/occupational disease, drug toxicity, infection, and other known causes. Major entities include IPF, idiopathic nonspecific interstitial pneumonia (iNSIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), respiratory bronchiolitis–ILD (RB-ILD), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), and pleuroparenchymal fibroelastosis (PPFE). Multidisciplinary discussion among pulmonology, radiology, pathology, and—when appropriate—rheumatology is the diagnostic standard. (kreuter2021thediagnosisand pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 9-10, kreuter2021thediagnosisand pages 2-4)

The current IPF model is repeated alveolar epithelial injury in an aging, genetically susceptible lung, followed by abnormal repair, fibroblast/myofibroblast activation, extracellular-matrix (ECM) deposition, tissue stiffening, and self-sustaining fibrosis. Genetics includes the common MUC5B rs35705950 susceptibility allele and rare pathogenic variants in telomere- and surfactant-related genes. Antifibrotics slow IPF progression but do not reverse established fibrosis; pulmonary rehabilitation, oxygen when hypoxemic, symptom-directed care, and timely transplant referral remain essential. (zhumagaliyeva2025geneticdeterminantsof pages 2-4, zuo2025idiopathicpulmonaryfibrosis pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 2-4, viswanathan2024patientprofilebasedmanagement pages 17-18)

The following table provides an ontology-oriented synopsis.

Domain Knowledge-base summary Suggested ontology terms
Scope / classification Idiopathic interstitial pneumonia (IIP) is a family of idiopathic diffuse parenchymal lung diseases, not a single entity. Idiopathic pulmonary fibrosis (IPF) is one major fibrotic subtype within IIP. Major adult IIP subtypes commonly referenced in modern practice include IPF, idiopathic nonspecific interstitial pneumonia (iNSIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), respiratory bronchiolitis–ILD (RB-ILD), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), and pleuroparenchymal fibroelastosis (PPFE); multidisciplinary clinico-radiologic-pathologic diagnosis is central. (kreuter2021thediagnosisand pages 1-2, kreuter2021thediagnosisand pages 2-4) MONDO: idiopathic interstitial pneumonia (MONDO_0002429); EFO: idiopathic pulmonary fibrosis (EFO_0000768); disease labels: idiopathic NSIP, COP, AIP, RB-ILD, DIP, LIP, PPFE; imaging/pathology labels: UIP, NSIP, OP
Core phenotypes Typical fibrotic IIP/IPF phenotype is adult-onset progressive exertional dyspnea and chronic dry cough, often with bibasilar crackles and digital clubbing; physiology usually shows a restrictive ventilatory defect with reduced FVC and DLCO. Clubbing is reported in roughly 25–50% of IPF cases; cough burden can be substantial and QoL-limiting. (senhaji2026idiopathicpulmonaryfibrosis pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 7-9, senhaji2026idiopathicpulmonaryfibrosis pages 16-18) HPO: Dyspnea, Cough, Clubbing, Abnormal respiratory crackles, Restrictive ventilatory defect, Decreased diffusing capacity of lung for carbon monoxide
Anatomy / cells Primary site is the lung parenchyma, especially distal lung/alveolar regions with subpleural-basal predominance in UIP/IPF. Key involved cell types include alveolar type 2 epithelial cells (AT2), aberrant basaloid/bronchiolized epithelial cells, fibroblasts/myofibroblasts, macrophages (including SPP1-high), endothelial cells, and other stromal/immune populations. (zuo2025idiopathicpulmonaryfibrosis pages 1-2, zuo2025idiopathicpulmonaryfibrosis pages 2-2, senhaji2026idiopathicpulmonaryfibrosis pages 7-9) UBERON: lung, alveolus, lung interstitium, bronchiole, pleura; CL: alveolar type 2 epithelial cell, fibroblast, myofibroblast, macrophage, endothelial cell
Genetic architecture Genetic contribution spans rare pathogenic variants and common susceptibility alleles. Strongest common risk allele is MUC5B promoter rs35705950; rare high-effect variants occur in telomere genes (TERT, TERC, RTEL1, PARN) and surfactant-related genes (SFTPA1, SFTPA2, SFTPC, ABCA3). Familial pulmonary fibrosis often shows autosomal dominant inheritance with incomplete, age-dependent penetrance for rare telomere-pathway variants; common alleles also involve DSP, FAM13A, TOLLIP, DPP9 and related loci. (zhumagaliyeva2025geneticdeterminantsof pages 2-4, zhumagaliyeva2025geneticdeterminantsof pages 1-2, zhumagaliyeva2025geneticdeterminantsof pages 7-8, cerri2024geneticriskfactors pages 2-4, OpenTargets Search: idiopathic pulmonary fibrosis) Genes: MUC5B, TERT, TERC, RTEL1, PARN, SFTPA1, SFTPA2, SFTPC, ABCA3, DSP, FAM13A, TOLLIP, DPP9; variation labels: pathogenic/likely pathogenic variant, susceptibility allele, autosomal dominant inheritance, incomplete penetrance
Mechanism / pathophysiology Current model emphasizes repetitive alveolar epithelial injury in a genetically susceptible, aging lung, followed by aberrant repair, fibroblast expansion, myofibroblast differentiation, extracellular matrix accumulation, increasing tissue stiffness, and feed-forward profibrotic signaling. Core pathways include TGF-beta, Wnt/beta-catenin, Hippo/YAP-TAZ, Hedgehog, epithelial ER stress, senescence/telomere dysfunction, and immune-metabolic remodeling. Single-cell/spatial studies highlight IR-AT2, aberrant basaloid cells, CTHRC1+ fibroblasts, meflin+ fibroblasts, and SPP1hi macrophages in spatial fibrotic niches. (zuo2025idiopathicpulmonaryfibrosis pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 2-4, zuo2025idiopathicpulmonaryfibrosis pages 2-2, senhaji2026idiopathicpulmonaryfibrosis pages 4-5) GO: fibrotic process / fibrosis, transforming growth factor beta signaling pathway, extracellular matrix organization, epithelial to mesenchymal transition, cellular senescence, wound healing, collagen fibril organization; CL: alveolar type 2 epithelial cell, fibroblast, myofibroblast, macrophage
Diagnostics Diagnosis relies on multidisciplinary discussion integrating exposure/autoimmune history, serology, HRCT, PFTs, and sometimes tissue sampling. For IPF, HRCT showing definite/probable UIP with exclusion of alternative causes can establish diagnosis; biopsy/cryobiopsy is considered when imaging is indeterminate. Useful biomarker candidates include KL-6, SP-A/SP-D, and MMP-7, though broad routine implementation remains limited. Differential diagnosis includes CTD-ILD, hypersensitivity pneumonitis, asbestosis, drug-induced ILD, and non-IPF IIP subtypes. (senhaji2026idiopathicpulmonaryfibrosis pages 7-9, senhaji2026idiopathicpulmonaryfibrosis pages 9-10) Imaging/pathology labels: usual interstitial pneumonia (UIP), probable UIP, indeterminate for UIP, NSIP pattern, organizing pneumonia pattern; HPO: Abnormality of pulmonary function test; specimen terms: surgical lung biopsy, transbronchial lung cryobiopsy
Treatment Antifibrotics are standard for IPF: nintedanib and pirfenidone slow FVC decline and reduce progression/exacerbation risk. Nonpharmacologic management includes pulmonary rehabilitation, supplemental oxygen when indicated, symptom-focused supportive/palliative care, vaccination and comorbidity management, and lung transplantation for appropriate candidates. Management differs across IIP subtypes: e.g., COP is typically corticosteroid-responsive, smoking-related RB-ILD/DIP emphasize smoking cessation, and non-IPF inflammatory phenotypes may involve immunomodulation rather than primary antifibrotic therapy. (kreuter2021thediagnosisand pages 1-2, viswanathan2024patientprofilebasedmanagement pages 17-18, senhaji2026idiopathicpulmonaryfibrosis pages 12-14, man2024acomparisonof pages 4-5) NCIT/intervention labels: Nintedanib, Pirfenidone, Pulmonary Rehabilitation, Oxygen Therapy, Lung Transplantation, Palliative Care, Corticosteroid Therapy, Smoking Cessation
Models / other species Human IIP/IPF is modeled mainly with induced pulmonary fibrosis systems rather than a fully faithful spontaneous animal disease. Common platforms include bleomycin-induced fibrosis (mouse and other species), xenograft models using human IPF fibroblasts, genetic/telomere-related models, and ex vivo/in vitro systems such as lung explants or organoid-like epithelial-fibroblast models. Naturally occurring canine pulmonary fibrosis, especially in West Highland White Terriers, shows similarities to human IPF but has limited utility because of low prevalence and incompletely defined pathogenesis; zoonotic transmission is not a feature. (frohlich2024animalsinrespiratory pages 17-18) NCBI Taxon labels: Homo sapiens, Mus musculus, Canis lupus familiaris; model labels: bleomycin-induced pulmonary fibrosis, xenograft model, genetic model, lung explant, organoid

Table: This compact table organizes the key knowledge-base domains for idiopathic interstitial pneumonia, explicitly distinguishing the IIP family from IPF as a subtype. It also provides ontology-ready term suggestions to support structured disease annotation.

1. Disease information

Definition and classification

IIPs are idiopathic disorders involving the lung interstitium, alveoli, small airways, and—in PPFE—the pleura/subpleural lung. Classification is clinicoradiologic-pathologic:

  • Chronic fibrosing: IPF/UIP, iNSIP; PPFE is a rare distinctive fibrosing entity.
  • Smoking-related: RB-ILD and DIP.
  • Acute/subacute: COP and AIP.
  • Rare lymphoid: idiopathic LIP.
  • Unclassifiable IIP: used when available clinical, imaging, or pathologic findings are discordant or insufficient.

UIP is a morphologic pattern and is not automatically IPF: it can occur with connective-tissue disease, chronic hypersensitivity pneumonitis, asbestosis, and other conditions. IPF requires an idiopathic clinical context plus a definite/probable UIP pattern and exclusion of alternatives. UIP pathology is temporally and spatially heterogeneous, with fibroblast foci, architectural destruction, and honeycomb change; NSIP is more temporally uniform. (drimus2025highresolutionctfindings pages 10-12, kreuter2021thediagnosisand pages 16-16, senhaji2026idiopathicpulmonaryfibrosis pages 9-10)

Identifiers and synonyms

  • MONDO: idiopathic interstitial pneumonia, MONDO_0002429.
  • IPF cross-resource identifier retrieved: EFO_0000768.
  • Common umbrella synonyms: idiopathic interstitial pneumonias, idiopathic diffuse parenchymal lung diseases.
  • Historical terms should be mapped cautiously: cryptogenic fibrosing alveolitis generally maps to IPF, while bronchiolitis obliterans organizing pneumonia is an older term for COP.
  • A reliable single OMIM or Orphanet entry does not represent the whole IIP family. Familial pulmonary fibrosis/telomere syndromes should be represented separately from sporadic IIP.
  • ICD coding is jurisdiction/version dependent and often conflates morphologic patterns and diseases; J84-series codes are generally used for other interstitial pulmonary diseases. Exact ICD-10-CM/ICD-11 subtype mapping should be validated against the release deployed by the knowledge base rather than inferred from literature.

The information in this report is aggregated disease-level evidence from guidelines, reviews, trials, and cohorts—not individual-patient EHR data.

2. Etiology and risk/protective factors

Causal framework

“Iidiopathic” means that no single external or systemic cause is demonstrable after evaluation; it does not mean absence of risk factors. In IPF, aging, inherited epithelial vulnerability, and repeated environmental microinjury interact. AIP is an idiopathic diffuse alveolar-damage syndrome; COP reflects idiopathic organizing injury; RB-ILD/DIP are strongly associated with tobacco smoke despite retaining historical IIP labels.

Genetic factors

Common susceptibility allele—not a Mendelian cause:

  • MUC5B rs35705950, a promoter variant, is the strongest common IPF susceptibility factor. Reported risk is approximately sixfold in heterozygotes and 20-fold in homozygotes, with about 34-fold higher expression in unaffected lung. Penetrance is incomplete, and carriers paradoxically tend to have better survival once IPF occurs. Minor-allele frequency is population dependent: approximately 0.11 in Europeans, 0.02 in African/African-American populations, and 0.007 in East Asians. (zhumagaliyeva2025geneticdeterminantsof pages 2-4, liu2025anoverviewof pages 1-3)
  • Other common susceptibility loci include DSP, FAM13A, TOLLIP, DPP9, ATP11A, SPPL2C, and telomere-associated loci. A 2024 systematic review found 88 associated SNPs across 58 genes/loci; observed odds ratios ranged from 0.27 to 7.82, but functional relevance remained unknown for about half of implicated genes. (dhooria2024commonsinglenucleotide pages 12-13)

Rare pathogenic/likely pathogenic variants:

  • Telomere maintenance: TERT, TERC, RTEL1, PARN, plus less frequent genes such as NAF1. These are generally germline loss-of-function or function-disrupting variants and can produce short-telomere syndromes with pulmonary fibrosis, bone-marrow failure, liver disease, premature graying, or related features.
  • Surfactant/epithelial homeostasis: SFTPA1, SFTPA2, SFTPC, ABCA3. Missense variants may cause protein misfolding, ER stress, impaired surfactant processing, and epithelial apoptosis; ABCA3 disease is often recessive, whereas adult familial disease involving SFTPC/SFTPA genes is commonly dominant.
  • Rare telomere variants occur in roughly 20–30% of familial and 2–5% of sporadic pulmonary-fibrosis cases. One review estimated pathogenic variants with frequency below 0.1% in about one-quarter of familial pulmonary-fibrosis families. (zhumagaliyeva2025geneticdeterminantsof pages 2-4, zhumagaliyeva2025geneticdeterminantsof pages 7-8, cerri2024geneticriskfactors pages 2-4)
  • Open Targets identifies evidence linking IIP/IPF to TERT, PARN, RTEL1, SFTPA2, MUC5B, and DSP, with supporting studies including PMIDs 25848748, 26116823, 23453664, 23959892, 19100526, 20502709, 21506741, and 26669357. (OpenTargets Search: idiopathic pulmonary fibrosis)

Inheritance: Familial pulmonary fibrosis is usually autosomal dominant with incomplete, age-dependent penetrance and variable expressivity. For TERT variants, penetrance after age 60 has been estimated at about 60% in men and 50% in women. Anticipation-like earlier disease may occur through inherited telomere shortening, but this is not a classical repeat-expansion disorder. Germline mosaicism, carrier frequency, and founder effects are variant/family specific; no general values are established for IIP. (zhumagaliyeva2025geneticdeterminantsof pages 1-2, zhumagaliyeva2025geneticdeterminantsof pages 7-8)

Variant annotation caveat: Pathogenicity, ACMG class, HGNC ID, exact consequence, and gnomAD frequency must be stored per variant, not assigned at gene level. MUC5B rs35705950 should be annotated as a common risk allele, not “pathogenic.” Chromosomal aneuploidy, recurrent translocation, mitochondrial inheritance, and repeat expansions are not established general causes of adult IIP.

Environmental and lifestyle factors

Human epidemiologic evidence implicates cigarette smoke, metal/wood/stone/silica-containing dusts, farming and livestock exposures, air pollution, and possibly chronic microaspiration. Male sex and older age are strong demographic correlates. Increased airway bacterial burden/dysbiosis has been observed, but no bacterium or virus is established as the primary cause of IPF. Gastroesophageal reflux and microaspiration are plausible epithelial-injury amplifiers, not proven universal causes. (zhumagaliyeva2025geneticdeterminantsof pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 4-5, senhaji2026idiopathicpulmonaryfibrosis pages 7-9)

Gene–environment interaction and protective factors

A useful causal model is: rare/common genetic susceptibility + aging → reduced epithelial resilience; smoking/dust/pollution/microaspiration → repeated injury; impaired repair → fibrosis. Environmental exposures markedly raise disease likelihood in telomere-variant carriers. (zhumagaliyeva2025geneticdeterminantsof pages 1-2, zhumagaliyeva2025geneticdeterminantsof pages 7-8)

No genetic or dietary factor is validated as broadly protective. Smoking avoidance/cessation, occupational exposure control, and air-quality improvement are prudent risk-reduction measures, but direct evidence that they prevent idiopathic IPF is limited. The apparent survival advantage of MUC5B rs35705950 after diagnosis is prognostic and should not be interpreted as protective against disease onset. TOLLIP–N-acetylcysteine pharmacogenetic findings remain investigational. (zhumagaliyeva2025geneticdeterminantsof pages 2-4, senhaji2026idiopathicpulmonaryfibrosis pages 4-5)

3. Phenotypes

Core IPF/fibrotic-IIP phenotype

  • Progressive exertional dyspnea: adult/late-adult onset; initially exertional, ultimately severe and activity limiting. Suggested HPO: Dyspnea, Exercise intolerance.
  • Chronic usually dry cough: progressive or persistent; reported in approximately 20–80% of IPF cohorts. Suggested HPO: Cough. (senhaji2026idiopathicpulmonaryfibrosis pages 16-18)
  • Fine bibasal inspiratory crackles: common physical sign. Suggested HPO: Abnormal respiratory crackles.
  • Digital clubbing: about 25–50% in IPF. Suggested HPO: Clubbing. (senhaji2026idiopathicpulmonaryfibrosis pages 7-9)
  • Restrictive physiology: reduced FVC/TLC with reduced DLCO; severity varies and typically progresses. Suggested HPO: Restrictive ventilatory defect, Decreased DLCO.
  • Exertional hypoxemia and reduced six-minute-walk distance: downstream gas-exchange and functional abnormalities; poor values predict worse outcome.
  • Fatigue, deconditioning, anxiety/depression: important secondary manifestations; depression was reported in 22% of pharmaceutical-trial cohorts. (walters2025comorbiditiesinthe pages 3-4)

Subtype variation

  • COP: subacute cough, dyspnea, fever/malaise, patchy peripheral or peribronchovascular consolidation; often steroid responsive but may relapse.
  • AIP: abrupt respiratory failure over days to weeks, bilateral opacities, diffuse alveolar damage; very severe.
  • iNSIP: subacute/chronic dyspnea and cough, usually more uniform ground-glass/reticular disease; cellular forms may improve, fibrotic forms may progress.
  • RB-ILD/DIP: smokers, cough/dyspnea and reduced DLCO; often mild-to-moderate but occasionally progressive.
  • LIP: cough/dyspnea with diffuse ground glass, nodules, septal thickening, and cysts; autoimmune/immunodeficiency causes must be excluded.
  • PPFE: upper-lobe pleural/subpleural fibrosis, reduced chest dimensions, low BMI, recurrent pneumothorax, and progressive restriction.

Robust phenotype frequencies for these rare subtypes are not consistently available. HPO terms should therefore be linked with evidence strength rather than assumed universal.

Quality of life

Dyspnea, cough, oxygen dependence, fatigue, and loss of mobility substantially impair health-related quality of life; one molecular-profiling report described mobility-limiting dyspnea and quality of life lower than in many malignancies. Pulmonary rehabilitation improves walk distance, dyspnea, and quality of life over 12–16 weeks, although benefits may diminish after six months. (jiang2025exploringthecellular pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 16-18)

4. Genetic and molecular information

Gene/protein consequences

  • TERT/TERC/RTEL1/PARN: deficient telomere maintenance → critically short telomeres → AT2-cell senescence/apoptosis and reduced regenerative capacity.
  • SFTPC/SFTPA1/SFTPA2/ABCA3: aberrant surfactant synthesis/processing → misfolding, ER stress, unfolded-protein response, epithelial death.
  • MUC5B rs35705950: excessive distal-airway MUC5B → impaired mucociliary clearance and altered epithelial microenvironment.
  • DSP: compromised epithelial adhesion/barrier integrity.
  • TOLLIP: altered innate immune signaling and possible treatment-response modification.

Telomere-variant carriers have aggressive disease: median transplant-free survival was reported as 4.2 years versus 7.2 years in noncarriers, with approximately 300 mL annual FVC decline and a 5.8-percentage-point annual DLCO decline. (zhumagaliyeva2025geneticdeterminantsof pages 7-8)

Modifier and epigenetic information

Common polygenic background modifies susceptibility and outcome around rare variants. DNA methylation, histone changes, miR-21/miR-29 and other noncoding RNAs regulate TGF-β signaling, ECM production, epithelial transition states, and fibroblast activation. Approximately one-fifth of gene-expression differences in IPF fibroblasts have been associated with altered methylation, but causality and clinical utility remain unproven. (senhaji2026idiopathicpulmonaryfibrosis pages 2-4, cerri2024geneticriskfactors pages 2-4)

Somatic copy-number changes on chromosomes 16 and 19 have been reported in abnormal epithelial cells, but they are research observations—not routine diagnostic lesions. No recurrent large chromosomal abnormality defines IIP. (zuo2025idiopathicpulmonaryfibrosis pages 2-2)

5. Environmental information

Relevant non-genetic exposures include tobacco smoke, occupational inorganic/organic dust, ambient particulate pollution, and recurrent aspiration. They should be recorded with exposure intensity, duration, latency, protective-equipment use, and temporal relationship. A disease remains “idiopathic” only after plausible causal exposure syndromes—especially hypersensitivity pneumonitis, pneumoconiosis/asbestosis, and drug-induced ILD—are reasonably excluded.

Infection may trigger acute worsening, and altered communities enriched for organisms such as Staphylococcus and Streptococcus have been reported, but microbiome association does not establish infectious causation. No vaccine prevents IIP itself. (senhaji2026idiopathicpulmonaryfibrosis pages 7-9)

Suggested CHEBI-level exposure labels include nicotine/tobacco-smoke constituents, crystalline silica, asbestos fibers, and particulate matter where supported by a patient-specific exposure history; these are risk/exclusion annotations, not universal IIP causes.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream susceptibility: aging, telomere shortening, surfactant/epithelial variants, MUC5B-associated mucociliary dysfunction, smoking/dust/pollution or aspiration.
  2. Initiating injury: repeated AT1/AT2 epithelial injury, ER and oxidative stress, mitochondrial dysfunction, apoptosis/senescence, basement-membrane disruption.
  3. Aberrant repair: AT2 regenerative failure and emergence of transitional/aberrant basaloid epithelium; TGF-β, PDGF, FGF, Wnt/β-catenin, Hedgehog, and Hippo/YAP–TAZ signaling become activated.
  4. Mesenchymal response: fibroblast recruitment/proliferation and myofibroblast differentiation; collagen, fibronectin, and other ECM accumulate.
  5. Feed-forward fibrosis: matrix stiffening further activates integrins and YAP/TAZ, maintaining TGF-β activity and fibroblast survival.
  6. Tissue/clinical outcome: fibroblastic foci, traction bronchiectasis, honeycomb remodeling, reduced compliance and diffusion, hypoxemia, pulmonary hypertension, and respiratory failure. (senhaji2026idiopathicpulmonaryfibrosis pages 2-4, zuo2025idiopathicpulmonaryfibrosis pages 2-2)

Cells, immunity, metabolism, and profiling

Single-cell/spatial studies identify IPF-related AT2 cells, KRT5−/KRT17+ aberrant basaloid cells, CTHRC1+ collagen-producing fibroblasts, meflin+ fibroblasts, and SPP1-high macrophages. These findings support disease as a spatially organized epithelial–mesenchymal–immune–vascular network rather than isolated fibroblast dysfunction. (zuo2025idiopathicpulmonaryfibrosis pages 1-2)

Immune cells provide profibrotic cytokines and metabolic signals; macrophage polarization changes as distal remodeling advances. Chronic inflammation is contributory, but IPF is no longer viewed primarily as an inflammatory disease. Altered glycolysis, lipid handling, mitochondrial energetics, iron homeostasis, and amino-acid metabolism are reported, but none is yet a routine biochemical diagnostic defect.

A recent multi-omics computational study identified GREM1, UGT1A6, CDH2, TDO2, HS3ST1, ADGRF5, and MPO and reported an AUC of 0.987; because protein-level and prospective validation are lacking, this should be stored as discovery-stage evidence. (jiang2025exploringthecellular pages 1-2)

Suggested annotations:

  • GO biological process: extracellular matrix organization; collagen fibril organization; wound healing; TGF-β receptor signaling; epithelial-cell apoptosis; cellular senescence; response to oxidative stress; epithelial-to-mesenchymal transition.
  • GO cellular component: extracellular matrix, endoplasmic reticulum, mitochondrion, telomere, basement membrane.
  • CL: alveolar type 1 cell, alveolar type 2 cell, airway basal cell, fibroblast, myofibroblast, macrophage, endothelial cell, plasma cell.

7. Anatomical structures affected

  • Primary organ/system: bilateral lungs; respiratory system.
  • Primary sites: distal parenchyma, alveoli, interstitium, alveolar-capillary interface. UIP/IPF is predominantly basal and subpleural; PPFE is upper-lobe pleural/subpleural.
  • Tissues: alveolar epithelium, basement membrane, interstitial connective tissue, pulmonary microvasculature, and distal airways.
  • Secondary effects: pulmonary vasculature/right ventricle through pulmonary hypertension; systemic skeletal muscle through hypoxemia and deconditioning.
  • Lateralization: generally bilateral, frequently heterogeneous and asymmetric in severity—not a unilateral disease.

Suggested UBERON labels: lung, pulmonary alveolus, lung interstitium, respiratory bronchiole, visceral pleura, pulmonary artery. Suggested GO-CC: extracellular matrix, basement membrane, endoplasmic reticulum, mitochondrion, telomere.

8. Temporal development

IPF usually begins insidiously after age 50, with a mean around 66 years in one review and male predominance. Symptoms evolve over months to years, followed by variable but usually irreversible progression. Some patients decline steadily, some remain temporarily stable, and others have stepwise loss from acute exacerbations. (senhaji2026idiopathicpulmonaryfibrosis pages 1-2, senhaji2026idiopathicpulmonaryfibrosis pages 7-9)

A practical stage model is:

  • Preclinical susceptibility/ILA: incidental interstitial lung abnormalities; reported progression risk approximately 20% at two years and up to 50% by four to six years.
  • Early disease: mild symptoms, preserved volumes but reduced DLCO, limited CT fibrosis.
  • Established progressive fibrosis: worsening symptoms, FVC/DLCO decline, increasing traction bronchiectasis/honeycombing.
  • Advanced/end stage: resting/exertional hypoxemia, pulmonary hypertension, respiratory failure, transplant or palliative-care needs. (senhaji2026idiopathicpulmonaryfibrosis pages 9-10)

For non-IPF fibrotic ILD, the 2022 PPF construct requires at least two of worsening symptoms, physiologic progression (absolute FVC decline ≥5% or DLCO decline ≥10%), and radiologic progression within one year, with no alternative explanation. Expert consensus also regards ≥10% FVC decline or unequivocal HRCT progression as sufficient evidence of clinically important progression. (senhaji2026idiopathicpulmonaryfibrosis pages 9-10)

COP and cellular NSIP may remit spontaneously or with corticosteroids; relapse can occur. AIP is acute and often fatal. IPF rarely remits, and current therapy slows rather than reverses it.

9. Inheritance and population epidemiology

Epidemiology

IIP-family incidence is difficult to aggregate because definitions and coding vary. For IPF, a meta-analysis of 26 studies through November 7, 2023 estimated:

  • Global incidence: 5.8/100,000/year; Asia 4.4, Europe 5.1, North America 9.0.
  • Global prevalence: 17.7/100,000; Asia 14.8, Europe 14.6, North America 27.2.

The authors emphasized substantial heterogeneity from case algorithms, referral populations, diagnostic definitions, and regional exposures. (golchin2025incidenceandprevalence pages 1-2)

IPF predominantly affects older adults and men; a roughly 3:1 male:female ratio is reported in one pooled overview, though registry ratios vary. MUC5B frequency and IPF burden are higher in European-ancestry populations, but underdiagnosis and ascertainment differences complicate ethnic comparisons. (liu2025anoverviewof pages 1-3, golchin2025incidenceandprevalence pages 1-2)

Familial disease

Familial pulmonary fibrosis accounts for approximately 5–20% of IPF/pulmonary-fibrosis presentations depending on definition and ascertainment. Inheritance is usually multifactorial/polygenic in sporadic disease and autosomal dominant with incomplete age-dependent penetrance in many rare-variant families. Consanguinity is particularly relevant to recessive surfactant disorders such as ABCA3 deficiency, but not to typical late-onset IPF. (zhumagaliyeva2025geneticdeterminantsof pages 1-2, liu2025anoverviewof pages 1-3)

10. Diagnostics

Clinical workflow

  1. Confirm ILD clinically and with HRCT.
  2. Obtain detailed drug, occupational, environmental, avian/mold, smoking, aspiration, and family history.
  3. Screen for connective-tissue disease using examination and targeted serology.
  4. Perform spirometry, lung volumes, DLCO, resting/exertional oximetry, and six-minute walk testing.
  5. Conduct multidisciplinary review.
  6. Use BAL, cryobiopsy, or surgical biopsy selectively when the diagnosis remains uncertain and results would change management. (senhaji2026idiopathicpulmonaryfibrosis pages 7-9, senhaji2026idiopathicpulmonaryfibrosis pages 9-10, kreuter2021thediagnosisand pages 2-4)

Imaging and pathology

Definite UIP HRCT: basal/subpleural reticulation, traction bronchiectasis/bronchiolectasis, and honeycombing without features suggesting another diagnosis. Probable UIP: similar distribution and traction change without honeycombing. NSIP is more uniform, commonly with ground-glass opacity, fine reticulation, and subpleural sparing. (drimus2025highresolutionctfindings pages 10-12, senhaji2026idiopathicpulmonaryfibrosis pages 7-9)

When tissue is needed, transbronchial cryobiopsy has reported diagnostic yields of 74–98% in selected experienced centers. Surgical lung-biopsy mortality is approximately 1.7% electively but 17% in nonelective procedures; reported complications include infection 6.5%, acute IPF exacerbation 6.4%, prolonged air leak 5.9%, and bleeding 0.8%. (senhaji2026idiopathicpulmonaryfibrosis pages 9-10)

Biomarkers and omics

Candidate serum markers include KL-6/MUC1, SP-A, SP-D, MMP-7, YKL-40, periostin, and collagen-turnover products. KL-6 tracks epithelial activation and disease extent; MMP-7 correlates with fibrosis burden, FVC/DLCO decline, and mortality. None replaces multidisciplinary diagnosis, and standardized broad clinical implementation remains limited. (senhaji2026idiopathicpulmonaryfibrosis pages 9-10)

RNA-seq, proteomics, metabolomics, epigenomics, liquid biopsy, xenon MRI, radiomics, and machine learning remain investigational. They should not be represented as validated routine diagnostics.

Genetic testing

Testing is most appropriate for familial pulmonary fibrosis, onset before approximately 50 years, syndromic short-telomere features, or suspected surfactant disorder. Recommended strategy is genetic counseling followed by a pulmonary-fibrosis panel including telomere and surfactant genes; WES/WGS can be used if panel testing is negative or phenotype is atypical. Telomere-length testing may support interpretation but is not gene specific. CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion assays are not routine for typical IIP.

Differential diagnosis

Exclude connective-tissue disease–ILD, fibrotic hypersensitivity pneumonitis, occupational pneumoconiosis/asbestosis, drug/radiation injury, sarcoidosis, infection, edema, aspiration, smoking-related disease, and other IIP subtypes. A UIP pattern alone does not settle etiology. (drimus2025highresolutionctfindings pages 10-12, senhaji2026idiopathicpulmonaryfibrosis pages 9-10)

Screening

No population screening is recommended. First-degree relatives in familial pulmonary fibrosis may be offered genetic counseling, symptom/PFT assessment, and individualized HRCT surveillance in specialist programs. Incidental ILA warrants risk-based follow-up, not automatic labeling as IPF.

11. Outcome and prognosis

IPF median survival is approximately 3–5 years after diagnosis, but individual trajectories vary. Telomere variants, older age, male sex, low or rapidly falling FVC/DLCO, reduced walk distance/desaturation, extensive HRCT fibrosis, pulmonary hypertension, and acute exacerbation predict worse outcome. (zhumagaliyeva2025geneticdeterminantsof pages 7-8, senhaji2026idiopathicpulmonaryfibrosis pages 1-2, golchin2025incidenceandprevalence pages 1-2)

Acute exacerbations occur in approximately 5–20% annually and carry extremely poor outcomes—reported mortality near 80% and median survival of 3–4 months. Pulmonary hypertension affects approximately 8–15% at diagnosis and up to 86% in advanced disease. Combined pulmonary fibrosis/emphysema occurs in 8–51% of IPF series and has reported median survival of 25 months. (senhaji2026idiopathicpulmonaryfibrosis pages 16-18, senhaji2026idiopathicpulmonaryfibrosis pages 18-20)

IPF is associated with about a fivefold increased lung-cancer risk; one synthesis reported cumulative incidence of 3.3% at one year, 15.4% at five years, and 54.7% at ten years, although the highest estimate may reflect selected long-term cohorts and competing-risk methods. (senhaji2026idiopathicpulmonaryfibrosis pages 16-18)

Common trial-cohort comorbidities include gastroesophageal reflux 45%, hypertension 45%, hyperlipidemia 38%, ischemic heart disease 18%, diabetes 16%, and depression 22%. Trial populations generally underrepresent multimorbid real-world patients. (walters2025comorbiditiesinthe pages 3-4)

COP and cellular NSIP usually have substantially better prognosis than IPF; fibrotic NSIP, PPFE, and some DIP/LIP cases may develop progressive fibrosis. AIP has high short-term mortality. No universal five- or ten-year survival statistic is valid across the entire IIP family.

12. Treatment

IPF pharmacotherapy

  • Nintedanib—intracellular tyrosine-kinase inhibitor targeting VEGFR/FGFR/PDGFR signaling; NCIT suggestion: Nintedanib Treatment. In INPULSIS, annual FVC decline was −113.6 mL versus −207.3 mL with placebo. Another synthesis reported −124 versus −218 mL/year. Diarrhea occurred in 52.5% versus 16.1% with placebo; nausea, anorexia, weight loss, transaminase elevation, and bleeding risk also require monitoring. (viswanathan2024patientprofilebasedmanagement pages 17-18, man2024acomparisonof pages 4-5)
  • Pirfenidone—antifibrotic with effects on TGF-β-associated signaling; NCIT suggestion: Pirfenidone Treatment. CAPACITY/ASCEND showed slower FVC decline and a pooled 48% relative reduction in risk of death in one review. Important adverse effects are nausea/dyspepsia, appetite/weight loss, photosensitivity/rash, and hepatotoxicity. (senhaji2026idiopathicpulmonaryfibrosis pages 12-14)

Neither therapy reverses fibrosis. Comparative evidence does not establish a universally superior agent; selection depends on comorbidities, interactions, adverse-effect profile, access, and patient preference. Routine prednisone/azathioprine/N-acetylcysteine combination therapy is inappropriate for IPF.

Subtype-specific strategy

  • iNSIP: identify occult autoimmune disease; corticosteroids with or without steroid-sparing immunomodulation for inflammatory disease; consider antifibrotic treatment if a progressive fibrotic phenotype emerges.
  • COP: systemic corticosteroids are typical; observe selected mild cases and treat relapses individually.
  • AIP: ICU supportive care, lung-protective ventilation; corticosteroids are often used despite weak evidence.
  • RB-ILD/DIP: smoking cessation and exposure removal; corticosteroids for clinically important persistent disease.
  • LIP: treat an identified autoimmune, immunodeficiency, or infectious driver; corticosteroids/immunomodulation in selected idiopathic cases.
  • PPFE: no proven disease-modifying drug; manage complications and refer early for transplantation if progressive.

Supportive and interventional care

Pulmonary rehabilitation, oxygen for resting/exertional hypoxemia, vaccination, nutrition, cough and dyspnea management, comorbidity treatment, advance-care planning, and palliative care are core components. Rehabilitation improves walk distance, dyspnea, and quality of life over 12–16 weeks. Lung transplantation is the only intervention capable of replacing the fibrotic lungs; approximately half of more than 4,600 annual lung transplants worldwide are performed for ILD. (senhaji2026idiopathicpulmonaryfibrosis pages 16-18)

Suggested NCIT interventions: oxygen therapy, pulmonary rehabilitation, lung transplantation, palliative care, smoking cessation, corticosteroid therapy.

Emerging trials

ClinicalTrials.gov searches identified ongoing/recent phase II–III IPF studies including:

  • BMS-986278, phase III, NCT06003426, approximately 1,255 participants; lysophosphatidic-acid receptor 1 antagonist.
  • SC1011, phase II/III, NCT06125327, 210 participants.
  • Axatilimab, phase II MAXPIRe, NCT06132256, 145 participants; CSF1R-directed monoclonal antibody.
  • DWN12088, phase II, NCT05389215, 102 participants; prolyl-tRNA synthetase inhibitor.
  • LYT-100/deupirfenidone, phase II, NCT05321420, 240 participants.
  • CAL101, phase II, NCT06736990, 150 participants.

Trial status and enrollment change over time; these entries are experimental and should be refreshed directly from https://clinicaltrials.gov before operational use.

No approved gene, RNA, or cell therapy exists for IIP/IPF. Cell therapies, senolytics, integrin inhibitors, telomere-directed approaches, and epithelial regenerative strategies remain experimental.

13. Prevention

There is no proven primary prevention for idiopathic disease. Reasonable measures are smoking avoidance/cessation, control of occupational dust and fumes, respiratory protection, air-pollution mitigation, and avoidance of unnecessary pneumotoxic drugs. Vaccination against influenza, COVID-19, pneumococcus, and other age/risk-appropriate infections is tertiary prevention of infection-related morbidity, not prevention of IIP.

Secondary prevention consists of earlier recognition in symptomatic or high-risk familial individuals, specialist review of incidental ILA, and surveillance for physiologic/radiologic progression. Tertiary prevention includes antifibrotics for IPF, oxygen, rehabilitation, infection prevention, comorbidity management, early transplant referral, and advance-care planning.

For families with a pathogenic variant, genetic counseling should address autosomal-dominant, age-dependent risk, variable expressivity, cascade testing, reproductive options, and possible preimplantation/prenatal testing. Such counseling is not indicated merely because a patient carries the common MUC5B risk allele.

14. Other species and natural disease

Naturally occurring canine pulmonary fibrosis, particularly in West Highland White Terriers (Canis lupus familiaris, NCBI Taxon 9615), can resemble human IPF through subpleural/peribronchiolar fibrosis, alveolar epithelial changes, and ground-glass opacities. Its low prevalence and incompletely defined pathogenesis limit its utility as a standardized model. (frohlich2024animalsinrespiratory pages 17-18)

Pulmonary fibrosis also occurs in cats and other animals, but veterinary entities should not be assumed orthologous to human IIP without molecular validation. Conserved TGF-β, ECM, epithelial-injury, senescence, and telomere mechanisms support comparative research. IIP is noninfectious and has no zoonotic transmission.

No confidently validated VBO breed identifier or single orthologous causal gene for canine idiopathic pulmonary fibrosis was retrieved; these should be left unassigned rather than inferred.

15. Model organisms and experimental systems

  • Bleomycin-induced fibrosis: most common mouse model; also produces fibrosis in nonhuman primates, dogs, and sheep. Strengths are reproducibility and utility for inflammatory/fibrotic pathways. Major limitation: injury is acute and often partially reversible, unlike heterogeneous, age-related, relentlessly progressive human IPF. (frohlich2024animalsinrespiratory pages 17-18)
  • Human-cell xenograft: injection of IPF fibroblasts into immunodeficient mice can generate a fibrotic phenotype within 30–35 days; useful for human mesenchymal behavior but lacks an intact immune system. (frohlich2024animalsinrespiratory pages 17-18)
  • Genetic models: telomerase/telomere, surfactant-processing, epithelial-injury, senescence, and TGF-β pathway perturbations dissect specific mechanisms but rarely recapitulate the full human disease.
  • Viral/aging models: murine gammaherpesvirus-68 in aged mice models infection–aging interaction, not idiopathic disease itself.
  • In vitro/ex vivo: primary AT2 cells, fibroblasts, precision-cut lung slices, air–liquid-interface cultures, organoids, iPSC-derived epithelium, and decellularized ECM permit human-specific perturbation and screening but lack whole-organ mechanics, circulation, and complete immunity.

No existing model reproduces the complete human phenotype. A translational strategy combining human tissue/single-cell data, organoid or explant systems, and more than one in-vivo model is preferable.

Recent developments and expert interpretation

The most important 2023–2024 developments were: systematic consolidation of common IPF risk alleles; greater clinical attention to telomere/surfactant genetics; maturation of single-cell/spatial maps of epithelial, fibroblast, and macrophage niches; consensus operationalization of progressive pulmonary fibrosis; and expanded real-world guidance for antifibrotic and holistic care. The 2024 SNP review concluded that “several common single nucleotide polymorphisms in over 50 genes have been found associated with susceptibility to idiopathic pulmonary fibrosis,” while noting that the function of more than half remains unexplored. (dhooria2024commonsinglenucleotide pages 12-13)

A 2024 treatment position statement emphasized a “multi-faceted approach to the management of IPF and progressive pulmonary fibrosis,” reflecting expert consensus that drug therapy alone is insufficient. (viswanathan2024patientprofilebasedmanagement pages 17-18)

The evidence base has important gaps: subtype-specific IIP epidemiology and phenotype frequencies are sparse; no biomarker panel is sufficiently validated to replace multidisciplinary diagnosis; polygenic scores are not ready for population screening; spatial/single-cell signatures remain discovery tools; and the absence of a faithful progressive animal model continues to impede translation.

Selected dated sources and URLs

  • Dhooria et al. July 2024, European Respiratory Review, common IPF SNP systematic review: https://doi.org/10.1183/16000617.0018-2024. (dhooria2024commonsinglenucleotide pages 12-13)
  • Cerri et al. November 2024, genetics/epigenetics of idiopathic and non-idiopathic ILD: https://doi.org/10.3390/medicina60121967. (cerri2024geneticriskfactors pages 2-4)
  • Viswanathan et al. September 2024, nintedanib and real-world management: https://doi.org/10.1007/s41030-024-00271-1. (viswanathan2024patientprofilebasedmanagement pages 17-18)
  • Man et al. February 2024, nintedanib versus pirfenidone systematic review: https://doi.org/10.7759/cureus.54268. (man2024acomparisonof pages 4-5)
  • Fröhlich. March 2024, respiratory animal models: https://doi.org/10.3390/ijms25052903. (frohlich2024animalsinrespiratory pages 17-18)
  • Wells et al. December 2024, expert consensus on progressive pulmonary fibrosis: https://doi.org/10.1186/s12931-024-03070-z.
  • Golchin et al. August 2025, epidemiologic meta-analysis using studies through November 2023: https://doi.org/10.1186/s12890-025-03836-1. (golchin2025incidenceandprevalence pages 1-2)

Evidence note: Exact abstract quotations are included only where directly available from retrieved abstracts. Where no source supported an exact ontology ID, subtype frequency, variant-level ACMG class, or population allele frequency, the report intentionally provides a qualified label or records the field as unavailable rather than extrapolating.

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References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 15
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