Nontuberculous Mycobacterial Lung Disease

Infectious Disease MONDO:0018469 Pathograph 24 Show in embeddings browser Bacterial Infection Lung disease

Nontuberculous mycobacterial (NTM) lung disease is a chronic pulmonary infection caused by environmental mycobacteria other than the Mycobacterium tuberculosis complex and M. leprae, most commonly Mycobacterium avium complex (MAC), and also M. kansasii and the rapidly growing M. abscessus. NTM are ubiquitous in water and soil and are acquired by inhalation of aerosols; disease develops preferentially in hosts with structural lung disease (bronchiectasis, COPD, cystic fibrosis) or impaired immunity, and in slender postmenopausal women without recognized immunodeficiency. It presents insidiously with chronic cough, sputum, fatigue, and weight loss, and follows nodular-bronchiectatic or fibrocavitary radiographic patterns. Cure is difficult and requires prolonged multidrug macrolide-based regimens.

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11
Pathophys.
9
Phenotypes
24
Pathograph
4
Medical Actions
1
Trials
1
Models
⚙

Pathophysiology

11
Environmental NTM Exposure and Aerosol Inhalation
NTM are environmental organisms ubiquitous in natural and engineered water systems (household plumbing, showerheads, hot tubs) and in soil. Their lipid-rich hydrophobic outer membrane promotes biofilm formation and ready aerosolization; inhalation of these aerosols is the major route by which pulmonary NTM disease is acquired.
Downstream
Alveolar Macrophage Infection and Intracellular Persistence Inhaled aerosolized NTM reach the distal airways and are taken up by alveolar macrophages.
Show evidence (3 references)
PMID:42437710 SUPPORT Other
"Nontuberculous mycobacteria (NTM) are environmental organisms increasingly recognized as important pathogens in pulmonary disease."
Establishes NTM as environmental organisms causing pulmonary disease. Evidence source is OTHER as this is a review.
PMID:30302953 SUPPORT Other
"NTM are readily aerosolized from natural water and soils due to its surface hydrophobicity"
Documents the aerosolization of NTM from water and soil that enables inhalational acquisition. Evidence source is OTHER as this is a review.
PMID:30302953 SUPPORT Other
"The most common routes for pulmonary NTM infection involve the inhalation of aerosols generated by hot tubs and showerheads."
Identifies inhalation of household aerosols as the dominant route of pulmonary NTM infection. Evidence source is OTHER as this is a review.
Structural Lung Disease Predisposition
Although exposure to NTM is nearly universal, clinical disease is uncommon, implicating host susceptibility. NTM lung disease develops preferentially in hosts with structural airway disease — non-cystic fibrosis bronchiectasis, COPD, cystic fibrosis, primary ciliary dyskinesia, prior TB, and pneumoconiosis — in which impaired mucociliary clearance permits the organism to establish and persist.
Downstream
Alveolar Macrophage Infection and Intracellular Persistence Impaired structural airway defenses permit inhaled NTM to establish infection of alveolar macrophages.
Show evidence (2 references)
PMID:30302953 SUPPORT Other
"Exposure to NTM is quite common. However, NTM disease is relatively rare. This observation suggests that host susceptibility likely plays a key role in the development of NTM lung disease."
Establishes that host susceptibility, not exposure alone, governs whether NTM lung disease develops. Evidence source is OTHER as this is a review.
PMID:30302953 SUPPORT Other
"NTM lung disease is more prevalent in patients with structural lung disease, such as cystic fibrosis, non-cystic fibrosis bronchiectasis, primary ciliary dyskinesia, chronic obstructive pulmonary disease (COPD), previous TB, and pneumoconiosis"
Lists the structural lung diseases that predispose to NTM lung disease. Evidence source is OTHER as this is a review.
Impaired Th1 Immune Defense
Impaired IL-12/IFN-gamma (Th1) immunity is the pivotal immune deficit that permits severe and disseminated MAC disease, and iatrogenic or acquired immunosuppression (HIV, transplantation, TNF-alpha inhibitors) likewise predisposes to NTM lung disease.
T-helper 1 type immune response GO:0042088 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T-helper 1 type immune response (GO:0042088). GO:0042088 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Alveolar Macrophage Infection and Intracellular Persistence Impaired Th1 immunity permits inhaled NTM to survive within alveolar macrophages and establish infection.
Show evidence (2 references)
PMID:33563837 SUPPORT Model Organism
"Th1 immune responses, particularly the interleukin 12 (IL-12)/gamma interferon (IFN-γ) axis, are thought to be pivotal host factors in protection against disseminated MAC disease"
Establishes the IL-12/IFN-gamma axis as the pivotal immune-defense pathway whose impairment predisposes to severe MAC disease. Evidence source is MODEL_ORGANISM as this is the framing of a mouse MAC-infection study.
PMID:30302953 SUPPORT Other
"An immunosuppressed status, which is related to HIV infection, transplantation, or the use of tumor necrosis factor α inhibitor, is also associated with NTM disease"
Documents iatrogenic and acquired immunosuppression as susceptibility factors. Evidence source is OTHER as this is a review.
Alveolar Macrophage Infection and Intracellular Persistence
Inhaled NTM are phagocytosed by alveolar macrophages, which are both the principal reservoir of infection and the main bacillus-killing cell. Like other intracellular mycobacteria, NTM subvert phagolysosomal maturation and persist intracellularly, shielded from humoral defenses and from poorly-cell-penetrant antibiotics such as the beta-lactams.
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.
Biological Process Involved in Interaction with Host GO:0051701 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Biological Process Involved in Interaction with Host (GO:0051701). GO:0051701 is a biological process from the Gene Ontology.
Animal models
Nrf2-deficient mouse MAC lung infection Mouse recapitulates Nrf2-deficient mice infected with MAC show impaired phagolysosome formation and heavy intracellular bacterial burden in alveolar macrophages, modeling the intracellular-persistence node.
Downstream
Granulomatous Inflammation Persistent intracellular NTM that individual macrophages cannot eradicate drive a chronic granulomatous immune response.
Requirement for Cell-Penetrant Antimicrobial Therapy The intracellular niche restricts effective therapy to agents that accumulate within host cells.
Nodular-Bronchiectatic Disease Chronic intracellular infection of the small airways sustains the inflammation that produces the nodular-bronchiectatic pattern.
Fibrocavitary Disease Chronic intracellular infection can instead progress to the upper-lobe fibrocavitary pattern.
Show evidence (3 references)
PMID:33563837 SUPPORT Model Organism
"The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells."
Establishes the alveolar macrophage as both the reservoir of MAC infection and the effector cell. Evidence source is MODEL_ORGANISM as this is the framing of a mouse MAC-infection study.
PMID:33563837 SUPPORT Model Organism
"many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes"
Demonstrates intracellular MAC persistence in alveolar macrophages with impaired phagolysosome formation. Evidence source is MODEL_ORGANISM as this is a mouse-infection study.
PMID:18611821 SUPPORT Other
"The intracellular location of some microorganisms allow them to resist antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam compounds."
Supports the intracellular-niche gating principle that excludes poorly-penetrant beta-lactams. Evidence source is OTHER as this is a review article.
Requirement for Cell-Penetrant Antimicrobial Therapy
Because NTM persist within host cells, therapeutic efficacy tracks the intracellular drug concentration achieved rather than the in vitro MIC alone. Effective regimens are built on cell-penetrant agents — macrolides (azithromycin/clarithromycin), rifamycins, and aminoglycosides — while cell-wall-active beta-lactams are not used as anchor therapy.
Response to Antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Response to Antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:28639230 SUPPORT Other
"Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."
Establishes the cell-penetrant requirement that constrains drug choice for intracellular infection. Evidence source is OTHER as this is a review.
Mycobacterial Ribosomal Translation (Macrolide Target)
Macrolides (azithromycin, clarithromycin) — the non-negotiable anchor of MAC therapy — bind the bacterial ribosome and arrest mycobacterial protein synthesis. Baseline macrolide susceptibility of the causative strain is the most consistent predictor of treatment success.
Translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology.
Downstream
Acquired Macrolide Resistance Under macrolide pressure, mutations at the ribosomal target select for acquired macrolide resistance.
Show evidence (2 references)
PMID:24336183 SUPPORT Other
"The ribosome is one of the main antibiotic targets in the bacterial cell."
Establishes the bacterial ribosome as the class-level macrolide target, the step this node represents. Evidence source is OTHER as this is a review article.
PMID:32636299 SUPPORT Other
"there is a clear correlation between baseline macrolide susceptibility of the causative strain and the outcome of treatment with macrolide-ethambutol-rifampicin regimens"
Grounds the macrolide-target node specifically in MAC: baseline macrolide susceptibility of the strain predicts treatment outcome. Evidence source is OTHER as this is a clinical practice guideline.
Acquired Macrolide Resistance
Loss of the macrolide target through mutation is the central resistance mechanism in NTM disease. In MAC, acquired macrolide resistance is due to point mutations in the 23S rRNA (rrl) gene; M. abscessus additionally carries inducible erm(41)-mediated resistance. Because macrolide susceptibility predicts cure, acquired resistance drives treatment failure.
Response to Antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Response to Antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Progressive Respiratory Decline Acquired macrolide resistance precipitates treatment failure and the lung-function decline that accompanies it.
Show evidence (1 reference)
PMID:32636299 SUPPORT Other
"Acquired macrolide resistance inM. aviumcomplex is due to point mutations in the 23S rRNA (rrl) gene"
Guideline states that acquired macrolide resistance in MAC arises from 23S rRNA (rrl) target mutations — resistance at the ribosomal target. Evidence source is OTHER as this is a clinical practice guideline.
Granulomatous Inflammation
Failure to clear intracellular NTM presents the immune system with a persistent stimulus that individual macrophages cannot eradicate, driving sustained macrophage recruitment and organization into granulomas. This response both contains the organism and, when the infection persists, contributes to progressive lung damage and chronic constitutional symptoms. Consistent with a non-redundant role for macrophage/TNF-dependent containment, TNF-inhibitor therapy predisposes to NTM disease.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Nodular-Bronchiectatic Disease Chronic granulomatous inflammation of the small airways underlies the nodular-bronchiectatic pattern.
Fibrocavitary Disease When the organism persists, granulomatous inflammation drives upper-lobe cavitary destruction.
Fatigue Chronic granulomatous infection produces constitutional fatigue.
Weight loss Chronic granulomatous infection produces progressive weight loss.
Night sweats Chronic granulomatous infection produces night sweats among its constitutional symptoms.
Show evidence (1 reference)
PMID:33563837 SUPPORT Model Organism
"Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively."
Establishes macrophage-driven granuloma formation as a component of the host response to pulmonary MAC. Evidence source is MODEL_ORGANISM as this is a mouse-infection study.
Nodular-Bronchiectatic Disease
The nodular-bronchiectatic form of NTM lung disease comprises small nodules and bronchiectasis, classically involving the right middle lobe and lingula, and is the more common, more indolent radiographic-pathological pattern.
Downstream
Bronchiectasis Bronchiectasis is the defining airway lesion of the nodular-bronchiectatic pattern.
Chronic cough Chronic airway infection and bronchiectasis produce persistent cough.
Increased sputum production Chronic airway infection and bronchiectasis produce chronic sputum.
Progressive Respiratory Decline Cumulative airway destruction contributes to progressive loss of lung function.
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
Documents the nodular-bronchiectatic radiographic pattern of NTM lung disease. Evidence source is OTHER as this is a review.
Fibrocavitary Disease
The fibrocavitary form comprises upper-lobe cavities resembling tuberculosis; it marks the more severe, faster-progressing phenotype with a stronger indication for treatment.
Downstream
Pulmonary cavity Upper-lobe cavitation is the defining lesion of the fibrocavitary pattern.
Hemoptysis Cavitary and bronchiectatic airway destruction produces hemoptysis.
Progressive Respiratory Decline Progressive cavitary parenchymal destruction drives loss of lung function.
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
Documents the fibrocavitary radiographic pattern of NTM lung disease. Evidence source is OTHER as this is a review.
Progressive Respiratory Decline
Untreated or refractory NTM lung disease is associated with progressive loss of lung function, impaired quality of life, and increased morbidity and mortality; treatment failure in particular is associated with substantial lung-function decline.
Downstream
Dyspnea Progressive loss of lung function produces exertional breathlessness.
Show evidence (1 reference)
PMID:30302953 SUPPORT Other
"treatment failure was associated with a substantial decline in lung function in individuals with NTM lung disease"
Documents progressive lung-function decline as an outcome of NTM lung disease. Evidence source is OTHER as this is a review.
⬡

Pathograph

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

Phenotypes

9
Respiratory 6
Chronic cough HP:0012735 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cough (HP:0012735), qualified as temporality chronic. HP:0012735 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
Review lists chronic cough as a cardinal symptom of NTM lung disease.
Increased sputum production HP:0033709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased sputum production (HP:0033709). HP:0033709 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
Review lists sputum production among the common symptoms.
Hemoptysis HP:0002105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemoptysis (HP:0002105). HP:0002105 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19020369 SUPPORT Other
"Other less common symptoms include dyspnea and hemoptysis."
Review lists hemoptysis among the symptoms of NTM pulmonary infection.
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:42070174 SUPPORT Human Clinical
"The concept elicitation interviews identified key symptoms of cough (100%), shortness of breath (98%), fatigue (95%), sputum production (90%), throat clearing (80%), mental fogging (75%), sensitivity to cold (62%), night sweats (55%), poor appetite (53%), chills/feverishness (50%/43%), weight..."
Patient concept-elicitation interviews in NTM-PD identify shortness of breath as a near-universal symptom. The 98% figure is the proportion of the PROM item-generation interview cohort who reported the symptom, not a disease prevalence estimate.
PMID:19020369 SUPPORT Other
"Other less common symptoms include dyspnea and hemoptysis."
Review lists dyspnea among the symptoms of NTM pulmonary infection.
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42437710 SUPPORT Other
"These infections commonly affect individuals with underlying structural lung disease, including bronchiectasis and chronic obstructive pulmonary disease, as well as immunocompromised patients."
Review documents the tight association of NTM lung disease with bronchiectasis.
PMID:30216086 SUPPORT Human Clinical
"Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%)."
Randomized-trial cohort of MAC lung disease quantifies the predominance of underlying bronchiectasis.
Pulmonary cavity HP:0033655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary cavity (HP:0033655). HP:0033655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
Review documents the fibrocavitary radiographic pattern of NTM lung disease.
Constitutional 2
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
Review lists fatigue among the common constitutional symptoms.
Night sweats HP:0030166 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night sweats (HP:0030166). HP:0030166 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42070174 SUPPORT Human Clinical
"The concept elicitation interviews identified key symptoms of cough (100%), shortness of breath (98%), fatigue (95%), sputum production (90%), throat clearing (80%), mental fogging (75%), sensitivity to cold (62%), night sweats (55%), poor appetite (53%), chills/feverishness (50%/43%), weight..."
Patient concept-elicitation interviews in NTM-PD identify night sweats as a frequent constitutional symptom. The 55% figure is the proportion of the PROM item-generation interview cohort who reported the symptom, not a disease prevalence estimate.
Growth 1
Weight loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42437710 SUPPORT Other
"Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
Review lists weight loss among the common constitutional symptoms.
💊

Medical Actions

4
Macrolide-based multidrug regimen for MAC pulmonary disease
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: azithromycin CHEBI:2955 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azithromycin (CHEBI:2955). CHEBI:2955 is a therapeutic agent from Chemical Entities of Biological Interest. clarithromycin CHEBI:3732 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clarithromycin (CHEBI:3732). CHEBI:3732 is a therapeutic agent from Chemical Entities of Biological Interest. ethambutol CHEBI:4877 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ethambutol (CHEBI:4877). CHEBI:4877 is a therapeutic agent from Chemical Entities of Biological Interest. rifampicin CHEBI:28077 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rifampicin (CHEBI:28077). CHEBI:28077 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Guideline-based therapy for macrolide-susceptible MAC pulmonary disease is a regimen of at least three drugs — a macrolide (azithromycin preferred over clarithromycin), ethambutol, and a rifamycin (rifampicin) — continued for at least 12 months after sputum culture conversion. Parenteral amikacin or streptomycin is added for cavitary, advanced, or macrolide-resistant disease.
Mechanism Target:
INHIBITS Mycobacterial Ribosomal Translation (Macrolide Target) — The macrolide component binds the mycobacterial ribosome and arrests protein synthesis — the anchor of the regimen.
Requirement for Cell-Penetrant Antimicrobial Therapy — Macrolides and rifamycins accumulate intracellularly, reaching NTM within alveolar macrophages.
Show evidence (2 references)
PMID:32636299 SUPPORT Other
"In patients with macrolide-susceptible MAC pulmonary disease, we recommend a three-drug regimen that includes a macrolide over a three-drug regimen without a macrolide"
ATS/ERS/ESCMID/IDSA guideline gives a strong recommendation for a macrolide-containing three-drug regimen. Evidence source is OTHER as this is a clinical practice guideline.
PMID:32636299 SUPPORT Other
"we suggest a treatment regimen with at least three drugs (including a macrolide and ethambutol) over a regimen with two drugs (a macrolide and ethambutol alone)"
Guideline specifies the at-least-three-drug macrolide-plus-ethambutol backbone. Evidence source is OTHER as this is a clinical practice guideline.
Rifampicin-based regimen for M. kansasii pulmonary disease
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: rifampicin CHEBI:28077 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rifampicin (CHEBI:28077). CHEBI:28077 is a therapeutic agent from Chemical Entities of Biological Interest. ethambutol CHEBI:4877 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ethambutol (CHEBI:4877). CHEBI:4877 is a therapeutic agent from Chemical Entities of Biological Interest. clarithromycin CHEBI:3732 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clarithromycin (CHEBI:3732). CHEBI:3732 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Rifampicin-susceptible M. kansasii pulmonary disease is treated with a regimen of rifampicin, ethambutol, and either isoniazid or a macrolide, with high rates of treatment success.
Mechanism Target:
Requirement for Cell-Penetrant Antimicrobial Therapy — Rifampicin and macrolides penetrate host cells to reach intracellular M. kansasii.
Show evidence (1 reference)
PMID:32636299 SUPPORT Other
"we suggest a regimen of rifampicin, ethambutol, and either isoniazid or macrolide"
Guideline recommendation for rifampicin-susceptible M. kansasii pulmonary disease. Evidence source is OTHER as this is a clinical practice guideline.
Amikacin liposome inhalation suspension for treatment-refractory MAC
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: amikacin CHEBI:2637 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amikacin (CHEBI:2637). CHEBI:2637 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
For MAC pulmonary disease that remains culture-positive after at least six months of guideline-based therapy, addition of amikacin liposome inhalation suspension (ALIS) to the oral regimen significantly increases sputum culture conversion (CONVERT trial). Parenteral amikacin is used instead for cavitary or advanced disease at initiation.
Mechanism Target:
Requirement for Cell-Penetrant Antimicrobial Therapy — Inhaled liposomal amikacin delivers a cell-penetrant aminoglycoside directly to the infected lung.
Show evidence (1 reference)
PMID:30216086 SUPPORT Human Clinical
"Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events."
The CONVERT randomized trial establishes the efficacy of ALIS added to guideline-based therapy in refractory MAC lung disease.
Surgical resection as adjuvant therapy
Action: surgical resectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical resection, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
In selected patients with focal disease, drug-resistant isolates, cavitation, or complications such as hemoptysis or severe bronchiectasis, surgical resection of the diseased lung is used as an adjuvant to medical therapy.
Show evidence (1 reference)
PMID:32636299 SUPPORT Other
"we suggest surgical resection as an adjuvant to medical therapy after expert consultation"
Guideline conditionally recommends adjuvant surgical resection in selected patients. Evidence source is OTHER as this is a clinical practice guideline.
🔬

Diagnosis

1
ATS/ERS/ESCMID/IDSA diagnostic criteria
Diagnosis of NTM lung disease requires the combination of compatible clinical and radiographic findings with microbiological confirmation (repeated culture of the same species from sputum, or a single positive bronchial wash/lavage, or compatible histopathology plus culture), and appropriate exclusion of alternative diagnoses. Culture confirmation is required to distinguish true disease from airway colonization.
Show evidence (2 references)
PMID:42437710 SUPPORT Other
"Diagnosis requires a combination of clinical, radiological, and microbiological criteria to distinguish true disease from colonization."
Review states the combined clinical/radiological/microbiological diagnostic requirement. Evidence source is OTHER as this is a review.
PMID:27134484 SUPPORT Other
"Positive culture results from at least two separate expectorated sputum samples."
States the microbiologic criterion (repeated positive sputum cultures) of the ATS/IDSA diagnostic criteria. Evidence source is OTHER as this is a review reproducing the consensus criteria.
📊

Prevalence

1
Oregon, United States
Annual Incidence 5.6 per 100,000 (4.8–5.6) 1–9 per 100,000 per year
First population-based US regional estimate; annual incidence of pulmonary NTM disease rose from 4.8 to 5.6 per 100,000 over 2007-2012 (not statistically significant), and rose steeply with age.
Show evidence (1 reference)
PMID:25692495 SUPPORT Human Clinical
"incidence increased from 4.8/100,000 in 2007 to 5.6/100,000 in 2012"
Population-based Oregon surveillance quantifies pulmonary NTM disease incidence.
🦠

Infectious Agent

3
Mycobacterium avium complex
The most common cause of NTM lung disease worldwide; a slowly growing NTM complex that includes M. avium, M. intracellulare, and M. chimaera.
Mycobacterium avium complex (MAC) NCBITaxon:120793 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:33563837 SUPPORT Model Organism
"Mycobacterium avium complex (MAC) is the most common cause of pulmonary NTM disease worldwide."
Identifies MAC as the most common causative organism of NTM lung disease. The claim is the framing of a mouse MAC-infection study, so evidence_source is MODEL_ORGANISM.
Mycobacteroides abscessus
The most common rapidly growing NTM causing pulmonary disease; frequently macrolide-resistant via an inducible erm(41) gene, and difficult to cure.
Mycobacterium abscessus NCBITaxon:36809 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:32636299 SUPPORT Other
"that results in inducible resistance to macrolides"
ATS/ERS/ESCMID/IDSA guideline documents that the M. abscessus erythromycin resistance methylase erm(41) gene results in inducible macrolide resistance. Quoted from a corruption-free span of the guideline text. Evidence source is OTHER as this is a clinical practice guideline.
Mycobacterium kansasii
A slowly growing NTM that is usually considered pathogenic when isolated and is treated with a rifampicin-based regimen.
Mycobacterium kansasii NCBITaxon:1768 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:32636299 SUPPORT Other
"we suggest a regimen of rifampicin, ethambutol, and either isoniazid or macrolide"
Guideline recommends a rifampicin-based regimen for rifampicin-susceptible M. kansasii pulmonary disease. Evidence source is OTHER as this is a clinical practice guideline.
🔬

Clinical Trials

1
NCT02344004 PHASE_III COMPLETED
CONVERT — a randomized, open-label study of amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy versus guideline-based therapy alone in treatment-refractory MAC lung disease.
Target Phenotypes: Pulmonary cavity HP:0033655 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Pulmonary cavity (HP:0033655). HP:0033655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT02344004 SUPPORT Other
"A study to evaluate the effectiveness of Liposomal Amikacin for Inhalation (LAI) 590 mg administered once daily (QD) when added to multi-drug regimen (MDR) in participants with Nontuberculous Mycobacterial (NTM) lung infection caused by Mycobacterium Avium Complex (MAC) that were refractory to treatment."
ClinicalTrials.gov record establishing the CONVERT trial's design and population. Evidence source is OTHER as this is a trial-registry record.
🐁

Animal Models

1
Nrf2-deficient mouse MAC lung infection
Species
Mouse
Genotype
Nrf2 (Nfe2l2) knockout
Publication
PMID:33563837
Pathograph links
Alveolar Macrophage Infection and Intracellular Persistence recapitulates fidelity: moderate Nrf2-deficient mice infected with MAC show impaired phagolysosome formation and heavy intracellular bacterial burden in alveolar macrophages, modeling the intracellular-persistence node.
Limitations: A single-gene knockout in mice; Nrf2 dependence and the murine granuloma response may not fully reproduce human MAC lung disease, which arises in structurally or immunologically abnormal human hosts.
Readouts
Intracellular MAC burden in alveolar macrophages
Direction: INCREASED
Interpretation: Nrf2 loss increases intracellular bacterial load with little phagolysosome formation, the structural correlate of intracellular persistence.
Show evidence (1 reference)
PMID:33563837 SUPPORT Model Organism
"many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes"
Reports the intracellular-burden measurement behind this readout.
Show evidence (1 reference)
PMID:33563837 SUPPORT Model Organism
"Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively."
Supports treating the Nrf2-deficient mouse as informative for the alveolar-macrophage intracellular-persistence node.
{ }

Source YAML

click to show 
name: Nontuberculous Mycobacterial Lung Disease
creation_date: "2026-08-27T00:00:00Z"
category: Infectious Disease
description: >-
  Nontuberculous mycobacterial (NTM) lung disease is a chronic pulmonary
  infection caused by environmental mycobacteria other than the Mycobacterium
  tuberculosis complex and M. leprae, most commonly Mycobacterium avium complex
  (MAC), and also M. kansasii and the rapidly growing M. abscessus. NTM are
  ubiquitous in water and soil and are acquired by inhalation of aerosols;
  disease develops preferentially in hosts with structural lung disease
  (bronchiectasis, COPD, cystic fibrosis) or impaired immunity, and in slender
  postmenopausal women without recognized immunodeficiency. It presents
  insidiously with chronic cough, sputum, fatigue, and weight loss, and follows
  nodular-bronchiectatic or fibrocavitary radiographic patterns. Cure is
  difficult and requires prolonged multidrug macrolide-based regimens.
disease_term:
  preferred_term: Nontuberculous Mycobacterial Lung Disease
  term:
    id: MONDO:0018469
    label: pulmonary non-tuberculous mycobacterial infection
parents:
- Bacterial Infection
- Lung disease
infectious_agent:
- name: Mycobacterium avium complex
  infectious_agent_term:
    preferred_term: Mycobacterium avium complex (MAC)
    term:
      id: NCBITaxon:120793
      label: Mycobacterium avium complex (MAC)
  description: >-
    The most common cause of NTM lung disease worldwide; a slowly growing NTM
    complex that includes M. avium, M. intracellulare, and M. chimaera.
  evidence:
  - reference: PMID:33563837
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mycobacterium avium complex (MAC) is the most common cause of pulmonary NTM disease worldwide."
    explanation: >-
      Identifies MAC as the most common causative organism of NTM lung disease.
      The claim is the framing of a mouse MAC-infection study, so evidence_source
      is MODEL_ORGANISM.
- name: Mycobacteroides abscessus
  infectious_agent_term:
    preferred_term: Mycobacterium abscessus
    term:
      id: NCBITaxon:36809
      label: Mycobacteroides abscessus
  description: >-
    The most common rapidly growing NTM causing pulmonary disease; frequently
    macrolide-resistant via an inducible erm(41) gene, and difficult to cure.
  evidence:
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "that results in inducible resistance to macrolides"
    explanation: >-
      ATS/ERS/ESCMID/IDSA guideline documents that the M. abscessus erythromycin
      resistance methylase erm(41) gene results in inducible macrolide
      resistance. Quoted from a corruption-free span of the guideline text.
      Evidence source is OTHER as this is a clinical practice guideline.
- name: Mycobacterium kansasii
  infectious_agent_term:
    preferred_term: Mycobacterium kansasii
    term:
      id: NCBITaxon:1768
      label: Mycobacterium kansasii
  description: >-
    A slowly growing NTM that is usually considered pathogenic when isolated and
    is treated with a rifampicin-based regimen.
  evidence:
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we suggest a regimen of rifampicin, ethambutol, and either isoniazid or macrolide"
    explanation: >-
      Guideline recommends a rifampicin-based regimen for rifampicin-susceptible
      M. kansasii pulmonary disease. Evidence source is OTHER as this is a
      clinical practice guideline.
pathophysiology:
- name: Environmental NTM Exposure and Aerosol Inhalation
  description: >-
    NTM are environmental organisms ubiquitous in natural and engineered water
    systems (household plumbing, showerheads, hot tubs) and in soil. Their
    lipid-rich hydrophobic outer membrane promotes biofilm formation and ready
    aerosolization; inhalation of these aerosols is the major route by which
    pulmonary NTM disease is acquired.
  role: trigger
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nontuberculous mycobacteria (NTM) are environmental organisms increasingly recognized as important pathogens in pulmonary disease."
    explanation: >-
      Establishes NTM as environmental organisms causing pulmonary disease.
      Evidence source is OTHER as this is a review.
  - reference: PMID:30302953
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NTM are readily aerosolized from natural water and soils due to its surface hydrophobicity"
    explanation: >-
      Documents the aerosolization of NTM from water and soil that enables
      inhalational acquisition. Evidence source is OTHER as this is a review.
  - reference: PMID:30302953
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most common routes for pulmonary NTM infection involve the inhalation of aerosols generated by hot tubs and showerheads."
    explanation: >-
      Identifies inhalation of household aerosols as the dominant route of
      pulmonary NTM infection. Evidence source is OTHER as this is a review.
  downstream:
  - target: Alveolar Macrophage Infection and Intracellular Persistence
    description: >-
      Inhaled aerosolized NTM reach the distal airways and are taken up by
      alveolar macrophages.
- name: Structural Lung Disease Predisposition
  description: >-
    Although exposure to NTM is nearly universal, clinical disease is uncommon,
    implicating host susceptibility. NTM lung disease develops preferentially in
    hosts with structural airway disease — non-cystic fibrosis bronchiectasis,
    COPD, cystic fibrosis, primary ciliary dyskinesia, prior TB, and
    pneumoconiosis — in which impaired mucociliary clearance permits the
    organism to establish and persist.
  role: predisposing_factor
  biological_scale: TISSUE
  evidence:
  - reference: PMID:30302953
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Exposure to NTM is quite common. However, NTM disease is relatively rare. This observation suggests that host susceptibility likely plays a key role in the development of NTM lung disease."
    explanation: >-
      Establishes that host susceptibility, not exposure alone, governs whether
      NTM lung disease develops. Evidence source is OTHER as this is a review.
  - reference: PMID:30302953
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NTM lung disease is more prevalent in patients with structural lung disease, such as cystic fibrosis, non-cystic fibrosis bronchiectasis, primary ciliary dyskinesia, chronic obstructive pulmonary disease (COPD), previous TB, and pneumoconiosis"
    explanation: >-
      Lists the structural lung diseases that predispose to NTM lung disease.
      Evidence source is OTHER as this is a review.
  downstream:
  - target: Alveolar Macrophage Infection and Intracellular Persistence
    description: >-
      Impaired structural airway defenses permit inhaled NTM to establish
      infection of alveolar macrophages.
- name: Impaired Th1 Immune Defense
  description: >-
    Impaired IL-12/IFN-gamma (Th1) immunity is the pivotal immune deficit that
    permits severe and disseminated MAC disease, and iatrogenic or acquired
    immunosuppression (HIV, transplantation, TNF-alpha inhibitors) likewise
    predisposes to NTM lung disease.
  role: predisposing_factor
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: T-helper 1 type immune response
    term:
      id: GO:0042088
      label: T-helper 1 type immune response
    modifier: DECREASED
  evidence:
  - reference: PMID:33563837
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Th1 immune responses, particularly the interleukin 12 (IL-12)/gamma interferon (IFN-γ) axis, are thought to be pivotal host factors in protection against disseminated MAC disease"
    explanation: >-
      Establishes the IL-12/IFN-gamma axis as the pivotal immune-defense pathway
      whose impairment predisposes to severe MAC disease. Evidence source is
      MODEL_ORGANISM as this is the framing of a mouse MAC-infection study.
  - reference: PMID:30302953
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An immunosuppressed status, which is related to HIV infection, transplantation, or the use of tumor necrosis factor α inhibitor, is also associated with NTM disease"
    explanation: >-
      Documents iatrogenic and acquired immunosuppression as susceptibility
      factors. Evidence source is OTHER as this is a review.
  downstream:
  - target: Alveolar Macrophage Infection and Intracellular Persistence
    description: >-
      Impaired Th1 immunity permits inhaled NTM to survive within alveolar
      macrophages and establish infection.
- name: Alveolar Macrophage Infection and Intracellular Persistence
  description: >-
    Inhaled NTM are phagocytosed by alveolar macrophages, which are both the
    principal reservoir of infection and the main bacillus-killing cell. Like
    other intracellular mycobacteria, NTM subvert phagolysosomal maturation and
    persist intracellularly, shielded from humoral defenses and from
    poorly-cell-penetrant antibiotics such as the beta-lactams.
  role: trigger
  biological_scale: CELLULAR
  conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  biological_processes:
  - preferred_term: Biological Process Involved in Interaction with Host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  evidence:
  - reference: PMID:33563837
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells."
    explanation: >-
      Establishes the alveolar macrophage as both the reservoir of MAC infection
      and the effector cell. Evidence source is MODEL_ORGANISM as this is the
      framing of a mouse MAC-infection study.
  - reference: PMID:33563837
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes"
    explanation: >-
      Demonstrates intracellular MAC persistence in alveolar macrophages with
      impaired phagolysosome formation. Evidence source is MODEL_ORGANISM as
      this is a mouse-infection study.
  - reference: PMID:18611821
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The intracellular location of some microorganisms allow them to resist antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam compounds."
    explanation: >-
      Supports the intracellular-niche gating principle that excludes
      poorly-penetrant beta-lactams. Evidence source is OTHER as this is a
      review article.
  downstream:
  - target: Granulomatous Inflammation
    description: >-
      Persistent intracellular NTM that individual macrophages cannot eradicate
      drive a chronic granulomatous immune response.
  - target: Requirement for Cell-Penetrant Antimicrobial Therapy
    description: >-
      The intracellular niche restricts effective therapy to agents that
      accumulate within host cells.
  - target: Nodular-Bronchiectatic Disease
    description: >-
      Chronic intracellular infection of the small airways sustains the
      inflammation that produces the nodular-bronchiectatic pattern.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
      explanation: >-
        Review documents the nodular-bronchiectatic structural pattern that
        chronic infection produces. Evidence source is OTHER as this is a review.
  - target: Fibrocavitary Disease
    description: >-
      Chronic intracellular infection can instead progress to the upper-lobe
      fibrocavitary pattern.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
      explanation: >-
        Review documents the fibrocavitary structural pattern that chronic
        infection produces. Evidence source is OTHER as this is a review.
- name: Requirement for Cell-Penetrant Antimicrobial Therapy
  description: >-
    Because NTM persist within host cells, therapeutic efficacy tracks the
    intracellular drug concentration achieved rather than the in vitro MIC
    alone. Effective regimens are built on cell-penetrant agents — macrolides
    (azithromycin/clarithromycin), rifamycins, and aminoglycosides — while
    cell-wall-active beta-lactams are not used as anchor therapy.
  role: therapeutic_vulnerability
  biological_scale: CELLULAR
  conforms_to: "intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials"
  biological_processes:
  - preferred_term: Response to Antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:28639230
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."
    explanation: >-
      Establishes the cell-penetrant requirement that constrains drug choice for
      intracellular infection. Evidence source is OTHER as this is a review.
- name: Mycobacterial Ribosomal Translation (Macrolide Target)
  description: >-
    Macrolides (azithromycin, clarithromycin) — the non-negotiable anchor of
    MAC therapy — bind the bacterial ribosome and arrest mycobacterial protein
    synthesis. Baseline macrolide susceptibility of the causative strain is the
    most consistent predictor of treatment success.
  role: therapeutic_vulnerability
  biological_scale: MOLECULAR
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  biological_processes:
  - preferred_term: Translation
    term:
      id: GO:0006412
      label: translation
  evidence:
  - reference: PMID:24336183
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The ribosome is one of the main antibiotic targets in the bacterial cell."
    explanation: >-
      Establishes the bacterial ribosome as the class-level macrolide target,
      the step this node represents. Evidence source is OTHER as this is a
      review article.
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "there is a clear correlation\nbetween baseline macrolide susceptibility of the causative strain and the\noutcome of treatment with macrolide-ethambutol-rifampicin regimens"
    explanation: >-
      Grounds the macrolide-target node specifically in MAC: baseline macrolide
      susceptibility of the strain predicts treatment outcome. Evidence source
      is OTHER as this is a clinical practice guideline.
  downstream:
  - target: Acquired Macrolide Resistance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Under macrolide pressure, mutations at the ribosomal target select for
      acquired macrolide resistance.
- name: Acquired Macrolide Resistance
  description: >-
    Loss of the macrolide target through mutation is the central resistance
    mechanism in NTM disease. In MAC, acquired macrolide resistance is due to
    point mutations in the 23S rRNA (rrl) gene; M. abscessus additionally
    carries inducible erm(41)-mediated resistance. Because macrolide
    susceptibility predicts cure, acquired resistance drives treatment failure.
  role: resistance_mechanism
  biological_scale: MOLECULAR
  conforms_to: "bacterial_protein_synthesis_inhibition#Ribosomal Target Resistance"
  biological_processes:
  - preferred_term: Response to Antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
    modifier: DECREASED
  evidence:
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Acquired macrolide resistance inM. aviumcomplex is due to point mutations in the 23S rRNA (rrl) gene"
    explanation: >-
      Guideline states that acquired macrolide resistance in MAC arises from 23S
      rRNA (rrl) target mutations — resistance at the ribosomal target. Evidence
      source is OTHER as this is a clinical practice guideline.
  downstream:
  - target: Progressive Respiratory Decline
    description: >-
      Acquired macrolide resistance precipitates treatment failure and the
      lung-function decline that accompanies it.
    evidence:
    - reference: PMID:30302953
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "treatment failure was associated with a substantial decline in lung function in individuals with NTM lung disease"
      explanation: >-
        Links treatment failure — the clinical consequence of acquired
        resistance — to lung-function decline. Evidence source is OTHER as this
        is a review.
- name: Granulomatous Inflammation
  description: >-
    Failure to clear intracellular NTM presents the immune system with a
    persistent stimulus that individual macrophages cannot eradicate, driving
    sustained macrophage recruitment and organization into granulomas. This
    response both contains the organism and, when the infection persists,
    contributes to progressive lung damage and chronic constitutional symptoms.
    Consistent with a non-redundant role for macrophage/TNF-dependent
    containment, TNF-inhibitor therapy predisposes to NTM disease.
  role: amplifier
  biological_scale: TISSUE
  conforms_to: "granuloma_formation#Persistent Indigestible Stimulus"
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: INCREASED
  evidence:
  - reference: PMID:33563837
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively."
    explanation: >-
      Establishes macrophage-driven granuloma formation as a component of the
      host response to pulmonary MAC. Evidence source is MODEL_ORGANISM as this
      is a mouse-infection study.
  downstream:
  - target: Nodular-Bronchiectatic Disease
    description: >-
      Chronic granulomatous inflammation of the small airways underlies the
      nodular-bronchiectatic pattern.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
      explanation: >-
        Documents the nodular-bronchiectatic structural pattern. Evidence source
        is OTHER as this is a review.
  - target: Fibrocavitary Disease
    description: >-
      When the organism persists, granulomatous inflammation drives upper-lobe
      cavitary destruction.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
      explanation: >-
        Documents the fibrocavitary structural pattern. Evidence source is OTHER
        as this is a review.
  - target: Fatigue
    description: >-
      Chronic granulomatous infection produces constitutional fatigue.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
      explanation: >-
        Review lists fatigue among the constitutional symptoms of NTM lung
        disease. Evidence source is OTHER as this is a review.
  - target: Weight loss
    description: >-
      Chronic granulomatous infection produces progressive weight loss.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
      explanation: >-
        Review lists weight loss among the constitutional symptoms of NTM lung
        disease. Evidence source is OTHER as this is a review.
  - target: Night sweats
    description: >-
      Chronic granulomatous infection produces night sweats among its
      constitutional symptoms.
    evidence:
    - reference: PMID:42070174
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The concept elicitation interviews identified key symptoms of cough (100%), shortness of breath (98%), fatigue (95%), sputum production (90%), throat clearing (80%), mental fogging (75%), sensitivity to cold (62%), night sweats (55%), poor appetite (53%), chills/feverishness (50%/43%), weight loss (48%), and chest congestion (45%)."
      explanation: >-
        Patient concept-elicitation interviews in NTM-PD identify night sweats
        as a frequent constitutional symptom. The 55% figure is the proportion
        of the PROM item-generation interview cohort who reported the symptom,
        not a disease prevalence estimate. Evidence source is HUMAN_CLINICAL as
        this is a patient-interview study.
- name: Nodular-Bronchiectatic Disease
  description: >-
    The nodular-bronchiectatic form of NTM lung disease comprises small nodules
    and bronchiectasis, classically involving the right middle lobe and lingula,
    and is the more common, more indolent radiographic-pathological pattern.
  role: consequence
  biological_scale: TISSUE
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
    explanation: >-
      Documents the nodular-bronchiectatic radiographic pattern of NTM lung
      disease. Evidence source is OTHER as this is a review.
  downstream:
  - target: Bronchiectasis
    description: >-
      Bronchiectasis is the defining airway lesion of the nodular-bronchiectatic
      pattern.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
      explanation: >-
        The nodular-bronchiectatic pattern is defined by bronchiectasis.
        Evidence source is OTHER as this is a review.
  - target: Chronic cough
    description: >-
      Chronic airway infection and bronchiectasis produce persistent cough.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
      explanation: >-
        Review lists chronic cough as a cardinal symptom. Evidence source is
        OTHER as this is a review.
  - target: Increased sputum production
    description: >-
      Chronic airway infection and bronchiectasis produce chronic sputum.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
      explanation: >-
        Review lists sputum production among the common symptoms. Evidence
        source is OTHER as this is a review.
  - target: Progressive Respiratory Decline
    description: >-
      Cumulative airway destruction contributes to progressive loss of lung
      function.
- name: Fibrocavitary Disease
  description: >-
    The fibrocavitary form comprises upper-lobe cavities resembling
    tuberculosis; it marks the more severe, faster-progressing phenotype with a
    stronger indication for treatment.
  role: consequence
  biological_scale: TISSUE
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
    explanation: >-
      Documents the fibrocavitary radiographic pattern of NTM lung disease.
      Evidence source is OTHER as this is a review.
  downstream:
  - target: Pulmonary cavity
    description: >-
      Upper-lobe cavitation is the defining lesion of the fibrocavitary
      pattern.
    evidence:
    - reference: PMID:42437710
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
      explanation: >-
        The fibrocavitary pattern is defined by pulmonary cavitation. Evidence
        source is OTHER as this is a review.
  - target: Hemoptysis
    description: >-
      Cavitary and bronchiectatic airway destruction produces hemoptysis.
    evidence:
    - reference: PMID:19020369
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Other less common symptoms include dyspnea and hemoptysis."
      explanation: >-
        Review lists hemoptysis among the symptoms of NTM pulmonary infection.
        Evidence source is OTHER as this is a review.
  - target: Progressive Respiratory Decline
    description: >-
      Progressive cavitary parenchymal destruction drives loss of lung function.
- name: Progressive Respiratory Decline
  description: >-
    Untreated or refractory NTM lung disease is associated with progressive loss
    of lung function, impaired quality of life, and increased morbidity and
    mortality; treatment failure in particular is associated with substantial
    lung-function decline.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:30302953
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "treatment failure was associated with a substantial decline in lung function in individuals with NTM lung disease"
    explanation: >-
      Documents progressive lung-function decline as an outcome of NTM lung
      disease. Evidence source is OTHER as this is a review.
  downstream:
  - target: Dyspnea
    description: >-
      Progressive loss of lung function produces exertional breathlessness.
    evidence:
    - reference: PMID:42070174
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The concept elicitation interviews identified key symptoms of cough (100%), shortness of breath (98%), fatigue (95%), sputum production (90%), throat clearing (80%), mental fogging (75%), sensitivity to cold (62%), night sweats (55%), poor appetite (53%), chills/feverishness (50%/43%), weight loss (48%), and chest congestion (45%)."
      explanation: >-
        Patient concept-elicitation interviews in NTM-PD identify shortness of
        breath as a near-universal symptom. The 98% figure is the proportion of
        the PROM item-generation interview cohort who reported the symptom, not
        a disease prevalence estimate. Evidence source is HUMAN_CLINICAL as this
        is a patient-interview study.
phenotypes:
- name: Chronic cough
  category: Respiratory
  description: Persistent cough is the most common presenting symptom.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
    temporality: CHRONIC
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
    explanation: Review lists chronic cough as a cardinal symptom of NTM lung disease.
- name: Increased sputum production
  category: Respiratory
  description: Chronic productive cough with sputum accompanies the airway infection.
  phenotype_term:
    preferred_term: Increased sputum production
    term:
      id: HP:0033709
      label: Increased sputum production
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
    explanation: Review lists sputum production among the common symptoms.
- name: Hemoptysis
  category: Respiratory
  description: >-
    Coughing up blood, arising from bronchiectatic and cavitary airway
    destruction.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:19020369
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other less common symptoms include dyspnea and hemoptysis."
    explanation: Review lists hemoptysis among the symptoms of NTM pulmonary infection.
- name: Dyspnea
  category: Respiratory
  description: >-
    Breathlessness, common with more advanced disease and progressive
    lung-function loss.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:42070174
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The concept elicitation interviews identified key symptoms of cough (100%), shortness of breath (98%), fatigue (95%), sputum production (90%), throat clearing (80%), mental fogging (75%), sensitivity to cold (62%), night sweats (55%), poor appetite (53%), chills/feverishness (50%/43%), weight loss (48%), and chest congestion (45%)."
    explanation: >-
      Patient concept-elicitation interviews in NTM-PD identify shortness of
      breath as a near-universal symptom. The 98% figure is the proportion of
      the PROM item-generation interview cohort who reported the symptom, not a
      disease prevalence estimate.
  - reference: PMID:19020369
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other less common symptoms include dyspnea and hemoptysis."
    explanation: Review lists dyspnea among the symptoms of NTM pulmonary infection.
- name: Fatigue
  category: Constitutional
  description: Constitutional fatigue is common and can be a major driver of treatment decisions.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
    explanation: Review lists fatigue among the common constitutional symptoms.
- name: Weight loss
  category: Constitutional
  description: Progressive weight loss and low body mass index accompany chronic infection and mark poor prognosis.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical presentation is often insidious, with symptoms such as chronic cough, sputum production, fatigue, and weight loss."
    explanation: Review lists weight loss among the common constitutional symptoms.
- name: Night sweats
  category: Constitutional
  description: >-
    Night sweats are a frequent constitutional symptom of chronic NTM lung
    infection.
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
  evidence:
  - reference: PMID:42070174
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The concept elicitation interviews identified key symptoms of cough (100%), shortness of breath (98%), fatigue (95%), sputum production (90%), throat clearing (80%), mental fogging (75%), sensitivity to cold (62%), night sweats (55%), poor appetite (53%), chills/feverishness (50%/43%), weight loss (48%), and chest congestion (45%)."
    explanation: >-
      Patient concept-elicitation interviews in NTM-PD identify night sweats as
      a frequent constitutional symptom. The 55% figure is the proportion of the
      PROM item-generation interview cohort who reported the symptom, not a
      disease prevalence estimate.
- name: Bronchiectasis
  category: Respiratory
  description: >-
    Bronchiectasis is both a predisposing structural lesion and a consequence of
    chronic NTM infection (the nodular-bronchiectatic pattern).
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These infections commonly affect individuals with underlying structural lung disease, including bronchiectasis and chronic obstructive pulmonary disease, as well as immunocompromised patients."
    explanation: >-
      Review documents the tight association of NTM lung disease with
      bronchiectasis.
  - reference: PMID:30216086
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%)."
    explanation: >-
      Randomized-trial cohort of MAC lung disease quantifies the predominance of
      underlying bronchiectasis.
- name: Pulmonary cavity
  category: Respiratory
  description: >-
    Upper-lobe cavitation characterizes the fibrocavitary form and marks more
    severe, rapidly progressive disease and a stronger indication for treatment.
  phenotype_term:
    preferred_term: Pulmonary cavity
    term:
      id: HP:0033655
      label: Pulmonary cavity
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radiological patterns include nodular bronchiectatic disease and fibrocavitary disease."
    explanation: >-
      Review documents the fibrocavitary radiographic pattern of NTM lung
      disease.
prevalence:
- population: Oregon, United States
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 5.6
  rate_low: 4.8
  rate_high: 5.6
  notes: >-
    First population-based US regional estimate; annual incidence of pulmonary
    NTM disease rose from 4.8 to 5.6 per 100,000 over 2007-2012 (not
    statistically significant), and rose steeply with age.
  evidence:
  - reference: PMID:25692495
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "incidence increased from 4.8/100,000 in 2007 to 5.6/100,000 in 2012"
    explanation: >-
      Population-based Oregon surveillance quantifies pulmonary NTM disease
      incidence.
diagnosis:
- name: ATS/ERS/ESCMID/IDSA diagnostic criteria
  description: >-
    Diagnosis of NTM lung disease requires the combination of compatible
    clinical and radiographic findings with microbiological confirmation
    (repeated culture of the same species from sputum, or a single positive
    bronchial wash/lavage, or compatible histopathology plus culture), and
    appropriate exclusion of alternative diagnoses. Culture confirmation is
    required to distinguish true disease from airway colonization.
  evidence:
  - reference: PMID:42437710
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis requires a combination of clinical, radiological, and microbiological criteria to distinguish true disease from colonization."
    explanation: >-
      Review states the combined clinical/radiological/microbiological
      diagnostic requirement. Evidence source is OTHER as this is a review.
  - reference: PMID:27134484
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Positive culture results from at least two separate expectorated sputum samples."
    explanation: >-
      States the microbiologic criterion (repeated positive sputum cultures) of
      the ATS/IDSA diagnostic criteria. Evidence source is OTHER as this is a
      review reproducing the consensus criteria.
treatments:
- name: Macrolide-based multidrug regimen for MAC pulmonary disease
  description: >-
    Guideline-based therapy for macrolide-susceptible MAC pulmonary disease is a
    regimen of at least three drugs — a macrolide (azithromycin preferred over
    clarithromycin), ethambutol, and a rifamycin (rifampicin) — continued for at
    least 12 months after sputum culture conversion. Parenteral amikacin or
    streptomycin is added for cavitary, advanced, or macrolide-resistant disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
    - preferred_term: clarithromycin
      term:
        id: CHEBI:3732
        label: clarithromycin
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Mycobacterial Ribosomal Translation (Macrolide Target)
    treatment_effect: INHIBITS
    description: >-
      The macrolide component binds the mycobacterial ribosome and arrests
      protein synthesis — the anchor of the regimen.
  - target: Requirement for Cell-Penetrant Antimicrobial Therapy
    description: >-
      Macrolides and rifamycins accumulate intracellularly, reaching NTM within
      alveolar macrophages.
  evidence:
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with macrolide-susceptible MAC pulmonary disease, we recommend a three-drug regimen that includes a macrolide over a three-drug regimen without a macrolide"
    explanation: >-
      ATS/ERS/ESCMID/IDSA guideline gives a strong recommendation for a
      macrolide-containing three-drug regimen. Evidence source is OTHER as this
      is a clinical practice guideline.
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we suggest a treatment regimen with at least three drugs (including a macrolide and ethambutol) over a regimen with two drugs (a macrolide and ethambutol alone)"
    explanation: >-
      Guideline specifies the at-least-three-drug macrolide-plus-ethambutol
      backbone. Evidence source is OTHER as this is a clinical practice guideline.
- name: Rifampicin-based regimen for M. kansasii pulmonary disease
  description: >-
    Rifampicin-susceptible M. kansasii pulmonary disease is treated with a
    regimen of rifampicin, ethambutol, and either isoniazid or a macrolide, with
    high rates of treatment success.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
    - preferred_term: clarithromycin
      term:
        id: CHEBI:3732
        label: clarithromycin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Requirement for Cell-Penetrant Antimicrobial Therapy
    description: >-
      Rifampicin and macrolides penetrate host cells to reach intracellular
      M. kansasii.
  evidence:
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we suggest a regimen of rifampicin, ethambutol, and either isoniazid or macrolide"
    explanation: >-
      Guideline recommendation for rifampicin-susceptible M. kansasii pulmonary
      disease. Evidence source is OTHER as this is a clinical practice guideline.
- name: Amikacin liposome inhalation suspension for treatment-refractory MAC
  description: >-
    For MAC pulmonary disease that remains culture-positive after at least six
    months of guideline-based therapy, addition of amikacin liposome inhalation
    suspension (ALIS) to the oral regimen significantly increases sputum culture
    conversion (CONVERT trial). Parenteral amikacin is used instead for cavitary
    or advanced disease at initiation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amikacin
      term:
        id: CHEBI:2637
        label: amikacin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Requirement for Cell-Penetrant Antimicrobial Therapy
    description: >-
      Inhaled liposomal amikacin delivers a cell-penetrant aminoglycoside
      directly to the infected lung.
  evidence:
  - reference: PMID:30216086
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events."
    explanation: >-
      The CONVERT randomized trial establishes the efficacy of ALIS added to
      guideline-based therapy in refractory MAC lung disease.
- name: Surgical resection as adjuvant therapy
  description: >-
    In selected patients with focal disease, drug-resistant isolates, cavitation,
    or complications such as hemoptysis or severe bronchiectasis, surgical
    resection of the diseased lung is used as an adjuvant to medical therapy.
  treatment_term:
    preferred_term: surgical resection
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:32636299
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we suggest surgical resection as an adjuvant to medical therapy after expert consultation"
    explanation: >-
      Guideline conditionally recommends adjuvant surgical resection in selected
      patients. Evidence source is OTHER as this is a clinical practice guideline.
clinical_trials:
- name: NCT02344004
  phase: PHASE_III
  status: COMPLETED
  description: >-
    CONVERT — a randomized, open-label study of amikacin liposome inhalation
    suspension (ALIS) added to guideline-based therapy versus guideline-based
    therapy alone in treatment-refractory MAC lung disease.
  target_phenotypes:
  - preferred_term: Pulmonary cavity
    term:
      id: HP:0033655
      label: Pulmonary cavity
  evidence:
  - reference: clinicaltrials:NCT02344004
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A study to evaluate the effectiveness of Liposomal Amikacin for Inhalation (LAI) 590 mg administered once daily (QD) when added to multi-drug regimen (MDR) in participants with Nontuberculous Mycobacterial (NTM) lung infection caused by Mycobacterium Avium Complex (MAC) that were refractory to treatment."
    explanation: >-
      ClinicalTrials.gov record establishing the CONVERT trial's design and
      population. Evidence source is OTHER as this is a trial-registry record.
animal_models:
- name: Nrf2-deficient mouse MAC lung infection
  species: Mouse
  genotype: Nrf2 (Nfe2l2) knockout
  publication: PMID:33563837
  modeled_mechanisms:
  - target: Alveolar Macrophage Infection and Intracellular Persistence
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Nrf2-deficient mice infected with MAC show impaired phagolysosome
      formation and heavy intracellular bacterial burden in alveolar
      macrophages, modeling the intracellular-persistence node.
    limitations: >-
      A single-gene knockout in mice; Nrf2 dependence and the murine granuloma
      response may not fully reproduce human MAC lung disease, which arises in
      structurally or immunologically abnormal human hosts.
    readouts:
    - name: Intracellular MAC burden in alveolar macrophages
      target: Alveolar Macrophage Infection and Intracellular Persistence
      direction: INCREASED
      interpretation: >-
        Nrf2 loss increases intracellular bacterial load with little
        phagolysosome formation, the structural correlate of intracellular
        persistence.
      evidence:
      - reference: PMID:33563837
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes"
        explanation: Reports the intracellular-burden measurement behind this readout.
    evidence:
    - reference: PMID:33563837
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively."
      explanation: >-
        Supports treating the Nrf2-deficient mouse as informative for the
        alveolar-macrophage intracellular-persistence node.
notes: >-
  MONDO:0018469 (pulmonary non-tuberculous mycobacterial infection) carries the
  exact synonym "Nontuberculous Mycobacterial Lung Disease". Pathophysiology
  conforms to the intracellular_pathogen_persistence,
  bacterial_protein_synthesis_inhibition (macrolide target and ribosomal target
  resistance), and granuloma_formation modules. Curated de novo from primary
  literature (no deep-research provider run); environmental exposure is modeled
  as a pathophysiology node rather than an ECTO-bound environmental block.
  Evidence classified MODEL_ORGANISM for the mouse MAC-infection findings
  (PMID:33563837) and OTHER for reviews and the clinical practice guideline.
  Host susceptibility is split into distinct structural-airway and Th1-immune
  predisposition nodes, and the radiographic disease pattern is split into
  distinct nodular-bronchiectatic and fibrocavitary nodes. MAC-vs-M. abscessus
  and fibrocavitary-vs-nodular-bronchiectatic subtyping (via has_subtypes) is a
  possible future refinement.