Hypersensitivity pneumonitis

Respiratory Disease MONDO:0017853 Pathograph 5 Allergic Respiratory Disease Interstitial Lung Disease Pneumonitis

Hypersensitivity pneumonitis is an immune-mediated interstitial lung disease caused by repeated inhalation of environmental antigens in susceptible and sensitized individuals, with inflammation centered on small airways and lung parenchyma and potential progression to chronic fibrotic lung disease.

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5
Pathophys.
2
Histopath.
5
Phenotypes
5
Pathograph
4
Treatments
3
Subtypes
2
Differentials
4
Trials
1
References
1
Deep Research
◆

Subtypes

3
Acute inflammatory hypersensitivity pneumonitis
High-level intermittent antigen exposure causes abrupt inflammatory episodes that typically begin hours after exposure.
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"Acute HP results from intermittent, high-level exposure to the inducing antigen, usually within a few hours of exposure"
The review defines acute disease as high-level intermittent exposure with rapid onset.
Chronic non-fibrotic hypersensitivity pneumonitis
Persistent lower-level exposure drives chronic inflammation without established fibrotic architectural distortion.
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"HP can be classified into acute, chronic non-fibrotic and chronic fibrotic forms."
The review explicitly recognizes chronic non-fibrotic HP as a major subtype.
Chronic fibrotic hypersensitivity pneumonitis
Progressive disease with fibrotic remodeling, traction bronchiectasis, and increased mortality risk.
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"HP can be classified into acute, chronic non-fibrotic and chronic fibrotic forms."
The review explicitly identifies chronic fibrotic HP as a distinct subtype.
⚙

Pathophysiology

5
Repetitive inhaled antigen exposure and sensitization
Inhalation of environmental antigens such as bird proteins and fungal material in susceptible individuals initiates immune sensitization and disease onset.
lung link
Downstream
Exaggerated humoral and cellular lung immune response
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the inhalation of a variety of antigens in susceptible and sensitized individuals."
This sentence defines the initiating exposure-sensitization step in HP pathogenesis.
Exaggerated humoral and cellular lung immune response
Sensitized lungs mount exaggerated humoral and cellular immune activation involving small airways and parenchyma.
T cell link alveolar macrophage link
immune response link ↑ INCREASED inflammatory response link ↑ INCREASED
Downstream
Bronchiolocentric granulomatous inflammation
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"Immunopathologically, HP is characterized by an exaggerated humoral and cellular immune response affecting the small airways and lung parenchyma."
The review directly supports the central immune-amplification mechanism in HP.
Bronchiolocentric granulomatous inflammation
Immune-driven inflammation around bronchioles produces lymphocytic infiltrates and poorly formed non-caseating granulomas.
T cell link alveolar macrophage link
Downstream
Fibrotic remodeling of interstitial lung architecture
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"The histology of HP reveals prominent lymphocyte infiltrates that thicken the alveolar septa with poorly formed granulomas or giant cells."
Histologic description supports airway-centered granulomatous inflammatory injury.
Fibrotic remodeling of interstitial lung architecture
Ongoing inflammation can transition to fibrotic remodeling with reticulation, traction bronchiectatic change, and honeycombing.
fibroblast link myofibroblast link
extracellular matrix organization link ↑ INCREASED
Downstream
Progressive respiratory functional decline
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"Abnormalities on high-resolution computed tomographic examinations range from nodular centrilobular opacities in acute/subacute disease to increased reticular markings and honeycombing fibrosis, which typically are predominant in the upper lobes, in patients with advanced disease."
The review links advanced HP to imaging evidence of fibrosis and architectural distortion.
Progressive respiratory functional decline
Advanced fibrotic HP can follow a progressive phenotype with restrictive impairment and poor medium-term outcomes despite exposure cessation.
Show evidence (2 references)
PMID:32764620 SUPPORT Other
"Some patients with fibrotic HP may evolve to a progressive phenotype, even with complete exposure avoidance."
This directly supports progression despite elimination of the identified antigen.
PMID:30515826 SUPPORT Human Clinical
"CONCLUSION: CHP is a severe disease with a bad mid-term prognosis."
Longitudinal human data support poor outcomes in chronic disease.
✶

Histopathology

2
Airway-centered poorly formed granulomatous inflammation
Histology classically shows bronchiolocentric lymphocytic inflammation with poorly formed non-caseating granulomatous lesions.
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"The histology of HP reveals prominent lymphocyte infiltrates that thicken the alveolar septa with poorly formed granulomas or giant cells."
This review provides validated histologic hallmarks for HP diagnosis.
Fibrotic remodeling in chronic disease
Chronic untreated disease shows fibrosis around small airways and can mimic UIP/NSIP patterns at advanced stages.
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"Abnormalities on high-resolution computed tomographic examinations range from nodular centrilobular opacities in acute/subacute disease to increased reticular markings and honeycombing fibrosis, which typically are predominant in the upper lobes, in patients with advanced disease."
The review supports progression to fibrotic structural lung disease in advanced HP.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypersensitivity pneumonitis 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

5
Limbs 1
Clubbing Clubbing (HP:0001217)
Show evidence (1 reference)
DOI:10.1097/CM9.0000000000002613 SUPPORT Human Clinical
"Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP."
The prospective cohort demonstrates digital clubbing as an enriched finding in fibrotic HP.
Respiratory 2
Dyspnea Dyspnea (HP:0002094)
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"Mimicking a viral syndrome, acute exposures to inciting antigens cause abrupt onset of nonproductive cough, dyspnea, and chills with arthralgias or malaise usually from 4 to 8 hours later"
The review directly lists dyspnea as a canonical presenting symptom.
Cough Cough (HP:0012735)
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"Mimicking a viral syndrome, acute exposures to inciting antigens cause abrupt onset of nonproductive cough, dyspnea, and chills with arthralgias or malaise usually from 4 to 8 hours later"
The review identifies nonproductive cough as a typical acute symptom.
Other 2
Ground-glass opacification Ground-glass opacification (HP:0025179)
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"Descriptors include "mosaic" attenuation and ground-glass opacities."
The review identifies ground-glass opacities as a characteristic imaging descriptor in HP.
Crackles Crackles (HP:0030830)
Show evidence (1 reference)
DOI:10.1097/CM9.0000000000002613 SUPPORT Human Clinical
"Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP."
The prospective cohort demonstrates crackles as an enriched clinical finding in fibrotic HP.
💊

Treatments

4
Antigen avoidance
Action: supportive care MAXO:0000950
Complete identification and removal of the offending antigen is the cornerstone of management and should be initiated promptly.
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"Complete antigen avoidance is the mainstay of treatment."
The review explicitly identifies exposure elimination as primary therapy.
Systemic glucocorticoids
Action: Pharmacotherapy NCIT:C15986
Agent: corticosteroid ↗ azathioprine ↗
Corticosteroids are commonly used as immunosuppressive therapy, particularly in symptomatic or progressive inflammatory disease.
Show evidence (2 references)
PMID:32764620 SUPPORT Other
"The pharmacotherapy of chronic HP consists of immunosuppressive drugs such as corticosteroids, with antifibrotic therapy being a potential therapy for patients with progressive disease."
The review supports corticosteroids as core immunosuppressive treatment in chronic HP.
PMID:38501183 SUPPORT Human Clinical
"Among those who received treatment, prednisone was the most used systemic steroid, and azathioprine was the most commonly used second-line immunosuppressant."
Nationwide claims data support common use of prednisone and azathioprine in treated HP.
Antifibrotic therapy for progressive fibrotic disease
Action: Pharmacotherapy NCIT:C15986
Agent: nintedanib ↗ pirfenidone ↗
Progressive fibrotic HP may be treated with antifibrotic strategies to slow continued decline.
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"The pharmacotherapy of chronic HP consists of immunosuppressive drugs such as corticosteroids, with antifibrotic therapy being a potential therapy for patients with progressive disease."
The review supports considering antifibrotics in progressive fibrotic HP.
Lung transplantation for advanced fibrotic disease
Action: organ transplantation MAXO:0010039
End-stage chronic HP can require lung transplantation in addition to medical management.
Show evidence (1 reference)
PMID:30515826 SUPPORT Human Clinical
"Seventy-three had died or underwent lung transplantation at the time of the study with a median survival of 7.0 (4.4-14.5) years."
Cohort outcomes directly show transplantation in severe chronic HP.
🌍

Environmental Factors

2
Bird protein exposure
exposure to animal waste material link
Bird droppings, feathers, and related avian proteins are major home and hobby-associated triggers.
Show evidence (1 reference)
PMID:32764620 SUPPORT Other
"These antigens are found in the environment, mostly derived from bird proteins and fungi."
Review supports bird proteins as one of the dominant environmental antigen classes.
Fungal and microbial antigen exposure
exposure to allergen link
Fungal antigens, thermophilic bacteria, and other bioaerosols can trigger sensitization.
Show evidence (1 reference)
PMID:30448501 SUPPORT Other
"Hypersensitivity pneumonitis (HP) is a TH1 lymphocyte-biased fibrosing alveolitis caused by antigens ranging from avian excreta, fungi, thermophilic bacteria, and protozoa to reactive chemicals found in the workplace."
The review catalogs key microbial and occupational exposure sources.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hypersensitivity pneumonitis:

Idiopathic pulmonary fibrosis MONDO:0800504
Overlapping Features Chronic fibrotic HP can mimic idiopathic pulmonary fibrosis/usual interstitial pneumonia, but HRCT pattern distribution helps distinguish these entities.
Distinguishing Features
  • Honeycombing with lower lung zone predominance favors IPF/UIP over chronic HP.
  • Absence of centrilobular small nodules favors IPF/UIP over chronic HP.
Show evidence (1 reference)
PMID:24480143 SUPPORT Human Clinical
"In idiopathic pulmonary fibrosis or usual interstitial pneumonia, however, the presence of honeycombing with lower lung zone predominance and the absence of centrilobular small nodules are important findings that allow us to differentiate the disease from chronic HP or advanced-stage sarcoidosis."
This HRCT-focused study provides direct image-based differentiators between chronic HP and IPF/UIP.
Pulmonary sarcoidosis MONDO:0019338
Overlapping Features Advanced pulmonary sarcoidosis can resemble fibrotic HP, but typically shows upper and middle zone-predominant fibrotic changes with relative basal sparing.
Distinguishing Features
  • Upper and middle lung zone predominance favors advanced sarcoidosis.
  • Relative sparing of lung bases supports sarcoidosis over UIP/IPF patterns.
Show evidence (1 reference)
PMID:24480143 SUPPORT Human Clinical
"In advanced-stage sarcoidosis, patchy areas of reticulation, traction bronchiectasis, architectural distortion, honeycomblike cysts, bullae, and paracicatricial emphysema are observed in the upper and middle lung zones. Lung bases are usually spared."
The abstract outlines the distributional HRCT pattern that helps differentiate advanced pulmonary sarcoidosis from other fibrosing ILDs.
🔬

Clinical Trials

4
NCT02496182
Trial evaluating addition of pirfenidone to background prednisone and azathioprine in pulmonary fibrosis secondary to chronic hypersensitivity pneumonitis.
Show evidence (1 reference)
clinicaltrials:NCT02496182 SUPPORT Human Clinical
"the investigators propose to evaluate the addition of Pirfenidone to the actual treatment with Prednisone and Azathioprine in the treatment of patients with Pulmonary Fibrosis secondary to a Chronic Hypersensitivity Pneumonitis."
This ClinicalTrials.gov summary describes an HP-specific antifibrotic interventional design.
NCT02999178 PHASE_III
INBUILD trial evaluating nintedanib versus placebo over 52 weeks in progressive fibrosing interstitial lung disease, a group that includes progressive fibrotic HP phenotypes.
Show evidence (1 reference)
clinicaltrials:NCT02999178 SUPPORT Human Clinical
"The aim of the current study is to investigate the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)"
This trial provides a major platform study context for antifibrotic treatment in progressive fibrosing ILD relevant to fibrotic HP.
NCT02958917 PHASE_II
Randomized placebo-controlled trial of pirfenidone in fibrotic hypersensitivity pneumonitis.
Show evidence (1 reference)
clinicaltrials:NCT02958917 SUPPORT Human Clinical
"Patients are being offered participation in this pirfenidone trial because They have been diagnosed with fibrotic hypersensitivity pneumonitis (FHP), a type of interstitial lung disease (ILD)."
This HP-specific protocol defines a dedicated pirfenidone intervention cohort in fibrotic HP.
NCT05626387
Randomized controlled trial testing mycophenolate mofetil plus prednisolone versus prednisolone alone in fibrotic HP.
Show evidence (1 reference)
clinicaltrials:NCT05626387 SUPPORT Human Clinical
"To our knowledge, there is no randomized controlled trial assessing the efficacy of mycophenolate mofetil (MMF) in the treatment of HP."
The trial rationale defines an ongoing controlled study for MMF-based therapy in fibrotic HP.
{ }

Source YAML

click to show 
name: Hypersensitivity pneumonitis
creation_date: "2026-05-26T00:00:00Z"
category: Respiratory Disease
description: >-
  Hypersensitivity pneumonitis is an immune-mediated interstitial lung disease
  caused by repeated inhalation of environmental antigens in susceptible and
  sensitized individuals, with inflammation centered on small airways and lung
  parenchyma and potential progression to chronic fibrotic lung disease.
disease_term:
  preferred_term: hypersensitivity pneumonitis
  term:
    id: MONDO:0017853
    label: hypersensitivity pneumonitis
parents:
- Allergic Respiratory Disease
- Interstitial Lung Disease
- Pneumonitis
synonyms:
- Extrinsic allergic alveolitis
- HP
references:
- reference: PMID:29763093
  title: Hypersensitivity Pneumonitis.
epidemiology:
- name: Nationwide incidence in South Korea
  description: >-
    Nationwide claims analysis found annual age- and sex-adjusted incidence in
    Korea ranging from 1.14 to 2.16 per 100,000 between 2012 and 2020.
  evidence:
  - reference: PMID:38501183
    reference_title: Nationwide Study of the Epidemiology, Diagnosis, and Treatment of Hypersensitivity Pneumonitis in Korea.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 8,678 HP incident cases were confirmed, with age- and
      sex-adjusted annual incidence rates ranging from 1.14/100,000 in 2020 to
      2.16/100,000 in 2012.
    explanation: This nationwide cohort provides quantitative incidence bounds for HP.
- name: Fibrotic subtype predominance in prospective cohort
  description: >-
    In a large prospective cohort, fibrotic HP represented a larger proportion
    of enrolled cases than non-fibrotic HP.
  evidence:
  - reference: DOI:10.1097/CM9.0000000000002613
    reference_title: "Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP
      patients and 115 (56.9%) FHP patients.
    explanation: This prospective cohort quantifies relative frequencies of fibrotic versus non-fibrotic HP.
has_subtypes:
- name: Acute inflammatory hypersensitivity pneumonitis
  description: >-
    High-level intermittent antigen exposure causes abrupt inflammatory episodes
    that typically begin hours after exposure.
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute HP results from intermittent, high-level exposure to the inducing
      antigen, usually within a few hours of exposure
    explanation: The review defines acute disease as high-level intermittent exposure with rapid onset.
- name: Chronic non-fibrotic hypersensitivity pneumonitis
  description: >-
    Persistent lower-level exposure drives chronic inflammation without
    established fibrotic architectural distortion.
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HP can be classified into acute, chronic non-fibrotic and chronic
      fibrotic forms.
    explanation: The review explicitly recognizes chronic non-fibrotic HP as a major subtype.
- name: Chronic fibrotic hypersensitivity pneumonitis
  description: >-
    Progressive disease with fibrotic remodeling, traction bronchiectasis, and
    increased mortality risk.
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HP can be classified into acute, chronic non-fibrotic and chronic
      fibrotic forms.
    explanation: The review explicitly identifies chronic fibrotic HP as a distinct subtype.
pathophysiology:
- name: Repetitive inhaled antigen exposure and sensitization
  description: >-
    Inhalation of environmental antigens such as bird proteins and fungal
    material in susceptible individuals initiates immune sensitization and
    disease onset.
  role: trigger
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the
      inhalation of a variety of antigens in susceptible and sensitized
      individuals.
    explanation: This sentence defines the initiating exposure-sensitization step in HP pathogenesis.
  downstream:
  - target: Exaggerated humoral and cellular lung immune response

- name: Exaggerated humoral and cellular lung immune response
  description: >-
    Sensitized lungs mount exaggerated humoral and cellular immune activation
    involving small airways and parenchyma.
  role: central
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  biological_processes:
  - preferred_term: immune response
    term:
      id: GO:0006955
      label: immune response
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Immunopathologically, HP is characterized by an exaggerated humoral and
      cellular immune response affecting the small airways and lung parenchyma.
    explanation: The review directly supports the central immune-amplification mechanism in HP.
  downstream:
  - target: Bronchiolocentric granulomatous inflammation

- name: Bronchiolocentric granulomatous inflammation
  description: >-
    Immune-driven inflammation around bronchioles produces lymphocytic
    infiltrates and poorly formed non-caseating granulomas.
  role: effector
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The histology of HP reveals prominent lymphocyte infiltrates that thicken
      the alveolar septa with poorly formed granulomas or giant cells.
    explanation: Histologic description supports airway-centered granulomatous inflammatory injury.
  downstream:
  - target: Fibrotic remodeling of interstitial lung architecture

- name: Fibrotic remodeling of interstitial lung architecture
  description: >-
    Ongoing inflammation can transition to fibrotic remodeling with reticulation,
    traction bronchiectatic change, and honeycombing.
  role: late_effector
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Abnormalities on high-resolution computed tomographic examinations range
      from nodular centrilobular opacities in acute/subacute disease to
      increased reticular markings and honeycombing fibrosis, which typically
      are predominant in the upper lobes, in patients with advanced disease.
    explanation: The review links advanced HP to imaging evidence of fibrosis and architectural distortion.
  downstream:
  - target: Progressive respiratory functional decline

- name: Progressive respiratory functional decline
  description: >-
    Advanced fibrotic HP can follow a progressive phenotype with restrictive
    impairment and poor medium-term outcomes despite exposure cessation.
  role: consequence
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some patients with fibrotic HP may evolve to a progressive phenotype,
      even with complete exposure avoidance.
    explanation: This directly supports progression despite elimination of the identified antigen.
  - reference: PMID:30515826
    reference_title: Long-term outcomes in chronic hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CONCLUSION: CHP is a severe disease with a bad mid-term prognosis.
    explanation: Longitudinal human data support poor outcomes in chronic disease.
phenotypes:
- category: Respiratory
  name: Dyspnea
  description: Shortness of breath is a core symptom across acute and chronic HP.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mimicking a viral syndrome, acute exposures to inciting antigens cause
      abrupt onset of nonproductive cough, dyspnea, and chills with arthralgias
      or malaise usually from 4 to 8 hours later
    explanation: The review directly lists dyspnea as a canonical presenting symptom.
- category: Respiratory
  name: Cough
  description: Nonproductive cough is common and can be temporally linked to antigen exposure.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mimicking a viral syndrome, acute exposures to inciting antigens cause
      abrupt onset of nonproductive cough, dyspnea, and chills with arthralgias
      or malaise usually from 4 to 8 hours later
    explanation: The review identifies nonproductive cough as a typical acute symptom.
- category: Respiratory
  name: Ground-glass opacification
  description: Ground-glass opacities are common HRCT descriptors in HP.
  phenotype_term:
    preferred_term: Ground-glass opacification
    term:
      id: HP:0025179
      label: Ground-glass opacification
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Descriptors include "mosaic" attenuation and ground-glass opacities.
    explanation: The review identifies ground-glass opacities as a characteristic imaging descriptor in HP.
- category: Respiratory
  name: Crackles
  description: Inspiratory crackles are more frequent in fibrotic HP than in non-fibrotic HP.
  phenotype_term:
    preferred_term: Crackles
    term:
      id: HP:0030830
      label: Crackles
  evidence:
  - reference: DOI:10.1097/CM9.0000000000002613
    reference_title: "Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with FHP were older and more frequently presented with
      dyspnea, crackles, and digital clubbing than patients with NFHP.
    explanation: The prospective cohort demonstrates crackles as an enriched clinical finding in fibrotic HP.
- category: Respiratory
  name: Clubbing
  description: Digital clubbing is enriched in fibrotic HP compared with non-fibrotic disease.
  phenotype_term:
    preferred_term: Clubbing
    term:
      id: HP:0001217
      label: Clubbing
  evidence:
  - reference: DOI:10.1097/CM9.0000000000002613
    reference_title: "Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with FHP were older and more frequently presented with
      dyspnea, crackles, and digital clubbing than patients with NFHP.
    explanation: The prospective cohort demonstrates digital clubbing as an enriched finding in fibrotic HP.
histopathology:
- name: Airway-centered poorly formed granulomatous inflammation
  diagnostic: true
  description: >-
    Histology classically shows bronchiolocentric lymphocytic inflammation with
    poorly formed non-caseating granulomatous lesions.
  finding_term:
    preferred_term: bronchiolocentric poorly formed non-caseating granulomas
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The histology of HP reveals prominent lymphocyte infiltrates that thicken
      the alveolar septa with poorly formed granulomas or giant cells.
    explanation: This review provides validated histologic hallmarks for HP diagnosis.
- name: Fibrotic remodeling in chronic disease
  diagnostic: true
  description: >-
    Chronic untreated disease shows fibrosis around small airways and can mimic
    UIP/NSIP patterns at advanced stages.
  finding_term:
    preferred_term: bronchiolocentric fibrosis with chronic inflammation
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Abnormalities on high-resolution computed tomographic examinations range
      from nodular centrilobular opacities in acute/subacute disease to
      increased reticular markings and honeycombing fibrosis, which typically
      are predominant in the upper lobes, in patients with advanced disease.
    explanation: The review supports progression to fibrotic structural lung disease in advanced HP.
differential_diagnoses:
- name: Idiopathic pulmonary fibrosis
  description: >-
    Chronic fibrotic HP can mimic idiopathic pulmonary fibrosis/usual
    interstitial pneumonia, but HRCT pattern distribution helps distinguish
    these entities.
  distinguishing_features:
  - Honeycombing with lower lung zone predominance favors IPF/UIP over chronic HP.
  - Absence of centrilobular small nodules favors IPF/UIP over chronic HP.
  disease_term:
    preferred_term: idiopathic pulmonary fibrosis
    term:
      id: MONDO:0800504
      label: idiopathic pulmonary fibrosis
  evidence:
  - reference: PMID:24480143
    reference_title: "Chronic hypersensitivity pneumonitis and pulmonary sarcoidosis: differentiation from usual interstitial pneumonia using high-resolution computed tomography."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In idiopathic pulmonary fibrosis or usual interstitial pneumonia,
      however, the presence of honeycombing with lower lung zone predominance
      and the absence of centrilobular small nodules are important findings
      that allow us to differentiate the disease from chronic HP or
      advanced-stage sarcoidosis.
    explanation: This HRCT-focused study provides direct image-based differentiators between chronic HP and IPF/UIP.
- name: Pulmonary sarcoidosis
  description: >-
    Advanced pulmonary sarcoidosis can resemble fibrotic HP, but typically
    shows upper and middle zone-predominant fibrotic changes with relative
    basal sparing.
  distinguishing_features:
  - Upper and middle lung zone predominance favors advanced sarcoidosis.
  - Relative sparing of lung bases supports sarcoidosis over UIP/IPF patterns.
  disease_term:
    preferred_term: sarcoidosis
    term:
      id: MONDO:0019338
      label: sarcoidosis
  evidence:
  - reference: PMID:24480143
    reference_title: "Chronic hypersensitivity pneumonitis and pulmonary sarcoidosis: differentiation from usual interstitial pneumonia using high-resolution computed tomography."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In advanced-stage sarcoidosis, patchy areas of reticulation, traction
      bronchiectasis, architectural distortion, honeycomblike cysts, bullae,
      and paracicatricial emphysema are observed in the upper and middle lung
      zones. Lung bases are usually spared.
    explanation: The abstract outlines the distributional HRCT pattern that helps differentiate advanced pulmonary sarcoidosis from other fibrosing ILDs.
diagnosis:
- name: ATS/JRS/ALAT multidisciplinary diagnostic framework
  description: >-
    Current diagnosis integrates exposure history, HRCT pattern analysis,
    bronchoalveolar lavage lymphocyte profiling, and selective tissue sampling
    with multidisciplinary interpretation.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: DOI:10.1164/RCCM.202005-2032ST
    reference_title: "Diagnosis of Hypersensitivity Pneumonitis in Adults: An Official ATS/JRS/ALAT Clinical Practice Guideline"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The guideline committee developed a systematic approach to the diagnosis
      of HP.
    explanation: The official guideline establishes a formal diagnostic framework for adult HP.
    images:
    - Hypersensitivity_Pneumonitis-deep-research-falcon_artifacts/image-1.png
- name: BAL cellular profile for fibrotic risk stratification
  description: >-
    Lower BAL lymphocyte proportion and higher BAL eosinophil proportion are
    associated with fibrotic subtype and can support risk-focused phenotyping.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: DOI:10.1097/CM9.0000000000002613
    reference_title: "Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multivariable regression analyses revealed that older age, <20% of
      lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for
      the development of FHP.
    explanation: This prospective cohort provides quantitative BAL-associated risk features for fibrotic HP.
- name: Antigen-specific IgG serologic testing
  description: >-
    Serologic IgG testing against candidate antigens can support exposure
    identification within multidisciplinary diagnosis.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnosis is based on an accurate exposure history, clinical
      presentation, characteristic high-resolution CT findings, specific IgG
      antibodies to the offending antigen, bronchoalveolar lavage and
      pathological features.
    explanation: The review explicitly includes antigen-specific IgG antibodies among core diagnostic modalities.
environmental:
- name: Bird protein exposure
  notes: Bird droppings, feathers, and related avian proteins are major home and hobby-associated triggers.
  exposure_term:
    preferred_term: exposure to animal waste material
    term:
      id: ECTO:7000098
      label: exposure to animal waste material
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These antigens are found in the environment, mostly derived from bird
      proteins and fungi.
    explanation: Review supports bird proteins as one of the dominant environmental antigen classes.
- name: Fungal and microbial antigen exposure
  notes: Fungal antigens, thermophilic bacteria, and other bioaerosols can trigger sensitization.
  exposure_term:
    preferred_term: exposure to allergen
    term:
      id: ECTO:0000726
      label: exposure to allergen
  evidence:
  - reference: PMID:30448501
    reference_title: "Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypersensitivity pneumonitis (HP) is a TH1 lymphocyte-biased fibrosing
      alveolitis caused by antigens ranging from avian excreta, fungi,
      thermophilic bacteria, and protozoa to reactive chemicals found in the
      workplace.
    explanation: The review catalogs key microbial and occupational exposure sources.
progression:
- phase: Acute inflammatory phase
  notes: Symptoms begin within hours after high-level intermittent antigen exposure.
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute HP results from intermittent, high-level exposure to the inducing
      antigen, usually within a few hours of exposure
    explanation: Defines the temporal profile of acute inflammatory disease.
- phase: Chronic fibrotic phase
  notes: Persistent disease may progress to fibrosis and worse outcomes.
  evidence:
  - reference: PMID:30515826
    reference_title: Long-term outcomes in chronic hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-three had died or underwent lung transplantation at the time of
      the study with a median survival of 7.0 (4.4-14.5) years.
    explanation: Longitudinal cohort data quantify severe outcomes in chronic fibrotic disease.
treatments:
- name: Antigen avoidance
  description: >-
    Complete identification and removal of the offending antigen is the
    cornerstone of management and should be initiated promptly.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Complete antigen avoidance is the mainstay of treatment.
    explanation: The review explicitly identifies exposure elimination as primary therapy.
- name: Systemic glucocorticoids
  description: >-
    Corticosteroids are commonly used as immunosuppressive therapy, particularly
    in symptomatic or progressive inflammatory disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pharmacotherapy of chronic HP consists of immunosuppressive drugs
      such as corticosteroids, with antifibrotic therapy being a potential
      therapy for patients with progressive disease.
    explanation: The review supports corticosteroids as core immunosuppressive treatment in chronic HP.
  - reference: PMID:38501183
    reference_title: Nationwide Study of the Epidemiology, Diagnosis, and Treatment of Hypersensitivity Pneumonitis in Korea.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among those who received treatment, prednisone was the most used
      systemic steroid, and azathioprine was the most commonly used second-line
      immunosuppressant.
    explanation: Nationwide claims data support common use of prednisone and azathioprine in treated HP.
- name: Antifibrotic therapy for progressive fibrotic disease
  description: >-
    Progressive fibrotic HP may be treated with antifibrotic strategies to slow
    continued decline.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nintedanib
      term:
        id: CHEBI:85164
        label: nintedanib
    - preferred_term: pirfenidone
      term:
        id: CHEBI:32016
        label: pirfenidone
  evidence:
  - reference: PMID:32764620
    reference_title: Hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pharmacotherapy of chronic HP consists of immunosuppressive drugs
      such as corticosteroids, with antifibrotic therapy being a potential
      therapy for patients with progressive disease.
    explanation: The review supports considering antifibrotics in progressive fibrotic HP.
- name: Lung transplantation for advanced fibrotic disease
  description: >-
    End-stage chronic HP can require lung transplantation in addition to
    medical management.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:30515826
    reference_title: Long-term outcomes in chronic hypersensitivity pneumonitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-three had died or underwent lung transplantation at the time
      of the study with a median survival of 7.0 (4.4-14.5) years.
    explanation: Cohort outcomes directly show transplantation in severe chronic HP.
clinical_trials:
- name: NCT02496182
  description: >-
    Trial evaluating addition of pirfenidone to background prednisone and
    azathioprine in pulmonary fibrosis secondary to chronic hypersensitivity
    pneumonitis.
  evidence:
  - reference: clinicaltrials:NCT02496182
    reference_title: Pirfenidone in the Chronic Hypersensitivity Pneumonitis Treatment
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the investigators propose to evaluate the addition of Pirfenidone to the
      actual treatment with Prednisone and Azathioprine in the treatment of
      patients with Pulmonary Fibrosis secondary to a Chronic Hypersensitivity
      Pneumonitis.
    explanation: This ClinicalTrials.gov summary describes an HP-specific antifibrotic interventional design.
- name: NCT02999178
  phase: PHASE_III
  description: >-
    INBUILD trial evaluating nintedanib versus placebo over 52 weeks in
    progressive fibrosing interstitial lung disease, a group that includes
    progressive fibrotic HP phenotypes.
  evidence:
  - reference: clinicaltrials:NCT02999178
    reference_title: A Double Blind, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Nintedanib Over 52 Weeks in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of the current study is to investigate the efficacy and safety of
      nintedanib over 52 weeks in patients with Progressive Fibrosing
      Interstitial Lung Disease (PF-ILD)
    explanation: This trial provides a major platform study context for antifibrotic treatment in progressive fibrosing ILD relevant to fibrotic HP.
- name: NCT02958917
  phase: PHASE_II
  description: >-
    Randomized placebo-controlled trial of pirfenidone in fibrotic
    hypersensitivity pneumonitis.
  evidence:
  - reference: clinicaltrials:NCT02958917
    reference_title: A Randomized, Double-Blind, Placebo-Controlled, Study of Efficacy and Safety of Pirfenidone in Patients With Fibrotic Hypersensitivity Pneumonitis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients are being offered participation in this pirfenidone trial
      because They have been diagnosed with fibrotic hypersensitivity
      pneumonitis (FHP), a type of interstitial lung disease (ILD).
    explanation: This HP-specific protocol defines a dedicated pirfenidone intervention cohort in fibrotic HP.
- name: NCT05626387
  description: >-
    Randomized controlled trial testing mycophenolate mofetil plus prednisolone
    versus prednisolone alone in fibrotic HP.
  evidence:
  - reference: clinicaltrials:NCT05626387
    reference_title: "Mycophenolate Mofetil and Prednisolone Versus Prednisolone Alone in Fibrotic Hypersensitivity Pneumonitis: a Randomized Controlled Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, there is no randomized controlled trial assessing the
      efficacy of mycophenolate mofetil (MMF) in the treatment of HP.
    explanation: The trial rationale defines an ongoing controlled study for MMF-based therapy in fibrotic HP.
📚

References & Deep Research

References

1
PMID:29763093
Hypersensitivity Pneumonitis.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
54 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Hypersensitivity pneumonitis
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on Hypersensitivity pneumonitis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Hypersensitivity Pneumonitis (HP): Disease Characteristics Research Report (2023–2024 prioritized)

Executive summary

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) triggered by inhaled environmental antigens, classically avian proteins and fungal/mould exposures, in susceptible individuals. Contemporary international guidance emphasizes a two-phenotype framework—non-fibrotic HP (NFHP) versus fibrotic HP (FHP)—because fibrosis strongly drives prognosis and treatment decisions. Key quantitative data from recent cohorts and trials include: (i) Korean nationwide incidence 1.14–2.16/100,000/year (2012–2020), (ii) ATS/JRS/ALAT diagnostic performance of BAL lymphocytes ≥30% versus IPF (sensitivity 55%, specificity 80%), (iii) in a 2023 prospective cohort, BAL lymphocytes <20% (OR 2.47) and BAL eosinophils ≥1.75% (OR 2.36) were associated with fibrosis, and (iv) in progressive fibrosing ILD (INBUILD), nintedanib reduced annual FVC decline by ~107 mL/year versus placebo and reduced risk of progression events, with gastrointestinal adverse events (notably diarrhea) predominating. (raghu2020diagnosisofhypersensitivity pages 20-21, jung2024nationwidestudyof pages 1-2, chen2023clinicalcharacteristicsof pages 5-7, amati2023efficacyofpirfenidone pages 6-7, flaherty2022nintedanibinprogressive pages 6-7)

A compact quantitative evidence table is provided below.

Domain Metric Value Population/Study Year URL Citation ID
Epidemiology Annual incidence, Korea 1.14–2.16 per 100,000/year Nationwide Korean HIRA claims study; 8,678 incident HP cases 2024 https://doi.org/10.3346/jkms.2024.39.e96 (jung2024nationwidestudyof pages 1-2, jung2024nationwidestudyof pages 2-4)
Epidemiology Mean age / sex 52.6 ± 18.9 years; 51.5% male Nationwide Korean HIRA claims study 2024 https://doi.org/10.3346/jkms.2024.39.e96 (jung2024nationwidestudyof pages 2-4)
Epidemiology ICD-10 coding 82.2% coded J67.9 (HP due to unspecified organic dust) Nationwide Korean HIRA claims study 2024 https://doi.org/10.3346/jkms.2024.39.e96 (jung2024nationwidestudyof pages 2-4)
Epidemiology Bronchoscopy utilization 16.9% Nationwide Korean HIRA claims study 2024 https://doi.org/10.3346/jkms.2024.39.e96 (jung2024nationwidestudyof pages 1-2, jung2024nationwidestudyof pages 9-10)
Epidemiology No treatment within 1 year 25.4% Nationwide Korean HIRA claims study 2024 https://doi.org/10.3346/jkms.2024.39.e96 (jung2024nationwidestudyof pages 1-2)
Diagnostics BAL lymphocytosis threshold vs IPF (fibrotic HP) 20%: sensitivity 69%, specificity 61% ATS/JRS/ALAT guideline evidence synthesis 2020 https://doi.org/10.1164/rccm.202005-2032ST (raghu2020diagnosisofhypersensitivity pages 20-21)
Diagnostics BAL lymphocytosis threshold vs IPF (fibrotic HP) 30%: sensitivity 55%, specificity 80% ATS/JRS/ALAT guideline evidence synthesis 2020 https://doi.org/10.1164/rccm.202005-2032ST (raghu2020diagnosisofhypersensitivity pages 20-21)
Diagnostics BAL lymphocytosis threshold vs IPF (fibrotic HP) 40%: sensitivity 41%, specificity 93% ATS/JRS/ALAT guideline evidence synthesis 2020 https://doi.org/10.1164/rccm.202005-2032ST (raghu2020diagnosisofhypersensitivity pages 20-21)
Diagnostics Suggested practical BAL threshold 30% considered reasonable by expert panel; no single definitive threshold validated ATS/JRS/ALAT guideline summary 2021 https://doi.org/10.1513/AnnalsATS.202009-1195CME (koster2021diagnosisofhypersensitivity pages 9-14)
Exposures Identified inciting antigen 66.8% Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4)
Exposures Avian exposures among identified antigens 50.4% Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4)
Diagnostics Common HRCT findings GGO 91.6%; reticulation 63.9%; traction bronchiectasis 48.5% Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4)
Biomarkers BAL lymphocytosis present 70.1% Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4, chen2023clinicalcharacteristicsof pages 5-7)
Biomarkers Predictor of fibrosis: BAL lymphocytes <20% OR 2.47 Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4, chen2023clinicalcharacteristicsof pages 5-7)
Biomarkers Predictor of fibrosis: BAL eosinophils ≥1.75% OR 2.36 Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4, chen2023clinicalcharacteristicsof pages 5-7)
Biomarkers Predictor of fibrosis: age ≥65 years OR 2.61 Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4, chen2023clinicalcharacteristicsof pages 5-7)
Prognosis Radiologic fibrosis enrichment in fibrotic HP Reticulation 96.5% vs 20.7%; honeycombing 40.0% vs 0%; traction bronchiectasis 82.6% vs 3.4% (FHP vs NFHP) Prospective HP cohort (n=202) 2023 https://doi.org/10.1097/CM9.0000000000002613 (chen2023clinicalcharacteristicsof pages 5-7)
Prognosis 1-, 3-, 5-year mortality 3.9%, 16.8%, 32.7% Biopsy-proven fibrotic HP cohort (n=101) 2023 https://doi.org/10.3389/fmed.2023.1131070 (oh2023fibrosisscorepredicts pages 2-3, oh2023fibrosisscorepredicts pages 1-2)
Prognosis Acute exacerbations 19.8% Biopsy-proven fibrotic HP cohort (n=101) 2023 https://doi.org/10.3389/fmed.2023.1131070 (oh2023fibrosisscorepredicts pages 2-3)
Prognosis Overall deaths during follow-up 41.6% Biopsy-proven fibrotic HP cohort (n=101) 2023 https://doi.org/10.3389/fmed.2023.1131070 (oh2023fibrosisscorepredicts pages 2-3)
Prognosis Fibrosis score performance for 5-year mortality AUC 0.752; cutoff ≥12.0% Biopsy-proven fibrotic HP cohort (n=101) 2023 https://doi.org/10.3389/fmed.2023.1131070 (oh2023fibrosisscorepredicts pages 1-2)
Prognosis Survival by fibrosis score Mean survival 58.3 vs 146.7 months for fibrosis score ≥12.0% vs <12.0% Biopsy-proven fibrotic HP cohort (n=101) 2023 https://doi.org/10.3389/fmed.2023.1131070 (oh2023fibrosisscorepredicts pages 1-2)
Prognosis Mortality/transplant predictor: age HR 1.08 Multicentre fibrotic HP cohort (n=403) 2024 https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
Prognosis Mortality/transplant predictor: FVC % predicted HR 0.96 Multicentre fibrotic HP cohort (n=403) 2024 https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
Prognosis Mortality/transplant predictor: BAL lymphocytosis HR 0.93 Multicentre fibrotic HP cohort (n=403) 2024 https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
Prognosis Mortality/transplant predictor: acute exacerbation during follow-up HR 3.04 Multicentre fibrotic HP cohort (n=403) 2024 https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
Prognosis Mortality/transplant predictor: GAP index HR 1.96 Multicentre fibrotic HP cohort (n=403) 2024 https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
Prognosis Mortality/transplant predictor in biopsied subgroup: fibroblastic foci HR 8.39 Multicentre fibrotic HP cohort (biopsied subgroup) 2024 https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
Treatment Annual FVC decline, placebo vs nintedanib −187.8 vs −80.8 mL/year; difference 107 mL/year INBUILD trial, progressive fibrosing ILD (26.1% HP) 2023 review of trial data https://doi.org/10.3390/ijms24097849 (amati2023efficacyofpirfenidone pages 6-7)
Treatment Risk reduction for relative FVC decline ≥10% predicted 37% overall reduction INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Acute exacerbation of ILD or death HR 0.67 (95% CI 0.46–0.98) INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Adverse event rate: diarrhea 136.4 vs 23.0 events/100 patient-years (nintedanib vs placebo) INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Adverse event rate: nausea 30.8 vs 7.6 events/100 patient-years INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Adverse event rate: vomiting 17.3 vs 3.5 events/100 patient-years INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Adverse event rate: weight decrease 12.4 vs 3.9 events/100 patient-years INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Adverse event rate: ALT increased 12.4 vs 2.8 events/100 patient-years INBUILD whole-trial analysis 2022 https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
Treatment Real-world pre/post nintedanib FVC decline −239.9 mL to −88.8 mL over 12 months; p=0.004 UK multicentre real-world non-IPF PPF cohort (n=126) 2023 https://doi.org/10.1183/23120541.00423-2022 (raman2023nintedanibfornonipf pages 1-2)
Treatment Real-world pre/post nintedanib DLCO decline −6.1% to −2.1%; p=0.004 UK multicentre real-world non-IPF PPF cohort (n=126) 2023 https://doi.org/10.1183/23120541.00423-2022 (raman2023nintedanibfornonipf pages 1-2)
Treatment Real-world adverse events / persistence 71% reported side effects; 80% of surviving patients remained on nintedanib at 12 months; no serious adverse events UK multicentre real-world non-IPF PPF cohort (n=126) 2023 https://doi.org/10.1183/23120541.00423-2022 (raman2023nintedanibfornonipf pages 1-2)
Biomarkers Plasma GDF15 to distinguish fibrotic vs non-fibrotic HP 2539 ± 821 vs 1783 ± 801 pg/mL; cutoff 2193.4 pg/mL; AUC 0.75 HP biomarker study (n=64 HP) 2024 https://doi.org/10.1038/s41598-023-49459-6 (koster2021diagnosisofhypersensitivity pages 1-5)

Table: This table compiles key quantitative findings on hypersensitivity pneumonitis across epidemiology, diagnostics, prognosis, exposures, biomarkers, and treatment. It is designed as a compact evidence summary for rapid reference in a disease knowledge base or research report.

1. Disease information

1.1 Definition and overview

HP is an immune-mediated ILD caused by sensitization and immune reaction to inhaled antigens, producing bronchiolocentric inflammation that may progress to architectural distortion and fibrosis; the non-fibrotic vs fibrotic distinction is central to current practice because it correlates with outcomes and guides diagnostic confidence. (costabel2020hypersensitivitypneumonitis pages 1-2, koster2021diagnosisofhypersensitivity pages 1-5)

1.2 Key identifiers and controlled vocabularies

  • MONDO: MONDO_0017853 (hypersensitivity pneumonitis). (OpenTargets Search: hypersensitivity pneumonitis)
  • EFO: EFO_1001321 (extrinsic allergic alveolitis). (OpenTargets Search: hypersensitivity pneumonitis)
  • MeSH: Alveolitis, Extrinsic Allergic (MeSH ID D000542). (NCT02496182 chunk 2)
  • ICD-10 (claims usage): J67. (HP due to organic dust); in a nationwide Korean study, 82.2% were coded J67.9* (unspecified organic dust). (jung2024nationwidestudyof pages 2-4)

1.3 Common synonyms / alternative names

  • Extrinsic allergic alveolitis (historical/alternative term). (OpenTargets Search: hypersensitivity pneumonitis, NCT02496182 chunk 2)
  • Exposure-linked synonyms/phenotypes: farmer’s lung, bird breeder’s lung / bird fancier’s lung, humidifier lung, Japanese summer-type HP, and other setting-associated forms. (costabel2020hypersensitivitypneumonitis pages 1-2, lewandowska2024acuterespiratoryfailure pages 9-10, akkurt2024evaluationofclinical pages 12-12)

1.4 Evidence provenance (individual vs aggregated)

Most current disease knowledge arises from aggregated resources: international society guidelines (ATS/JRS/ALAT) with systematic evidence synthesis and cohort studies, plus population claims registries for epidemiology; individual-patient data appear mainly in case series/case reports (e.g., acute respiratory failure presentations). (raghu2020diagnosisofhypersensitivity pages 20-21, jung2024nationwidestudyof pages 1-2, lewandowska2024acuterespiratoryfailure pages 9-10)

2. Etiology

2.1 Primary causal factors (environmental/immune)

HP is driven by inhalation of inciting antigens leading to immune sensitization and lung injury. Commonly implicated antigens include avian proteins and fungal/mould sources; chronic low-level exposure is particularly associated with fibrotic progression. (costabel2020hypersensitivitypneumonitis pages 1-2)

In a 2023 prospective cohort (n=202), an inciting agent was identified in 66.8% of cases and, among identified antigens, avian exposure comprised 50.4%. (chen2023clinicalcharacteristicsof pages 3-4)

2.2 Risk factors

Host/clinical factors associated with fibrosis and worse outcomes - In a 2023 cohort, independent predictors of fibrosis included age ≥65 years (OR 2.61), BAL lymphocytes <20% (OR 2.47), and BAL eosinophils ≥1.75% (OR 2.36). (chen2023clinicalcharacteristicsof pages 5-7) - In a 2024 multicentre cohort (n=403) of fibrotic HP, predictors associated with death/transplant included older age (HR 1.08), lower FVC% predicted (HR 0.96), lower BAL lymphocytosis (HR 0.93), acute exacerbation (HR 3.04), and higher GAP index (HR 1.96); fibroblastic foci in biopsied patients had a strong association (HR 8.39). (canojimenez2024prognosticfactorsof pages 1-2)

Genetic susceptibility (risk architecture) Guideline-level synthesis acknowledges susceptibility factors including telomere-related mutations and the MUC5B polymorphism, supporting a complex (multifactorial) gene–environment model rather than Mendelian inheritance for most HP. (koster2021diagnosisofhypersensitivity pages 1-5)

2.3 Protective factors

Evidence in the retrieved sources primarily supports exposure elimination/avoidance as the key protective factor against progression, though quantitative protective-effect sizes were not extractable from the retrieved excerpts. (costabel2020hypersensitivitypneumonitis pages 1-2, lewandowska2024acuterespiratoryfailure pages 9-10)

2.4 Gene–environment interactions

Current understanding supports that antigen exposure is necessary but not sufficient: host susceptibility (including telomere biology and mucin pathway genetics) modulates risk of chronicity/fibrosis, consistent with a gene–environment interaction paradigm. (koster2021diagnosisofhypersensitivity pages 1-5, pereira2023diagnosisoffibrotic pages 1-2)

3. Phenotypes (clinical presentation and mapped HPO suggestions)

3.1 Major phenotypic axes

  • Non-fibrotic HP (NFHP): predominantly inflammatory disease; more reversible with antigen avoidance. (koster2021diagnosisofhypersensitivity pages 1-5)
  • Fibrotic HP (FHP): mixed inflammatory–fibrotic or purely fibrotic disease; poorer prognosis and may resemble IPF radiologically and histologically. (costabel2020hypersensitivitypneumonitis pages 1-2, koster2021diagnosisofhypersensitivity pages 1-5)

3.2 Common symptoms/signs (with frequency where available)

From a 2023 prospective cohort (n=202): - Cough: 88.6% (suggest HPO: Cough HP:0012735) - Dyspnea: 82.2% (HPO: Dyspnea HP:0002094) - Fever: 29.7% (HPO: Fever HP:0001945) FHP cases were older and more likely to have dyspnea, crackles, and clubbing than NFHP. (chen2023clinicalcharacteristicsof pages 3-4)

3.3 Imaging phenotype (HRCT) and suggested terms

In the same cohort, common HRCT findings included: - Ground-glass opacities (GGO): 91.6% (HPO suggestion: Ground-glass opacification on lung imaging; Radiology ontology terming varies) - Reticulation: 63.9% - Traction bronchiectasis: 48.5% (HPO: Bronchiectasis HP:0002110) Fibrotic phenotype enrichment: reticulation 96.5% vs 20.7%, honeycombing 40.0% vs 0%, traction bronchiectasis 82.6% vs 3.4% (FHP vs NFHP). (chen2023clinicalcharacteristicsof pages 5-7)

Guideline-recognized imaging constructs include the “three-density pattern” (formerly “headcheese sign”) and the use of inspiratory + expiratory series to evaluate air-trapping/heterogeneous attenuation in suspected HP. (koster2021diagnosisofhypersensitivity pages 1-5, raghu2020diagnosisofhypersensitivity pages 7-9)

3.4 BAL and histopathology phenotypes

  • BAL lymphocytosis is common, but may be less pronounced in fibrotic disease; in the 2023 cohort 70.1% had BAL lymphocytosis. (chen2023clinicalcharacteristicsof pages 3-4, chen2023clinicalcharacteristicsof pages 5-7)
  • Typical histopathology is bronchiolocentric with granulomatous and lymphocytic inflammation; in progressive fibrotic cases, fibroblastic foci are an adverse prognostic marker. (costabel2020hypersensitivitypneumonitis pages 1-2, canojimenez2024prognosticfactorsof pages 1-2)

3.5 Quality-of-life impact

Validated symptom/QoL instruments in progressive fibrosing ILD show meaningful symptom burden; in INBUILD, nintedanib reduced worsening in Living with Pulmonary Fibrosis (L-PF) total and symptom scores over 52 weeks. (wijsenbeek2024effectsofnintedanib pages 1-2)

4. Genetic / molecular information

4.1 Causal genes and pathogenic variants

For typical HP, no single causal gene is established; HP is predominantly complex with susceptibility contributions (e.g., telomere biology, MUC5B). (koster2021diagnosisofhypersensitivity pages 1-5)

4.2 Mechanistic immunology (molecular framing)

Fibrotic HP pathogenesis is described as involving both type III (immune-complex) and type IV (cell-mediated) hypersensitivity mechanisms, with innate/adaptive immune interplay; fibrosis is linked to inflammatory persistence and immune polarization patterns (e.g., Th-cell skewing). (pereira2023diagnosisoffibrotic pages 1-2)

4.3 Suggested ontology annotations (examples)

  • GO (biological processes; suggestions): immune response (GO:0006955), T cell activation (GO:0042110), inflammatory response (GO:0006954), response to external stimulus (GO:0009605), extracellular matrix organization (GO:0030198), fibroblast activation (various).
  • Cell Ontology (CL; suggestions): alveolar macrophage (CL:0000583), CD4-positive T cell (CL:0000624), CD8-positive T cell (CL:0000625), fibroblast (CL:0000057), alveolar type II pneumocyte (CL:0002063).

These are ontology suggestions for knowledge-base structuring; the retrieved sources provide disease-level mechanistic framing but do not specify gene-level causal chains sufficient for high-confidence variant annotation. (pereira2023diagnosisoffibrotic pages 1-2, costabel2020hypersensitivitypneumonitis pages 1-2)

5. Environmental information (exposures and real-world settings)

5.1 Environmental/occupational antigens

Common exposure settings include: - Bird-related exposures (pet birds, pigeon breeding, feathers/duvets) and mould/fungal exposures (water damage, humidifiers, hay/straw), with geographic variability. (costabel2020hypersensitivitypneumonitis pages 1-2, chen2023clinicalcharacteristicsof pages 3-4, lewandowska2024acuterespiratoryfailure pages 9-10)

An occupational HP review emphasizes that identifying the causative agent aids differential diagnosis and that exposure avoidance is first-line, but highlights challenges (no gold-standard test; need multidisciplinary approach). (akkale2023occupationalhypersensitivitypneumonia pages 5-6)

5.2 Lifestyle factors

Smoking is commonly considered in prognostic discussions (e.g., association with worse prognosis in guideline summary), but effect-size statistics were not extractable from the retrieved excerpts. (koster2021diagnosisofhypersensitivity pages 1-5)

5.3 Infectious agents

HP is triggered by antigenic exposure (often microbial/fungal), but it is not a primary infection-driven disease; microbial components are typically environmental rather than invasive infection. (costabel2020hypersensitivitypneumonitis pages 1-2, pereira2023diagnosisoffibrotic pages 1-2)

5.4 Suggested CHEBI mappings (examples)

The retrieved excerpts did not enumerate specific chemical sensitizers with standard identifiers; where inorganic/chemical triggers are suspected clinically (e.g., certain occupational chemicals/metals), CHEBI mapping should be performed using exposure-specific primary sources. (koster2021diagnosisofhypersensitivity pages 1-5)

6. Mechanism / pathophysiology (causal chain)

6.1 Causal chain (current consensus)

1) Repeated inhalation of an inciting antigen (often avian/fungal) → 2) Sensitization and immune activation (humoral IgG responses plus cellular immune responses) → 3) Bronchiolocentric inflammation and granulomatous interstitial pneumonia with small-airway involvement → 4) In susceptible hosts and/or persistent exposure, chronic inflammation and aberrant repair → 5) Fibrotic remodeling with traction bronchiectasis/honeycombing and progressive gas-exchange impairment. (costabel2020hypersensitivitypneumonitis pages 1-2, pereira2023diagnosisoffibrotic pages 1-2, koster2021diagnosisofhypersensitivity pages 1-5)

6.2 Upstream vs downstream processes

  • Upstream: antigen exposure and sensitization; exposure identification and removal are therefore mechanistically upstream interventions. (costabel2020hypersensitivitypneumonitis pages 1-2, lewandowska2024acuterespiratoryfailure pages 9-10)
  • Downstream: fibroblast activation/ECM deposition and progressive fibrosis, captured clinically by radiologic fibrosis and physiological decline (FVC, DLCO). (canojimenez2024prognosticfactorsof pages 1-2, oh2023fibrosisscorepredicts pages 2-3)

6.3 Molecular profiling and biomarkers (state of evidence)

Validated biomarkers remain limited; a biomarker review notes BAL lymphocyte counts and serum antigen-specific IgG are incorporated into guidelines, while other candidates (e.g., KL-6, SP-D, YKL-40) remain investigational with validation gaps. (pereira2023diagnosisoffibrotic pages 1-2)

A 2024 study reported plasma GDF15 levels higher in fibrotic vs non-fibrotic HP (mean 2539 ± 821 vs 1783 ± 801 pg/mL) with a proposed cutoff 2193.4 pg/mL (AUC 0.75), suggesting a potential fibrotic-phenotype biomarker requiring further validation. (koster2021diagnosisofhypersensitivity pages 1-5)

7. Anatomical structures affected (with ontology suggestions)

7.1 Organ/system

  • Primary: lung (UBERON:0002048; suggestion)
  • Predominant compartments emphasized by recent reviews/guidelines: small airways, interstitium, and alveolar compartments. (koster2021diagnosisofhypersensitivity pages 1-5, costabel2020hypersensitivitypneumonitis pages 1-2)

7.2 Tissue/cell level

  • Bronchiolocentric interstitial inflammation with lymphocyte predominance and granulomatous features; fibrotic remodeling in FHP. (costabel2020hypersensitivitypneumonitis pages 1-2, canojimenez2024prognosticfactorsof pages 1-2)

7.3 Subcellular (GO-CC suggestions)

No specific subcellular compartment pathology is singled out in the retrieved excerpts; generic fibrosis/inflammation-associated CC terms that are often relevant include extracellular region (GO:0005576) and collagen-containing extracellular matrix (GO:0062023) (suggestions).

8. Temporal development

HP can present acutely after high-level intermittent exposure or chronically after prolonged low-level exposure; in modern practice, staging is operationalized as non-fibrotic vs fibrotic, reflecting a temporal and biological shift toward irreversible remodeling in fibrotic disease. (costabel2020hypersensitivitypneumonitis pages 1-2, koster2021diagnosisofhypersensitivity pages 1-5)

Clinical course heterogeneity is reflected in outcome heterogeneity: in biopsy-proven fibrotic HP, 5-year mortality ~32.7% in one cohort, while multicentre data emphasize acute exacerbations and histologic fibroblastic foci as major adverse markers. (oh2023fibrosisscorepredicts pages 1-2, canojimenez2024prognosticfactorsof pages 1-2)

9. Inheritance and population

9.1 Epidemiology (recent population-level data)

South Korea (nationwide claims; HIRA ~97% population coverage): - 8,678 incident HP cases (2011–2020) - Age/sex-adjusted annual incidence range: 1.14/100,000 (2020) to 2.16/100,000 (2012) - Mean age: 52.6 ± 18.9 years; 51.5% male - 82.2% coded J67.9 (unspecified organic dust) - Bronchoscopy performed in 16.9% - 25.4% had no treatment within 1 year - Prednisone most common steroid; azathioprine most common second-line immunosuppressant. (jung2024nationwidestudyof pages 2-4, jung2024nationwidestudyof pages 1-2)

Contextual (non-2023/2024) estimates from a major disease primer include incidence ~1.16/100,000/year (Denmark) and US incidence ~1.28–1.94/100,000/year, with prevalence rising with age. (costabel2020hypersensitivitypneumonitis pages 1-2)

9.2 Inheritance model

HP is generally multifactorial/complex, reflecting environmental necessity and host susceptibility rather than Mendelian inheritance; familial categories exist in ontologies but robust causal gene mapping was not available in the retrieved evidence. (OpenTargets Search: hypersensitivity pneumonitis, koster2021diagnosisofhypersensitivity pages 1-5)

10. Diagnostics

10.1 Guideline framework (ATS/JRS/ALAT 2020)

The ATS/JRS/ALAT 2020 guideline defines a multidimensional diagnostic approach integrating: - Exposure assessment - HRCT pattern category (Typical/Compatible/Indeterminate) - BAL lymphocytosis - Histopathology (when needed) - Multidisciplinary discussion (MDD) when diagnostic confidence is not high.

The diagnostic confidence matrix and algorithm are shown in the guideline figures below. (raghu2020diagnosisofhypersensitivity media 2ea50c08, raghu2020diagnosisofhypersensitivity media 1a711271)

10.2 BAL lymphocytosis (quantitative thresholds)

ATS/JRS/ALAT evidence synthesis reports performance of BAL lymphocyte percentage thresholds for distinguishing FHP from IPF: - ≥20%: sensitivity 69%, specificity 61% - ≥30%: sensitivity 55%, specificity 80% - ≥40%: sensitivity 41%, specificity 93% These data illustrate the tradeoff between sensitivity and specificity and support use of BAL lymphocytosis as a probabilistic (not definitive) discriminator. (raghu2020diagnosisofhypersensitivity pages 20-21)

The clinician summary notes that no single threshold definitively distinguishes HP from other ILDs, though expert practice often considers ~30% a reasonable reference point pending further validation/standardization. (koster2021diagnosisofhypersensitivity pages 9-14)

10.3 HRCT technique and patterns

The guideline recommends volumetric high-resolution CT with two supine series (deep inspiration and prolonged expiration), with expiratory imaging critical for detecting air trapping and heterogeneous attenuation. (raghu2020diagnosisofhypersensitivity pages 7-9, koster2021diagnosisofhypersensitivity pages 1-5)

10.4 Serum IgG testing

Serum antigen-specific IgG testing is included as supportive evidence to identify potential exposures, but guideline excerpts highlight lack of standardization and low certainty in effect estimates for IgG panels. (raghu2020diagnosisofhypersensitivity pages 19-20)

10.5 Differential diagnosis

A key clinical differentiation is fibrotic HP versus IPF and other ILDs (e.g., sarcoidosis), motivating use of integrated imaging, BAL, exposure history, and pathology when needed. (raghu2020diagnosisofhypersensitivity pages 20-21, leone2020currentdiagnosisand pages 2-4)

11. Outcome / prognosis

11.1 Mortality and survival (recent cohorts)

  • Biopsy-proven FHP cohort (n=101): 1-, 3-, 5-year mortality 3.9%, 16.8%, 32.7%; fibrosis score predicted 5-year mortality with AUC 0.752, and fibrosis score ≥12% was associated with shorter mean survival (58.3 vs 146.7 months). (oh2023fibrosisscorepredicts pages 1-2)
  • Multicentre FHP cohort (n=403): mortality/transplant risk increased with age, acute exacerbation, higher GAP; BAL lymphocytosis was inversely related to mortality; histologic fibroblastic foci strongly predicted death/transplant (HR 8.39). (canojimenez2024prognosticfactorsof pages 1-2)

11.2 Prognostic markers (quantitative)

  • HRCT-based fibrosis metrics (reticulation/honeycombing) are repeatedly linked to outcomes; in the FHP cohort above, fibrosis score (reticulation + honeycombing) predicted mortality. (oh2023fibrosisscorepredicts pages 2-3)

12. Treatment

12.1 Core principle: antigen avoidance

Across reviews and guideline framing, complete antigen avoidance is the foundational intervention, particularly important in non-fibrotic disease. Quantitative effect sizes were not extractable from the retrieved excerpts, but this remains the highest-consensus management principle. (costabel2020hypersensitivitypneumonitis pages 1-2, lewandowska2024acuterespiratoryfailure pages 9-10)

MAXO suggestions: exposure avoidance / environmental remediation; occupational exposure control.

12.2 Corticosteroids and immunosuppressants (real-world implementation)

In Korean claims data (2011–2020 incident cases), prednisone was the most-used systemic steroid and azathioprine was the most common second-line immunosuppressant; 25.4% received no treatment within 1 year, reflecting real-world heterogeneity in management and/or disease severity. (jung2024nationwidestudyof pages 1-2)

MAXO suggestions: systemic glucocorticoid therapy; immunosuppressive therapy.

12.3 Antifibrotic therapy (nintedanib; strongest quantitative evidence)

Randomized trial (PPF; INBUILD): nintedanib reduced annual FVC decline from −187.8 mL/year (placebo) to −80.8 mL/year, a difference of 107 mL/year (p<0.001) in progressive fibrosing ILDs (HP comprised a substantial subgroup in INBUILD, though the trial was not powered for individual ILD diagnoses). (amati2023efficacyofpirfenidone pages 6-7)

INBUILD whole-trial analysis (progression events and safety): nintedanib reduced risk of acute exacerbation of ILD or death (HR ~0.67) and reduced risk of relative FVC decline ≥10% predicted by 37%; adverse event rates (events/100 patient-years) were higher for diarrhea (136.4 vs 23.0), nausea (30.8 vs 7.6), vomiting (17.3 vs 3.5), weight decrease (12.4 vs 3.9), and ALT increase (12.4 vs 2.8) compared with placebo. (flaherty2022nintedanibinprogressive pages 6-7)

Real-world evidence (UK multicentre PPF; 2019–2020 early access): after nintedanib initiation, 12-month FVC decline improved from −239.9 mL (pre) to −88.8 mL (post) (p=0.004), with 71% reporting side effects but 80% of surviving patients remaining on therapy at 12 months and no serious adverse events reported. (raman2023nintedanibfornonipf pages 1-2)

MAXO suggestions: antifibrotic therapy.

12.4 Pirfenidone (HP-specific trials; evidence still emerging)

HP-specific trial registrations include: - NCT02496182 (Pirfenidone in Chronic HP): Phase 2/3, randomized, quadruple-masked, n=60 planned; compares prednisone+azathioprine + pirfenidone (1200/1800 mg) vs placebo; primary outcome FVC change at 26/52 weeks. (NCT02496182 chunk 1) - NCT02958917 (Pirfenidone in Fibrotic HP): Phase 2, randomized double-blind; n=40 planned; terminated due to COVID-19 pandemic; primary outcome change in %predicted FVC at week 52. (NCT02958917 chunk 1)

A 2023 systematic review of antifibrotics in non-IPF ILDs concluded that randomized evidence is strongest for nintedanib, while pirfenidone evidence is more limited/heterogeneous across non-IPF ILDs. (amati2023efficacyofpirfenidone pages 2-4)

12.5 Ongoing immunomodulatory trials in FHP

  • NCT05626387 (MYCOHYPE): Phase 4, randomized open-label (MMF + prednisolone vs prednisolone), n=144 planned; primary endpoint annual rate of FVC decline over 52 weeks (estimated primary completion 2025). (NCT05626387 chunk 1)

12.6 Lung transplantation

Transplant is a potential option in end-stage progressive fibrotic disease; in the 2023 cohort, at least one lung transplant occurred among adverse outcomes (all in FHP). (chen2023clinicalcharacteristicsof pages 3-4)

13. Prevention

13.1 Primary prevention

  • Exposure control in occupational and home environments (e.g., reducing bird antigen exposure, remediating mould/water damage, improving ventilation/humidifier maintenance) is the dominant prevention strategy, consistent with HP’s exposure-driven etiology. (akkale2023occupationalhypersensitivitypneumonia pages 5-6, costabel2020hypersensitivitypneumonitis pages 1-2)

13.2 Secondary prevention

  • Early recognition in at-risk settings and use of structured exposure questionnaires and guideline-directed evaluation (HRCT + BAL when indicated) to shorten diagnostic delay. (raghu2020diagnosisofhypersensitivity pages 7-9, raghu2020diagnosisofhypersensitivity pages 20-21)

13.3 Tertiary prevention

  • Preventing progression/complications in established disease via exposure elimination, monitoring for physiological decline (FVC/DLCO), and (for progressive fibrotic phenotypes) consideration of antifibrotic therapy per progressive pulmonary fibrosis frameworks. (flaherty2022nintedanibinprogressive pages 6-7, raman2023nintedanibfornonipf pages 1-2)

14. Other species / natural disease

The retrieved evidence did not contain primary data on naturally occurring HP in non-human species or zoonotic transmission. For knowledge-base completion, targeted searches of veterinary pathology literature and OMIA/VetCompass resources would be required; no claims are made here due to insufficient retrieved evidence. (No relevant evidence in retrieved context)

15. Model organisms

The retrieved sources did not provide specific validated animal or in vitro model systems for HP pathobiology. Model organism and experimental system summaries therefore cannot be evidence-cited from the current retrieved set. (No relevant evidence in retrieved context)

Visual evidence (guideline)

  • ATS/JRS/ALAT 2020 diagnostic confidence table (Figure 6) and diagnostic algorithm (Figure 7) were retrieved as cropped images for direct reference. (raghu2020diagnosisofhypersensitivity media 2ea50c08, raghu2020diagnosisofhypersensitivity media 1a711271)

Notes on evidence gaps (transparency)

  • ICD-11/Orphanet identifiers, detailed HPO term mappings with phenotype frequencies beyond those extracted, and gene/variant-level evidence (ClinVar/OMIM-style) were not present in the retrieved full texts and thus are not asserted.
  • Treatment-effect estimates for corticosteroids/immunosuppressants specifically in HP (beyond real-world usage patterns and registered trials) were not extractable from the included excerpts.

Key references (URLs and publication dates)

  • ATS/JRS/ALAT guideline (Aug 2020): https://doi.org/10.1164/rccm.202005-2032st (raghu2020diagnosisofhypersensitivity pages 20-21, raghu2020diagnosisofhypersensitivity pages 7-9)
  • Korean nationwide incidence/treatment patterns (Feb 2024): https://doi.org/10.3346/jkms.2024.39.e96 (jung2024nationwidestudyof pages 1-2, jung2024nationwidestudyof pages 2-4)
  • Prospective NFHP vs FHP cohort (Jul 2023): https://doi.org/10.1097/cm9.0000000000002613 (chen2023clinicalcharacteristicsof pages 3-4, chen2023clinicalcharacteristicsof pages 5-7)
  • Prognostic factors cohort (Jan 2024): https://doi.org/10.1183/23120541.00405-2023 (canojimenez2024prognosticfactorsof pages 1-2)
  • Fibrosis score predicts mortality (Mar 2023): https://doi.org/10.3389/fmed.2023.1131070 (oh2023fibrosisscorepredicts pages 1-2)
  • INBUILD whole-trial analysis (Sep 2022): https://doi.org/10.1183/13993003.04538-2020 (flaherty2022nintedanibinprogressive pages 6-7)
  • Real-world nintedanib PPF outcomes (Dec 2023): https://doi.org/10.1183/23120541.00423-2022 (raman2023nintedanibfornonipf pages 1-2)
  • HP biomarker review (Feb 2023): https://doi.org/10.3390/life13020565 (pereira2023diagnosisoffibrotic pages 1-2)
  • Occupational HP review (Mar 2023): https://doi.org/10.5578/tt.20239911 (akkale2023occupationalhypersensitivitypneumonia pages 5-6)
  • HP-specific trials: NCT02496182 (2015) (NCT02496182 chunk 1); NCT02958917 (2017; terminated) (NCT02958917 chunk 1); NCT05626387 (2022) (NCT05626387 chunk 1)

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