Lung nontumor
Granulomatous (non-infectious) inflammation
Hypersensitivity pneumonitis

Topic Completed: 1 June 2017

Minor changes: 13 December 2019

Revised: 29 January 2019, last major update June 2017

Copyright: (c) 2003-2018,, Inc.

PubMed search: Hypersensitivity pneumonitis [title] or Extrinsic allergic alveolitis [title]

Akira Yoshikawa, M.D.
Andrey Bychkov, M.D., Ph.D.
Page views in 2019: 6,490
Page views in 2020 to date: 4,096
Cite this page: Yoshikawa A. Hypersensitivity pneumonitis. website. Accessed August 6th, 2020.
Definition / general
  • Also known as extrinsic allergic alveolitis
  • A complex health syndrome of varying intensity, clinical presentation and natural history
  • Due to immunologically induced inflammation of lung parenchyma in response to inhalation of a large variety of antigens (Am J Respir Crit Care Med 2005;171:792)
Essential features
  • An interstitial pneumonia with acute to chronic respiratory failure caused by inhalation exposure to a variety of natural or chemical antigens
  • Histologically characterized by airway centered inflammation with fibrosis and poorly formed nonnecrotizing granulomas
  • Also called extrinsic allergic alveolitis
ICD coding
  • J67.8
  • 4 - 15% of interstitial lung diseases (Eur Respir J Suppl 2001;32:114s)
  • Prevalence and incidence vary by climate, geographical condition, living environment and agricultural practice
  • UK incidence is 0.9 per 100,000 person per year (QJM 2007;100:233)
  • Higher prevalence and mortality rate in farmers and agricultural industries (Am J Ind Med 2006;49:997)
  • Mean age is 50 - 60 years old
  • No sexual predominance
  • Smoking is related to lower prevalence but worse prognosis (Intern Med 1995;34:966)
  • Predominant in middle to upper lobes of the lung; usually bilateral
  • Gene polymorphisms related to the acquired immune response may predispose to HP (Am J Respir Crit Care Med 2012;186:314):
    • Major histocompatibility complex class 2 (MHC class II)
    • Proteasome subunit beta type 8 (PSMB8)
    • Transporter associated with Antigen Processing 1 (TAP1)
  • Malfunction of regulatory T cells (Eur Respir J 2011;37:632)
  • Antigen exposure results in early formation of type III immune complexes, followed by type IV delayed hypersensitivity
  • HP is developed through inhalation and exposure to a causative antigen
  • Causative agents: spores of bacteria, fungi, mycobacteria, animal proteins and chemicals from hay, grain, sugar cane, bark, cheese, cork and animal feces (J Investig Allergol Clin Immunol 2015;25:237)
  • According to the causative antigen, HP may have different names:
    • Air conditioner lung: due to thermophilic bacteria
    • Byssinosis: in textile workers due to fibers from cotton, linen and hemp
      • Resembles asthma clinically
      • Disease mechanism may not be immune mediated, endotoxin from bacterial contamination of cotton may play a role
    • Farmer's lung: from moldy hay containing spores of thermophilic actinomycetes
    • Maple bark stripper’s lung: fungal spores
    • Pigeon breeder's lung: also called bird fancier's disease; proteins from serum, feathers excreta
    • Hot tub lung: nontuberculous Mycobacterium
Clinical features
  • HP is classified into acute, subacute and chronic, however there is a lack of consensus for the criteria
  • Acute hypersensitivity pneumonitis
    • Influenza-like syndrome a few hours after exposure to an antigen: fever, dyspnea, cough, crackles may be detected on chest auscultation
    • Symptoms resolve several hours after antigen removal
    • Repeated acute episodes of farmer’s lung leads to centriacinar emphysema (Eur Radiol 2003;13:2212)
  • Subacute hypersensitivity pneumonitis
    • Slowly progressive respiratory failure over weeks to months
    • Fever, dyspnea, cough, fatigue, crackles may be detected on chest auscultation
    • Pulmonary function may be normal
    • Probably results from continuous low level exposure to the antigen
  • Chronic hypersensitivity pneumonitis
    • Slowly progressive and insidious respiratory failure; often without acute episodes
    • Dyspnea, cough, fatigue, weight loss, fine crackles on chest auscultation
    • Restrictive pattern on pulmonary function tests
      • Decreased total lung capacity (TLC)
      • Decreased forced vital capacity (FVC)
      • Decreased diffusing capacity of the lung for carbon monoxide (DLCO)
    • Often associated with bird antigen exposure
    • Acute exacerbation followed by respiratory deterioration within 1 - 2 months can occur; usually without further antigen exposure (Chest 2008;134:844, Chest 2008;134:1265)
  • Diagnosis is based on clinical, radiological (high resolution computed tomography, HRCT) and pathological examination
  • Surgical lung biopsy is often necessary to differentiate subacute and chronic hypersensitivity pneumonitis from other interstitial lung disease; however, it is rare for acute hypersensitivity pneumonitis to be biopsied
  • Although several diagnostic criteria have been proposed, none are widely accepted
  • A large cohort study by HP Study Group suggested clinical predictors for the diagnosis of HP (Am J Respir Crit Care Med 2003;168:952)
    • Exposure to a known offending antigen
    • Positive precipitating antibodies
    • Recurrent episodes of symptoms
    • Inspiratory crackles
    • Symptoms 4 - 8 hours after exposure
    • Weight loss
  • Bronchoalveolar lavage is supportive in the diagnosis but lacks standardization (Chest 2012;142:208, Am J Respir Crit Care Med 2012;186:314)
    • Increased total cell count
    • Increased lymphocyte percentage ≥ 30% for nonsmokers or exsmokers or ≥ 20% for current smokers; a normal lavage rules out the presence of active HP (Am Rev Respir Dis 1990;141:S169, Br J Ind Med 1986;43:401)
    • CD4 / CD8 ratiois usually decreased in HP but can be increased as high as in sarcoidosis; CD4 / CD8 ratio is now considered to vary by clinical conditions such as causative antigen and smoking status
  • Inhalation challenge is supportive but lacks standardization (Chest 2012;142:208, Am J Respir Crit Care Med 2012;186:314, Eur Respir J 2014;44:1658)
    • Antigen exposure at the workplace or home or direct inhalation of the specific antigen after a period of avoidance provokes symptoms of HP and decreases FVC in 8 - 12 hours
    • The patient should be monitored at least for 24 hours after the inhalation in case of severe attack of HP
  • Serum IgG antibody to causative antigens may be increased; however, serum antibody could be positive in 31% of non HP subjects (Am J Respir Crit Care Med 2003;168:952)
    • Avian antigens: pigeon, parakeet, budgerigar, chicken
    • Fungus: trichosporon, aspergillus
    • Bacteria: actinomycete
    • Mycobacteria: Mycobacterium avium-intracellulare
    • Chemicals
  • Increased serum KL-6, often over 1000 IU (normal limit is < 500 IU)
Radiology description
Radiology images

Images hosted on other servers:

Chest X-ray and CT image of HP

CT of HP

CT of acute HP due to isocyanate

CT of subacute HP of a farmer

CT of chronic HP of a plastic industrial worker

CT of HP due to nontuberculous mycobacterium

Prognostic factors
Case reports
  • Avoidance of antigen is the key of HP management
  • Oral or systemic corticosteroids are considered for severe case or when the antigen is not removable; however, steroids do not change long term outcome and are not standardized (Chest 2013;144:1644)
    Gross description
    • Diffuse involvement with mild to moderate increase in lung weight
    • Bronchocentric fibrotic changes may be seen
      Microscopic (histologic) description
      • Common findings(J Clin Pathol 2013;66:888, Am J Respir Crit Care Med 2012;186:314, J Investig Allergol Clin Immunol 2015;25:237, Arch Pathol Lab Med 2008;132:199):
        • Airway centered (peribronchiolar) change
        • Interstitial cellular infiltration
        • Poorly formed nonnecrotizing granulomas or interstitial giant cells with cholesterol clefts
          • Well formed granulomas can be found but may raise differential diagnosis with sarcoidosis if the granulomas are numerous and predominant
      • Acute HP
        • Airway centered inflammation with little fibrosis
        • Neutrophilic infiltration with / without capillaritis
        • Intra-alveolar fibrin deposition
      • Subacute HP
        • Airway centered infiltration with fibrosis
        • Lymphocytic infiltration with granulomas or giant cells
      • Chronic HP
        • Predominantly airway centered inflammation with diffuse fibrotic change
        • Lymphocytic infiltration with granulomas or giant cells
        • Often overlaps with NSIP, UIP, organizing pneumonia and airway centered interstitial fibrosis
        • Bridging fibrosis (fibrotic band connecting bronchioles with each other and with lobular septa) and peribronchiolar metaplasia can be a diagnostic clue to differentiate HP from IPF (J Clin Pathol 2013;66:888, Histopathology 2012;61:1026)
      • Additional findings
        • Byssinosis bodies (hemosiderin coated strands of fiber within fibrous tissue) can be found in byssinosis
        • Foamy macrophages in alveolar spaces
        • Organizing pneumonia
      Microscopic (histologic) images

      Scroll to see all images:

      Images hosted on PathOut server:

      Images contributed by Akira Yoshikawa

      Case 1: 69 year old woman with history of exposure to bird antigen

      Case 2: 67 year old man with history of exposure to garden chemicals

      Case 3: 72 year old male woodcutter

      Images hosted on other servers:

      Airway centered lymphocytic infiltration with granuloma

      Airway centered lymphocytic infiltration with fibrosis

      Poorly formed granulomas

      Peribronchiolar metaplasia

      Intra-alveolar fibrindeposition

      Comparison of
      granulomatous lesions
      of different diseases

      Giant cells

      Cytology description
      • Bronchoalveolar lavage fluid shows lymphocytosis (see Diagnosis)
      Cytology images

      Images hosted on other servers:

      Bronchoalveolar lavage fluid

      Positive stains
      Differential diagnosis
      Board review style question #1
      Which two clinical and morphological findings are suggestive for HP?

      1. Intra-alveolar fibrin deposition
      2. Monocytosis in bronchoalveolar lavage
      3. Necrotizing granuloma
      4. Organizing pneumonia
      5. Weight loss
      Board review answer #1
      A. and E.

      1. Intra-alveolar fibrin deposition is suggestive for acute HP, also for acute fibrinous and organizing pneumonia
      2. Typical bronchoalveolar lavage of HP shows lymphocytosis
      3. Necrotizing granuloma is more suggestive for tuberculosis
      4. Organizing pneumonia can be seen in HP but it is not specific
      5. Weight loss is suggestive for HP according to the large cohort study (see Diagnosis)
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