Hypersensitivity Pneumonitis - Extrinsic Allergic Alveolitis

Diagnosis

Indications for Testing

• Recurring pneumonias or pneumonitis in patient with pertinent exposure
  • Cough, wheezing, shortness of breath
• Interstitial lung disease of unknown cause

Criteria for Diagnosis

• No validated diagnostic criteria; however, Richerson or recent Schuyler and Cormier criteria may be used
  • Most apply only to acute cases
  • All rely upon abnormal chest radiograph 
  • Diagnostic criteria

    Schuyler and Cormier	Combination of ≥4 major and ≥2 minor criteria supports the diagnosis of HP Major criteria History of symptoms compatible with HP appearing within hours of exposure to the antigen Confirmation of inciting antigen by history, investigation of environment, serum precipitin test, or BAL antibody X-ray or HRCT of chest showing changes consistent with HP BAL lymphocytosis (usually >40%) Histopathological changes on lung biopsy consistent with HP Positive inhalation provocation test Minor criteria Bibasilar rales Decreased DLCO Arterial hypoxemia, either at rest or during exercise
    Richerson	History, physical findings, and pulmonary function tests indicate interstitial lung disease Radiographs consistent with disease Exposure to recognized antigen Antibody to recognized antigen
    BAL, bronchoalveolar lavage; DLCO, diffusion capacity of the lung for carbon monoxide; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography Source: Compiled from Richerson, 1989; Schuyler and Cormier, 1997

Laboratory Testing

• Nonspecific testing
  • CBC – neutrophilic leukocytosis most common abnormality
  • C-reactive protein (CRP)
    • Preferred test to detect inflammatory processes (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
    • Frequently elevated
    • If CRP not available, order erythrocyte sedimentation rate (ESR)
  • IgE – usually normal
• Serum precipitating antibodies – testing based on suspected exposure
  • Positive findings are only suggestive and help document patient exposure to antigen
  • Low titers do not exclude disease
  • Enzyme-linked immunosorbent assay (ELISA) more sensitive than immunodiffusion

Histology

• Lung biopsy if clinical uncertainty remains after initial testing and bronchoscopic bronchoalveolar lavage (BAL)
  • Multiple biopsies from affected area should be taken
• Histologic features of clinical subtypes of hypersensitivity pneumonitis (HP)

  • Histologic Features of Clinical Subtypes of Hypersensitivity Pneumonitis

    Acute HP	Subacute HP	Chronic HP
    Peribronchiolar inflammation without fibrosis Neutrophilic interstitial and intra-alveolar inflammation Intra-alveolar fibrin Capillaritis in some reports	Chronic peribronchiolar inflammation Peribronchiolar fibrosis and/or metaplasia Poorly formed nonnecrotizing granulomas Cellular NSIP pattern exclusively in some cases	Chronic fibrosis resembling UIP or NSIP or with overlapping features Retained subacute features providing diagnostic clues Chronic peribronchiolar inflammation and fibrosis Poorly formed nonnecrotizing granulomas or Schaumann bodies
    HP, hypersensitivity pneumonia; NSIP, nonspecific interstitial pneumonia; UIP, usual interstitial pneumonia Source: Compiled from Grunes, 2013

Imaging Studies

• Chest x-ray
  • Acute ground glass appearance suggesting pneumonia
  • Mainly used to rule out other diseases
  • ~20% are normal
• High-resolution computed tomography (HRCT)
  • More sensitive than chest x-ray; perform at end of expiration
  • Central lobular ground glass attenuation and multiple poorly defined nodular opacities <5 mm in diameter (usually in lower lobes)
  • Absence of honeycombing
  • Upper- and mid-zone predominance
  • Air trapping
  • Normal CT argues against HP

Other Testing

• Pulmonary function studies
  • Restrictive or mixed obstructive and restrictive patterns with decrease in diffusing capacity of lung for carbon monoxide (DL_CO) usually <80% – normal results do not exclude disease
  • No discriminatory power to differentiate HP from other interstitial lung diseases
• Arterial blood gases – demonstrate hypoxemia only with exercise in acute and subacute disease
• Invasive testing – BAL using bronchoscopy
  • Lymphocytosis
    • Usual presentation is ≥30% in nonsmokers and ≥20% in smokers 
    • CD3+/CD8+/CD56+/CD57+/CD10-
  • CD4+/CD8+
    • Usually <1 in acute disease but may be >1 in chronic disease
    • May help differentiate HP from sarcoidosis, where ratio is usually >1
  • Eosinophilia common (75%) in advanced disease

Differential Diagnosis

• Acute presentation
  • Infectious pneumonia
  • Mycobacterium tuberculosis
  • HIV
  • Asthma
  • Eosinophilic lung disease – allergic bronchopulmonary aspergillosis
  • Pulmonary edema
  • Drug-induced pneumonitis
  • Vasculitis
• Subacute presentation
  • Sarcoidosis
  • Idiopathic pulmonary fibrosis
  • Bronchiolitis obliterans
  • Infectious pneumonia – especially M. tuberculosis
  • Usual interstitial pneumonia
  • Desquamative interstitial pneumonia
  • Nonspecific interstitial pneumonia
  • Drug-induced pneumonitis
• Chronic presentation
  • Nonspecific interstitial pneumonia
  • Unusual interstitial pneumonia
  • Bronchiolitis obliterans
  • Chronic obstructive pulmonary disease (COPD)
  • Idiopathic pulmonary fibrosis
  • Sarcoidosis
  • Asthma
  • Silicosis
  • Drug-induced pneumonitis 

Background

Epidemiology

• Incidence
  • Interstitial lung disease – 30/100,000
  • 20% are hypersensitivity pneumonitis (HP)
• Sex – M>F (minimal)

Etiologies

• More than 300 different antigens have been associated with HP involving a range of occupations
  • Common provoking antigens

    Antigen	Type of Hypersensitivity Pneumonitis
    Thermophilic actinomyces	Farmer's lung, bagassosis, humidifier fever, suberosis, potato riddler’s lung, mushroom worker’s lung
    Mycobacterium species	Hot-tub lung, machine operator’s lung
    Fungi/mold (eg, aspergillus sp, botrytis sp, mucor sp)	Maple bark stripper’s lung, malt worker's lung, suberosis, sequoiosis, woodworker’s lung, cheese washer’s lung, paprika slicer’s lung, wine maker’s lung, tobacco grower’s lung
    Animal proteins	Pituitary snuff taker’s lung, pigeon breeder's lung, bird fancier’s disease, furrier’s lung, poultry worker's lung
    Chemicals	Bathtub finisher's lung, Coptic lung

Pathophysiology

• Type III immune complex disease and type IV cell-mediated immunity
• Repeated exposure to antigen activates alveolar macrophages that release enzymes and cause inflammation and fibrosis
• Repeated exposure leads to recrudescence of symptoms

Clinical Presentation

• Acute
  • Symptoms typically begin 4-8 hours after exposure
  • Influenza-like presentation
  • Usually resolves within 48 hours
• Subacute
  • Dyspnea, cough, fatigue over weeks to months
• Chronic
  • Airway obstruction with increasing cough and dyspnea
  • Weight loss
  • In progressive disease – eventual fibrotic lung disease after insidious onset