Hypersensitivity Pneumonitis - Extrinsic Allergic Alveolitis

Hypersensitivity pneumonitis (HP) (also called extrinsic allergic alveolitis) is a hypersensitivity syndrome that causes diffuse interstitial lung disease as a result of inhalation of antigenic organic particles. Nonspecific laboratory testing includes CBC, C-reactive protein (CRP), and IgE. Serum precipitating antibody testing is selected based on suspected exposure.

Tabs Content

Clinical Overview

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 DL_CO
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; DL_CO, 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

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Hypersensitivity Pneumonitis I 0055076
Method: Qualitative Immunodiffusion

Recommended Use

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus fumigatus, Thermoactinomyces vulgaris, Aureobasidium pullulans, or Micropolyspora faeni

Hypersensitivity Pneumonitis II 0055226
Method: Qualitative Immunodiffusion

Recommended Use

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus flavus, Aspergillus fumigatus, Saccharomonospora viridis, Thermoactinomyces candidus, and Thermoactinomyces sacchari

Hypersensitivity Pneumonitis Panel 3000477
Method: Qualitative Immunodiffusion

Recommended Use

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus fumigatus, Thermoactinomyces vulgaris, Aurebasidium pullulans, Micropolyspora faeni, Aspergillus flavus, Saccharomonospora viridis, Thermoactinomyces candidus, or Thermoactinomyces sacchari

Hypersensitivity Pneumonitis Extended Panel (Farmer's Lung Panel) 0050157
Method: Qualitative Immunodiffusion/Quantitative ImmunoCAP® Fluorescent Enzyme Immunoassay

Recommended Use

Panel includes allergen and antibody testing from hypersensitivity pneumonitis I and II as well as allergen testing, Phoma betae, food, beef, pork, epidermals, and animal proteins and feathers

Lymphocyte Subset Panel 4 - T-Cell Subsets Percent and Ratio, Bronchoalveolar Lavage 0093420
Method: Flow Cytometry

Recommended Use

Support the diagnosis of sarcoidosis

Medical Experts

Peterson, Lisa K., PhD, D(ABMLI), Medical Director, Immunology, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Slev, Patricia R., PhD, Laboratory Section Chief, Immunology, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Richerson HB, Bernstein IL, Fink JN, Hunninghake GW, Novey HS, Reed CE, Salvaggio JE, Schuyler MR, Schwartz HJ, Stechschulte DJ. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin Immunol. 1989; 84(5 Pt 2): 839-44. PubMed
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Oct 2018]
Miller R, Allen TC, Barrios RJ, Beasley MB, Burke L, Cagle PT, Capelozzi VL, Ge Y, Hariri LP, Kerr KM, Khoor A, Larsen BT, Mark EJ, Matsubara O, Mehrad M, Mino-Kenudson M, Raparia K, Roden AC, Russell P, Schneider F, Sholl LM, Smith ML. Hypersensitivity pneumonitis: a perspective from members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2017; PubMed

General References

Cordeiro CR, Jones JC, Alfaro T, Ferreira AJ. Bronchoalveolar lavage in occupational lung diseases. Semin Respir Crit Care Med. 2007; 28(5): 504-13. PubMed

Grunes D, Beasley MB. Hypersensitivity pneumonitis: a review and update of histologic findings. J Clin Pathol. 2013; 66(10): 888-95. PubMed

Madison M. Hypersensitivity pneumonitis: clinical perspectives. Arch Pathol Lab Med. 2008; 132(2): 195-8. PubMed

Myers JL. Hypersensitivity pneumonia: the role of lung biopsy in diagnosis and management. Mod Pathol. 2012; 25 Suppl 1: S58-67. PubMed

Ohshimo S, Bonella F, Guzman J, Costabel U. Hypersensitivity pneumonitis. Immunol Allergy Clin North Am. 2012; 32(4): 537-56. PubMed

Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest. 1997; 111(3): 534-6. PubMed

Selman M, Pardo A, King TE. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012; 186(4): 314-24. PubMed

Woda BA. Hypersensitivity pneumonitis: an immunopathology review. Arch Pathol Lab Med. 2008; 132(2): 204-5. PubMed

Content Review:

November 2017

Last Update: September 2018

Hypersensitivity Pneumonitis - Extrinsic Allergic Alveolitis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Imaging Studies

Other Testing

Differential Diagnosis

Background

Epidemiology

Etiologies

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Hypersensitivity Pneumonitis - Extrinsic Allergic Alveolitis. ARUP Consult^©. Retrieved February 20, 2019, from: https://arupconsult.com/content/hypersensitivity-pneumonitis