Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. The clinical presentation of acute HP includes cough, fever, and malaise, while subacute and chronic forms present as insidious onset of a cough and dyspnea over weeks to months. Diagnosis is aided by high-resolution CT scans and bronchoalveolar lavage. Management includes avoiding the inciting agent and administration of steroids in subacute and chronic cases. Early treatment has a good prognosis, but long-term exposure can cause permanent scarring and fibrosis.

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Overview

Definition

Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the lung parenchyma, alveoli, and bronchioles. This disorder is caused by repeated inhalation of inciting agents in a susceptible host.

Interstitial lung disease caused by hypersensitivity reactions:

  • Acute phase: type III (immune-complex–mediated)
  • Subacute and chronic phases: type IV (delayed hypersensitivity/T-cell–mediated)

Categorization of interstitial lung diseases
ILD: interstitial lung disease

Image by Lecturio.

Classification

Classification is based on duration of illness and frequency, duration, and intensity of exposure. There is considerable variability in presentation and course.

  • Acute HP: 
    • Acute onset of symptoms following a massive exposure to the inciting agent
    • Duration < 6 months
    • Disease is reversible.
  • Subacute HP:  mild, intermittent, or progressive symptoms developing over weeks due to repeated and continued exposure to the inciting antigen
  • Chronic HP: 
    • Repeated and continuous low-level exposure to the inciting antigenic agent 
    • Duration > 6 months
    • Disease is less reversible with ↑ chance of progression.

Epidemiology

  • Exact prevalence unknown
  • Approximate prevalence: 
    • 1–3 per 100,000 persons
    • 11 per 100,000 persons age ≥ 65 years
  • Age at onset: usually 30–60 years
  • Gender: 
    • Men > women due to gender bias in affected occupations 
    • Women are equally as susceptible as men when exposed.
  • Most common types:
    • Farmer’s lung
    • Bird fancier’s lung
    • Chemical worker’s lung

Etiology

More than 300 etiologies of HP have been reported across a wide range of exposures involving airborne antigens.

Selected etiologic agents for HP
DiseaseExposureAntigens
Farmer’s lung
  • Forking moldy hay
  • Moldy vegetable material
  • Thermophilic actinomycetes
  • Fungi (e.g., Aspergillus umbrasus)
Bird fancier’s lung
  • Pigeons
  • Parakeets
  • Chickens
  • Turkeys
Proteins present on feathers and in excreta
Chemical worker’s lungMany different chemicalsIsocyanates
ByssinosisWorking in the textile industry
  • Cotton
  • Linen
  • Hemp fibers
BagassosisMoldy sugar caneThermophilic actinomycetes
Silo filler’s lungFermentation in silosNitrogen dioxide gas
Maltworker’s lungTurning germinating barley
  • A. clavatus
  • A. fumigatus
Humidifier feverContaminated humidifying systems in air conditioners
  • Thermophilic actinomycetes
  • Mycobacterium
  • Candida albicans
  • Aureobasidium pullulans
Mushroom workers lungTurning mushroom compostThermophilic actinomycetes
Cheese washer’s lungMoldy cheesePenicillin casei
Winemaker’s lungMold on grapesBotrytis

Pathophysiology

Initially during acute HP, the disease process is driven by a type III (immune-complex–mediated) hypersensitivity reaction. Continued exposure shifts the process to a type IV delayed hypersensitivity reaction mediated by T cells.

Pathogenesis is directly related to antibodies targeting specific protein antigens:

  • Proteins are often on microbes, but disease is not caused by direct infection by these microbial agents.
  • Inciting proteins may be organic or nonorganic.

Acute HP (type III immune-complex–mediated hypersensitivity reaction):

  • Immune-complex formation: 
    • Specific antigens trigger IgG antibody formation.
    • Antigens bind antibodies and form circulating immune complexes.
  • Immune-complex deposition within the lung parenchyma, alveoli, and bronchioles
  • Activation of complement via the classical pathway:
    • Leads to infiltration of PMNs (primarily neutrophils) and macrophages
    • Inflammatory tissue damage

Subacute and chronic HP (type IV delayed hypersensitivity reaction mediated by T cells):

  • Macrophages and monocytes engulf and present antigens to T cells.
  • T cells release inflammatory mediators (e.g., cytokines, chemokines).
  • Result in tissue damage and interstitial pneumonitis 
  • T cells are not able to fully destroy antigens engulfed by macrophages → noncaseating granuloma formation
  • May progress to fibrosis (mechanism poorly understood)

Clinical Presentation

Acute hypersensitivity pneumonitis

Acute HP usually follows massive exposure to an inciting agent:

  • Abrupt onset of symptoms (4–8 hours) after exposure
  • Symptom resolution within 12–48 hours after removal of inciting antigen
  • Aside from history of exposure, may appear clinically similar to a viral or bacterial infection
  • Symptoms:
    • Abrupt onset of a cough
    • Chest tightness
    • Dyspnea without wheezing
    • Fever
    • Chills
    • Malaise
    • Nausea
    • Headache
  • Clinical exam:
    • Tachypnea
    • Diffuse fine crackles

Subacute and chronic hypersensitivity pneumonitis

  • Insidious, gradual onset over weeks to months
  • The patient may not have a history of acute HP or may not be able to identify a trigger.
  • Symptoms:
    • Progressive cough 
    • Dyspnea
    • Fatigue
    • Anorexia and weight loss
  • Clinical exam:
    • Tachypnea
    • Diffuse crackles
    • More severe findings in chronic disease with fibrosis:
      • Cyanosis
      • Digital clubbing
      • Reduced chest expansion

Diagnosis

Laboratory and pathology

  • Serum:
    • ↑ Serum IgGs 
      • Only confirms exposure, not that it is causing HP
      • High false positive and false negative rates
    • Nonspecific tests of inflammation:
      • ↑ ESR
      • ↑ CRP
      • ↑ LDH in the acute phase
      • + Rheumatoid factor
    • CBC following acute exposure: 
      • Neutrophilia 
      • Lymphopenia 
      • Eosinophilia is typically not present.
  • Bronchoalveolar lavage:
    • Most sensitive test for HP
    • Shows marked lymphocytosis (due to ↑ T lymphocytes present in type IV hypersensitivity reactions)
    • ↓ CD4 (helper T cells) to CD8 (cytotoxic T cells) ratio
    • ↑ PMNs (neutrophils) in acute disease
  • Biopsy:
    • Transbronchial (lower diagnostic yield) or surgical specimens may be obtained.
    • Lymphocyte infiltration into the:
      • Peribronchial tissue
      • Alveolar walls
    • Poorly formed granulomas located near respiratory or terminal bronchioles
    • Fibrosis in chronic disease

Hypersensitivity pneumonitis (HP):
The cellular interstitium of subacute HP (A) is dominated by plasma cells (magnification in B). A typical poorly formed granuloma of HP is present in (B).
(A,B) H&E stain; (A) 40× original magnification; (B) 400× original magnification

Image: “My approach to interstitial lung disease using clinical, radiological and histopathological patterns” by Leslie KO. License: CC BY 2.0

Spirometry

  • Restrictive pattern:
    • ↓ Forced vital capacity (FVC; total forced exhaled volume)
    • ↓ Total lung capacity (TLC; total volume in lungs at the end of a maximal inspiration)
    • ↓ Compliance (lungs have difficulty expanding)
  • Obstructive (or mixed) patterns are also possible; more common in severe disease:
    • ↓ Forced expiratory volume in 1 second (FEV1):FVC ratio
    • ↓ Airflow (bronchioles are partially obstructed by inflammation and fibrosis)
  • Impaired gas diffusion across the alveolar membrane:
    • ↓ Diffusing capacity of the lung for carbon monoxide (DLCO)
    • Always seen in chronic HP, usually in subacute HP, and occasionally in acute HP
  • Pulmonary function test results may revert to normal in acute/subacute forms with no further exposure.

Imaging

  • High-resolution CT of the chest:
    • More sensitive for HP than chest X-ray
    • Findings develop with worsening disease:
      • Mid-to-upper zone predominance of centrilobular ground-glass or nodular opacities
      • Signs of air trapping (compare inspiratory and expiratory images)
    • As disease progresses:
      • ↑ Reticulation (indicates fibrosis)
      • Traction bronchiectasis
      • Honeycombing
      • Signs of emphysema
  • Chest X-ray:
    • No specific or distinctive changes in HP
    • Often normal and/or revert to normal following an acute episode
    • Typical findings: 
      • Poorly defined, patchy, or diffuse infiltrates 
      • Micronodular or reticular opacities 
      • Progressive fibrotic changes in more severe disease
      • Findings are classically in the upper lobes (different from other pulmonary fibrosis).

Radiological and pathological assessment for a husband and wife in Japan who both developed hypersensitivity pneumonitis caused by inhalation of Trichosporon asahii which was growing in the straw mats of their home.
Wife: Chest x-ray on the day of admission shows mild infiltrates predominantly in the middle to lower lung fields with multiple scattered nodular lesions (Panel A).
Thoracic CT (computed tomography) taken on the same day confirms that these lesions correspond to ground-glass opacities and abundant centrilobular nodules, predominantly located in the bilateral lower lobes (Panel B).
Specimens obtained from transbronchial lung biopsy (TBLB) demonstrate organization within the peribronchial area with alveolitis, suggesting transbronchial spread (Panel C).
Husband: Chest x-ray (Panel D) and thoracic CT (Panel E) show ground glass opacities in the upper lungs on both sides.
The specimens obtained from TBLB at his local hospital reveals organizing tissue within the peribronchial area with alveolitis, suggesting transbronchial spread (Panel F).

Image: “Familial summer-type hypersensitivity pneumonitis in Japan: two case reports and review of the literature” by Nakajima A, Saraya T, Mori T, Ikeda R, Sugita T, Watanabe T, Fujiwara M, Takizawa H, Goto H. License: CC BY 2.0

Inhalation challenge testing

  • Reexpose patient to the suspected environmental trigger.
  • Should be done in a hospital setting with appropriate support
  • Look for development of symptoms and for spirometry and radiographic findings consistent with HP.

Diagnostic criteria

Exact diagnostic criteria are still being debated but generally include the following:

  1. Known exposure to an offending antigen identified by:
    • History of exposure
    • IgG serum antibodies against the antigen
  2. Compatible clinical, radiographic, or physiologic findings:
    • Respiratory symptoms: cough, dyspnea, crackles
    • High-resolution CT (HRCT) findings: reticular, nodular, or ground-glass opacities
    • Abnormal spirometry: usually a restrictive pattern, but may be obstructive or mixed; ↓ DLCO
  3. Bronchoalveolar lavage (BAL) with lymphocytosis > 20% (often > 50%)
  4. Positive inhalation challenge test:
    • Reexposure to the environment
    • Inhalation challenge in a hospital setting
  5. Histopathology consistent with HP:
    • Poorly formed, noncaseating granulomas
    • Mononuclear-cell infiltrates (mostly lymphocytes)

Management

  • Eliminate (preferred) or reduce exposure to the inciting antigen:
    • Remove the patient from the environment where the antigen exists.
    • Remove the antigen from the environment.
    • Purify the inhaled air: 
      • Pollen masks
      • Airstream helmets
      • Supply fresh air 
  • Glucocorticoids:
    • Prednisone 
    • Rarely needed in acute cases
    • Short trial (7–14 days) helpful in subacute and chronic cases
    • More likely to help patients with inflammatory features:
      • Ground-glass opacities on HRCT
      • Lymphocytosis on BAL
      • Granulomas on pathology
  • Immunosuppressive agents:
    • Options:
      • Azathioprine
      • Mycophenolate mofetil
    • Poorly studied in HP
    • May be tried in patients with chronic HP who have not responded to steroids
  • Lung transplantation

Differential Diagnosis

  • Inhalation fevers: a group of conditions (e.g., metal fume fever) caused by inhalation of chemicals and organic agents that directly damage the lungs, but are not true forms of HP (which are hypersensitivity reactions): Inhalation fevers are characterized by fevers, chills, malaise, headaches, and myalgias without prominent pulmonary findings. Symptom onset is usually 4–12 hours after exposure. Management is supportive.
  • Organic dust toxic syndrome: occurs after exposure to bioaerosols contaminated with toxin-producing fungi: Symptoms start after exposure to contaminated dust and include fever, chills, dyspnea, myalgias, and cough. Workup may reveal leukocytosis, diffuse opacities on chest radiography, and restrictive pattern on spirometry, and biopsies show obliterative bronchiolitis without granulomas. Cases can arise without prior sensitization, which is why they are not true forms of HP.
  • Chronic obstructive pulmonary disease (COPD): an inflammatory respiratory disease characterized by airflow obstruction: This disease includes emphysema, chronic bronchitis, and chronic obstructive asthma. Chronic bronchitis is the most common cause of lung disease in agricultural workers, even in those without a history of cigarette smoking. Diagnosis involves spirometry demonstrating an obstructive pattern. Management is with beta-agonists, muscarinic antagonists, and steroids.
  • Idiopathic pulmonary fibrosis: spontaneously occurring, diffuse, progressive parenchymal lung disease resulting in chronic fibrosis without an identifiable cause: Patients typically present at an older age with gradual onset of cough and dyspnea over months. The condition can be difficult to distinguish from HP and often requires a lung biopsy in addition to spirometry and HRCT for diagnosis. Management is mostly supportive, and the prognosis is poor.
  • Sarcoidosis: a granulomatous disorder affecting multiple organ systems without a known etiology: The most common presenting findings include pulmonary reticular opacities, bilateral hilar adenopathy, and skin, joint, or eye lesions. Patients are often asymptomatic, though they may present with cough, dyspnea, fever, and malaise. Diagnosis involves imaging, spirometry, and BAL and often requires a biopsy. Management is usually with glucocorticoids.

References

  1. King TE (2020). Approach to the adult with interstitial lung disease: Diagnostic testing. In Hollingsworth H (Ed.), UpToDate. Retrieved January 26, 2021, from https://www.uptodate.com/contents/approach-to-the-adult-with-interstitial-lung-disease-diagnostic-testing
  2. King TE (2019). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis. In Hollingsworth H (Ed.), UpToDate. Retrieved February 26, 2021, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-clinical-manifestations-and-diagnosis
  3. King TE (2019). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis. In Hollingsworth H (Ed.), UpToDate. Retrieved March 2, 2021, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-epidemiology-causes-and-pathogenesis
  4. King TE (2019). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention. In Hollingsworth H (Ed.), UpToDate. Retrieved March 2, 2021, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-treatment-prognosis-and-prevention 
  5. Johannson KA, Elicker BM, Vittinghoff E, et al. (2016). A diagnostic model for chronic hypersensitivity pneumonitis. Thorax 71:951.
  6. Hsieh C (2020). Hypersensitivity pneumonitis. Emedicine. Retrieved January 26, 2021, from https://emedicine.medscape.com/article/299174-overview#a7
  7. Kline JN, Hunninghake GW (2008). Hypersensitivity pneumonitis and pulmonary infiltrates with eosinophilia. In Fauci AS, Braunwald E, Kasper DL, et al. (Eds.) Harrison’s Internal Medicine (17th ed., pp. 1607-1610).

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