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Hypersensitivity Pneumonitis
Han Q. Bui, MD, MPH
image BASICS
  • Hypersensitivity pneumonitis (HP) is also called extrinsic allergic alveolitis (EAA).
  • HP is a diffuse inflammatory disease of the lung parenchyma caused by an immunologic reaction to aerosolized antigenic particles found in a variety of environments. Classification depends on time frame involved:
    • Acute: fever, chills, diaphoresis, myalgias, nausea; cough and dyspnea common but not necessarily present. Occurs 4 to 12 hours after heavy exposure to an inciting agent. Symptoms subside within 12 hours to several days after removal from exposure. Complete resolution occurs within weeks.
    • Subacute: mainly caused by continual low-level antigen exposure, could have a low-grade fever in first week; cough, dyspnea, fatigue, anorexia, weight loss—develops over days to weeks
    • Chronic: from recurrent exposure either acute or subacute cases, prolonged and progressive cough, dyspnea, fatigue, weight loss, could lead to fibrosis and respiratory failure
  • Farmer's lung is an old term of this disease, a type of HP, particular to the farmer population; causative agent is a bacterium found in moldy hay or straw. Farmer's lung now has new and different etiologies due to modernization of farming practices (1,2).
EPIDEMIOLOGY
  • Not well defined. Tends to occur in adults as a result of occupation-related exposure, but some home environmental exposures are also seen.
  • HP is increasingly recognized as an important cause of fibrotic interstitial lung disease (3).
Incidence
0.9 per 100,000
Prevalence
  • Farmers: 1-19% exposed farmers
  • Bird fanciers: 6-20% exposed individuals
  • Others: 1-8% exposed
ETIOLOGY AND PATHOPHYSIOLOGY
  • Hypersensitivity reaction involving immune complexes: inhaled antigens bind to IgG, triggering complement cascade (types III and IV immunologic reactions) (4)
  • Cellular-mediated reaction: T cell-mediated immune inflammatory response
  • Farming, vegetable, or dairy cattle workers (1,2)
    • Moldy hay, grain, silage: thermophilic actinomycetes, such as Faenia rectivirgula
    • Mold on pressed sugar cane: Thermoactinomyces sacchari, Thymus vulgaris
    • Tobacco plants: Aspergillus sp., Scopulariopsis brevicaulis
    • Mushroom worker's lung: Saccharopolyspora rectivirgula, T. vulgaris, Aspergillus spp.
    • Potato riddler's lung: Thermophilic actinomycetes, T. vulgaris, Faenia rectivirgula, Aspergillus sp.
    • Wine maker's lung: Mucor stolonifer
    • Cheese washer's lung: Penicillium casei, Aspergillus clavatus
    • Coffee worker's lung: coffee bean dust
    • Tea grower's lung: tea plants
  • Ventilation and water-related contamination (1,2)
    • Contaminated humidifiers and air conditioners: amoebae, nematodes, yeasts, bacteria
    • Unventilated shower: Epicoccum nigrum
    • Hot-tub lung: Cladosporium sp., Mycobacterium avium complex
    • Sauna taker's lung: Aureobasidium sp.
    • Summer-type pneumonitis: Trichosporon cutaneum
    • Swimming pool lung (lifeguard) lung: aerosolized endotoxin and M. avium complex
    • Contaminated basement pneumonitis: Cephalosporium and Penicillium spp.
  • Bird and poultry handling (1)
    • Bird fancier's lung: droppings, feathers, serum proteins
    • Poultry worker's lung: serum proteins
    • Turkey-handling disease: serum proteins
    • Canary fancier's lung: serum proteins
    • Duck fever: feathers, serum proteins
  • Veterinary work and animal handling (1,2)
    • Laboratory worker's lung: urine, serum, pelts, proteins
    • Pituitary snuff taker's disease: dried, powdered neurohypophysis
    • Furrier's lung: animal pelts
    • Bat lung: bat serum protein
    • Fish meal worker's lung: fish meal
    • Coptic lung: cloth wrapping of mummies
    • Mollusc shell HP: sea-snail shell
    • Pearl oyster shell pneumonitis: oyster shells
  • Grain and flour (1,2)
    • Grain measurer's lung: cereal grain, grain dust
    • Miller's lung: Sitophilus granarius
    • Malt worker's disease: A. fumigatus, A. clavatus
  • Lumber milling, construction, wood stripping, paper, wallboard manufacture (1,2)
    • Wood dust pneumonitis: Alternaria sp., Bacillus subtilis
    • Sequoiosis: Graphium, Pullularia, Trichoderma sp., Aureobasidium pullulans
    • Maple bark disease: Cryptostroma corticale
    • Wood trimmer's disease: Rhizopus sp., Mucor sp.
    • Wood pulp worker's disease: Penicillium sp.
    • Suberosis: T. viridis, P. glabrum
  • Plastic manufacturing, painting, electronics, chemicals (1)
    • Chemical HP: diphenyl diisocyanate, toluene diisocyanate
    • Detergent worker's lung: B. subtilis enzymes
    • Pauli reagent alveolitis: sodium diazobenzene sulfate
    • Vineyard sprayer's lung: copper sulfate
    • Pyrethrum: Pyrethrum
    • Epoxy resin lung: phthalic anhydride
    • Bible printer's lung: moldy typesetting water
    • Machine operator's lung: Pseudomona fluorescens, aerosolized metal working fluid
  • Textile workers
    • Byssinosis: cotton mill dust
    • Velvet worker's lung: nylon, tannic acid, potato starch
    • Upholstery fabric: aflatoxin-producing fungus, Fusarium sp.
    • Lycoperdonosis: puffball spores
Genetics
No evidence of clear genetic susceptibility. Possible genetic predisposition involving tumor necrosis factor alpha (TNF-&agr;) and major histocompatibility complex (MHC) class II genes (1,4)[B]
RISK FACTORS
  • Contact with organic antigens increases the risk of developing HP. Viral infection at time of exposure could also increase risk (5).
  • Nonsmokers have an increased incidence of HP compared with smokers (nicotine could have a protective effect) (5).
    • Smokers have a diminished antibody response to inhaled antigens.
    • However, smokers that develop disease tend to have the chronic form, and mortality is higher.
GENERAL PREVENTION
Avoidance of offending antigen and/or use of protective equipment
COMMONLY ASSOCIATED CONDITIONS
Constrictive bronchiolitis
image DIAGNOSIS
  • Diagnosis criteria most widely used but not validated: (i) history and physical and pulmonary function tests (PFTs) indicating restriction or diffusion disease, (ii) radiologic imaging consent with interstitial lung disease, (iii) exposure to a recognized cause, (iv) proof of sensitization in BAL fluids (serum precipitins and/or lymphocytosis) (2)
  • Six significant predictors: exposure to a known antigen, positive precipitating antibodies, recurrent episodes of symptoms, inspiratory crackles, symptoms 4 to 8 hours after exposure, weight loss (6)
  • Acute form: develops 4 to 12 hours following exposure. Cough, dyspnea without wheezing, fever, chills, diaphoresis, headache, nausea, malaise, chest tightness. Symptoms last hours to days.
  • Sequela (prior subacute, chronic): gradual or progressive productive cough, dyspnea, fatigue, anorexia, weight loss can lead to respiratory failure; develops over days, weeks to months.
  • Symptomatic improvement when away from work or home
PHYSICAL EXAM
  • Acute: fever, tachypnea, diffuse fine rales
  • Sequela or chronic: inspiratory crackles, progressive hypoxia, weight loss, diffuse rales, clubbing, rarely wheezing
P.517

DIAGNOSTIC TESTS & INTERPRETATION
  • Testing for antibodies (Ab) is NOT diagnostic as up to 40% may have positive AB without disease. Antigens that cover most cases: pigeon and parakeet sera, dove feather, Aspergillus sp., Penicillium, S. rectivirgula, and T. viridans.
  • PFTs: Typical profile is a restrictive pattern with low diffusing capacity, could also have an obstructive pattern (6).
  • Bronchoalveolar lavage (BAL) with serum precipitins and lymphocytosis: usually with low CD4-to-CD8 ratio. Findings not unique to HP (1,6)
  • Positive antigen-specific inhalation challenge testing: reexposure to the environment, inhalation challenge to the suspected antigen in a hospital setting but it lacks standardization (7)
  • Chest x-ray (CXR): used to rule out other diseases
    • Acute: ground-glass infiltrates, nodular or striated patchy opacities, interstitial pattern in a variety of distributions in lung field. Up to 20% could be normal.
    • Sequela/chronic: upper lobe fibrosis, nodular or ground-glass opacities, volume loss, emphysematous changes
  • CT scan of chest. Patterns not specific to HP:
    • Acute: ground-glass opacities, poorly defined centrilobular nodules and ground-glass opacities and air trapping on expiratory images (7,8)
    • Chronic: fibrosis, ground-glass attenuation, irregular opacities, bronchiectasis, loss of lung volume, honeycombing, emphysematous changes (7,8)
  • High-resolution CT (HRCT) mid-to-upper zone predominance of centrilobular ground glass or nodular opacities with signs of air trapping (7).
  • Usually start with CXR; may progress to HRCT based on findings (1,7)
Diagnostic Procedures/Other
Lung biopsy:
  • Transbronchial: reveals small, poorly formed noncaseating granulomas near respiratory or terminal bronchioles, large foam cells, peribronchial fibrosis
  • Open lung biopsy: highest yield in advanced disease. Reveals varying patterns of organizing pneumonia, centrilobular and perilobular fibrosis, multinucleated giant cells with clefts
DIFFERENTIAL DIAGNOSIS
  • Acute: acute infectious pneumonia: influenza (or other viral pneumonia), mycoplasma, Pneumocystis jiroveci pneumonia, asthma, aspiration (4)
  • Chronic: sarcoidosis, chronic bronchitis, chronic obstructive pulmonary disease, tuberculosis, collagen vascular disease, idiopathic pulmonary fibrosis, lymphoma, fungal infections, P. jiroveci pneumonia (4)
image TREATMENT
GENERAL MEASURES
Outpatient, except for acute pneumonitis cases and admission for workup (BAL, lung biopsy)
First Line
  • Avoidance of offending antigen is primary therapy and results in disease regression (1,2).
  • Corticosteroids: help control the symptoms of exacerbations but do not improve long-term outcomes
    • Prednisone: 20 to 50 mg daily (6)
    • For severe symptomatic patients, initial course of 1 to 2 weeks with taper (6)
Second Line
  • Bronchodilators and inhaled corticosteroids may symptomatically improve patients with wheeze and chest tightness (5,6)[B].
  • Oxygen may be needed in advanced cases.
  • Lung transplantation may be the last resort in severe cases unresponsive to therapy.
ISSUES FOR REFERRAL
Referral to pulmonologist/immunologist
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Supportive management, as needed, to maintain oxygenation and ventilation:
  • Unstable ventilation, oxygen requirement, mental status changes
  • Need for invasive evaluation (lung biopsy)
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Initial follow-up should be weekly to monthly, depending on severity and course
  • Follow treatments with serial CXR, PFTs, and circulating antibody levels
DIET
No dietary restrictions
PATIENT EDUCATION
Note that chronic exposure may lead to a loss of acute symptoms with exposure (i.e., the patient may lose awareness of exposure-symptom relationship).
PROGNOSIS
  • Presence of fibrosis is a poor prognosis factor (1,2).
  • Acute: good prognosis with reversal of pathologic findings if elimination of offending antigen early in disease (2,5)
  • Sequela/chronic: Corticosteroids have been found to improve lung function acutely but offer no significant difference in long-term outcome (5,6)[C].
REFERENCES
1. Girard M, Cormier Y. Hypersensitivity pneumonitis. Curr Opin Allergy Clin Immunol. 2010;10(2): 99-103.
2. Costabel U, Bonella F, Guzman J. Chronic hypersensitivity pneumonitis. Clin Chest Med. 2012;33(1):151-163.
3. Glazer CS. Chronic hypersensitivity pneumonitis: important considerations in the work-up of this fibrotic lung disease. Curr Opin Pulm Med. 2015;21(2):171-177.
4. Grunes D, Beasley MB. Hypersensitivity pneumonitis: a review and update of histologic findings. J Clin Pathol. 2013;66(10):888-895.
5. Selman M, Buendía-Roldán I. Immunopathology, diagnosis, and management of hypersensitivity pneumonitis. Semin Respir Crit Care Med. 2012;33(5):543-554.
6. Lacasse Y, Girard M, Cormier Y. Recent advances in hypersensitivity pneumonitis. Chest. 2012;142(1):208-217.
7. Ohshimo S, Bonella F, Guzman J, et al. Hypersensitivity pneumonitis. Immunol Allergy Clin North Am. 2012;32(4):537-556.
8. Hirschmann JV, Pipavath SN, Godwin JD. Hypersensitivity pneumonitis: a historical, clinical, and radiologic review. Radiographics. 2009;29(7):1921-1938.
Additional Reading
&NA;
Girard M, Lacasse Y, Cormier Y. Hypersensitivity pneumonitis. Allergy. 2009;64(3):322-334.
Codes
&NA;
ICD10
  • J67.9 Hypersensitivity pneumonitis due to unspecified organic dust
  • J67.0 Farmer's lung
  • J67.2 Bird fancier's lung
Clinical Pearls
&NA;
  • Skin testing is not useful for the diagnosis of HP.
  • Diagnosis should be suspected in every patient with unexplained cough and dyspnea on exertion, functional impairment (restriction or diffusion defect), and unclear fever, especially if exposure to potential antigens is known (workplace, domestic bird keeping, moldy walls in the home) (2).
  • Once the disease is established, smoking does not appear to attenuate its severity, and it may predispose to more chronic and severe course.
  • Use of protective gear on individual with high-risk exposure occupations can prevent HP.
  • Chronic hypersensitivity pneumonitis is increasingly recognized as an important mimic of other fibrotic lung diseases (3).