Hypersensitivity Pneumonitis

All cases of hypersensitivity pneumonitis result from immunological reactivity occurring after exposure to a foreign antigen, often in individuals who have some degree of genetic susceptibility. More than 300 antigens have been identified as triggers for hypersensitivity pneumonitis. Antigens encountered through farming, contact with birds, and water contamination account for about 75% of cases.

Antigens are commonly categorized by type and occupation (see table Examples of Hypersensitivity Pneumonitis); farmer’s lung, caused by inhalation of hay dust containing thermophilic actinomycetes, is the prototype. Substantial overlap exists between hypersensitivity pneumonitis and chronic bronchitis in farmers, in whom chronic bronchitis is far more common, occurs independently of smoking status, is linked to thermophilic actinomycete exposure, and leads to findings similar to those of hypersensitivity pneumonitis on diagnostic testing.

The disorder seems to represent a type IV hypersensitivity reaction, in which repeated exposure to antigen in genetically susceptible people leads to acute or subacute inflammation followed by chronic inflammation and fibrosis. Initially, in the acute phase, neutrophilic and mononuclear alveolitis prevail. Subsequently, in the subacute phase, interstitial Th1 and Th17 lymphocytic infiltration and formation and deposition of immune complexes target the foreign antigen. In more chronic cases, granulomatous reactions may occur due to influxes of CD4+ Th1 cells (similar to the pathogenesis in sarcoid or tuberculous granulomas). Finally, with continued exposure, invasion of fibroblasts may cause fibrosis with bronchiolar obliteration. The primary role of the immune response appears to be an attempt to eliminate or if unsuccessful, to isolate the offending antigen. Certain genetic polymorphisms, such as MUC5B, may influence a patient's risk of developing hypersensitivity pneumonitis and contribute to increased disease morbidity (1).

Circulating IgG precipitins (antibodies sensitized to antigen) seem not to have a primary etiologic role, and clinical history of allergy (such as asthma and seasonal allergies) is not a predisposing factor. Cigarette smoking seems to delay or prevent development, perhaps through down-regulation of the lung’s immune response to inhaled antigens. However, smoking may exacerbate the disease once established.

Hypersensitivity pneumonitis has clinical similarities to other disorders that have different pathophysiologies.

• Organic dust toxic syndrome (pulmonary mycotoxicosis, grain fever), for example, is a syndrome consisting of fever, chills, myalgias, and dyspnea that does not require prior sensitization and is thought to be caused by inhalation of toxins produced by fungi or other contaminants of organic dust.

• Silo filler’s disease may lead to respiratory failure, acute respiratory distress syndrome (ARDS), and bronchiolitis obliterans or bronchitis but is caused by inhalation of toxic nitrogen oxides produced by freshly fermented corn or alfalfa silage.

• Work-related asthma causes dyspnea in people previously sensitized to an inhaled antigen, but features such as airflow obstruction, airway eosinophilia, and negative history of contact or exposure and resultant differences in triggering antigens help to distinguish it from hypersensitivity pneumonitis.

Symptoms and signs tend to depend on whether onset is

• Acute (days)

• Subacute (weeks)

• Chronic (months to years)

Only a small proportion of exposed people develop symptoms and in most cases only after weeks to months of exposure and sensitization.

• High-resolution CT (HRCT)

• Pulmonary function tests

• Serologic tests for antigen-specific immunoglobulins

• Bronchoalveolar lavage

• Histologic examination

The diagnosis of hypersensitivity pneumonitis requires a high index of suspicion in patients with compatible symptoms and a compatible occupational, avocational, or domestic exposure history. Hypersensitivity pneumonitis must be considered in patients with newly identified interstitial lung disease (1, 2). HRCT is performed to identify the characteristic radiographic findings. Pulmonary function tests may also be performed to assess for the degree of respiratory impairment. Serum antigen-specific immunoglobulin (Ig) G or IgA against suspected antigens may be obtained, but their diagnostic utility is limited and a negative result does not exclude the diagnosis (1). Bronchoalveolar lavage and/or lung biopsy may be necessary if results are inconclusive. The differential diagnosis is broad and includes environmental pulmonary diseases, sarcoidosis, bronchiolitis obliterans, systemic rheumatic–associated pulmonary disease, and other interstitial lung diseases.

Clues in the history include:

• Recurring atypical pneumonias

• Symptom onset after moving to a new job or home

• A hot tub, a sauna, a swimming pool, or other sources of standing water or water damage in the home or regular exposure to them elsewhere

• Having birds as pets

• Working on a farm

• Working in certain industries (eg, woodworking; cheese, wine, or bread making; animal husbandry; textiles)

• Exacerbation and relief of symptoms in and away from specific settings

Physical examination often is not useful in making the diagnosis, although abnormal lung sounds (eg, inspiratory squeaks, basilar crackles) and clubbing may be present.

Imaging tests

Imaging tests are typically done for patients with appropriate history, symptoms, and signs.

Chest radiograph is neither sensitive nor specific for detecting disease and is frequently normal in patients with acute and subacute forms. It may show reticular or nodular opacities, usually when symptoms are present. Chest radiographs of patients with chronic disease are more likely to show reticular or nodular opacities in the upper lobes with reduced lung volumes and honeycombing, similar to that of idiopathic pulmonary fibrosis.

Chronic Hypersensitivity Pneumonitis

Image

Image courtesy of Joyce Lee, MD, MAS.

High-resolution CT is the preferred imaging modality for evaluating parenchymal changes in hypersensitivity pneumonitis, and is more likely to show abnormalities than standard CT or radiographs (2).

In acute and subacute hypersensitivity pneumonitis, the most typical HRCT findings are centrilobular micronodules, typically measuring less than 3 mm in diameter, usually located near the central airways of those lobules. Occasionally, ground-glass opacification (attenuation) is the predominant or sometimes the only finding. It is usually diffuse but sometimes spares the periphery of the secondary lobule. Focal areas of hyperlucency, similar to those present in bronchiolitis obliterans, may be a prominent feature in some patients (eg, mosaic attenuation with air trapping on expiratory HRCT).

In chronic hypersensitivity pneumonitis, there are findings of lung fibrosis, which include lobar volume loss, linear or reticular opacities, honeycombing, and traction bronchiectasis. Centrilobular micronodules, ground-glass opacification, and areas of hyperlucency may occur but are less prominent. Some patients with chronic hypersensitivity pneumonitis who do not smoke have findings of upper lobe emphysema. Mediastinal lymphadenopathy is uncommon, thereby distinguishing hypersensitivity pneumonitis from sarcoidosis.

• Antigen identification and mitigation

• glucocorticoids

• Sometimes antifibrotic therapy

Treatment of acute or subacute hypersensitivity pneumonitis is with glucocorticoids, usually high-dose prednisone for 1 to 2 weeks, which is subsequently tapered over the next few weeks until the medication is discontinued. This regimen relieves initial symptoms but does not appear to alter long-term outcome. Treatment of acute or subacute hypersensitivity pneumonitis is with glucocorticoids, usually high-dose prednisone for 1 to 2 weeks, which is subsequently tapered over the next few weeks until the medication is discontinued. This regimen relieves initial symptoms but does not appear to alter long-term outcome.

Treatment of chronic hypersensitivity pneumonitis is usually with longer courses of low-dose maintenance prednisone with tapering dependent on clinical response. Some patients require corticosteroid-sparing agents (eg, mycophenolate mofetil, azathioprine) for long-term treatment. Treatment of chronic hypersensitivity pneumonitis is usually with longer courses of low-dose maintenance prednisone with tapering dependent on clinical response. Some patients require corticosteroid-sparing agents (eg, mycophenolate mofetil, azathioprine) for long-term treatment.

In patients with progressive fibrosis despite immunosuppressive therapy, antifibrotic therapy can be considered. Nintedanib, a tyrosine kinase inhibitor, appears to slow the rate of decline in lung function in patients with progressive pulmonary fibrosis, including those with chronic hypersensitivity pneumonitis (In patients with progressive fibrosis despite immunosuppressive therapy, antifibrotic therapy can be considered. Nintedanib, a tyrosine kinase inhibitor, appears to slow the rate of decline in lung function in patients with progressive pulmonary fibrosis, including those with chronic hypersensitivity pneumonitis (1). Pirfenidone, another antifibrotic medication, is sometimes used as an alternative if nintedanib is not tolerated. It has been less well-studied in hypersensitivity pneumonitis, but may also slow progression of lung disease (). Pirfenidone, another antifibrotic medication, is sometimes used as an alternative if nintedanib is not tolerated. It has been less well-studied in hypersensitivity pneumonitis, but may also slow progression of lung disease (2).

The pathologic changes of acute hypersensitivity pneumonitis are completely reversible if detected early and if antigen exposure is eliminated. Acute disease is self-limiting with antigen avoidance; symptoms usually lessen within hours. Nonfibrotic forms of subacute hypersensitivity pneumonitis generally have a favorable prognosis if the inciting antigen is identified and exposure is avoided. The prognosis is less favorable for patients with fibrotic hypersensitivity pneumonitis. In chronic disease, fibrosis is usually irreversible and may progress even if the patient is no longer exposed to the antigen.

The most important aspect of long-term management of hypersensitivity pneumonitis is avoidance of exposure to antigens. A complete change of environment is rarely realistic, especially for farmers and other workers, in which case dust control measures (such as wetting down compost before disturbing it) or using air filters or protective masks may be effective. Fungicides may be used to prevent the growth of antigenic microorganisms (eg, in hay or on sugar cane), but the long-term safety of this approach is unknown. Extensive cleaning of wet ventilation systems, removal of moist carpets, and maintenance of low humidity by dehumidifiers are also effective in some settings. Patients must be informed, however, that these measures may be inadequate if exposure continues.