Hypersensitivity Pneumonitis

Dominic A. Munafo, Jr.

ETIOLOGY

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, results from an exaggerated immunologic response to various inhaled biologic and chemical antigens. Most cases of HP occur through occupational, environmental, or avocational exposures. Examples of HP include the classic farmer’s lung (thermophilic actinomycetes in moldy hay), pigeon breeder’s lung (serum proteins in pigeon droppings), bagassosis (bagasse in sugarcane), maple bark disease (fungi in moldy bark), hot-tub lung (mycobacteria), and humidifier lung (amoebae in humidifier water). Additional antigens include a wide range of animal and insect proteins, molds from wind instruments, and chemicals such as isocyanates and anhydrides. New inciting antigens are reported regularly in the literature. Inhaled antigens are typically 1 to 5 μm in diameter; therefore, the site of lung injury is the distal airway and alveolus. An antigen’s ability to trigger an immune response depends on its solubility, resistance to digestion by macrophages, and properties as an immunologic adjuvant. Prevalence rates vary widely (0.5%–30%) in an exposed population and appear to depend on intensity and duration of exposure as well as antigen type and host susceptibility. In studies conducted on exposed farmers, the estimated prevalence was 0.5% to 3%. HP is more prevalent among pigeon breeders than among farmers, perhaps in part because of the more chronic nature of the exposure in pigeon breeding.

PRESENTATION

Although HP classically has been categorized as acute, subacute, or chronic in presentation, these distinctions were not substantiated by a cluster analysis of patients performed by the HP Study Group. They found that most patients fit into one of two clusters and suggested that patients be considered as having either active or residual disease based on clinical evaluation, pulmonary function tests and high-resolution computed tomography (HRCT). The study group further concluded that the assumption that patients move temporally from acute to subacute and finally chronic disease in sequence had not been clearly established. Therefore, the group recommended that classifications of acute, subacute, and chronic not be used. This newly suggested classification will require prospective validation.

Active disease occurs after a previous sensitizing exposure to a particular antigen. Approximately 4 to 8 hours following reexposure, the individual experiences the abrupt onset of a flu-like syndrome. Symptoms typically include nonproductive cough, fever, chills, dyspnea, myalgias, and malaise. The most prominent physical findings are tachypnea, tachycardia, and bibasilar inspiratory crackles. Wheezing is uncommon. Symptoms typically peak within 24 hours and remit spontaneously within 72 hours. Symptoms recur with subsequent exposures, and the severity depends on the intensity and duration of exposure as well as a particular individual’s sensitivity. Chronic exposure to lower levels of antigen may be accompanied by mild or absent symptoms and disease progression can be insidious. Continued exposure is associated with increasing dyspnea, cough, anorexia, and weight loss.

Residual disease refers to the end-stage findings of emphysematous change or fibrosis present long after the acute inflammatory reaction has dissipated. Inspiratory crackles and resting hypoxemia would be characteristic.

DIAGNOSIS

The diagnosis of HP is suggested by a history that relates symptoms to exposure, but may be particularly difficult in those patients with chronic low-level exposure. Most of the signs and symptoms of disease are nonspecific. Numerous recommendations have been made as to the appropriate diagnostic criteria; however, most have not been validated. The HP Study Group published a logistic regression model that identified six significant predictors of HP: (1) exposure to a known offending antigen, (2) precipitating antibodies to the offending antigen, (3) recurrent symptoms, (4) inspiratory crackles on examination, (5) symptoms within 4 to 8 hours of exposure, and (6) weight loss. Depending on a patient’s particular constellation of findings, the probability of HP can be predicted by the model.

Laboratory findings are largely nonspecific. IgG serum precipitating antibodies to the offending antigen are present in most patients, but only a fraction actually develop disease. IgA and IgM antibodies may also be seen. Immunoglobulin levels are usually elevated in both serum and bronchoalveolar lavage fluid (BALF); however, IgE levels remain normal. The presence of antibodies is not diagnostic of disease but only indicates previous significant exposure.

Leukocytosis with a left shift typically accompanies acute episodes. Eosinophilia is uncommon and should suggest the possibility of another diagnosis. BALF shows a dramatic increase in the number of T lymphocytes recovered. Although the percentage of alveolar macrophages recovered is markedly reduced, the absolute number of macrophages is elevated. BALF findings are not diagnostic of HP but rather serve to support the diagnosis and help to rule out other processes. A normal BALF lymphocyte count would only be found in residual disease.

Histologically, a neutrophilic alveolitis in the first 24 hours gives way to an intense peribronchial inflammatory infiltrate of lymphocytes, plasma cells, macrophages, and giant cells. Noncaseating granulomas are often seen in the interstitium. In residual disease, both granulomas and interstitial fibrosis are seen. The fibrotic patterns seen include elements suggestive of usual interstitial pneumonia and nonspecific interstitial pneumonia. Bronchiolitis obliterans is found frequently (25%–50%) with or without organizing pneumonia (15%–25%). Vasculitis is not present.

Chest radiographic findings of HP are highly variable. Initially, radiographs may be normal (20%–30%) or show bilateral, ill-defined alveolar and interstitial nodular infiltrates. The distribution can be patchy or diffuse, with some predilection for the lower lobes. Hilar adenopathy and pleural effusions are rare. In residual disease, the chest radiograph shows a reticulonodular pattern with interstitial fibrosis, honeycombing, and loss of lung volume. The fibrotic changes are often more prominent in the upper lobes and periphery of the lung. HRCT is more sensitive than chest radiography in demonstrating the characteristic centrilobular nodules and emphysematous changes; however, its sensitivity and specificity appear to vary, depending on disease severity and chronicity.

Pulmonary function tests during an acute episode usually show a restrictive defect. Mild to moderate hypoxemia, hypocapnia, and a decrease in the diffusing capacity of the lung for carbon monoxide (DLCO) are often present. As many as 60% of patients may demonstrate a positive methacholine challenge. Patients who experience recurring attacks most commonly develop airway obstruction and a persistent decrement in DLCO

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