Risk Factors

It is unclear why some individuals exposed to an antigen develop EAA and others residing or working in the same environment do not. Because only 1% to 15% of persons exposed to etiologic antigens develop EAA, a combination of antigen dose, host-specific factors, and underlying genetics likely contributes to the development of EAA.

Intensity, frequency, and duration of exposure; particle size; antigen solubility; climate; work practices; and use of respiratory protection combine to alter the risk of disease. Farmer’s lung is associated with exposure to moldy hay, which is more common in harsh winter environments with heavy rainfall, where damp hay is fed to livestock in indoor barns with poor ventilation. Summer-type EAA, the most prevalent form of EAA in Japan, occurs in the wet summer months when indoor microbial contamination is at its height. Moreover, EAA associated with bird exposure occurs more frequently during the sporting (bird-hunting) season.

As with other granulomatous disorders, EAA occurs more often in individuals who do not smoke. However, when the disease occurs in smokers, they typically have a more severe course with increased mortality compared to nonsmokers. Concurrent high exposures to carbamate and organochlorine pesticides are associated with a higher risk of developing EAA in at-risk farmers. Pesticide exposure has been shown to activate the immune system, with increased inflammatory cytokine production and differential functional effects on macrophages, which may serve to enhance the inflammatory response to antigen.

There is also evidence that viral infections may be associated with disease development. Dakhama et al. found viral nucleic acids in more than half of the bronchoalveolar lavage (BAL) specimens and alveolar macrophages in subjects with acute EAA; influenza A was isolated in the majority of subjects. Infection with respiratory syncytial virus (RSV) and Sendai virus in mouse models of EAA are associated with a more robust inflammatory response to the inhaled antigens that cause farmer’s lung. Fetal microchimerism (fetal cells in maternal tissues) may also be an important mechanism to help explain the observation that EAA is more common in antigen-exposed women who have had children.

Several genetic studies suggest that individuals with certain major histocompatibility complex (MHC) class II haplotypes and alleles as well as tumor necrosis factor alpha (TNF-α) promoter polymorphisms are at increased risk of developing EAA. Specific single nucleotide polymorphisms (SNPs) in the transporter associated with antigen processing (TAP-1) and proteasome subunit beta type 8 (PSMB8) genes, involved in antigen processing and presentation by MHC classes I and II, may have affected disease susceptibility in a population of Mexican patients with EAA. Interestingly, two studies in different populations showed that allelic variants in the promoter region of tissue inhibitor of metalloproteinase 3 (TIMP-3), which inhibits the proteolytic activity of matrix metalloproteinases and thus extracellular matrix turnover, are protective against the development of EAA.

Clinical Features

The clinical presentation of patients with EAA can vary depending on the duration and intensity of exposure. Presentation does not seem to change with the type of antigen (organic vs. inorganic). Traditionally, the clinical presentation of EAA has been classified according to Richerson’s scheme, which describes acute, subacute, and chronic forms. Symptoms of acute EAA generally occur within 4 to 12 hours of antigen exposure. Flulike symptoms predominate, including fever, cough, dyspnea, chills, malaise, chest tightness, and myalgias. Physical examination frequently reveals fever, tachypnea, tachycardia, and rales. With subacute and chronic forms, the temporal relationship between antigen exposure and symptom onset is more difficult to assess. Typically, these patients report more insidious onset of progressive dyspnea on exertion, dry or minimally productive cough, fatigue, malaise, anorexia, and weight loss. The physical examination may reveal bibasilar rales; right-sided heart failure and digital clubbing may be present in patients with advanced fibrosis.

Notably, Richerson’s classification system was described before the use of computed tomography (CT) and does not correlate well with lung pathology. Lacasse et al., using data from the hypersensitivity pneumonitis (HP) study, used a cluster analysis (e.g., symptomatology, physiology, imaging, BAL data) and found that subacute EAA is likely an attenuated form of acute EAA. Thus, they proposed a binary scheme in which patients are classified according to disease activity, whether active or sequelae. This classification scheme, however, needs further validation before it is integrated into clinical practice.

Several diagnostic criteria have been proposed to differentiate EAA from other interstitial lung diseases (ILDs). A prospective multicenter cohort study of patients who had a pulmonary syndrome with EAA in the differential diagnosis adopted a “clinical prediction rule” for the diagnosis of active EAA (Table 55-2). Significant predictors in the final model included exposure to a known offending antigen, positive precipitating antibodies, recurrent episodes of symptoms, inspiratory crackles, symptoms 4 to 8 hours after exposure, and weight loss. These criteria are helpful when combined with BAL and high-resolution CT in determining the likelihood of EAA.

Table 55-2 Clinical Prediction Rule for Diagnosis of Extrinsic Allergic Alveolitis