HYPERSENSITIVITY PNEUMONITIS
Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is an inflammatory disease caused by immune responses to inhaled antigenic organic particles or fumes. Episodes of acute and subacute HP usually resolve when antigen exposure ceases, although chronic HP may be progressive and irreversible, leading to debilitating fibrotic lung disease. HP can be caused by a wide variety of antigens that result in a common pattern of immune responses and clinical features. Colorful names such as pigeon breeder’s disease, bagassosis, and maple bark stripper’s lung have been attached to HP when caused by specific occupational exposures, but the patterns of disease and the features of the immune responses appear to be common to all forms. The classic example of HP is “farmer’s lung disease,” an illness initially described in dairy farmers who developed episodes of cough, shortness of breath, sometimes fever, and pulmonary infiltrates when exposed to the spores of bacteria that grew in bales of moldy hay. Hay that was wet when baled would support mold growth, and the heat of fermentation would then support growth of thermophilic Actinomyces bacteria. As the heated bales dried, the bacteria would convert from replication to the formation of hardy spores of small respirable size and light weight. When cracked open, a cloud of spores would rise from the moldy bale like a puff of smoke and readily be inhaled by the farmer handling it. Because only the occasional bale might be moldy, illness might be intermittent. HP is remarkable for the diversity of occupations and exposures that can cause the disease. Agents include spores from bacteria and molds, amoebae, bird and animal danders, and fragments of plant materials; more than 200 antigens have been identified.
The pathogenesis of HP is based on combined humoral
and cell-mediated immune responses. The humoral response is dominated by IgG
antibodies that may form immune complexes in vivo and precipitating complexes
in vitro in laboratory tests (serum precipitins). The cell-mediated immune
response is driven by sensitized T lymphocytes with activated macrophages. Only
a small minority of individuals with exposure develop clinical disease,
implying a genetically determined immune response capability. A substantial
number of exposed individuals may demonstrate serum antibodies but no cell-mediated
immune response or clinical illness, indicating that positive laboratory test
results for antibodies confirm exposure but are not sufficient to allow diagnosis
without other confirmatory evidence.
Three patterns of HP are recognized: (1) an acute form
with episodes that occur within 4 to 8 hours of antigen exposure and clear
within about 48 hours, (2) a subacute form that last from 48 hours to several
months, and (3) a chronic form lasting 4 months or longer. It is believed that
occasional, intermittent, intense exposures may favor the acute form (e.g., the
rare bale of moldy hay fed in the winter), and continuous or daily exposure may
favor the subacute form (e.g., a pet parakeet in the home). With frequent or
prolonged exposure, the chronic form of the
disease may develop with permanent pulmonary fibrosis.
The clinical features of acute HP include the abrupt
onset of flulike symptoms with fever, aches, malaise, cough, and dyspnea within
a few hours of known (or unsuspected) exposure. The patient appears ill, and
crackles (rales) may be present on lung auscultation. Chest radiographs may
reveal infiltrates that lead to an initial diagnosis and treatment of community-acquired
pneumonia. Chest computed tomography (CT) scans show scattered ground-glass opacities
with small centrilobular nodular opacities. The lung pathology of acute HP
features an inflammatory interstitial infiltrate consisting of lymphocytes
(predominantly CD8 T cells), plasma cells, mast cells, and macrophages.
Scattered, poorly formed, noncaseating granulomas and occasional multinucleated giant
cells may be seen, particularly adjacent to small airways. Neutrophils may be
present, but eosinophils are notably not a prominent part of this immune
response. Bronchoalveolar lavage (BAL) reflects the alveolar inflammatory exudate
with a very high proportion of lymphocytes (30%) and usually a predominance of
CD8 cells (in contrast to sarcoidosis, in which CD4 cells are increased). If
the exposure has been limited, the symptoms clear within 48 hours and the
radiographs within 4 weeks. Repeated episodes may prompt suspicion for HP
rather than infection.
Subacute HP occurs with repeated or continuous
exposure to the sensitizing antigen and resembles the acute form with less
abrupt onset and fewer systemic symptoms. Cough and dyspnea predominate and may
become progressively severe. The chest CT scan may show less ground-glass
opacity and centrilobular nodules that are more distinct. Subacute HP exhibits
granulomas that may be better formed but with interstitial inflammation away
from the granulomas as well. Symptoms and radiographs may clear more slowly
when exposure ends, but resolution is usually complete. Chronic HP may be
indolent, progressive, and easily confused with idiopathic pulmonary fibrosis.
Symptoms feature dyspnea with exertion and nonproductive cough. Crackles are
heard on lung examination, and rarely digital clubbing may be present. The CT
scan shows areas of linear and reticular opacities as well as ground glass, and
honeycombing may be evident. Chronic HP demonstrates interstitial fibrosis and
may sometimes include traction bronchiectasis and honey-comb formation that
closely resembles usual interstitial pneumonitis. A predominantly lymphocytic
interstitial infiltration and occasional granulomas permit distinction in most
cases.
The diagnosis of HP depends on establishing a combination of exposure to a plausible antigen, a compatible clinical syndrome,
appropriate radiologic findings, demonstration of an immunologic response to the
antigen, and typical lung pathology. BAL with a CD8 lymphocytosis is
confirmatory but not diagnostic. In most cases, all of these dimensions are not
needed or available for diagnosis. Historically, most cases of HP were
associated with occupational exposures, but hobbies (pet birds), hot tubs, and
home environmental exposures now predominate in developed countries. A recent
large case series from the United States reported that a specific cause was
identified in only 75% of cases despite vigorous attempts; thus, the clinical
picture and lung biopsy were needed in the others. Serologic testing offered
diagnosis in only 25%. The most common identified causes were avian antigens
(34%; parakeets, parrots, pigeons), hot tub lung (21%; Mycobacterium avium),
and mold (20%; farmer’s lung, household exposure).
Removal from exposure to the antigen is the key to the
treatment of HP, so correct identification of the antigen is critically
important but not successful in many cases. It is very important to establish a
diagnosis with confidence because for those with occupational exposures,
avoiding the antigen may involve loss of a job or a very costly modification of
the workplace. For home or hobby exposures, excluding a beloved pet or a major
change in lifestyle may be needed. Systemic corticosteroid therapy is useful in
relieving acute symptoms and
short-term reversal of lung pathology. Long-term steroid treatment is not
recommended because of side effects and uncertain efficacy; fibrosis may continue
if exposure does not end. Resolution and a favorable outcome can usually be
expected with prompt diagnosis and successful removal from the antigen.
