Microbial Agents

Microbial organisms, including bacteria and fungi, are common in indoor environments. Warm, moist environments often provide ideal circumstances for the amplification and proliferation of microbial antigens that, if aerosolized and inhaled, can cause lung disease in a susceptible and previously sensitized host.

Bacteria have adapted to a wide variety of ecologic habitats and segregate under different physical and chemical conditions in indoor and outdoor environments. Thermophilic actinomycetes in hay are associated causally with the prototypical example of HP, farmer’s lung disease (FLD), first described in 1932. These bacteria are ubiquitous in the environment and thrive in 50° C to 55° C temperatures and moist conditions. They secrete enzymes that facilitate decay of vegetable matter, but that can also cause immunologic lung reactions when inhaled. In addition to hay, thermophilic bacteria can be found in sugar cane (bagassosis) and mushroom compost (mushroom worker’s lung) and can contaminate ventilation and humidification systems (humidifier lung) where temperatures can reach 60° C and stagnant water is present. Indoor bacteria that thrive at lower temperatures also can cause HP, and case reports have been associated with Bacillus spp. in contaminated wood dust, Klebsiella spp. in humidifiers, and Epicoccum spp. associated with moisture from a basement shower. Nontuberculous mycobacteria are an increasingly recognized cause of HP, mainly from workplace and recreational exposure to hot tub aerosols, but also from exposure to nontuberculous mycobacteria contaminants in shower heads. There have also been outbreaks of HP from exposure to indoor swimming pools, termed “lifeguard lung,” and to metalworking fluid aerosols contaminated with nontuberculous mycobacterial antigens.

Exposure to fungal antigens is implicated in some HP cases. Components of fungi capable of becoming airborne include spores, mycelial fragments, metabolites and partially degraded substrates, and toxins. Among the interior sites for mold growth are garbage containers, food storage areas, wallpaper, upholstery, areas of increased moisture such as shower curtains, window moldings, window air conditioners, damp basements, and emissions from cool mist vaporizers. Many fungal species have been associated causally with HP. Aspergillus spp. have been associated with HP in soy sauce brewers; bird breeders; farmers; compost, sawmill, mushroom, greenhouse, tobacco, cane mill, grain, and brewery workers; and in those exposed to contaminated esparto grass used in the production of ropes, canvas, sandals, mats, baskets, and paper paste. Similarly, Penicillium spp. may cause HP in cork workers, cheese workers, peat moss processors, laboratory workers, farmers, onion and potato sorters, sausage makers, and tree cutters. Alternaria, Cladosporium, Aureobasidium, Paecilomyces, Fusarium, and many other fungal species have been associated with HP in sawmill workers, tree cutters, hardwood processors, chicory leaf handlers, and other wood and plant handlers. There are several case reports of musical instruments (trombone and saxophone player’s lung) contaminated with fungal species that caused HP in their users. A case of childhood HP from Aureobasidium contamination of indoor hydroponic cultivation has been described, with marked improvement with removal of the offending plants. Summer-type HP, the most prevalent form of HP in Japan, is caused by seasonal mold contamination (mainly Trichosporon asahii, formerly Trichosporon cutaneum serotype II) in the home, often from moldy wood flooring. Domestic fungal exposure associated with decaying wood and damp walls in inner city dwellings is the most common cause of HP in Australia. There, multiple fungal species were identified in the homes of individuals with disease, suggesting that sensitizing microbial exposures may be complex mixtures and that disease is not always attributable to a single, well-defined exposure.

Animal Proteins

Particulates from a variety of animal sources can cause HP when inhaled. Exposure to bird protein antigens, first described in 1960, is the most clinically important and well recognized and is referred to as “bird breeder’s” or “bird fancier’s lung.” Avian antigens are complex high- and low-molecular-weight proteins found in the feathers, droppings, and serum of turkeys, chickens, geese, ducks, parakeets (budgerigars), parrots, pigeons, doves, love birds, canaries, and even native birds and are highly immunogenic. Immunoglobulins, particularly immunoglobulin (Ig) A and IgG, are released from birds’ feathers, creating a fine dust called “bloom.” Flying birds such as pigeons and parakeets produce the largest amount of bloom and are the birds most often associated with HP. Pigeon fancier’s lung may also be caused by IgG secreted on pigeon intestinal mucin. Highest exposures to respirable avian antigens are associated with cleaning out bird lofts, cages, and coops. Indirect and apparently trivial antigen exposures also have been associated with avian HP. Goose feather duvets, down comforters and pillows, feathers used for making fishing lures, and those contained in decorative wreaths have all been associated with HP. These findings suggest that avian antigens are extremely potent inducers of immunologic lung disease, and a careful search for their presence must be included in the history taking of patients with suspected HP. These antigens can also be highly resistant to degradation, and antigenic similarity across various bird species mandates a thorough removal of all bird and feather products for a patient with bird fancier’s lung. Even with extensive cleanup following removal of birds from indoor environments, antigen exposure may persist for months to years, perhaps explaining the lack of improvement in some patients with this form of HP.

There are several other animal exposures less commonly associated with HP. Animal handlers, including laboratory and veterinary workers, can develop HP from exposure to inhaled proteins in serum and excreta from rats and gerbils. Inhalation of grain dust infested with the wheat weevil Sitophilus granarius can cause a form of HP known as “miller’s lung.” Sericulturists engaged in silk production can develop HP from exposure to larval secretions and cocoon particulates. Production workers exposed to mollusk shell dusts during cutting and polishing to make buttons may develop HP.

Chemical Sensitizers

HP from inhalation exposure to low-molecular-weight chemicals is probably less common than from the other causes. Isocyanates are used for large-scale production of polyurethane polymers for flexible and rigid foams, as elastomers, adhesives, and surface coatings, and in two-part paints and are becoming increasingly recognized as a cause of HP. Acid anhydrides used in plastics, paints, and epoxy resins have been associated with an HP-like syndrome. Rare case reports of HP have been described from exposure to the pesticide pyrethrum; from Pauli’s reagent (sodium diazobenzene sulfate) used in chromatography; from copper sulfate in Bordeaux mixture used to spray vineyards; and from the enzyme phytase used as a cattle feed additive. Other chemical exposures reported to cause HP include formaldehyde, dimethyl phthalate, and styrene, the latter used in boat manufacturing.

Host Factors

Following antigen exposure, more people develop precipitating antibodies than develop symptomatic HP. Susceptibility to or protection from HP may be explained in part by genetic polymorphisms. Polymorphisms in the major histocompatibility complex and in tumor necrosis factor-α are associated with the development of HP. Within the major histocompatibility complex, polymorphisms of human leukocyte antigen genes and of the transporters associated with antigen processing 1 ( TAP1 ) gene have been associated with increased risk for HP. Several polymorphisms have also been associated with decreased disease risk. Overexpression of GATA3, a regulator of Th2 differentiation, attenuates disease perhaps by correcting the Th1 immune response. Variants in the tissue inhibitor of metalloproteinase-3 also appears to be protective.

Nongenetic host factors are also important disease determinants. HP develops more frequently in nonsmokers than in smokers. Compared with former and never smokers, pigeon fanciers who smoked had lower levels of serum IgG and IgA antibodies to pigeon proteins; this suggests that factors associated with cigarette smoking depress both T-cell–dependent and T-cell–independent responses to inhaled antigens. In an experimental HP model, nicotine exposure was associated with reductions in cellular responses, lymphocyte and total cell counts in BAL, and lung tissue inflammation. Other studies have shown that smoking induces relative increases in lung macrophages and decreases in lymphocytes and dendritic cells, perhaps promoting more effective clearance of antigens from terminal airways.

In addition to the risk factors for developing disease, variations in immune responses due to patient characteristics are also important determinants of the clinical phenotype of HP. Although HP is more common in nonsmokers, the prognosis is poorer in those with HP who smoke. In one study, smokers with FLD had more frequent illness recurrence, had lower percent predicted vital capacity, and had poorer 10-year survival in comparison with nonsmokers with FLD. Smokers are more likely to have insidious than acute symptoms, which may delay clinical recognition. In addition to smoking status, age may play a role in the phenotype of disease, where immune responses change with age. In a study of clinical features of patients with nonacute HP, those who developed fibrosis were significantly older than those who did not develop fibrosis.

Signs and Symptoms

Acute HP typically begins hours after antigen exposure, with the abrupt onset of flulike respiratory and constitutional symptoms, including cough, dyspnea, chest tightness, fevers, chills, malaise, and myalgias. Symptoms may be accompanied by physical findings of fever, tachypnea, tachycardia, and inspiratory crackles on lung examination. A peripheral blood leukocytosis with neutrophilia and lymphopenia may be present. Eosinophilia is unusual. If antigen exposure ceases, symptoms of acute HP typically begin to resolve within days. Subacute HP has a more insidious presentation, in which progressive dyspnea on exertion and decreased activity tolerance are common. Cough is variably present. Although there may be low-grade fevers and weight loss, systemic symptoms are not as prominent or as prevalent in subacute HP as in acute HP. On lung examination, inspiratory crackles are common, and squeaks are variably present. Alternatively, the lung examination findings may be entirely normal. Patients with chronic fibrotic HP often present with slowly progressive dyspnea on exertion and a nonproductive cough; they may uncommonly report wheezing, sputum production or chest tightness. Weight loss, if present, is often mild, and patients may report fatigue and decreased stamina. Similar to subacute HP, fever and other systemic symptoms are not as prominent in chronic fibrotic HP as in acute HP. Examination may reveal hypoxemia, at rest or with exertion, and basilar crackles are common. Cyanosis and right-sided heart failure can be seen in severe fibrotic disease. Digital clubbing, when present, is associated with a poorer prognosis.

Lung Function

Complete pulmonary function tests (PFTs), including lung volumes, spirometry, and diffusing capacity for carbon monoxide, should be obtained in all patients with suspected HP who are clinically stable enough for testing. Although PFT results may be normal, most often abnormalities are detected, although none are specific for HP. A reduction in the diffusion capacity is common in all HP phenotypes and may be the most sensitive pulmonary function alteration. Lung function abnormalities in HP are classically restrictive. Alternatively, obstruction or mixed deficits may be observed. The response to bronchodilators is variable, and HP should be considered in the differential diagnosis of nonsmokers presenting with either fixed or reversible obstruction. Obstruction in HP may be more common in those with fibrosis, where periairway fibrosis may contribute to airflow impairment. Nonspecific bronchial hyperreactivity on methacholine challenge can be observed. An exercise-induced decrease in arterial oxygen saturation is an early sign of functional impairment in patients with mild disease. In patients with significant airway or parenchymal involvement, gas exchange abnormalities can be significant with exercise or may be evident at rest. After an initial assessment, serial PFTs should be followed to assess response to therapy and to guide treatment decisions until recovery or stability of lung function is achieved. In acute HP, lung function typically normalizes after recovery from the acute event. In subacute HP, lung function may normalize if permanent damage has not ensued. In chronic fibrotic HP, however, lung function may be permanently and severely impaired.

Imaging

In acute HP, chest imaging typically reveals diffuse ground-glass opacities, although a fine micronodular pattern may also be observed ( Fig. 64-2 ). Ground-glass opacities reflect underlying alveolitis; although they can be seen in any stage of HP, ground-glass opacities are the predominant finding in acute HP. Paralleling the clinical response, radiographic abnormalities in acute HP resolve over days to weeks if further exposure is avoided ( eFig. 64-1 ).

Acute hypersensitivity pneumonitis.

A, Chest radiograph of a patient with HP shows diffuse micronodules. B, High-resolution (1.5-mm thin section) CT (HRCT) image through the lung of the same patient shows profuse centrilobular micronodules. C, HRCT scan of a different patient with bird breeder’s lung shows diffuse ground-glass attenuation with reticular opacities and centrilobular micronodules.

In subacute HP, the imaging manifestations include ground-glass opacities, centrilobular nodules ( eFig. 64-2A and B ), and mosaic attenuation. These findings are best appreciated on computed tomography (CT) imaging (see eFig. 64-2C and D ). Occasionally the centrilobular nodules may be small (≤3 mm) and circumscribed and may be referred to as “micronodules” ( eFig. 64-3 ), although the diagnostic and prognostic significance of this designation is unclear. Similar to acute HP, ground-glass opacities reflect an underlying alveolitis. Accompanying cellular bronchiolitis manifests as centrilobular nodules (see eFigs. 64-2B, C and 64-3C-E ;Video 64-1A ) and “air trapping” (seeVideo 64-1B ). Mosaicism due to air trapping is common in HP, in which hyperlucent areas are the result of hypoxemic vasoconstriction and decreased arterial blood flow in hypoventilated regions ( Fig. 64-3 ). Air trapping is best assessed by comparing inspiratory (seeVideo 64-1A ) and expiratory CT images (seeVideo 64-1B ), where expiratory views accentuate hyperlucent areas. Lung cysts, similar to those described in lymphoid interstitial pneumonia, have been reported in HP (see eFig. 69-8 ). Hilar or mediastinal lymphadenopathy rarely is seen at chest radiography. In contrast, mild mediastinal lymphadenopathy, typically involving only a few nodes, is variably observed on CT imaging in any subtype of HP.

Hypersensitivity pneumonitis.

Bilateral, diffuse ground-glass opacities with mosaic perfusion reflect alveolitis and bronchiolitis, respectively.

In chronic fibrotic HP, although radiographic findings of subacute HP are often also present, fibrotic changes predominate. The chest radiograph often reveals volume loss, architectural distortion, and fibrotic lines ( eFig. 64-4A ). CT findings include volume loss, traction bronchiectasis, fibrotic reticular or linear opacities, and honeycombing ( Fig. 64-4 ; see eFig. 64-4B-D ). Usual interstitial pneumonia and fibrotic NSIP are well-recognized radiographic patterns of chronic fibrotic HP, and CT imaging alone is often unreliable in differentiating chronic fibrotic HP from other fibrotic interstitial lung diseases, with an accurate diagnosis in only 50% of patients in one series. The degree of fibrosis on CT is associated with a poorer prognosis in patients with HP (see Fig. 64-4 ). Notably, in chronic fibrotic FLD, emphysema not related to smoking is a more common radiographic finding than fibrosis.

Chronic fibrotic hypersensitivity pneumonitis.

Areas of ground-glass opacity admixed with a few small areas of fairly normal-appearing lung are associated with extensive reticulation, traction bronchiectasis, and architectural distortion.

Bronchoalveolar Lavage and Other Laboratory Testing

Typically, acute and subacute HP are characterized by a marked increase in BAL white blood cell count and a BAL lymphocytosis (30% to 70%), often with a CD8 ⁺ lymphocyte predominance; this is less true in fibrotic HP. The absolute number of macrophages is similar to that in controls, although their percentage is reduced because of the high percentage of lymphocytes. These typical findings notwithstanding, the BAL cellular profile may vary considerably, depending on the stage of illness and on the time since the last antigen exposure. There appears to be little correlation between BAL findings and other clinical abnormalities, including radiographic changes, pulmonary function, and the presence of precipitating antibodies.

Mild serum elevations in erythrocyte sedimentation rate, C-reactive protein level, and immunoglobulins of IgG, IgM, or IgA isotypes are variable findings. Rheumatoid factor can be elevated. However, antinuclear antibodies and other autoantibodies rarely are detected and, if found, suggest an underlying connective tissue disease.