Version May 2024
INTRODUCTION — Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, is a complex syndrome of varying intensity, clinical presentation, and natural history rather than a single, uniform disease [1-3]. It represents an immunologic reaction to an inhaled agent, particularly an organic antigen, occurring within the pulmonary parenchyma. Numerous inciting agents have been described, including, but not limited to, agricultural dusts, bioaerosols, and certain reactive chemical species.
The epidemiology, pathogenesis, and etiologic agents of HP will be reviewed here. The major sources of these agents are discussed in the text, while the individual causes are listed in the tables. The clinical features, diagnosis, management, and prognosis of HP are discussed separately.
●(See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention".)
EPIDEMIOLOGY — The overall prevalence and incidence of HP are thought to be low, but estimates vary considerably depending upon case definitions, intensity of exposure to inciting antigens, season, geographical conditions, local practices and customs, proximity to certain industries, and host risk factors [2-6]. Much of the epidemiologic information regarding HP has been derived from studies of farmers and bird fanciers. Mild or subclinical HP can escape detection or be misdiagnosed as a viral illnesses or asthma, either of which may have nonspecific clinical findings that mimic HP.
In an analysis of a large healthcare database (150 million unique enrollees), a search algorithm was used to estimate prevalence and incidence of HP [5]. Between 2004 and 2013, 7498 cases of HP were identified. The one-year prevalence rate ranged from 1.67 to 2.71 per 100,000 persons and increased with age up to 11.2 per 100,000 among those age 65 years and older. Approximately half of the HP cases (3902) were classified as chronic hypersensitivity pneumonitis with half of those (1852) being classified as fibrotic HP. Prevalence varied by geographic location.
Farmer’s lung — Farmer's lung is one of the most common forms of HP, affecting 0.4 to 7 percent of the farming population [7-11]. Prevalence (the number of cases in the population at risk at a given time) varies by region, climate, and farming practices from approximately 9 percent of farmers at risk in humid zones to <2 percent in drier zones [9,12].
The incidence of farmer’s lung (number of new cases in the population at risk in a given year) varies considerably and is influenced by similar factors. In Finland, for example, significant variation in incidence according to season has been noted: most cases of farmer's lung occur in April near the end of the indoor feeding season for cattle, while the incidence is lowest in October, when outdoor feeding is the norm. The incidence of farmer's lung also correlates positively with the average daily rainfall during the preceding haymaking period.
Bird fanciers disease — The reported prevalence of HP among bird fanciers is even more variable than farmer’s lung; estimates range from 20 to 20,000 affected individuals per 100,000 persons at risk [13,14]. The prevalence of HP is likely to be higher among bird fanciers than among farmers because contact with the inciting avian antigens is less limited by season or geographic location. The species of birds raised and the handling practices employed may affect prevalence, but data regarding such variables are sparse.
Despite some variation among study populations, the incidence rate of HP among pigeon breeders clearly is higher than that among farmers (see 'Farmer’s lung' above). Whereas the incidence rate of HP among farmers is between 8 and 540 per 100,000 per year, pigeon breeders have rates of 6000 to 21,000 per 100,000 per year (ie, 6 to 21 percent per year) [8,15-18].
The reason that only a small proportion of exposed individuals develop clinically significant HP is not known, although genetic factors have been postulated to play a major role in determining an individual's risk of disease. It is likely that the immunologic abnormalities underlying HP reflect the interplay of multiple genes involved in the immune response. (See 'Pathogenesis' below.)
Sporadic outbreaks of HP — High attack rates have been documented during sporadic outbreaks of HP in a variety of settings:
●52 percent of exposed office workers with humidifier lung [19]
●37 percent of lifeguards exposed to a public swimming pool [20]
●27 percent of workers at an injection molding plant manufacturing polyurethane foam parts for automobiles [21]
●15 percent of office workers exposed to a contaminated forced air system [22]
Summer type HP accounts for 74 percent of cases of HP in Japan and is caused by Trichosporon cutaneum and other Trichosporon species [23,24]. The number of cases tends to increase in summers with high temperature and humidity, but overall have been on the decline since 1980 [23]. Over the same period, the proportion of houses made of wood has declined. Symptom onset is typically described in August, but hospitalization increases in September and October. Females aged 50 to 59 years are the most commonly affected group.
Effect of cigarette smoking — Cigarette smoking is associated with a decreased risk of HP [6,25]. As examples, smoking appears to diminish the risk of developing farmer's lung, pigeon breeder's disease, HP associated with contaminated air conditioners, and Japanese summer-type HP caused by Trichosporon cutaneum [26,27]. Once the disease is established, however, smoking does not appear to attenuate its severity, and may predispose to a more chronic and severe course [28].
These observations may reflect diminished antibody responses to inhaled antigens among smokers despite similar degrees of exposure [27,29,30]. In a survey of 102 pigeon breeders, for example, an IgG antibody response to inhaled pigeon antigens was much less common among smokers (4 versus 55 percent in nonsmokers). This effect of smoking appeared to be reversible, since former smokers had a response similar to that of nonsmokers [27].
ETIOLOGIC AGENTS — A wide range of occupations and avocations result in contact with airborne organic antigens and increase the risk of developing HP. Over 300 etiologies of HP have been reported. Some of these entities are derived from reports of a single or small number of cases and require further study. The following sections describe reported etiologies of HP by occupation and the major causative antigens [3,8,31-52]. A few organic chemical compounds (eg, isocyanates, mellitic anhydrides) are associated with HP [53]. A standardized exposure questionnaire has been proposed as a tool to increase the diagnostic confidence of HP and reduce the proportion of antigen-indeterminate HP cases [54].
Farming, vegetable, or dairy cattle workers — Farmer's lung is, as noted above, one of the most common forms of HP (see 'Epidemiology' above). There are several types of exposure and many different antigens that must be considered in farmers and cattle workers (table 1) [35,36,55,56]. The main source of antigens is proliferation of thermophilic actinomycetes (eg, Saccharopolyspora rectivirgula) in hay or dust in areas of high humidity and temperatures between 40 to 60˚C [55]. Round bales of hay with greater compaction tend to have higher humidity leading to increased microbial growth. Improved ventilation and protective respiratory equipment can reduce exposure to these microbial antigens.
HP in farmers must be distinguished from febrile, toxic reactions to inhaled mold dusts (organic dust toxic syndrome [ODTS]). ODTS is a nonimmunologic reaction that occurs 30 to 50 times more commonly than HP in farmers. HP is associated with high exposure on most days for prolonged periods, while ODTS is associated with intense exposure occurring on a single day. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Other processes caused by inhalation of organic agents'.)
Ventilation and water-related contamination — HP can be caused by exposure to antigens of microorganisms that colonize forced air systems, heated water reservoirs, portable ultrasonic humidifiers, cool-mist vaporizers, wooden water buckets, swimming pools, whirlpools, hot tubs, spas, water flume slides, water-damaged carpeting, shower curtains, musical instruments, or metal working aerosols (table 2) [20,37-39,57-60].
In many of these humid environments, the HP can be caused by fungi, in particular Penicillium spp and Aspergillus spp [61,62].
Mycobacterium avium complex (MAC) is a pathogenic organism in patients with underlying lung disease or compromised immunity; in addition, MAC may cause HP in immunocompetent hosts [58,63-68]. Affected individuals often have a history of exposure to hot tubs or hot water aerosols, and the resulting HP has been referred to as "hot tub lung." This condition results in granulomatous inflammation, and avoidance of ongoing exposure is the cornerstone of therapy [63,69]. In contrast, true MAC infection may require long-term antibiotic therapy. (See "Overview of nontuberculous mycobacterial infections" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)
Bird and poultry handling — HP can be induced by exposure to excreta and proteinaceous material on dried, finely dispersed dust from pigeons, budgerigars and other parakeets, canaries, chickens, turkeys, and other birds and fowl (table 3) [70-73]. In addition to poultry workers and feather pickers, individuals can develop HP from aerosol spread of droppings by the vent of a clothes dryer, contamination of heating vents from a garage where birds are housed, and exposure to feather pillows, wreaths, and down comforters [70,74].
Veterinary work and animal handling — Animal handling and other occupations that involve significant contact with animals and their associated organic antigens can result in a variety of HP syndromes, such as laboratory worker’s lung due to exposure to urine, serum, and pelts of rats and gerbils and furrier’s lung due to exposure to animal pelts in the process of sewing furs (table 4).
Grain and flour processing and loading — During the course of processing, grain can become colonized with a variety of microorganisms and insect pathogens, such as Sporobolomyces, Aspergillus fumigatus, Aspergillus clavatus, and Sitophilus granarius (weevil). The grain and associated micro-organisms are easily aerosolized, and significant exposure to inhaled organic antigens may ensue, leading to HP (table 5) [40,75,76].
Lumber milling, construction, wood stripping, paper and wallboard manufacture — Trees, plants, and their products can become colonized with mold. Occupations that place an individual in contact with colonized plant products can lead to several varieties of HP (table 6) [41-43,77,78].
Plastic manufacture, painting, electronics industry, other chemicals — Some inciting agents capable of causing HP may be synthetic in origin. Occupational exposure to aerosolized or gas phase organic chemicals may result in HP (table 7) [44-50,53,79]. These workers are also at increased risk for the development of occupational asthma or rhinitis. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors" and "Occupational rhinitis".)
Textile workers — The pulmonary manifestations in exposures such as cotton mill dust, upholstery fabric, and nylon velvet are probably not true forms of HP, but they are included for completeness (table 8). These exposures lead to lung injury characterized pathologically by diffuse alveolar damage, desquamative interstitial pneumonitis, or other forms of pulmonary pathology [52]. A specific form of textile-related lung disease has been identified in workers exposed to rotary-cut nylon flock, and is discussed elsewhere. (See "Flock worker's lung".)
PATHOGENESIS
Immunopathogenesis — The immunopathogenesis of HP is complex and varies with the affected individual, provocative antigen, frequency and intensity of exposure, and duration of disease [80]. It remains unclear why only few of the individuals exposed to the antigen develop the disease, consequently, a two-hit hypothesis has been suggested, wherein antigen exposure acts as the inducing factor, and genetic or environmental factors act as promoting risk factors.
In acute HP, individuals exposed to a culprit antigen elaborate specific IgG antibodies to that antigen, and with subsequent exposures develop episodic lung inflammation with immune complex formation and an influx of neutrophils [80-82].
Subacute and chronic HP are thought to result from CD4+ T helper (Th)-1 lymphocyte-mediated delayed hypersensitivity causing granuloma formation [80], likely with contributions from toll-like receptor (TLR)- 2 and 9 pathways [83]. Th 1 and Th 17 lymphocytes appear to promote lung inflammation, while T regulatory cells downregulate inflammation [84,85].
It is not known why certain individuals develop progressive lung fibrosis due to HP. An increase in CD4+ T lymphocytes relative to CD8+ T cells and increased Th 17 cells may contribute [81,86].
Genetic predisposition — A genetic predisposition to HP has been suggested based on several lines of evidence [24,80,87,88]. Among exposed individuals (eg, farmers, pigeon breeders), only a minority develop HP, suggesting varying susceptibility [80]. As an example, a study of 44 patients with HP related to pigeon exposure, 50 exposed but asymptomatic individuals, and 99 healthy, unexposed controls found significant associations between HP and the presence of a number of specific MHC class II alleles [89].
A separate report describes family members with hypersensitivity due to avian antigens, but associated with different exposures, such as a feather sleeping bag or having a bird as a pet [88]. Cohorts of familial HP have been described, predominantly in Japanese summer-type HP, although the familial clustering could be related to common exposures as family members spend the summer in wooden dwellings with high ambient humidity [24,87].
An association between MUC5B rs35705950 minor alleles and the risk of chronic hypersensitivity pneumonitis has been identified [90]. Moreover, a substantial portion of patients with chronic HP have rare, protein-altering variants in telomere-related genes, which are associated with short telomere length and reduced transplant-free survival [91].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)
SUMMARY AND RECOMMENDATIONS
●Definition – Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, represents an immunologic reaction occurring within the pulmonary parenchyma caused by hypersensitivity to an inhaled agent, such as microbial, avian, and animal antigens and, less commonly, organic compounds. (See 'Introduction' above.)
●Prevalence and incidence – The prevalence and incidence of HP appear to vary considerably depending upon case definitions, intensity of exposure to inciting antigens, season, geographical conditions, local practices and customs, proximity to certain industries, and host risk factors. (See 'Epidemiology' above.)
●Etiologic agents and at-risk populations – A wide range of occupations and avocations result in inhalation of airborne organic antigens that increase the risk of developing HP; over 300 etiologies of HP have been reported. Occupations and activities associated with HP and their associated antigens are listed in the tables:
•Farming, vegetable and dairy cattle workers (table 1). (See 'Farming, vegetable, or dairy cattle workers' above.)
•Exposure to ventilation systems and water reservoirs (table 2). (See 'Ventilation and water-related contamination' above.)
•Bird and poultry handlers (table 3). (See 'Bird and poultry handling' above.)
•Animal handlers (table 4). (See 'Veterinary work and animal handling' above.)
•Grain and flour processing (table 5). (See 'Grain and flour processing and loading' above.)
•Lumber milling, construction, bark stripping (table 6). (See 'Lumber milling, construction, wood stripping, paper and wallboard manufacture' above.)
•Plastics, paint/epoxy, electronics industries (table 7). (See 'Plastic manufacture, painting, electronics industry, other chemicals' above.)
•Textile workers (table 8). The pulmonary manifestations of textile exposures such as byssinosis and flock workers’ lung are probably not true forms of HP. (See 'Textile workers' above and "Flock worker's lung".)
●Pathogenesis – The immunopathogenesis of HP is complex and varies with the affected individual, provocative antigen, frequency and intensity of exposure, and duration of disease. Acute HP is predominantly mediated by antigen-antibody complex formation, while subacute and chronic HP result from an interplay of T helper (Th 1), T17, and T regulatory lymphocytes leading to lymphocyte infiltration and granuloma formation (delayed hypersensitivity) and, in some patients, progressive fibrotic lung disease. (See 'Pathogenesis' above.)
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