Practice Essentials
Hypersensitivity pneumonitis (HP) refers to a group of disorders caused by a nonatopic immunologic response to an inhaled agent. In its acute or subacute form, hypersensitivity pneumonitis may be a cause of recurrent pneumonitis. In its chronic form, hypersensitivity pneumonitis may insidiously lead to pulmonary fibrosis and end-stage lung disease.
Severe acute or subacute flares can be life threatening, [1] and recurrent or chronic disease can lead to permanent, severe lung damage. [2] Although rare, fatal cases of chronic hypersensitivity pneumonitis have been reported in children. [3] Hypersensitivity pneumonitides are classically considered occupational illnesses and have colorful names reflecting the associated occupation. New sources of exposure causing hypersensitivity pneumonitis are continuing to be identified.
Some of these illnesses and their associated causes are as follows [4] :
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Farm worker's lung - Thermophilic actinomycetes and other pathogens
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Winemaker's lung -Botrytis cinerea
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Coffee worker's lung - Coffee bean dust
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Lifeguard's lung - Aerosolized endotoxin
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Poultry worker's lung - Avian antigens
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Laboratory worker's lung - Rodent antigens
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Miller's lung - Wheat weevil
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Woodworker's lung -Penicillium chrysogenum
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Detergent worker's lung -Bacillus subtilis
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Epoxy-resin lung - Phthalic anhydride
Pathophysiology
Numerous organic and inorganic antigens can cause hypersensitivity pneumonitis. To cause pneumonitis, the antigen must penetrate into the small airways; therefore, its size must be within the respirable range (< 5 mm). Implicated antigens include avian (bird) antigens, mammalian proteins, fungi and fungal spores, bacterial antigens, and small-molecular-weight chemicals. [11] (See Etiology.)
Immune responses
Although much research has been done, how immune dysregulation causes the disease is still unclear. An exuberant production of antibody (especially immunoglobulin G [IgG]) against the offending antigen is frequently identified. However, many patients with precipitating antibodies against antigens associated with hypersensitivity pneumonitis have no disease, suggesting that the precipitating antibodies by themselves are not the cause of the disease. [12, 13]
Although bronchoalveolar lavage (BAL) fluid (BALF) from adults with hypersensitivity pneumonitis reveals a decreased CD4/CD8 ratio of T lymphocytes and increased natural killer cells, this finding has not been consistently demonstrated in pediatric studies. Healthy children tend to naturally have a CD8 predominance, and this does not appear to be significantly altered in children with hypersensitivity pneumonitis. However, in all ages, lymphocytosis appears to be present. [13, 14, 15]
An important role for Th1 immune response is suggested by the production and release of tumor necrosis factor (TNF), interferon-gamma, interleukin (IL)-12 and IL-18 by patients with hypersensitivity pneumonitis and animal models of hypersensitivity pneumonitis. [16, 17, 18] The inflammatory responses observed in chronic hypersensitivity pneumonitis differ from those of acute and subacute hypersensitivity pneumonitis. Patients with chronic hypersensitivity pneumonitis did not have as prominent a bronchoalveolar lavage lymphocytosis and had an increase of the CD4+:CD8+ ratio compared with those with subacute disease.
Cytokine profiles resembled more the Th2-like phenotype with BAL fluid demonstrating increased CXCR4 expression and decreased CXCR3 expression. Supernatants from antigen-specific–stimulated cells from chronic hypersensitivity pneumonitis produced higher levels of IL-4 and lower levels of IFN-gamma compared with subacute HP. [19]
IL-8 (a chemoattractant of neutrophils) is released by a cell line with properties of alveolar lung cells when stimulated by thermophilic bacteria. [20] High levels of IL-8 are released by alveolar macrophages in patients with acute hypersensitivity pneumonitis. [21] This corresponds to the BAL fluid neutrophilia observed immediately upon antigen challenge in acute hypersensitivity pneumonitis. [22]
A role for interferon-gamma is suggested by the observation that interferon-gamma knockout mice lack granulomatous inflammation in response to stimulation by thermophilic bacteria, whereas granulomatous inflammation develops in both knockout mice given interferon-gamma replacement and wild-type mice. [23]
Hypersensitivity pneumonitis seems to be least common among active smokers of tobacco products. This relative infrequency might result from suppression of alveolar macrophage function. [24, 25, 26] However, a review of an outbreak of hypersensitivity pneumonitis among metalworkers suggested that low disease rates among tobacco smokers may reflect a high proportion of false-negative results instead of a truly low rate of disease. [27] Another study suggested that hypersensitivity pneumonitis may be insidious and is most often associated with low survival rates when it occurs in smokers. [28]
Genetics
Familial clustering of cases suggests a genetic predisposition, but a clear genetic locus has not yet been identified. Likewise, associations with different human leukocyte antigen (HLA) phenotypes have been suggested, but no clear or consistent pattern has emerged. [29, 30, 31] A study of BALF from children with hypersensitivity pneumonitis compared with healthy patients without lung disease showed an increase in lymphocytes expressing HLA-DR phenotype. [15]
Viral infections
Animal models have suggested that viral infections may play a role in triggering or augmenting hypersensitivity pneumonitis flares in genetically susceptible subjects. [32] Examination of BALF from persons with farmer’s lung showed respiratory viruses during acute exacerbations of farmer’s lung. [23]
Etiology
Types and causes of hypersensitivity pneumonitis in children
A wide spectrum of respirable antigens can trigger hypersensitivity pneumonitis, including avian antigens, rodent antigens, fungi, bacteria, and low molecular weight chemicals. Fungal spores can be present wherever sufficient humidity is present; for example, in piles of moldy hay (farmer's lung), in mold-contaminated ventilation systems (humidifier lung), or in old homes seasonally contaminated by mold (summer-type pneumonitis). [11, 33] Mycobacterial antigens aerosolized by the mist that surrounds an operating hot tub can cause hypersensitivity pneumonitis, colorfully described as hot-tub lung.
Table 1. Commonly Described Causes of Hypersensitivity Pneumonitis [34] (Open Table in a new window)
Exposure |
Disease |
Source of Antigen |
Avian |
Bird fancier's lung, pigeon breeder's lung, poultry worker's lung, feather duvet lung |
Feathers, droppings, serum proteins, intestinal mucins, avian immunoglobulin A |
Agriculture |
Farmer's lung, Bagasse (sugar cane) lung, mushroom worker's lung, potato riddler's lung, paprika slicer's lung, wine maker's lung |
Thermophilic actinomycetes, Aspergillus species, and other fungi in moldy hay or grains; moldy sugar cane; mushroom spores and thermophilic actinomycetes; moldy hay around potatoes, thermophilic actinomycetes, and others; Mucor stolonifer (on moldy paprika pods); B cinerea (noble rot on grapes) |
Water-based systems |
Humidifier lung, hot-tub lung, sauna taker's lung, lifeguard's lung, sewage pneumonitis, wind instrument lung |
Aerosolized molds, endotoxins, mycobacteria, thermophilic actinomycetes, Penicillium species, others |
Home environment |
Summer-type pneumonitis, mold-contaminated walls, humidifiers, wallpaper |
Trichosporon species, mold contamination in older and/or water-damaged homes
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Chemicals |
Chemical worker's lung, epoxy-resin lung, pyrethrum pneumonitis |
Exposure to chemicals in manufacturing, laboratories, spray paints, heated epoxy resins, insecticides |
The most common type of hypersensitivity pneumonitis in children is bird fancier's lung. Most often, the bird is a household pet, but, in many cases, the contact may be less obvious. Hypersensitivity pneumonitis has been reported after bird exposure from parental hobbies or occupations, including parental pigeon breeding, [35] pheasant raising, [36] and working on a turkey farm. [37]
Relevant exposures may be from nearby bird activity, with reported cases of hypersensitivity pneumonitis resulting from birds congregating by a backyard pool, [35] goose droppings tracked inside from a contaminated outdoor environment, [38] wild city pigeons nesting just outside the home, [39] birds nesting near the air intake of an air-conditioning system, [40] and neighbors engaged in bird breeding. [41] Live birds are not necessary to cause bird fancier's lung. Exposure to avian antigens from a feather duvet (feather duvet lung) has been linked to hypersensitivity pneumonitis. [42, 43, 10]
Exposure to mold–contaminated moist organic material is a frequent cause of hypersensitivity pneumonitis. Farmer's lung has been reported among children living on farms, especially in children exposed to moist or moldy hay or grains. [44, 45] Summer-type pneumonitis is classically described in the mid and southern parts of Japan, although not exclusively, with onset during summer, resolution by mid autumn, and recurrence the following summer. It is caused by fungal growth (Trichosporon cutaneum) in older wooden homes stimulated by warm, moist summers. [33, 46, 47]
Sources of mold in the child's environment may not be obvious. A compost heap in a play area caused hypersensitivity pneumonitis in one child. [48] Hypersensitivity pneumonitis was diagnosed in a child exposed to moldy hay at a horseback-riding school. [49] A familial cluster of chronic hypersensitivity pneumonitis was caused by mold that collected behind torn wallpaper and beneath worn carpets. [50] Mold that contaminated a basement shower was identified as the cause of hypersensitivity pneumonitis in several children. [51]
Wherever aerosolized water is present, hypersensitivity pneumonitis can occur. Mold contamination of humidifiers has led to the disease in adults and children. [52, 53] A central humidification system that nebulized water into the heating system caused a cluster of hypersensitivity pneumonitis cases in a family. [52] Aerosolized endotoxin generated from a water spray in an indoor swimming pool has been implicated in lifeguard's lung. [54] Hot-tub lung is believed to be a hypersensitivity reaction to contamination of hot-tub water by Mycobacterium avium intracellulare complex or mold in a hot tub. [55, 56]
One case report described antibody-confirmed chronic hypersensitivity pneumonitis to Aureobasidium pullulans, a fungus associated with indoor hydroponics, in a 14 year-old girl. Her lung function normalized after removal of the hydroponics from the home. [57] . Wind instruments, with bacterial and fungal colonization within the instrument, have been implicated as a cause of hypersensitivity pneumonitis. [6, 7]
Low molecular weight chemicals, such as isocyanates (eg, in spray paint and glue), phthalic anhydride (in epoxy resin), and pyrethrum (an insecticide), are thought to cause hypersensitivity pneumonitis by combining with human proteins to form complete antigens. [58]
Epidemiology
United States statistics
The frequency in children is unknown.
International statistics
Acute hypersensitivity pneumonitis in children is more common in areas where pigeon racing and pigeon breeding are popular. Chronic disease is more common in areas where caged birds are typical house pets.
Summer-type hypersensitivity pneumonitis has been classically described in the southern and western parts of Japan and is associated with older housing and shady, damp, poorly ventilated rooms. Exacerbations in the summer are followed by remissions in the fall and winter. [59, 60] The causative agent has been identified as Trichosporon cutaneum. The fungus grows on warm, decaying organic matter. [61, 62] Although more common in adults, summer-type hypersensitivity pneumonitis has been reported in children. [63, 64, 65]
Prognosis
Overall, the prognosis is good if the antigen is identified and the antigenic exposure is eliminated. In acute hypersensitivity pneumonitis, removal from exposure generally results in improvement within 12 hours to several days. Complete resolution of clinical and radiographic findings may take several weeks. [66] Longer periods are needed for resolution of subacute disease.
Digital clubbing, pulmonary fibrosis, and prolonged (>2 y) exposure all suggest permanent lung damage and a risk for disease progression. Reports have described this progression among adults with chronic hypersensitivity pneumonitis despite a reduction or elimination of their antigenic exposures.
To understand the predictors of mortality in fibrotic hypersensitivity pneumonitis (fHP), a study investigated the impact of short-term lung function changes in fHP on mortality. [67] The researchers noted that baseline lung function severity, age, presence of honeycombing on chest CT, and echocardiographic pulmonary arterial systolic pressure >40 mm Hg were associated with early mortality, whereas BAL lymphocytosis was associated with improved survival. A decline in forced vital capacity (FVC) >5% and diffusion capacity of the lung for carbon monoxide (DLCO) > 15% at 1 year was associated with markedly reduced survival.
Morbidity/mortality
In contrast to the disease in adults, mortality due to hypersensitivity pneumonitis in childhood is uncommon. Fatal cases in childhood, however, have been reported. [3] Significant morbidity can result if the child is not removed from the causative environment because flares of acute hypersensitivity pneumonitis can be severe and life-threatening.
Progression of chronic disease can lead to pulmonary fibrosis and end-stage lung disease. Severe pulmonary fibrosis with honeycombing and spontaneous pneumothorax as a consequence of chronic hypersensitivity pneumonitis has been described in an adolescent. [2] Such clinical picture is associated with high mortality rates. [68]
Complications
Complications may include the following:
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Spontaneous pneumothorax
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Pulmonary fibrosis
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Emphysema
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Respiratory insufficiency or failure
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Cor pulmonale
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Death
Patient Education
Educate the patient and his or her family about the importance of eliminating exposure to the offending antigen.
Resources for patients and their families include the following from WebMD:
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Photomicrograph of a lung biopsy specimen reveals marked interstitial inflammation with lymphocytic predominance and a multinucleated giant cell (hematoxylin-eosin stain, original magnification 40X). Reprinted with permission from Farber and Budson, 2000.
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Photomicrograph of a lung biopsy sample reveals interstitial fibrosis with active interstitial inflammation (hematoxylin-eosin stain, original magnification 10X). Reprinted with permission from Farber and Budson, 2000.
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Photograph reveals precipitin lines produced by means of Ouchterlony immunodiffusion assay. Central wells contain the patient's serum. Peripheral wells contain serum or droppings from various birds. Reprinted with permission from Farber and Budson, 2000.
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14-year-old girl with subacute hypersensitivity pneumonitis from avian antigen exposure. Chest radiograph demonstrates numerous tiny pulmonary nodules bilaterally.
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Chest CT from same patient as previous image reveals widespread poorly-defined centrilobular ground-glass nodules related to bronchiolocentric cellular interstitial pneumonia with poorly-formed granulomas.
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A 10-year-old girl with chronic hypersensitivity pneumonitis from avian antigen exposure. Chest CT image shows reticular pulmonary opacities and architectural distortion at the lung bases indicative of pulmonary fibrosis.
Tables
Exposure |
Disease |
Source of Antigen |
Avian |
Bird fancier's lung, pigeon breeder's lung, poultry worker's lung, feather duvet lung |
Feathers, droppings, serum proteins, intestinal mucins, avian immunoglobulin A |
Agriculture |
Farmer's lung, Bagasse (sugar cane) lung, mushroom worker's lung, potato riddler's lung, paprika slicer's lung, wine maker's lung |
Thermophilic actinomycetes, Aspergillus species, and other fungi in moldy hay or grains; moldy sugar cane; mushroom spores and thermophilic actinomycetes; moldy hay around potatoes, thermophilic actinomycetes, and others; Mucor stolonifer (on moldy paprika pods); B cinerea (noble rot on grapes) |
Water-based systems |
Humidifier lung, hot-tub lung, sauna taker's lung, lifeguard's lung, sewage pneumonitis, wind instrument lung |
Aerosolized molds, endotoxins, mycobacteria, thermophilic actinomycetes, Penicillium species, others |
Home environment |
Summer-type pneumonitis, mold-contaminated walls, humidifiers, wallpaper |
Trichosporon species, mold contamination in older and/or water-damaged homes
|
Chemicals |
Chemical worker's lung, epoxy-resin lung, pyrethrum pneumonitis |
Exposure to chemicals in manufacturing, laboratories, spray paints, heated epoxy resins, insecticides |
