Pediatric Hypersensitivity Pneumonitis

Updated: Jan 28, 2022

Author: Naga Jaya Smitha Yenduri, MD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP

Overview

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] :

Farm worker's lung - Thermophilic actinomycetes and other pathogens
Winemaker's lung -Botrytis cinerea
Coffee worker's lung - Coffee bean dust
Lifeguard's lung - Aerosolized endotoxin
Poultry worker's lung - Avian antigens
Laboratory worker's lung - Rodent antigens
Miller's lung - Wheat weevil
Woodworker's lung -Penicillium chrysogenum
Detergent worker's lung -Bacillus subtilis
Epoxy-resin lung - Phthalic anhydride
Wind instrument lung – Bacteria and/or mold contamination of wind instruments[5, 6, 7]
Feather duvet lung - Organic dust due to goose or duck feathers in duvets or pillows[8, 9, 10]

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
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:

Spontaneous pneumothorax
Pulmonary fibrosis
Emphysema
Respiratory insufficiency or failure
Cor pulmonale
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:

Presentation

History

A comprehensive environmental history and high index of suspicion are critical for diagnosis. Hypersensitivity pneumonitis (HP) should be considered in patients with chronic or recurrent cough, shortness of breath, or a history of recurrent acute respiratory symptoms without definite infectious triggers.

Inquire about specific exposures; the patient may not volunteer them. Because bird fancier’s lung is the most common hypersensitivity pneumonitis in children, be sure to ask about bird exposure. Contact may not necessarily be in the home and may not be obvious. Exposures may be in or near the home, at school, at play locations, as a part of hobbies, at the place of employment, or anywhere else the child spends time. Repeated questioning, home inspection, and/or inspection of sites where the child spends time may be needed to identify the causative antigen.

As new exposures leading to hypersensitivity pneumonitis continue to be identified, exposure to any area likely to contain high concentrations of respirable organic antigens, particularly fungal or avian antigens, should lead one to include hypersensitivity pneumonitis in the differential diagnosis.

Clues that suggest the diagnosis of hypersensitivity pneumonitis are as follows:

History of recurrent pneumonia, particularly with regularity or a pattern
Other people at home or school who have similar symptoms
Development of respiratory symptoms after the patient moves to a new home or new school
Improvement of symptoms when the patient is away from home or school for an extended period
Contact with birds
Water damage to the patient's home or school facility
Use of a hot tub, sauna, or swimming pool

The key to diagnosing hypersensitivity pneumonitis lies in a detailed history. The clinician has to maintain a high index of suspicion. Reaching the diagnosis can be difficult because symptoms are often nonspecific and the available diagnostic tests are imperfect. Taking appropriate, effective action to eliminate the inciting exposure can prevent substantial pulmonary morbidity and mortality.

A multicenter study was designed to derive and validate a clinical prediction rule in adult patients who presented with a pulmonary condition for which hypersensitivity pneumonitis was in the differential diagnosis. The study noted 6 significant predictors of a final diagnosis of hypersensitivity pneumonitis, as follows[69] :

Exposure to a known offending antigen
Positive precipitating antibodies to the offending antigen
Recurrent episodes of symptoms
Inspiratory crackles upon physical examination
Symptoms occurring 4-8 hours after exposure
Weight loss

Although the associated probabilities of hypersensitivity pneumonitis from these predictors cannot be generalized to children who have a different spectrum of illnesses, they are useful questions to incorporate into the history.

Manifestations of hypersensitivity pneumonitis are classified as acute, subacute, or chronic. These classifications should be considered as points along a spectrum of illness rather than clearly delineated, discrete types of illness.[70] This classification is based on clinical presentation, not histopathology. In patients with acute disease, a temporal relation between the respiratory symptoms and antigenic exposure can usually be identified. In cases of subacute or chronic exposure, the association between antigenic exposure and development of disease may not be obvious.

Physical Examination

Acute hypersensitivity pneumonitis is characterized by the abrupt onset (4-6 h after exposure) of fever, chills, malaise, nausea, dry cough, chest tightness, and dyspnea. Physical examination may reveal tachypnea and fine crackles localized to the lung bases; wheezing is unusual. The presentation is easily confused with that of an infectious pneumonia. Removal from exposure usually results in resolution of symptoms within hours to days.

Subacute hypersensitivity pneumonitis is characterized by the gradual development of productive cough, dyspnea, fatigue, anorexia, weight loss, and low-grade fever. Physical examination and chest auscultation may reveal tachypnea and diffuse crackles. In patients with very severe disease, cyanosis may be present.[1] Resolution of disease may take weeks to months after removal from exposure.

Chronic hypersensitivity pneumonitis may be difficult to diagnose in its early stages. A chronic cough with normal physical examination findings may be the first presentation. Over time, the disease may progress to dyspnea, fatigue, weight loss, and exercise intolerance. Auscultation of the chest may reveal crackles. An “inspiratory squawk” or “chirping rales” have been described.[71, 72] Digital clubbing may be seen in the advanced stages of the disease.

DDx

Diagnostic Considerations

Other conditions to consider in the differential diagnosis include the following:

Acute hypersensitivity pneumonitis (HP) closely resembles viral or bacterial infections of the lower respiratory tract.
Bird exposure can place the patient at risk for psittacosis.
Granulomatous lung diseases (eg, tuberculosis, histoplasmosis, coccidiomycosis, sarcoidosis) can also produce findings similar to those of subacute hypersensitivity pneumonitis.[11]
Lymphoid interstitial pneumonitis observed in patients with acquired immunodeficiency syndrome (AIDS) can manifest as dyspnea, crackles, interstitial infiltrates, and hypergammaglobulinemia.
For patients residing or working in a farm setting, organic toxic dust syndrome can be provoked by bacterial endotoxins or fungal toxins.[73]
Zamboni disease (a toxic reaction to nitrogen oxides emitted from an ice-smoothing machine operated in an indoor ice rink) can mimic acute or subacute hypersensitivity pneumonitis.[74]
Differentiating chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis is particularly important because the prognosis for the former improves when the offending antigen is identified and eliminated.
Subacute and chronic hypersensitivity pneumonitis has been misdiagnosed as asthma, a condition that can also cause cough, dyspnea, and exercise intolerance.[2]
Chronic hypersensitivity pneumonitis may be misdiagnosed as anorexia nervosa. Anorexia, weight loss, and exercise intolerance are manifestations of both diseases.
Connective-tissue disease (eg, systemic lupus erythematosus) can cause noninfectious pneumonitis with fever and weight loss, but other clinical and laboratory features of the connective tissue disease are expected.
Drug-induced pneumonitis is considered separately from pneumonitis triggered by inhaled antigens. Medications most often implicated in drug-induced pneumonitis include gold salts, methotrexate, and amiodarone. Rare causes of drug-induced pneumonitis are the nonsteroidal anti-inflammatory drugs aspirin and ibuprofen; the anticonvulsants carbamazepine and phenytoin; the antibiotics nitrofurantoin and dapsone; the sulfonamides sulfasalazine and sulfadoxine; the antimalarial chloroquine; the immunosuppressants penicillamine and cyclophosphamide; and the cytotoxic agents azathioprine, bleomycin, chlorambucil, cyclophosphamide, mitomycin, and vinblastine.

Differential Diagnoses

Workup

Approach Considerations

The most recent American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) guidelines on hypersensitivity pneumonitis published in August 2020 includes a proposed diagnostic algorithm by expert consensus that is helpful to make a provisional diagnosis in clinical practice.[75]

Laboratory Studies

Precipitating antibodies to the offending antigen are commonly present in hypersensitivity pneumonitis (HP); however it is not a specific finding as exposed persons without disease may have precipitating antibodies to the antigen.[76, 77] Reports have attributed missed diagnoses to false-negative results of precipitin studies, although repeat testing showed true-positive findings of precipitin in many cases.[78] The offending antigen may not be present on commonly used commercial hypersensitivity pneumonitis panels; sometimes a home inspection may be needed with immunodiffusion testing for the specific antigens found in the home.{ref98) See the image below.

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.

The erythrocyte sedimentation rate and C-reactive protein levels may be elevated, a rheumatoid factor may be present, and circulating immune complexes may be observed. However, these findings are not considered sufficiently specific to be useful for diagnosis.[70]

Hypergammaglobulinemia is a common finding but is neither sensitive nor specific.

Imaging Studies

Radiography

Chest radiography is a useful first step because it is widely available, inexpensive, and can be used to screen for other cardiopulmonary disorders. However, chest radiography cannot be used to exclude hypersensitivity pneumonitis because normal chest radiography findings can be observed in subjects who meet other diagnostic criteria for hypersensitivity pneumonitis.

CT scanning

Chest CT scanning is more sensitive than chest radiography, and about 40% of cases of hypersensitivity pneumonitis with normal chest radiography findings show pulmonary abnormalities on chest CT scanning. The imaging findings depend on the phase of the disease, and findings of more than one phase may be observed if exposure to the causative antigen is ongoing.[79, 80]

Acute hypersensitivity pneumonitis

Nodular, ground glass, or consolidative airspace opacities resembling edema or infectious pneumonia can be seen on chest radiography or chest CT scanning in the acute setting, especially after heavy exposure to causative antigens. These opacities can be fleeting.

Subacute hypersensitivity pneumonitis

Imaging findings are similar to those observed in acute disease, with the additional chest CT scan findings of widespread, poorly-defined centrilobular ground-glass nodules corresponding to bronchiolocentric cellular interstitial pneumonia with poorly-formed granulomas on lung biopsy, and hyperlucent foci accentuated on expiratory images, corresponding to sites of air trapping. See the images below.

14-year-old girl with subacute hypersensitivity pneumonitis from avian antigen exposure. Chest radiograph demonstrates numerous tiny pulmonary nodules bilaterally.

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.

Chronic hypersensitivity pneumonitis

Chest CT scanning may reveal ground-glass pulmonary opacities without or with findings of pulmonary fibrosis, such as reticular pulmonary opacities, architectural distortion, traction bronchiectasis, honeycombing, or volume loss. See the image below.

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.

Imaging results

The imaging findings of acute and subacute hypersensitivity pneumonitis may take several weeks to resolve with treatment. The chest CT findings of pulmonary fibrosis persist despite elimination of exposure to the causative antigen and provide important prognostic information.[81]

Pulmonary hypertension has been reported in older adults with advanced chronic hypersensitivity pneumonitis complicated by moderate to severe pulmonary restriction and hypoxemia on room air.[82] Given this finding, screening children with severe chronic hypersensitivity pneumonitis for pulmonary hypertension using Doppler echocardiography is reasonable.

Other Tests

Pulmonary function studies

Acute hypersensitivity pneumonitis

Pulmonary function may be normal between acute episodes of hypersensitivity pneumonitis. Normal diffusing capacity observed between exacerbations of acute or subacute hypersensitivity pneumonitis does not exclude the diagnosis. Testing during acute episodes of hypersensitivity pneumonitis reveals predominately restrictive changes; however, obstruction and bronchial hyperreactivity can also be seen. Obstruction alone does not preclude a diagnosis of hypersensitivity pneumonitis. Hypoxemia can be seen in patients with active pneumonitis whether the affected patient is at rest or exercising.[34]

Subacute hypersensitivity pneumonitis

Pulmonary function testing may demonstrate mild hypoxemia, restriction and/or obstruction, and a reduced capacity for diffusing carbon monoxide.

Chronic hypersensitivity pneumonitis

A reduced diffusing capacity of the lung for carbon monoxide may be the earliest abnormality observed. Pulmonary restriction, hypoxemia at rest, and/or desaturation during the 6-minute walk test indicates the presence of more advanced disease.

Provocation challenge

The role of inhalation challenge is controversial because it can provoke clinically significant disease and standardized antigen preparations are not yet available. Because of the risk for the late-phase severe reactions, patients should be closely observed for at least 24 hours after the inhalation challenge is administered.[83]

Natural challenge

The development of signs and symptoms after the patient is re-exposed to the antigenic environment supports a diagnosis of acute or subacute hypersensitivity pneumonitis.

Skin testing

Skin testing is not helpful in assessing hypersensitivity pneumonitis.[84]

Procedures

Analysis of bronchoalveolar lavage (BAL) fluid (BALF) is the most sensitive tool for alveolitis detection in patients with suspected hypersensitivity pneumonitis. Analysis of BALF in hypersensitivity pneumonitis typically reveals the following[15, 83] :

Lymphocytosis (>20% of WBCs recovered)
Elevated proportion of neutrophils (may be elevated to >5%), especially after recent antigenic exposure or in advanced disease
Elevated proportion of eosinophils (may be >5%), particularly in advanced disease

Analysis of bronchoalveolar lavage fluid in adults with hypersensitivity pneumonitis frequently reveals a CD4/CD8 ratio of less than 1. As stated above (see Pathophysiology), children naturally have a low CD4/CD8 ratio due to an elevated number of CD8 cells. Thus, this finding is neither sensitive nor specific for hypersensitivity pneumonitis in children.[85, 86]

One study of BALF cytology reported that adults with hypersensitivity pneumonitis have a greater percentage of natural killer T cells than adults with sarcoidosis.[13] The natural killer T cells observed in patients with hypersensitivity pneumonitis were predominantly of the CD8+CD56+ population. The clinical use of this observation has yet to be determined.

Induced sputum has been proposed as a noninvasive alternative to BAL. In adults with hypersensitivity pneumonitis, the distribution of T-cell subpopulations is similar in induced sputum and BALF; however the percentage of lymphocytes was substantially lower in the induced sputum.[87] Although lymphocytosis and elevated proportion of CD8+ cells on induced sputum is consistent with hypersensitivity pneumonitis, induced sputum should not be relied on to exclude the diagnosis.

Lung biopsy can be considered if the diagnosis cannot be established by other less-invasive methods. The role of transbronchial biopsy is controversial, with some authors advocating it as a less invasive test;[83] others are much less enthusiastic because the diagnostic yield is poor and interpretation is not consistent.[88] The extent to which invasive testing should be performed should be based on the probability of the diagnosis, the impact on patient and family of making the diagnosis, and the need to rule out alternative diagnoses.[12] Examples of lung biopsy findings are shown in the images below.

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.

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.

Histologic Findings

Hypersensitivity pneumonitis is a diffuse, predominantly mononuclear cell inflammation of the small airways and pulmonary parenchyma. The inflammation is often associated with poorly formed, nonnecrotizing granulomas.[89] A bronchiolocentric distribution of the interstitial inflammation is believed to result from the airway being the portal of entry for the offending agent. Histologic findings may include the following[90, 91] :

Bronchiolocentric, chronic interstitial inflammation in which lymphocytes predominate
Poorly formed, noncaseating necrotizing interstitial granulomas
Foamy macrophages within airspaces
Intra-alveolar foci of organizing pneumonia
Dense fibrosis, honeycombing, and fibroblastic foci in advanced, chronic disease with potential upper lobe contraction.

Nonclassic and nonspecific pathology has been described in patients who otherwise met criteria for hypersensitivity pneumonitis. Cases of clinical hypersensitivity pneumonitis have been documented with biopsy results showing only nonspecific interstitial pneumonitis (NSIP) or a bronchiolitis obliterans organizing pneumonia (BOOP)–like picture.[15, 92]

Treatment

Medical Care

The key to effective treatment of hypersensitivity pneumonitis (HP) is identifying the offending antigen and eliminating further exposure. These goals can be hard to achieve because the offending antigen may not be obvious and may endure long after the antigenic source is removed (ie, avian antigens).[93]

Removal from exposure usually results in complete resolution of symptoms, although substantially more time is required in subacute than in acute disease. In many patients, complete resolution requires weeks to months. Permanent lung damage, continued progression, or both may be seen in advanced cases of chronic hypersensitivity pneumonitis.

Corticosteroids can speed resolution of hypersensitivity pneumonitis; however, corticosteroid therapy does not eliminate or reduce the need to identify the causative antigen and elimination of exposure to it, nor does it change the long-term prognosis. If systemic corticosteroid therapy is used, the same dosage regimen should be continued until clinical improvement of pulmonary function is observed. The dosage should then be gradually tapered downward. In advanced chronic disease, progression of pulmonary fibrosis and death can occur despite aggressive corticosteroid therapy. If the patient has risk factors for tuberculosis, latent tuberculosis infection should be excluded prior to starting corticosteroid therapy.

Antibiotic therapy is not indicated for treatment of hypersensitivity pneumonitis. However, in many cases, antibiotic drugs are administered until a diagnosis of infectious pneumonia is ruled out.

A few case reports have described clinical improvement with rituximab when used as salvage therapy in adults with severe progressive chronic hypersensitivity pneumonitis.[94, 95] Rituximab is an anti-CD20 monoclonal antibody that depletes B cells from the peripheral circulation. One of the reports of clinical experience with rituximab in 6 adults with severe progressive hypersensitivity pneumonitis found that lung function stabilized or improved in 3 and continued to deteriorate in the other 3, all of whom died within 4 months of treatment.[95] There are no reports of pediatric experience with this medication in hypersensitivity pneumonitis.

In this author’s opinion, rituximab should not be considered standard therapy for chronic hypersensitivity pneumonitis. Rituximab may be considered as salvage therapy in a patient with severe, progressive, and life-threatening chronic hypersensitivity pneumonitis in whom standard therapies (including aggressive attempts to identify and eliminate exposure to the offending antigen) have clearly failed. This would be very unusual for a child.

A recent clinical trial showed that antifibrotic drugs could reduce disease progression in patients with progressive ILD, including hypersensitivity pneumonitis.[96]

Consultations

Consulting a pediatric pulmonologist, an allergist, or both who have experience in treating hypersensitivity pneumonitis can be helpful for confirming the diagnosis, assessing complications, educating the patient and family, and providing long-term follow-up care for the patient.

Diet and Activity

Diet

No dietary restrictions are needed.

Activity

If the patient has pulmonary fibrosis, subpleural blebs, or airway obstruction, activities that may increase intrathoracic pressure (eg, scuba diving, playing horn instruments) are contraindicated because of the risk of pneumothorax. Otherwise, activity levels should be adjusted according to the patient's comfort; dyspnea causes most patients to spontaneously reduce their physical activity. If needed, tolerance of physical activity can be objectively assessed with 6-minute walk testing.

Guidelines

Guidelines Summary

The American College of Chest Physicians (ACCP) published clinical guidelines on the diagnosis and evaluation of hypersensitivity pneumonitis.[81] The guidelines note that the disease can occur at any age.

The ACCP suggests classifying patients with suspected hypersensitivity pneumonitis based on the likelihood of inciting antigen exposure.

The ACCP suggests classifying the disease as fibrotic or nonfibrotic based on the presence or absence of fibrosis on high-resolution computed tomography (CT) scanning of the chest.

The ACCP suggests bronchoalveolar lavage fluid analysis may not be needed in patients with a compelling exposure history within the appropriate clinical context and a pattern typical of hypersensitivity pneumonitis on high-resolution CT scanning of the chest.

The ACCP suggests that histologic lung biopsy may be considered when clinical, laboratory, and radiologic findings (along with bronchoscopic results) do not yield a confident diagnosis, and the results may help guide management.

Medication

Medication Summary

Systemic corticosteroid therapy speeds resolution of symptoms but progression of pulmonary fibrosis and death can occur despite corticosteroid therapy. Corticosteroid therapy is not a substitute for identifying and eliminating the offending antigen.

Corticosteroids

Class Summary

These agents decrease inflammation, suppress leukocyte migration, reverse increased capillary permeability, and dampen the immune system.

Prednisone (Deltasone, Sterapred)

Decreases inflammation by reversing increased capillary permeability and suppressing neutrophil activity. Must be metabolized to the active metabolite prednisolone for effect.

Follow-up

Further Care

Further outpatient care

Serial pulmonary function testing with assessment of lung volumes and diffusion capacity is indicated (if the patient is able to perform the maneuvers) to document resolution of abnormalities. Monitor adherence to recommendations to eliminate exposure to the offending antigen.

The patient with hypersensitivity pneumonitis (HP) should be strongly advised to eliminate exposure to the offending antigen. In cases of severe disease, the patient may need to be moved to a new setting to avoid the offending antigen. In some cases, antigen avoidance may include interventions that are very disruptive to the individual’s life or the family’s life, such as removing a family pet, moving from the home, changing occupations or both.

Corticosteroid doses and adverse effects must be monitored. Once a clinical response has been achieved, the acute dosing should be gradually tapered. Markers of clinical response consist of resolution of abnormalities on physical and radiologic examination, improvement in pulmonary function measures including vital capacity, diffusing capacity, and oxygen saturation.

Further inpatient care

Monitor corticosteroid doses and adverse effects. Gradually taper dose after clinical response, visible clearing on radiographs, and improved pulmonary function are achieved.

Deterrence/prevention

The immediate family of children with chronic HP should be screened for subclinical disease because both the exposure and genetic predisposition may be shared.

Author

Naga Jaya Smitha Yenduri, MD Assistant Professor, Division of Pediatrics, Pulmonary Section, Texas Children's Hospital, Baylor College of Medicine

Naga Jaya Smitha Yenduri, MD is a member of the following medical societies: American Thoracic Society

Disclosure: Nothing to disclose.

Coauthor(s)

R Paul Guillerman, MD Professor, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center

R Paul Guillerman, MD is a member of the following medical societies: American Roentgen Ray Society, Children's Oncology Group, Radiological Society of North America, Society for Pediatric Radiology

Disclosure: Nothing to disclose.

Harold J Farber, MD, MSPH Professor of Pediatrics, Section of Pediatric Pulmonology, Baylor College of Medicine, Texas Children's Hospital; Associate Medical Director, Texas Children's Health Plan

Harold J Farber, MD, MSPH is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Texas Children's Health Plan (a not-for-profit Medicaid Manged Care program owned by Texas Children's Hospital).

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Charles Callahan, DO Professor, Chief, Department of Pediatrics and Pediatric Pulmonology, Tripler Army Medical Center

Charles Callahan, DO is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American College of Osteopathic Pediatricians, American Thoracic Society, The Society of Federal Health Professionals (AMSUS), Christian Medical and Dental Associations

Disclosure: Nothing to disclose.

Chief Editor

Girish D Sharma, MD, FCCP, FAAP Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush Children's Hospital, Rush University Medical Center

Girish D Sharma, MD, FCCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Bettina Hilman, MD, Nidhy Paulose Varghese, MD, Lori R Johnson, MD, and Laurianne Wild, MD. Leland Fan, MD, reviewed previous versions and provided helpful suggestions.

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