Hypersensitivity Pneumonitis

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Background

Hypersensitivity pneumonitis (HP; or extrinsic allergic alveolitis) is an inflammatory syndrome of the lung caused by repetitive inhalation of antigenic agents in a susceptible host. The syndrome varies in intensity, clinical presentation, and natural history depending on the inciting agent, as well as the intensity of exposure. In most cases, disease can be reversed with prompt diagnosis followed by identification and removal of exposure risks. Accordingly, the prognosis is generally very good.

The antigens responsible for HP come from a variety of sources. In general, these are classified into three major categories: microbes, animal proteins, and low-molecular-weight chemicals. HP from sources in these three categories most commonly manifest as farmer’s lung, bird fancier’s lung, and chemical worker’s lung, respectively.[1]

Pathophysiology

HP comprises a spectrum of immune-mediated disorders characterized by diffuse inflammation of interstitial lung, terminal bronchioli, and alveoli. Inflammation is caused by prolonged or frequent exposure of inhaled antigens that are generally smaller than 5 µm. Although offending antigens are ubiquitous, the incidence of disease is comparatively small.

A two-hit mechanism has been proposed in which the first hit is greater susceptibility, either because individuals are genetically predisposed to the development of HP or because they are at greater risk for developing the disease because of heavy environmental exposure. Antigen exposure constitutes the second hit, resulting in disease or disease progression. That said, to date, no genetic factors have been identified as consistently associated with HP.[2]

The list of potential exposures responsible for HP is constantly growing. In general, these have been grouped into the following three major categories:

For example, dust from grain products, plant material (eg, wood, bark, and compost), or water reservoir vaporizers (eg, hot tubs and air conditioners), though not intrinsically antigenic, are often colonized by any of a variety of antigenic microbes. High- and low-molecular-weight animal proteins found in feathers, feces, furs, and other animal products commonly cause disease in bird fanciers, animal handlers, or even in those with down-filled pillows and furniture. Finally, low-molecular-weight molecules and inorganic materials (eg, isocyanates, zinc, and nickel) are known haptens that may form antigenic complexes with host proteins.[3]

After exposure to antigens, most individuals do not mount the sustained inflammatory response necessary to develop HP. This is likely secondary to the development of immune tolerance.[4] These individuals may develop a mild lymphocytic alveolitis, but they generally remain asymptomatic. Regulatory T cells suppress the helper T (Th) cell type 1 and 2 immune responses. In experimental studies, the inability to suppress such T-cell proliferation was associated with disease progression.[2]

In patients who go on to develop symptoms, HP is generally classified as follows[5, 6] :

The mechanisms of disease are not completely understood. Acute HP is thought to occur primarily via a type III hypersensitivity reaction. Most patients show evidence of specific antibodies in their serum, and bronchoalveolar lavage (BAL) studies may demonstrate high levels of proinflammatory chemokines. This is further supported by the discovery of complement and immunoglobulin deposition in vessel walls on immunofluorescence.[7]

Subacute and chronic forms of HP are thought to transition more toward type IV T cell–mediated hypersensitivity reactions. Antigen-presenting cells (ie, dendritic cells and alveolar macrophages) present antigens to CD4+ Th1 and Th17 cells. This triggers an inflammatory cascade with release of many factors, including interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-17, and IL-22.

The milieu of cytokines and chemokines ultimately results in sustained infiltration of mononuclear cells, macrophages, and fibroblasts. The apoptosis of lung tissue lymphocytes is inhibited by IL-17, resulting in the high prevalence of lymphocytes in the lung. This, in turn, results in the pattern of noncaseating granulomas and bronchiolitis seen on pathology. In chronic stages, a CD4+ Th2 cytokine pattern dominates. This correlates with fibrotic progression in late disease.[2, 8, 7]

Histologically, chronic HP is characterized by interstitial inflammation and alveolar destruction (honeycombing). Cholesterol clefts or asteroid bodies are present within or outside noncaseating granulomas. Areas of cellular interstitial pneumonia with giant cells or granulomas surrounding bronchioles may help distinguish chronic HP from usual interstitial pneumonia (UIP) or fibrotic nonspecific interstitial pneumonia (NSIP). Centrilobular fibrosis and peribronchiolar and bridging fibrosis are also important hallmarks.[9, 10, 11]

It should be noted that some bodies have recommended replacing the acute-subacute-chronic categorization with a classification that defines HP as either nonfibrotic (no radiologic or histopathologic evidence of fibrosis) or fibrotic (radiologic and/or histopathologic evidence of fibrosis).[12, 13]  In addition, the American College of Chest Physicians (AACP) has suggested classifying patients according to the likelihood of an occupational or environmental inciting antigen exposure.[13]

Etiology

More than 300 causes of HP have been reported from a wide range of exposures involving airborne antigens (see Table 1 below).

Table 1. Selected Etiologic Agents for Hypersensitivity Pneumonitis



View Table

See Table

Reported occupations and major causative antigens

Farmers and cattle workers develop the most common form of HP. The major causative antigen is thermophilic Actinomycetes species. Farmer's lung must be distinguished from febrile toxic reactions to inhaled mold dusts (organic dust toxic syndrome). This nonimmunologic reaction occurs 30-50 times more commonly than HP does.

Ventilation workers and those exposed to water-related contamination may be exposed to microorganism-colonized forced-air systems, humidifiers, whirlpools, hot tubs, and spas.[16, 17, 18, 19] Antigens are various species of Thermoactinomyces,Cladosporium, or Mycobacterium avium complex (MAC).

Poultry and other bird handlers are commonly exposed to droppings, feathers, and serum proteins of pigeons, other birds, and fowl.[15]

Veterinarians and animal handlers have significant contact with animals and organic antigens.

Grain and flour processors and loaders are exposed to grain that may become colonized with a variety of microorganisms that are easily aerosolized. Exposure may lead to HP.

Lumber mill workers and paper and wallboard manufacturers are exposed to wood products colonized with molds.[20, 21]

Plastic manufacturers, painters, and electronics industry workers may be exposed to inciting agents that are synthetic in origin, possibly including diphenylmethane diisocyanate or toluene diisocyanate.

Metalworking fluid handlers, including those involved in the shaping of metal parts, are at risk for the development of HP from microbial contamination of metalworking fluids, frequently with Mycobacterium immunogenum.[22]

Textile workers may have exposures that lead to lung injury characterized by diffuse alveolar damage or airway dysfunction (eg, byssinosis or nylon worker's lung). These adverse reactions are not true forms of HP.

A case-control study investigated the agricultural practices and the microbiologic composition of hay handled by patients with farmer's lung disease.[23] The location, type of farm, and working conditions were similar to those of the control farms. However, the microbiologic composition of the hay differed. Significantly higher amounts of Eurotium amstelodami, Absidia corymbifera, mesophilic Streptomyces, thermophilic Streptomyces, and Saccharomonosporaviridis were present in the hay. Farmer's lung resulted from handling hay with high amounts of these five microorganisms.

An HP-like syndrome has been described in patients exposed to aerosolized MAC. Hot-tub lung is a term used to describe these HP-like cases because they have generally been associated with hot tub use (linked to the high levels of infectious aerosols containing organisms found in the water).[24, 25, 26, 27, 28, 29] Whether this pulmonary response to MAC represents true infection or classic HP remains controversial.[30]

Conditions mimicking HP that occur from inhalation of organic agents but are not true HP

Patients with inhalation fever present with fever, chills, headaches, and myalgias without pulmonary findings (although mild dyspnea may occur). Onset is 4-8 hours following exposure, but no long-term sequelae occur.

Organic dust toxic syndrome results from exposure to bioaerosols contaminated with toxin-producing fungi (mycotoxins). Fever, chills, and myalgias occur 4-6 hours after exposure, and chest radiographs may show diffuse opacities. Bronchiolitis or diffuse alveolar damage may be present on lung biopsy specimens. These are not true forms of HP, because no prior sensitization is required.

Chronic bronchitis can result from chronic obstructive pulmonary disease, which is the most common respiratory syndrome among agricultural workers. The prevalence of chronic bronchitis is 10%, compared with 1.4% for HP. Smoking and atopy have additive effects.[31, 32] An association may exist between chronic bronchitis and HP.

Epidemiology

US and international statistics

The exact US prevalence of HP is unknown. Difficulties determining prevalence arise from uncertainties in detection and misdiagnosis. This is compounded by the lack of standardized epidemiologic criteria for diagnosis.[33]

Estimated prevalence varies by region, climate, and farming practices. A study in New Mexico calculated the yearly incidence of interstitial lung disease (ILD) to be roughly 30 per 100,000; HP accounted for less than 2% of that population.[34] A highly cited 1981 Wisconsin-based study of 1400 individuals estimated the prevalence to be 4.2%.[35] In other studies, HP has been estimated to affect anywhere from 0.5% to 19.0% of exposed farmers.[33] Again, these figures are likely to have evolved in accordance with changes in farming practices and diagnostic criteria.

Outside the United States, the prevalence of HP varies significantly, depending on the type of exposure. Bird fancier’s lung is the most common form of HP worldwide, given a growing poultry husbandry industry. Other interesting causes described in the literature include suberosis (cork worker’s lung—ie, HP associated with contaminated corks) in Spain, mushroom exposures in Asia, and Chrysonilia sitophila HP associated with logging in Canada, among others. Farmer’s lung appears to be becoming less common as a consequence of increased use of protective measures.[36]

The prevalence of farmer's lung has been reported to be 420-3000 cases per 100,000 persons at risk in the United Kingdom, 4370 cases per 100,000 persons at risk in France,[37, 38] and 1400-1700 cases per 100,000 persons at risk in Finland.[39]

One epidemiologic study estimated the incidence of ILD to be 7.6 cases per 100,000 persons per year, with HP accounting for 6.6% of those cases.[40, 8]

Age- and sex-related demographics

HP is usually encountered in the fourth, fifth, or sixth decade of life. One study examined 85 consecutive patients with HP and found a mean age of 53 ± 14 years.[41]

A clear role for sex has not been defined. Although the majority of deaths occur in males, such differences in prevalence may be confounded by skewed sex representation in various occupations.[8]

Prognosis

Most patients with HP experience total recovery of lung function, but this may take several years and also may depend on the intensity of exposure and chronicity.[42]  Features often associated with a poorer prognosis include the following:

Patients with evidence of pulmonary fibrosis on surgical lung biopsy have been shown to have a poorer prognosis then those without such changes.[43]

Most patients diagnosed with farmer's lung recover with only minor functional abnormalities; very few patients advance to disability. A significant number of farmers develop mild chronic lung impairment, which is predominantly obstructive airflow disease associated with mild emphysematous changes on high-resolution computed tomography (CT). Bird fancier's lung, though not as well studied as farmer's lung, appears to have a much worse prognosis. The poorer outcome may be due to higher antigenic exposure and persistence of avian antigens in the home environment even after birds are removed. These factors may account for the substantial 5-year mortality of 30%.

High-resolution CT (HRCT) can serve as a potential prognostic tool. A retrospective series of 69 patients demonstrated that the presence and degree of fibrosis on CT scans was associated with increased mortality.[44] However, a retrospective series of 26 patients did not draw a similar conclusion.[43]

A retrospective analysis of 103 patients diagnosed with HP found survival to be worse for older patients, those with desaturation during clinical exercise, and those without a mosaic pattern/air trapping on HRCT.[45]

Morbidity and mortality

The morbidity and mortality of HP vary widely, depending on the type, duration, and severity of exposure. Genetic factors may also play a significant role. In general, acute HP and subacute HP without fibrotic changes respond completely or almost completely to removal of the inciting exposure. Once fibrotic changes occur, however, the prognosis is less favorable.[46, 47]

Rarely, patients may progress to chronic HP despite exposure control and treatment. Similar to chronic hypersensitivity pneumonitis, emphysema develops initially with progression to irreversible pulmonary fibrosis. Survival at that point is similar to that observed in idiopathic pulmonary fibrosis (IPF). Pulmonary hypertension is seen in 20% of cases of chronic HP and carries a worse prognosis.[2]  A study of 38 patients with fibrotic or nonfibrotic chronic HP reported 5-year survival rates of 72% in fibrotic HP and 100% in nonfibrotic HP.  Honeycombing on imaging was associated with decreased survival.[48]

A study investigating the predictors of mortality in fibrotic HP looked at the impact of short-term changes in lung function.[49] Baseline lung function severity, age, presence of honeycombing on chest CT, and echocardiographic pulmonary arterial systolic pressure greater than 40 mm Hg were found to be associated with early mortality, whereas BAL lymphocytosis was associated with improved survival. A greater than 5% decline in forced vital capacity (FVC) and a greater than 10% decline in diffusion capacity of the lung for carbon monoxide (DLCO) at 1 year were associated with markedly reduced survival.

Patient Education

Below is a brief informational summary suitable for patients to gain a general understanding of HP.

What is hypersensitivity pneumonitis?

HP is an inflammatory condition of the lung caused by the inhalation of irritating microscopic particles or antigens. These antigens may be from many different sources. The most common sources are various different types of molds or proteins from animals (especially birds). Once inhaled, these antigens cause inflammation and can ultimately cause significant damage to the lung. It is important to establish a diagnosis of HP early because it has a very good prognosis if caught and treated before its later stages. In the later stages of HP, the lung damage can be irreversible and may result in a significantly decreased quality of life.  

HP is not contagious, though it is possible that other people around you may contract the disease as a consequence of having been exposed to the same antigens.

What are the symptoms of hypersensitivity pneumonitis?

In the early stages, symptoms may be similar to those of the flu. Fevers, chills, and a dry cough are common. These symptoms usually go away once the responsible particles or antigens are removed, and they generally do not cause long-term damage.

Continuous or repeated exposures over the course of weeks to months to years may eventually lead to a more severe group of symptoms (eg, persistent cough, shortness of breath, weight loss, or fatigue).

How is hypersensitivity pneumonitis diagnosed?

The first step in diagnosis is a thorough history. Your doctor may ask you questions about your current and past jobs, your pets, or any hobbies to screen for exposures to various antigens.

A high-risk history combined with the appropriate symptoms may lead your doctor to start with a chest radiograph or even a CT scan. A lung function test may help your doctor decide how severely your lungs are involved. Depending on the severity of the disease or the possibility of other diseases, your doctor may choose to perform more invasive testing.

How is hypersensitivity pneumonitis treated? 

In most circumstances, HP can be adequately treated by simply avoiding inhalation of the responsible antigen, especially soon after disease onset. Elimination of mold, use of personal protective equipment (eg, a mask), or removal of a pet can significantly reduce symptoms and result in a dramatic change in the course of HP. In more severe circumstances, your doctor may choose to use a type of medication called a corticosteroid to help reduce inflammation.

History

The clinical presentation of hypersensitivity pneumonitis (HP; or extrinsic allergic alveolitis) is commonly categorized as acute, subacute, or chronic, according to duration of illness. (Alternatively, some authorities have recommended categorizing it as fibrotic or nonfibrotic.[12, 13] )

Acute HP presents clinically as follows:

Subacute (intermittent) HP presents clinically as follows:

Chronic HP presents clinically as follows:

Development and validation of a questionnaire to identify potential HP inciting agents would be desirable. Until a validated questionnaire becomes available, it is vital that clinicians take a thorough history to identify potential exposures associated with HP.[12]

 

Physical Examination

The physical examination findings of HP vary according to the clinical presentation.

Patients with acute HB present with fever, tachypnea, and diffuse fine bibasilar crackles upon auscultation.

Patients with subacute HP present similarly to patients with acute HP, but symptoms are generally less severe and have lasted longer.

Patients with chronic HP present with muscle wasting and weight loss. Clubbing is observed in 50% of patients. Tachypnea, respiratory distress, and inspiratory crackles over lower lung fields often are present.

Acute-on-chronic HP is generally severe and often presents with respiratory distress requiring ventilation assistance.

Approach Considerations

ATS/JRS/ALAT recommendations

Guidelines from the American Thoracic Society (ATS), the Japanese Respiratory Society (JRS), and the Asociación Latinoamericana del Tórax made the following specific recommendations for the evaluation of hypersensitivity pneumonitis (HP; or extrinsic allergic alveolitis)[12]

ACCP recommendations

The 2021 CHEST guidelines from the American College of Chest Physicians (AACP) stated that the following findings should be integrated to support a diagnosis of HP but that none should be used as the sole basis of diagnosis[13] :

BAL fluid analysis may not be needed in patients with a compelling exposure history within the appropriate clinical context and a pattern typical of HP on high-resolution CT (HRCT) of the chest.[13]

As in the ATS/JRS/ALAT guidelines, histologic lung biopsy may be considered when clinical, laboratory, and radiologic findings (along with bronchoscopic results) do not yield a confident diagnosis and when the results may help guide management.[13]

Laboratory Studies

There are no unique diagnostic laboratory tests for the diagnosis of HP. Neutrophilia is commonly seen in acute illness. Nonspecific markers of inflammation such as erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are also observed in many patients. It should be noted that peripheral blood eosinophilia is often absent. Elevated quantitative serum immunoglobulins have been reported.

Diagnostic criteria

Various diagnostic criteria have been proposed for HP; however, definitive consensus guidelines have yet to be established by the major thoracic or immunological societies. In general, the diagnosis of HP remains heavily dependent on clinical judgment. That said, each of the proposed diagnostic criteria incorporate some subset of the findings described below.

Exposure to a known offending antigen, as follows:

Clinical signs and symptoms on physical examination and history, as follows:

Chest radiography or CT shows radiographic evidence.

BAL fluid shows evidence of lymphocytic predominance.

Pathologic evidence, as follows:

In areas of especially high incidence, a high degree of suspicion may obviate the need for more invasive testing with BAL fluid analysis or biopsy.[51]

Precipitating antibodies against potential antigens may be present in serum and BAL specimens. Antibodies may be present in as many as 40-50% of exposed individuals, even those without disease. Precipitins thus indicate prior exposure and sensitization but do not necessarily represent active disease. This is further confounded by the finding that many patients with clinical disease have no detectable antibodies, because of either testing with an inappropriate antibody or cessation of exposure.

Some groups have suggested testing for a wider array of precipitins to increase sensitivity; however, utility and cost-effectiveness have yet to be verified. Some centers may offer enzyme-linked immunosorbent assay (ELISA) testing, which can be more sensitive for precipitins.

Imaging Studies

Chest radiography

No findings on chest radiography are typical of HP. That said, pleural effusions, pleural thickening, or significant hilar adenopathy are rare in HP and may suggest alternative differential diagnoses.

In acute HP, a poorly defined micronodular or diffuse interstitial pattern is typical. Lower-to-middle lung zone predominance is variably reported and may be better appreciated on HRCT.[53] Findings are normal in approximately 10% of patients. Radiograph findings may also revert back to normal following resolution of the acute episode.

Subacute HP chest radiographs may be similar to those of acute HP, with a predominantly reticulonodular pattern.[54] (See the image below.)



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A 60-year-old dairy farmer had an 8-year history of intermittent dyspnea. Chest radiograph shows bilateral reticulonodular interstitial infiltration s....

In chronic HP, progressive fibrotic changes with loss of lung volume and coarse linear opacities are common. Features of emphysema are found on significant chest films and CT scans. (See the image below.)



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Chest radiograph of a patient with chronic hypersensitivity pneumonitis from pigeon breeder's disease. Bilateral reticulonodular densities are present....

High-resolution computed tomography

On HRCT, nonspecific ground-glass opacities or diffusely increased radiodensities are present in the acute phase of disease.[55]  (See the image below.) Opacities may be either central or peripheral, but tend to involve the lower lobes preferentially to upper lobes. This may be suggestive of correlation with inhaled antigen load.



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High-resolution CT scan of lungs shows ground-glass opacification in the acute phase of hypersensitivity pneumonitis.

In subacute HP, diffuse micronodules, ground-glass attenuation, focal air trapping, mosaic perfusion, occasional thin-walled cyst, and mild fibrotic changes are observed. (See the image below.)



View Image

High-resolution chest CT scan of a patient with subacute hypersensitivity pneumonitis demonstrates centrilobular nodules. These nodules are unlike tho....

In chronic HP, several patterns may be observed, including multiple centrilobular nodules with some ground-glass attenuation, radiolucency or air trapping, extensive fibrosis, traction bronchiectasis, and honeycombing.[56] (See the image below.)



View Image

The chronic phase of hypersensitivity pneumonitis shows honeycombing in the right upper lung and traction bronchiectasis.

It may be difficult to distinguish the imaging features of HP from those of NSIP and idiopathic pulmonary fibrosis (IPF); thus, these should be considered as well. Features that may favor HP include mosaic perfusion, upper- or middle-zone predominance, centrilobar nodules, and air trapping.

American College of Radiology appropriateness criteria

The American College of Radiology (ACR) has published appropriateness criteria for imaging occupational lung diseases and for diffuse lung disease. Chest radiography and chest CT without intravenous (IV) contrast are usually appropriate for initial imaging of suspected diffuse lung disease or suspected interstitial lung disease with a known occupational exposure. These procedures are complementary and should be performed simultaneously; each provides unique diagnostic information.[57, 58]  There are newer and evolving occupational exposures causing HP, and evaluation with HRCT can provide information to guide treatment choices.[57]

Other Tests

Pulmonary function studies

A restrictive ventilatory pattern, with reduced forced vital capacity (FVC), total lung capacity (TLC), and preserved airflow, is observed in acute or subacute disease. A restrictive (severe) or mixed obstructive-restrictive pattern is common in chronic HP. Diffusing capacity of lungs for carbon monoxide is reduced in all forms of HP. Many patients have hypoxemia at rest, and most patients desaturate with exercise.

Procedures

Inhalation challenge

Repeat exposure to the environment of the supposed agent may help establish a causal relation between symptoms and the environment. Inpatient inhalation of known antigens has been suggested as a means of observing reactions in a controlled setting. As yet, however, no standardized antigen preparations are available. Patients generally develop fever, malaise, headache, crackles upon chest examination, and decreased FVC 8-12 hours after exposure. Although potentially helpful for diagnosis, reexposure must be attempted with caution in view of the risk of a severe attack and the propensity for disease progression.

Bronchoalveolar lavage

BAL may provide supportive information for the diagnosis of HP.[59, 60] Initial BAL in the acute phase may be remarkable for the presence of more than 5% neutrophils. This is generally followed by marked lymphocytosis.

The characteristic BAL finding in HP is a lymphocytosis with at least 20% and generally more than 50% of white blood cells (WBCs). This finding makes IPF less likely, but other conditions (eg, sarcoidosis, silicosis, or the organizing pneumonias) may have similar WBC count profiles.

Otherwise, mast cells, eosinophils, and plasma cells are also characteristically seen in hypersensitivity pneumonitis. Mast cells are also often characteristic of acute exposures as their numbers tend to decline within approximately 3 months of exposure. The presence of mast cells may help distinguish hypersensitivity pneumonitis from organizing pneumonias. Eosinophilia may be present in conjunction with neutrophilia. The presence of plasma cells often correlates with immunoglobulin levels. High levels if IgA, IgG, IgM and free light chains in the presence of plasma cells may further favor a diagnosis of active hypersensitivity pneumonitis.

Use of CD4+/CD8+ ratios for diagnosis of HP has been controversial. Some evidence has suggested that a ratio lower than 1.0 (ie, predominance of CD8+) is consistent with acute/subacute disease, whereas a CD4+ predominance and a high CD4+/CD8+ ratio occur most often in chronic disease. However, there has been a trend away from using the CD4+/CD8+ ratio, based on the belief that multiple factors, including type of antigen, severity of exposure, and disease stage, confound interpretation. Thus, interpretation of CD4+/CD8+ ratio is generally not effective.

Lung biopsy

Lung biopsy is rarely necessary, especially for acute cases, but it can be helpful in cases where usual studies are inconclusive. Transbronchial biopsy has a fair diagnostic yield in acute and subacute disease. Yield can be maximized by obtaining multiple samples (usually six or more) from the most affected lobes as determined by imaging. Surgical open lung biopsy or video-assisted thoracic surgery (VATS) biopsy may provide higher yield in chronic disease or when HRCT findings are not typical for HP.[61] The diagnostic utility of these more invasive procedures should always be decided via discussion between the pulmonologist and surgeon.

Histologic Findings

Histologic findings for acute, subacute, and chronic HP are as follows.[62]

Acute hypersensitivity pneumonitis

Because biopsy is generally not indicated, relatively little is known about the gross pathologic features of acute HP. The most characteristic pathologic feature is neutrophilic interstitial infiltrate. (See the image below.) Other features may include small-vessel vasculitis with immunoglobulin and complement deposition, diffuse alveolar damage, and/or intra-alveolar fibrin accumulation.[9]



View Image

Light microscopy shows mononuclear infiltration and noncaseating granulomas usually observed in association with acute hypersensitivity pneumonitis, b....

Subacute hypersensitivity pneumonitis

 Subacute HP characteristically reveals a triad of diffuse lymphocyte-dominant interstitial inflammatory cell infiltration, poorly formed nonnecrotizing granulomas, and cellular bronchiolitis. Foci of bronchiolitis obliterans and intra-alveolar fibrosis have also been described.[9] Granulomas may be absent in as many as 30% of biopsies. It has been suggested that staining with cathepsin K may increase detection of microgranulomas.[2] Plasma cells, mast cells, giant cells, B-cell follicular formations, and bronchiolitis obliterans may also be noted.

Chronic hypersensitivity pneumonitis

The pathological features of chronic HP include a usual interstitial pneumonia (UIP)-like pattern with subpleural patchy fibrosis, honeycombing, alternating normal alveoli, and fibroblastic foci with centrilobular fibrosis. These fibrotic changes may be superimposed on findings of subacute HP and may be indistinguishable from UIP. In contrast to acute and subacute HP, granulomas may be sparse or absent. Interstitial multinucleated giant cells, often containing cholesterol clefts, strongly suggest HP. Bridging fibrosis between peribronchiolar areas and perilobular areas also favor a diagnosis of HP over IPF.[9] (See the images below.)



View Image

Giant cells are a characteristic feature of hypersensitivity pneumonitis.



View Image

Chronic hypersensitivity pneumonitis shows interstitial inflammation associated with fibrosis.

Medical Care

Early diagnosis is imperative in management of hypersensitivity pneumonitis (HP; or extrinsic allergic alveolitis), given that progression is largely preventable and adverse effects are largely reversible. Environmental and exposure control is the cornerstone of treatment. In cases where elimination of antigen exposure does not result in full regression of disease, treatment with corticosteroids may be warranted.

Antigen avoidance

If the responsible inhaled antigen can be identified, the most effective therapy is complete avoidance. Acute disease remits without specific therapy. This may prove difficult or impractical when a new home or new job would be required.

When complete elimination or avoidance of the allergen exposure is not possible, exposure minimization with protective equipment or environmental treatment is a potential alternative. Respirators may provide satisfactory personal air purification for workplace environments. Alternatively, use of fungicides, dehumidification, mold removal or other remediation services may also sufficiently reduce ambient antigen burden. Patients with disease progression in the setting of ongoing exposure should still be strongly counseled on antigen avoidance even if drastic measures such as relocation to a new job or home are required.

Corticosteroid therapy

Corticosteroid therapy may be indicated for acute symptomatic relief and may accelerate the initial recovery in persons with severe disease.[63] In long-term prospective follow-up studies, however, prognosis was not affected.

Treatment regimens for HP vary according to the prescriber. A conceivable initial empiric treatment dose is prednisone 0.5-1 mg/kg/day for 1-2 weeks in acute HP or 4-8 weeks for subacute/chronic HP followed by a gradual taper to off or maintenance dosage of approximately 10 mg/day. Continued therapy should be guided by clinical response, pulmonary function, and radiographic improvement. Maintenance doses are not always required, particularly if the patient is removed from exposure.

Other therapies

Outside of oral corticosteroids, several other alternative therapies have been explored in select cases. Inhaled corticosteroids, bronchodilators, cromolyn sodium, and antihistamines may be helpful in cases with obstructive physiology with reversibility. The use of low-dose macrolide antibiotics have been suggested for inflammation reduction: however, beneficial effects have not been verified in human studies.[64] The use of immunosuppressive agents such as azathioprine or cyclosporine has been documented in select pediatric cases but not in the adult population.[2]

Prevention

Reduce the chances of contracting hypersensitivity pneumonitis (HP) by minimizing exposure to provocative antigens, reducing microorganism contamination in the environment, and/or using protective equipment.

Reduce the antigenic burden by altering the handling and storage of microbial antigens, wetting compost to decrease aerosolization, and using fungicides to decrease fungal growth.

Dehumidify the environment and remove stagnant water to discourage microbial overgrowth.

Perform preventive maintenance routinely on all heating, ventilation, and air-conditioning equipment. Remove water-damaged furnishings and carpeting.

When avoidance of causative antigens cannot be achieved easily, use protective devices such as personal respirators or air-purifier. Dust respirators do not provide adequate protection, and helmet-type air purifying respirators are efficacious but can be cumbersome to wear.

Guidelines Summary

The following organizations have published guidelines for the diagnosis and evaluation of hypersensitivity pneumonitis (HP), and key treatment recommendations have been reviewed and integrated into the article:

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context: 

What is hypersensitivity pneumonitis (HP) (HP)?What is the pathophysiology of hypersensitivity pneumonitis (HP)?How is hypersensitivity pneumonitis (HP) classified?Which features of hypersensitivity pneumonitis (HP) are associated with a poorer prognosis?What is the role of hot tubs in the etiology of hypersensitivity pneumonitis (HP)?What causes hypersensitivity pneumonitis (HP)?Which occupations increase the risk for hypersensitivity pneumonitis (HP)?Which conditions may mimic hypersensitivity pneumonitis (HP)?What is the prevalence of hypersensitivity pneumonitis (HP) in the US?What is the global prevalence of hypersensitivity pneumonitis (HP)?What is the sexual predilection of hypersensitivity pneumonitis (HP)?Which age groups have the highest prevalence of hypersensitivity pneumonitis (HP)?What is the prognosis of hypersensitivity pneumonitis (HP)?What is the morbidity and mortality associated with hypersensitivity pneumonitis (HP)?What is included in patient education about hypersensitivity pneumonitis (HP)?What are the signs and symptoms of acute hypersensitivity pneumonitis (HP)?What are the signs and symptoms of subacute (intermittent) hypersensitivity pneumonitis (HP)?What are the signs and symptoms of chronic hypersensitivity pneumonitis (HP)?Which physical findings are characteristic of hypersensitivity pneumonitis (HP)?Which conditions should be included in the differential diagnoses of hypersensitivity pneumonitis (HP)?What are the differential diagnoses for Hypersensitivity Pneumonitis?What is the role of lab testing in the workup of hypersensitivity pneumonitis (HP)?How is hypersensitivity pneumonitis (HP) diagnosed?What is the role of radiography in the workup of hypersensitivity pneumonitis (HP)?What is the role of high-resolution CT scanning in the diagnosis of hypersensitivity pneumonitis (HP)?What is the role of pulmonary function testing in the workup of hypersensitivity pneumonitis (HP)?What is the role of an inhalation challenge in the workup of hypersensitivity pneumonitis (HP)?What is the role of bronchoalveolar lavage (BAL) in the workup of hypersensitivity pneumonitis (HP)?What is the role of lung biopsy in the workup of hypersensitivity pneumonitis (HP)?Which histologic findings are characteristic of acute hypersensitivity pneumonitis (HP)?Which histologic findings are characteristic of subacute hypersensitivity pneumonitis (HP)?Which histologic findings are characteristic of chronic hypersensitivity pneumonitis (HP)?How is hypersensitivity pneumonitis (HP) treated?What is the role of antigen avoidance in the treatment of hypersensitivity pneumonitis (HP)?What is the role of corticosteroid therapy in the treatment of hypersensitivity pneumonitis (HP)?Which medications are used in the treatment of hypersensitivity pneumonitis (HP)?How is hypersensitivity pneumonitis (HP) prevented?What is the role of medications in the treatment of hypersensitivity pneumonitis (HP)?Which medications in the drug class Corticosteroids are used in the treatment of Hypersensitivity Pneumonitis?

Author

Caleb Hsieh, MD, MS, Clinical Instructor in Pulmonary, Critical Care, and Sleep Medicine, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jacqueline H Nguyen, DO, Resident Physician, Department of Internal Medicine, Olive View - UCLA Medical Center

Disclosure: Nothing to disclose.

Nader Kamangar, MD, FACP, FCCP, FCCM, Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Division of Pulmonary and Critical Care Medicine, Vice-Chair, Department of Medicine, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Stephanie Lin Ong, MD, Resident Physician, Department of Internal Medicine, Olive View - UCLA Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director, Pulmonary Medicine General Practice Unit (F2), Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital

Disclosure: Received research grant from: Sanofi Pharmaceutical; AstraZeneca Pharaceutical; aTyr Pharmaceutical; Dompe Pharmaceutical.

Chief Editor

John J Oppenheimer, MD, Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Amgen; GSK; Aquestive; Aimmune<br/>Clinical Adjudication/Data Safety Monitoring Board for AZ, GSK, Abbvie, Sanofi; Executive Editor for Annals of Allergy, Asthma & Immunology; Editor for Medscape; Reviewer for UpToDate; Honoraria from American Board of Allergy and Immunology.

Additional Contributors

Michael Peterson, MD, Chief of Medicine, Vice-Chair of Medicine, University of California, San Francisco, School of Medicine; Endowed Professor of Medicine, University of California, San Francisco-Fresno, School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Marine Demirjian, MD Resident Physician, Department of Internal Medicine, Ronald Reagan University of California in Los Angeles Medical Center

Marine Demirjian, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Women's Association, and California Medical Association

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

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A 60-year-old dairy farmer had an 8-year history of intermittent dyspnea. Chest radiograph shows bilateral reticulonodular interstitial infiltration secondary to subacute hypersensitivity pneumonitis.

Chest radiograph of a patient with chronic hypersensitivity pneumonitis from pigeon breeder's disease. Bilateral reticulonodular densities are present.

High-resolution CT scan of lungs shows ground-glass opacification in the acute phase of hypersensitivity pneumonitis.

High-resolution chest CT scan of a patient with subacute hypersensitivity pneumonitis demonstrates centrilobular nodules. These nodules are unlike those of sarcoidosis, in which the nodules are subpleural and along bronchovascular bundles.

The chronic phase of hypersensitivity pneumonitis shows honeycombing in the right upper lung and traction bronchiectasis.

Light microscopy shows mononuclear infiltration and noncaseating granulomas usually observed in association with acute hypersensitivity pneumonitis, but it also can be observed in subacute and chronic disease.

Giant cells are a characteristic feature of hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis shows interstitial inflammation associated with fibrosis.

A 60-year-old dairy farmer had an 8-year history of intermittent dyspnea. Chest radiograph shows bilateral reticulonodular interstitial infiltration secondary to subacute hypersensitivity pneumonitis.

Chest radiograph of a patient with chronic hypersensitivity pneumonitis from pigeon breeder's disease. Bilateral reticulonodular densities are present.

High-resolution CT scan of lungs shows ground-glass opacification in the acute phase of hypersensitivity pneumonitis.

The chronic phase of hypersensitivity pneumonitis shows honeycombing in the right upper lung and traction bronchiectasis.

High-resolution chest CT scan of a patient with subacute hypersensitivity pneumonitis demonstrates centrilobular nodules. These nodules are unlike those of sarcoidosis, in which the nodules are subpleural and along bronchovascular bundles.

Light microscopy shows mononuclear infiltration and noncaseating granulomas usually observed in association with acute hypersensitivity pneumonitis, but it also can be observed in subacute and chronic disease.

Giant cells are a characteristic feature of hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis shows interstitial inflammation associated with fibrosis.

Disease Source of Exposure Major Antigen
Farmer's lungMoldy hay Saccharopolyspora rectivirgula



(Micropolyspora faeni)



BagassosisMoldy sugar cane fiber Thermoactinomyces sacchari
Grain handler's lungMoldy grain S rectivirgula, Thermoactinomyces vulgaris
Humidifier/air-conditioner lungContaminated forced-air systems, heated water reservoirs[14] S rectivirgula, T vulgaris, Candida guilliermondii
Bird breeder's lungPigeons, parakeets, fowl, rodentsAvian or animal proteins[15]
Cheese worker's lungCheese mold Penicillium casei
Malt worker's lungMoldy malt Aspergillus clavatus
Paprika splitter's lungPaprika dust Mucor stolonifer
Wheat weevilInfested wheat Sitophilus granarius
Mollusk shell hypersensitivityShell dustSea snail shells
Chemical worker's lungManufacture of plastics, polyurethane foam, rubberTrimellitic anhydride, diisocyanate, methylene diisocyanate