Hypersensitivity Pneumonitis 

Updated: Jul 24, 2018
Author: Caleb Hsieh, MD, MS; Chief Editor: John J Oppenheimer, MD 

Overview

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. As such, prognosis is generally very good.

In 1700, Bernardino Ramazzini, an Italian physician, published the first description of hypersensitivity pneumonitis when he noticed that sifters and measurers of grain experienced acute reactions after repeated exposure to grain dust. This same phenomenon often seen in farmers was noted independently by many subsequent physicians. In 1874, Dr. Jon Finsen of Iceland, provided a more detailed description of “Heykatarr,” now known as Farmer’s lung, in his graduate thesis after noting that men “whose job it is to loosen the hay in the barn and handle it before it is fed to cattle,” became ill after inhalation of the dust.[1]

The antigens responsible for hypersensitivity pneumonitis come from a variety of sources. In general, these are classified into three major categories: microbes, animal proteins, and low-molecular-weight chemicals. These most commonly manifest as farmer’s lung, bird fancier’s lung, and chemical worker’s lung, respectively.[2]

Pathophysiology

Hypersensitivity pneumonitis (HP) is 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 generally less than 5 µm in size. Although offending antigens are ubiquitous, the incidence of disease is comparatively small. A two-hit mechanism has been proposed in which individuals either genetically predisposed to the development of hypersensitivity pneumonitis or those with heavy environmental exposure are at increased risk of developing the disease. Antigen exposure constitutes the second hit, resulting in disease or disease progression. That said, to date, there have been no genetic factors consistently associated with hypersensitivity pneumonitis.[3]

The list of potential exposures responsible for hypersensitivity pneumonitis is constantly growing. In general, these have been grouped into three major categories: microbes, animal proteins, and low-molecular-weight chemicals. For example, dust from grain products, plant material (eg, wood, bark, compost), or water reservoir vaporizers (eg, hot tubs, air conditioners), while 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 may 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, nickel) are known haptens that may form antigenic complexes with host proteins.[4]

Following exposure to antigens, the majority of individuals do not develop the sustained inflammatory response necessary to develop hypersensitivity pneumonitis. This is likely secondary to the development of immune tolerance.[5] These individuals may develop a mild lymphocytic alveolitis, but generally they remain asymptomatic. Regulatory T cells suppress the Th1 and Th2 cell immune responses. In experimental studies, the inability to suppress such T-cell proliferation was associated with disease progression.[3]

In patients who go on to develop symptoms, hypersensitivity pneumonitis is classified as acute, subacute (intermittent), or chronic progressive.[6, 7] The mechanisms of disease are incompletely understood. Acute hypersensitivity pneumonitis is thought to occur primarily via type III hypersensitivity reaction. Most patients show evidence of specific antibodies in their serum and bronchoalveolar lavage studies may demonstrate high levels of proinflammatory chemokines. This is further supported by the finding of complement and immunoglobulin deposition in vessel walls on immunofluorescence.[8]

Subacute and chronic forms of hypersensitivity pneumonitis are thought to transition more towards 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, bronchiolitis seen on pathology. In chronic stages, a CD4+ Th2 cytokine pattern dominates. This correlates with fibrotic progression in late disease.[3, 9, 8]

Histologically, chronic hypersensitivity pneumonitis 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 hypersensitivity pneumonitis from usual interstitial pneumonia (UIP) or fibrotic nonspecific interstitial pneumonia (NSIP). Centrilobular fibrosis, peribronchiolar and bridging fibrosis are also important hallmarks.[10, 11, 12]

Features often associated with poorer prognosis include:

  • Predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci similar to UIP

  • Homogeneous linear fibrosis similar to fibrotic NSIP

  • Irregular predominantly peribronchiolar fibrosis

Etiology

More than 300 etiologies of hypersensitivity pneumonitis (HP) have been reported from a wide range of exposures involving airborne antigens.

Table. Selected Etiological Agents for Hypersensitivity Pneumonitis (Open Table in a new window)

Disease

Source of Exposure

Major Antigen

Farmer's lung

Moldy hay

Saccharopolyspora rectivirgula

(Micropolyspora faeni)

Bagassosis

Moldy sugar cane fiber

Thermoactinomyces sacchari

Grain handler's lung

Moldy grain

S rectivirgula,Thermoactinomyces vulgaris

Humidifier/air-conditioner lung

Contaminated forced-air systems, heated water reservoirs[13]

S rectivirgula, T vulgaris, Candida guilliermondii

Bird breeder's lung

Pigeons, parakeets, fowl, rodents

Avian or animal proteins[14]

Cheese worker's lung

Cheese mold

Penicillium casei

Malt worker's lung

Moldy malt

Aspergillus clavatus

Paprika splitter's lung

Paprika dust

Mucor stolonifer

Wheat weevil

Infested wheat

Sitophilus granarius

Mollusk shell hypersensitivity

Shell dust

Sea snail shells

Chemical worker's lung

Manufacture of plastics, polyurethane foam, rubber

Trimellitic anhydride, diisocyanate, methylene diisocyanate

Reported occupations and major causative antigens

Farmers and cattle workers develop the most common form of hypersensitivity pneumonitis. 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 hypersensitivity pneumonitis.

Ventilation workers and those exposed to water-related contamination may be exposed to microorganism-colonized forced-air systems, humidifiers, whirlpools, hot tubs, and spas.[15, 16, 17, 18] 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.[14]

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 hypersensitivity pneumonitis.

Lumber mill workers and paper and wallboard manufacturers are exposed to wood products colonized with molds.[19, 20]

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 of developing hypersensitivity pneumonitis from microbial contamination of metalworking fluids, frequently with Mycobacterium immunogenum.[21]

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

A case-control study investigated the agricultural practices and the microbiological composition of hay handled in patients with farmer's lung disease. The location, type of farm, and working conditions were similar to those of the control farms. However, the microbiological composition of 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.[22]

Hypersensitivity pneumonitis–like syndrome in patients exposed to aerosolized MAC has been described. Hot-tub lung is a term used to describe these hypersensitivity pneumonitis–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).[23, 24, 25, 26, 27, 28] Whether this pulmonary response to MAC represents true infection or classic hypersensitivity pneumonitis remains controversial.[29]

Conditions that mimic hypersensitivity pneumonitis that occur from inhalation of organic agents but are not true forms of hypersensitivity pneumonitis

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 hypersensitivity pneumonitis 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 hypersensitivity pneumonitis. Smoking and atopy have additive effects.[30, 31] An association may exist between chronic bronchitis and hypersensitivity pneumonitis.

Epidemiology

Frequency

United States

The exact prevalence of hypersensitivity pneumonitis (HP) is unknown. Difficulties determining prevalence arise from uncertainties in detection and misdiagnosis. This is compounded by the lack of standardized epidemiological criteria for diagnosis.[32] That said, 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. hypersensitivity pneumonitis accounted for less than 2% of that population.[33] A highly cited 1981 Wisconsin-based study of 1400 individuals estimated prevalence at 4.2%.[34] In other studies, hypersensitivity pneumonitis is estimated to affect anywhere from 0.5–19.0% of exposed farmers.[32] Again, these figures are likely to have evolved based on changing farming practices and diagnostic criteria.

International

Hypersensitivity pneumonitis prevalence outside of the United States varies significantly based on type of exposures. Bird fancier’s lung is the most form of hypersensitivity pneumonitis worldwide given a growing poultry husbandry industry. Other interesting causes described in literature include suberosis (cork worker’s lung, hypersensitivity pneumonitis associated with contaminated corks in Spain), mushroom exposures in Asia, and Chrysonilia sitophila hypersensitivity pneumonitis associated with logging in Canada among others. Farmer’s lung is ostensibly becoming less common due to increased use of protective measures.[35]

The prevalence of farmer's lung in the United Kingdom is reported to be 420-3,000 cases per 100,000 persons at risk, in France is 4,370 cases per 100,000 persons at risk,[36, 37] and in Finland is 1,400-1,700 cases per 100,000 persons at risk.[38]

One epidemiologic study estimated incidence of interstitial lung disease to be 7.6 cases per 100,000 persons per year. Hypersensitivity pneumonitis accounted for 6.6% of those cases.[39, 9]

Sex

A clear role for sex has not been defined. While the majority of deaths occur in males, such differences in prevalence may be confounded by skewed sex representation in various occupations.[9]

Age

Hypersensitivity pneumonitis is usually encountered in the fourth to sixth decade of life. One study examined 85 consecutive patients with hypersensitivity pneumonitis and found a mean age of 53 +/- 14 years.[40]

Prognosis

Most patients experience total recovery of lung function, but this may take several years.[41] Patients with evidence of pulmonary fibrosis on surgical lung biopsy have a poorer prognosis then those without such changes.[42]

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 CT scans. Bird fancier's lung, although not as well studied, appears to have a much worse prognosis compared with farmer's lung. The poorer outcome may be due to higher antigenic exposure and persisting avian antigens in the home environment, even after birds are removed. These factors may account for the substantial 5-year mortality rate of 30%.

High-resolution CT scanning can serve as a possible tool for predicting a prognosis. A retrospective series of 69 patients demonstrated that the presence and degree of fibrosis on CT scans was associated with increased mortality.[43] However, a retrospective series of 26 patients failed to draw a similar conclusion.[42]

A retrospective analysis of 103 patients diagnosed with hypersensitivity pneumonitis (HP) found that survival is worse with older patients, those with desaturation during clinical exercise, and those without a mosaic pattern/air trapping on high-resolution CT scanning.[44]

Morbidity and mortality

Morbidity and mortality in the United States is tracked closely by the Centers for Disease Control and Prevention (CDC) and the Work Related Lung Disease Surveillance System (eWoRLD). For a more in-depth analysis and breakdown of demographics, see Hypersensitivity Pneumonitis from the CDC Web site.

Morbidity and mortality of hypersensitivity pneumonitis varies widely based on type, duration, and severity of exposure. Genetic factors may also play a significant role. In general, acute hypersensitivity pneumonitis and subacute hypersensitivity pneumonitis without fibrotic changes respond completely or near completely to removal of the inciting exposure. Once fibrotic changes occur, however, prognosis is less favorable.[45, 46]

Rarely, patients may progress to chronic hypersensitivity pneumonitis 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 hypersensitivity pneumonitis and carries worse prognosis.[3]

From 2001-2010, there were 744 recorded deaths in the United States from hypersensitivity pneumonitis. Of these recorded deaths, 95.2% were white and 3% were black; 58.5% were male. This represents roughly 0.2-0.3 deaths per million, although this may be an underrepresentation due to underreporting.[47]

Patient Education

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

What is hypersensitivity pneumonitis?

Hypersensitivity Pneumonitis (or HP for short) 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 any of a number of different types of mold 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 hypersensitivity pneumonitis early since it has a very good prognosis if caught and treated before its later stages. In its later stages, the lung damage from hypersensitivity pneumonitis can be irreversible and may result in a significantly decreased quality of life.  

It is not contagious, although it is possible that other people around you may be exposed to the same antigens

What are the symptoms?

In the early stages, symptoms may be similar to the flu. Fevers, chills, and a dry cough are common. These symptoms usually go away once the responsible particles or antigens are removed and 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 such as a 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, hypersensitivity pneumonitis 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 (such as a mask), or removal of a pet can significantly reduce symptoms and result in a dramatic change in the course of hypersensitivity pneumonitis. In more severe circumstances, your doctor may choose to use a type of medication called a corticosteroid to help reduce inflammation.

 

Presentation

History

The clinical presentation of hypersensitivity pneumonitis (HP) is categorized as acute, subacute, or chronic, according to duration of illness.

Acute hypersensitivity pneumonitis clinical presentation is as follows:

  • Flulike syndrome including fever, chills, malaise, cough, chest tightness, dyspnea, and headache

  • Develops within hours following significant exposure

  • Symptoms typically resolve gradually within 12 hours to several days following exposure removal

  • May recur following re-exposure

Subacute (intermittent) hypersensitivity pneumonitis clinical presentation is as follows:

  • Insidious onset of productive cough, dyspnea, fatigue over weeks to months

  • Progression to persistent cough and dyspnea

  • May occur in individuals with frequent acute reactions

  • May note anorexia and/or weight loss

Chronic hypersensitivity pneumonitis clinical presentation is as follows:

  • May have unrecognized or untreated acute/subacute disease

  • Often presents with no obvious acute episodes, presents as insidious disease

  • Progressive dyspnea, cough, fatigue, malaise, and/or weight loss

Physical Examination

Physical examination findings of hypersensitivity pneumonitis (HP) vary according to clinical presentation.

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

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

Patients with chronic hypersensitivity pneumonitis 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 hypersensitivity pneumonitis is generally severe and often presents with respiratory distress requiring ventilation assistance.

 

DDx

 

Workup

Laboratory Studies

There are no unique diagnostic laboratory tests for the diagnosis of hypersensitivity pneumonitis (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 hypersensitivity pneumonitis; however, definitive consensus guidelines have yet to be established by the major thoracic or immunological societies. In general, the diagnosis of hypersensitivity pneumonitis 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:

  • Confirmed history of exposure

  • Positive precipitating antibodies to the offending antigen

  • Recurrent episodes of symptoms

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

  • Crackles

  • Weight loss

  • Wheezing (generally less prominent feature)

  • Febrile episodes

  • Symptoms occurring within 4-8 hours of exposure

Chest radiograph or CT scan shows radiographic evidence.

Bronchoscopic alveolar lavage (BAL) shows evidence of lymphocytic predominance.

Pathologic evidence, as follows:

  • Often evidence of poorly formed noncaseating granulomas

  • Mononuclear cellular infiltrates

  • Fibrotic scarring

In areas of especially high incidence, a high degree of suspicion may obviate the need for more invasive testing with BAL or biopsy.[49]

Precipitating antibodies against potential antigens may be present in serum and BAL specimens. Antibodies may be present in up to 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 fact that many patients with clinical disease have no detectable antibodies, because of either testing with an inappropriate antibody or cessation of exposure. Some groups suggest testing for a wider array of precipitins to increase sensitivity; however, utility and cost-effectiveness have yet to be verified. Some centers may offer ELISA testing, which can be more sensitive for precipitins.

Imaging Studies

Chest radiography

No findings on chest radiograph that are typical of hypersensitivity pneumonitis (HP). That said, pleural effusions, pleural thickening, or significant hilar adenopathy are rare in hypersensitivity pneumonitis and may suggest alternative differential diagnoses.

In acute hypersensitivity pneumonitis, a poorly defined micronodular or diffuse interstitial pattern is typical. Lower to middle lung zone predominance is variably reported and may be better appreciated in high-resolution CT scans.[51] Findings are normal in approximately 10% of patients. Radiograph findings may also revert back to normal following resolution of the acute episode.

Subacute hypersensitivity pneumonitis chest radiographs may be similar to acute hypersensitivity pneumonitis with a predominantly reticulonodular pattern.[52] Note the image below:

A 60-year-old dairy farmer had an 8-year history o 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.

In chronic hypersensitivity pneumonitis, 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. Note the image below:

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

High-resolution CT scanning

Nonspecific ground-glass opacities or diffusely increased radiodensities are present in the acute phase of disease.[53] 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. Note the image below:

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

In subacute disease, diffuse micronodules, ground-glass attenuation, focal air trapping, mosaic perfusion, occasional thin-walled cyst, and mild fibrotic changes are observed.

In chronic hypersensitivity pneumonitis, several patterns may be observed, including multiple centrilobular nodules with some ground-glass attenuation, radiolucency or air trapping, extensive fibrosis, traction bronchiectasis, and honeycombing.[54] Note the images below:

The chronic 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 su 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.

It may be difficult to distinguish imaging features of hypersensitivity pneumonitis from those of NSIP and IPF; thus, these should be considered as well. Features that may favor hypersensitivity pneumonitis include mosaic perfusion, upper- or mid-zone predominance, centrilobar nodules and air-trapping.

Other Tests

Pulmonary function studies

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

Procedures

Inhalation challenge

Re-exposure to the environment of the supposed agent may help establish a causal relationship between symptoms and the environment. Inpatient inhalation of known antigens has been suggested as a way to observe reactions in a controlled setting. However, as of yet, no standardized antigen preparations are available. Patients generally develop fever, malaise, headache, crackles upon chest examination, and decreased forced vital capacity 8-12 hours after exposure. Although potentially helpful for diagnosis, re-exposure must be attempted with caution given the risk of a severe attack and the propensity for disease progression.

Bronchoalveolar lavage

BAL may provide supportive information for the diagnosis of hypersensitivity pneumonitis.[55, 56] Initial BAL in the acute phase may be remarkable for more than 5% neutrophils. This is generally followed by marked lymphocytosis.

The characteristic BAL found in hypersensitivity pneumonitis (HP) is a lymphocytosis with at least 20% and generally over 50% of white blood cells. This finding makes IPF less likely, but other conditions such as sarcoidosis, silicosis, or the organizing pneumonias may have similar white 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 hypersensitivity pneumonitis is controversial. Some evidence suggests that a ratio of < 1.0 (ie, predominance of CD8+) is consistent with acute/subacute disease, whereas a CD4+ predominance and high CD4+/CD8+ ratio occurs most often in chronic disease. However, recently the trend has moved away from using the CD4+/CD8+ ratio, as it is believed 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 in which usual studies are inconclusive. Transbronchial biopsy has fair diagnostic yield in acute and subacute disease. Yield can be maximized by obtaining multiple samples (usually 6 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 high-resolution CT scanning (HRCT) findings are not typical for hypersensitivity pneumonitis.[57] 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 hypersensitivity pneumonitis (HP), subacute hypersensitivity pneumonitis, and chronic hypersensitivity pneumonitis are as follows:[58]

Acute hypersensitivity pneumonitis

Because biopsy is generally not indicated, relatively little is known about the gross pathologic features of acute hypersensitivity pneumonitis. The most characteristic pathologic feature is neutrophilic interstitial infiltrate. Other features may include small-vessel vasculitis with immunoglobulin and complement deposition, diffuse alveolar damage, and/or intraalveolar fibrin accumulation.[10] Note the image below.

Light microscopy shows mononuclear infiltration an 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.

Subacute hypersensitivity pneumonitis

 Subacute hypersensitivity pneumonitis 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 also are described.[10] 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.[3] 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 hypersensitivity pneumonitis include a usual interstitial pneumonia–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 hypersensitivity pneumonitis or may often be indistinguishable from UIP. In contrast to acute and subacute hypersensitivity pneumonitis, granulomas may be sparse or absent. Interstitial multinucleated giant cells often containing cholesterol clefts strongly suggest hypersensitivity pneumonitis. Bridging fibrosis between peribronchiolar areas and perilobular areas also favor a diagnosis of hypersensitivity pneumonitis over IPF.[10] Note the images below.

Giant cells are a characteristic feature of hypers Giant cells are a characteristic feature of hypersensitivity pneumonitis.
Chronic hypersensitivity pneumonitis shows interst Chronic hypersensitivity pneumonitis shows interstitial inflammation associated with fibrosis.
 

Treatment

Medical Care

Early diagnosis is imperative in management of hypersensitivity pneumonitis (HP), given that progression is largely preventable and adverse effects are largely reversible. Environmental and exposure control is the cornerstone of treatment. In cases in which 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.[59] In long-term prospective follow-up studies, however, prognosis was not affected.

Treatment regimens for hypersensitivity pneumonitis 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 hypersensitivity pneumonitis or 4-8 weeks for subacute/chronic hypersensitivity pneumonitis followed by a gradual taper to off or maintenance dose 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.[60] The use of immunosuppressive agents such as azathioprine or cyclosporine has been documented in select pediatric cases, but not in the adult population.[3]

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.

 

Medication

Medication Summary

Acute hypersensitivity pneumonitis (HP) abates with antigen avoidance and without specific therapy. Otherwise corticosteroids may speed recovery in patients with severe symptoms or significant lung dysfunction.

Corticosteroids

Class Summary

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

Prednisone (Sterapred)

Prednisone is prescribed for severe symptoms or significant lung dysfunction despite antigen avoidance. It is often used for chronic disease.

 

Questions & Answers

Overview

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)?

Presentation

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)?

DDX

Which conditions should be included in the differential diagnoses of hypersensitivity pneumonitis (HP)?

What are the differential diagnoses for Hypersensitivity Pneumonitis?

Workup

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)?

Treatment

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?

Medications

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?