Hypersensitivity Pneumonitis

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:

• Microbes
• Animal proteins
• Low-molecular-weight chemicals

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]} :

• Acute
• Subacute (intermittent)
• Chronic progressive

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]

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 (Open Table in a new window)

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.

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]

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:

• 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

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.

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.