Hypersensitivity Pneumonitis

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]

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

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)

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.

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]

Most patients experience total recovery of lung function, but this may take several years and also may depend on the intensity of exposure and chronicity. ^[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 likely is an underrepresentation due to underreporting. ^[47]

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.