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Last updated:
April 28, 2022
Years published: 1987, 1989, 1996, 1998, 2005, 2022
NORD gratefully acknowledges Lara Bajakian and Lacey White, Master of Science candidate and Postbaccalaureate Premedical Certificate (PPC) graduate, NORD Editorial Interns from the Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, and Derick Han, PhD, Associate Professor of Biopharmaceutical Sciences in Keck Graduate Institute School of Pharmacy and Health Sciences for assistance in the preparation of this report.
Summary
Extrinsic allergic alveolitis (EAA) is a lung disorder resulting from repeated inhalation of environmental agents including, but not limited to: (1) fungal and microbial agents, (2) agricultural dust or proteins, (3) bioaerosols and (4) various reactive chemicals. These agents, frequently found in certain occupational settings, cause a reaction from the immune system (allergic reaction) that causes inflammation in the lungs. It is important to note that EAA does not occur on the first day of exposure, since repeated and prolonged exposure is necessary for the immune system to become ‘sensitized’ to the foreign matter (antigens) and cause an allergic reaction. Even with repeated exposure, 10-40% of people show no symptoms.
The allergic reactions and inflammation associated with EAA occurs in the alveoli, the air sacs inside the lungs that are responsible for breathing and gas exchange. This distinguishes EAA from allergic asthma, as EAA occurs in the alveoli, while asthma occurs in the airways or bronchi of the lungs. EAA is a complex respiratory syndrome with varying intensity and clinical presentation. EAA can occur for a short duration (acute form) with respiratory symptoms and fever lasting from hours to several weeks after a subsequent exposure. The chronic form arises from long-term exposure to the irritant and may last from weeks to years. Chronic EAA can ultimately lead to permanent lung scarring (pulmonary fibrosis) and inadequate oxygen intake (respiratory insufficiency).
Introduction
Extrinsic means that the cause originates outside the body. Allergic means that it involves an exaggerated immune system response. Alveolitis is inflammation of the alveoli, the small air sacs of the lungs responsible for breathing (exchange of carbon dioxide and oxygen).
Also known as hypersensitivity pneumonitis (HP), EAA was first described in farmers more than a century ago, but it was not until the early 1960s that its causes and immune mechanisms were identified by Dr. Jack Pepys.
EAA can be categorized as acute, subacute or chronic, depending on the intensity and frequency of exposure to the causative allergens. In general, symptoms of all forms of EAA include shortness of breath (dyspnea) and cough. Less common symptoms include chest tightness and constitutional symptoms like fever, chills, weight loss and a general feeling of discomfort (malaise).
Most cases of this condition are characterized by mild, short (acute) episodes that may be ‘flu-like’ and occur several hours after subsequent exposures to the antigen. Chronic cases develop with repeated episodes or prolonged exposure to the irritant and may result in more serious symptoms like fever, crackling sounds during breathing (rales), difficulty breathing, bluish appearance of the skin (cyanosis) and possibly coughing blood. Chronic cases can lead to serious damage to the lungs involving permanent lung scarring and decreased lung capacity. Lung biopsies may show abnormal formation of white blood cells (granulomas) in the air sacs, which are generally not compact (poorly formed or loose). Since many of its characteristics and symptoms overlap with other lung diseases, EAA is easily misdiagnosed.
EAA is caused by an allergic response to an environmental irritant (allergen) that triggers an allergic reaction. These irritants could have a range of possible sources, including but not limited to, agricultural (animal and vegetable) dusts, funguses, molds and reactive chemicals. The particulates must also be very small (under 5 microns in diameter) to reach the alveoli where oxygen exchange occurs (a micron is one-millionth of a meter in size). As stated earlier, repeated exposure is required to develop an immune or allergic response to the irritant.
This sort of repeated inhalation of microscopic particles is generally associated with certain occupational settings or geographic regions. A wide variety of substances encountered in occupational settings may be linked to this disorder, including irritants associated with birds (avian dust), cheese manufacturing (mold), sugar manufacturing (moldy sugar cane dust), bath tub refinishing (paint catalyst), farming (moldy hay dust), mushroom farming (mushroom compost), working in a laboratory (rat or gerbil urine residue), tobacco (snuff), heating and cooling systems (moldy water), malt working/beer brewing (moldy barley), maple bark disease (moldy maple bark dust), sequoiosis (moldy redwood bark dust), suberosis (moldy cork dust), plastic working (plastic residue), epoxy resin (heated epoxy residue), enzyme detergent (dust) or wheat weevil disease (wheat mold or dust).
EAA is predominantly an occupational disease and is more likely to affect those who have repeated exposure to certain air particulates. Some occupations put workers at higher risk for this condition, such as those in which animal or vegetable dusts are inhaled. For this reason, some subtypes of EAA are named after specific occupations: farmer’s lung, mushroom picker’s disease, and bird breeder’s or bird fancier’s lung, which has a worse prognosis than farmer’s lung, and humidifier lung which is caused by the inhalation of fungus growing in humidifiers, air conditioners and heating systems.
Prevalence depends on climate, pollution levels, geographic conditions, occupational, and industry factors. EAA also occurs more commonly among older individuals, with the average patient’s diagnosis occurring around 50-60 years of age, though it can also be diagnosed in younger adults and children.
Because this condition develops only in certain exposed individuals, a genetic predisposition was hypothesized and tested. Studies investigating genetic susceptibility of EAA have been limited, but human leukocyte antigen (HLA class II) genes, which play a major role in the immune response, have been identified as critical factors contributing to EAA. Additionally, depending on individual genetics, variable amounts of signaling molecules used by the immune system (cytokines) during inflammation may be responsible for EAA’s varying severity.
Due to the varied presentation of symptoms and low prevalence, EAA is easily misdiagnosed. Prompt diagnosis, however, is important because avoiding the causative allergens may provide relief, especially in the early stages. Diagnosis may be reached through a physical or historical information but often requires a combination of findings.
The first step in a patient’s evaluation is to gather a detailed history of potential exposures. EAA can be categorized as either acute, subacute or chronic. Patients with acute EAA may experience symptoms such as fever, cough, difficulty breathing, chills, malaise, chest tightness and muscle pain (myalgias) within 4 to 12 hours after exposure. Patients with subacute and chronic EAA report a gradual onset of difficulty breathing, fatigue and weight loss. These signs and symptoms may be identified during a physical examination.
Typical lung sounds associated with EAA include bubbling or crackling sound from the base of the lungs (bibasilar crackles) and mid-inspiratory squeaks. Wheezing is rarely present with EAA. Airway obstruction or restriction may be revealed in pulmonary function testing, often alongside exercise-induced gas exchange abnormalities.
A chest X-ray of someone with EAA could be either normal or abnormal, depending on the severity of the condition. X-rays also may differ between different types of EAA. For example, the upper lung zone frequently appears to be affected in patients with bird fanciers’ lung, whereas the lower lung zone is more frequently affected in individuals with summer-type hypersensitivity pneumonitis (SHP), which is the most prevalent type of EAA in Japan, caused by seasonal mold contamination. X-rays may also reveal air trapping, scarring, or air-filled sacs of lung tissue (lung cysts).
Antibody testing of the patient’s blood serum may enable identification of the causative allergen (since antibodies are produced to the specific allergen). Most patients have high serum concentrations of circulating antibodies specific for the causative antigen. Unfortunately, there are over 300 known antigens to cause EAA, so pinpointing the cause can be challenging.
For further analysis, it may be recommended to obtain a sample of the lung fluids (bronchoalveolar lavage (BAL) fluid) for analysis of white blood cells in the lungs or a biopsy of the lung (transbronchial lung biopsy or a surgical lung biopsy). Patients with more advanced EAA (fibrotic EAA – lung tissue has been replaced with scar tissue) are generally older (above 65 years old), tend to have lower lung capacity (maximal expiratory volume) and decreased oxygen uptake by the lungs (decrease rate of gas exchange in the alveoli). In advanced cases of lung fibrosis, heart failure and abnormally rounded fingertips (digital clubbing) may occur.
All symptoms can usually be resolved in acute cases if they are diagnosed and treated early before permanent changes in the lungs can develop. If permanent lung changes such lung scarring are present at the time of diagnosis, it is possible that the patient may not respond well to treatment.
Treatment of EAA initially depends on identifying the allergen. Once the causative antigen is identified, preventative measures can be taken to avoid or reduce exposure. For example, in an occupational setting, mild cases may be alleviated by improved ventilation or use of air filtering masks, while severe or prolonged cases may warrant a career change.
If symptoms persist after avoiding exposure, an anti-inflammatory drug such as corticosteroid may be helpful. In acute cases, avoidance measures, in combination with corticosteroids, can often reduce the severity of symptoms. Studies have shown that corticosteroid use is significantly more helpful in acute cases of EAA patients in which no fibrosis has occurred. Drugs that suppress the immune system may also be used to reduce the allergic response in EAA patients. It is important to note that while these drugs may alleviate symptoms and improve breathing capacity in EAA patients, they do suppress the immune system. As a result, patients may be more susceptible to infections. In patients with advanced EAA, some supportive therapies may be prescribed, such as oxygen therapy to increase oxygen uptake by the lungs or drugs that open the airways (bronchodilator). In addition, opioids to control shortness of breath or chronic cough may be prescribed as supportive care for advanced EAA.
Pirfenidone has been studied as a treatment for fibrotic diseases with success and was recently in clinical trials for the treatment of chronic EAA. Because its mechanism of action has anti-inflammatory and anti-fibrotic properties, investigators are evaluating the efficacy of this drug in combination with prednisone (a commonly used steroid drug) and azathioprine (an immunosuppressant) in the treatment of chronic EAA patients with pulmonary fibrosis.
Another active clinical trial is exploring the effects of pulmonary rehabilitation training on symptoms of EAA. This is essentially physical therapy for the lungs, which includes inspiratory muscle training, upper extremity aerobic exercise and progressive resistance training.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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