Chronic Hypersensitivity Pneumonitis: Important Considerations
Agents capable of inducing hypersensitivity pneumonitis are found in a variety of settings including the workplace, home and in recreational activities. Although the list of causative environments continues to expand, the antigens reported are similar to prior publications (see below).
Causes of hypersensitivity pneumonitis:
The most common causes remain exposure to avian antigen and moldy environments. Over the past 5–10 years, mycobacterial antigens, typically encountered in hot tubs, pools or metal working fluids, have also become an accepted cause of hypersensitivity pneumonitis. The latency between the onset of the exposure and the onset of disease is variable, ranging from months to decades. A recent population-based study from the Czech Republic reported a range of 1 month to 49 years and a median latency of 12.5 years. Other series report a similar range with median latency of 8.7 years.
Recent publications have expanded our knowledge regarding several features of exposure in chronic hypersensitivity pneumonitis including: the importance of finding the relevant exposure, the importance of occult or low level exposure as a cause of disease and the difficulty in detecting the exposure in the setting of fibrotic hypersensitivity pneumonitis. Identification and removal of exposure is a cornerstone of management and is important for prognosis in subacute hypersensitivity pneumonitis. However, in chronic hypersensitivity pneumonitis, progression even after removal from exposure is well described and data regarding the importance of exposure removal were lacking. A recent study by Fernandez Perez et al. addressed this important issue. They identified 142 cases with surgical lung biopsies where a multidisciplinary review found a diagnosis of chronic hypersensitivity pneumonitis. Antigen avoidance and abatement procedures were recommended for all patients with a detected causative exposure. They found improved mortality in those with an identifiable exposure and this benefit remained statistically significant after multivariate analysis. The average survival for the cohort declined from 18.2 to 9.3 years when a causative exposure was not discovered.
Another study highlights the importance of occult exposure as a cause of disease and the ability of hypersensitivity pneumonitis to mimic IPF. Morrell et al. performed a case-cohort study on 46 consecutive patients diagnosed with IPF according to 2011 guidelines. A standardized questionnaire designed to look for occult exposure was then administered at follow-up visits. They found previously undetected avian antigen in 19 patients, usually in bedding, mold in 4 patients and isocyanates in 1 patient. This led to additional testing including inhalational challenge to the putative antigen, precipitin testing, bronchoalveolar lavage (BAL) and additional surgical biopsies. In the end, the diagnosis was changed from IPF to hypersensitivity pneumonitis in 20 of the 46 (46%) patients.
Detecting relevant exposures is thus critically important in the evaluation of patients with fibrosing lung disease for an accurate diagnosis and in the management of patients when hypersensitivity pneumonitis is diagnosed. Unfortunately, finding the inciting antigen is extremely difficult in fibrotic hypersensitivity pneumonitis. When computed tomography (CT) findings typical of subacute or acute hypersensitivity pneumonitis are present (ground glass and/or diffuse centrilobular nodules), the exposure is detectable by an experienced clinician over 90% of the time. However, when the high-resolution computed tomography (HRCT) is more typical of a fibrotic IIP, it becomes much more challenging. In a series of 85 consecutive cases seen at the Mayo clinic, an antigen was not found in 25%. In the series by Fernandez Perez et al. discussed above, an inciting antigen was not discovered in 53% of the patients. Likewise, an exposure was not detected in 60% of the 206 patients from the University of California San Francisco cohort. In this trial, the study cohort was enrolled in their database from 2001 to 2012. Patients had ILD of at least 3 months duration and both initial and follow-up pulmonary function tests. Hypersensitivity pneumonitis was diagnosed by multidisciplinary conference, and in only 40% of the 207 cases was an inciting exposure identified. Taken together, these studies illustrate the challenge and importance of determining the relevant exposure, not just for the management of hypersensitivity pneumonitis, but also in the evaluation of fibrotic lung diseases. A thorough exposure history looking for exposures associated with hypersensitivity pneumonitis, including attention to seemingly minor exposures, is thus an essential part of the evaluation of patients presenting with diffuse parenchymal lung disease (see below).
The exposure history for chronic hypersensitivity pneumonitis:
Exposure
Agents capable of inducing hypersensitivity pneumonitis are found in a variety of settings including the workplace, home and in recreational activities. Although the list of causative environments continues to expand, the antigens reported are similar to prior publications (see below).
Causes of hypersensitivity pneumonitis:
Microbial agents
Fungi, for example, Aspergillus, Penicillium, Cladosporium, Trichosporon, Aureobasidium
Bacteria, for example, thermophilic actinomyces, Bacillus subtilis, Klebsiella, Epicoccum nigrum
Mycobacteria, for example, Mycobacterium avium, M. immunogen
Amoebae
Animal proteins
Common – avian
Rare – fish meal, rat urine, silkworm larvae
Chemical sensitizers
Isocyanates, anhydrides, pyrethrum, sodium diazobenzene sulfate, copper sulfate
The most common causes remain exposure to avian antigen and moldy environments. Over the past 5–10 years, mycobacterial antigens, typically encountered in hot tubs, pools or metal working fluids, have also become an accepted cause of hypersensitivity pneumonitis. The latency between the onset of the exposure and the onset of disease is variable, ranging from months to decades. A recent population-based study from the Czech Republic reported a range of 1 month to 49 years and a median latency of 12.5 years. Other series report a similar range with median latency of 8.7 years.
Recent publications have expanded our knowledge regarding several features of exposure in chronic hypersensitivity pneumonitis including: the importance of finding the relevant exposure, the importance of occult or low level exposure as a cause of disease and the difficulty in detecting the exposure in the setting of fibrotic hypersensitivity pneumonitis. Identification and removal of exposure is a cornerstone of management and is important for prognosis in subacute hypersensitivity pneumonitis. However, in chronic hypersensitivity pneumonitis, progression even after removal from exposure is well described and data regarding the importance of exposure removal were lacking. A recent study by Fernandez Perez et al. addressed this important issue. They identified 142 cases with surgical lung biopsies where a multidisciplinary review found a diagnosis of chronic hypersensitivity pneumonitis. Antigen avoidance and abatement procedures were recommended for all patients with a detected causative exposure. They found improved mortality in those with an identifiable exposure and this benefit remained statistically significant after multivariate analysis. The average survival for the cohort declined from 18.2 to 9.3 years when a causative exposure was not discovered.
Another study highlights the importance of occult exposure as a cause of disease and the ability of hypersensitivity pneumonitis to mimic IPF. Morrell et al. performed a case-cohort study on 46 consecutive patients diagnosed with IPF according to 2011 guidelines. A standardized questionnaire designed to look for occult exposure was then administered at follow-up visits. They found previously undetected avian antigen in 19 patients, usually in bedding, mold in 4 patients and isocyanates in 1 patient. This led to additional testing including inhalational challenge to the putative antigen, precipitin testing, bronchoalveolar lavage (BAL) and additional surgical biopsies. In the end, the diagnosis was changed from IPF to hypersensitivity pneumonitis in 20 of the 46 (46%) patients.
Detecting relevant exposures is thus critically important in the evaluation of patients with fibrosing lung disease for an accurate diagnosis and in the management of patients when hypersensitivity pneumonitis is diagnosed. Unfortunately, finding the inciting antigen is extremely difficult in fibrotic hypersensitivity pneumonitis. When computed tomography (CT) findings typical of subacute or acute hypersensitivity pneumonitis are present (ground glass and/or diffuse centrilobular nodules), the exposure is detectable by an experienced clinician over 90% of the time. However, when the high-resolution computed tomography (HRCT) is more typical of a fibrotic IIP, it becomes much more challenging. In a series of 85 consecutive cases seen at the Mayo clinic, an antigen was not found in 25%. In the series by Fernandez Perez et al. discussed above, an inciting antigen was not discovered in 53% of the patients. Likewise, an exposure was not detected in 60% of the 206 patients from the University of California San Francisco cohort. In this trial, the study cohort was enrolled in their database from 2001 to 2012. Patients had ILD of at least 3 months duration and both initial and follow-up pulmonary function tests. Hypersensitivity pneumonitis was diagnosed by multidisciplinary conference, and in only 40% of the 207 cases was an inciting exposure identified. Taken together, these studies illustrate the challenge and importance of determining the relevant exposure, not just for the management of hypersensitivity pneumonitis, but also in the evaluation of fibrotic lung diseases. A thorough exposure history looking for exposures associated with hypersensitivity pneumonitis, including attention to seemingly minor exposures, is thus an essential part of the evaluation of patients presenting with diffuse parenchymal lung disease (see below).
The exposure history for chronic hypersensitivity pneumonitis:
Part 1: search for the antigen
Avian antigen – birds at work or in the home, feather pillows, feather duvets or mattress covers, feather decorations
Microbial products
A – visible contamination with mold or mildew on walls, floors, furniture, air conditioning vents or filters, the presence of musty odors in the home or workplace
B – liquid sources that could allow growth – humidifiers, vaporizers, hot tubs, pools, swamp coolers, indoor fountains, metal working fluids, including questions regarding clarity, slime and odors
C– potential for water contamination – known water damage from floods, leaks, broken pipes in the home or workplace. High-humidity environments or products from those environments including greenhouses, compost, mushroom farming, other food production where mold growth can occur, use of water-damaged materials including wood or wood with bark in place, moldy hay or animal feed.
Chemical sources: use of isocyanates (two part paint use, furniture manufacture, spray foam use), anhydrides, Pauli's reagent (in chromatography), use of pyrethrum insecticide or copper sulfate
Part 2: timing – exposure must precede disease onset but still be present at disease onset to be causative. These antigens do not persist in tissue.
Part 3: latency – widely variable ranging from a few weeks to decades
Part 4: symptoms – association of constitutional and/or increased respiratory symptoms within 12 h of any of the above exposures (less likely in chronic than subacute or acute disease).
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