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What every physician needs to know:
Hypersensitivity pneumonitis (HP) is a respiratory disease caused by an exaggerated immune response to inhaled antigens, usually organic in nature. In Europe, it is often referred to as “extrinsic allergic alveolitis.” It can present as acute HP, characterized by acute bouts of fever or dyspnea three to eight hours after the exposure, or it can present as chronic HP, with progressive dyspnea and evidence of lung fibrosis on radiographic studies.
If a typical offending agent is known, the diagnosis of HP can be made with confidence. CXRs may be normal in active HP; high-resolution CT is sensitive but not specific for the diagnosis of HP.
Antigen-specific IgG antibodies analysis can be useful as supportive evidence for HP, but the result should always be considered in conjunction with the rest of the data and not as a singular and definitive test to either rule HP in or out. Surgical lung biopsy should be considered in a patient with interstitial lung disease that lacks a specific diagnosis, but careful consideration must be given to the ability of the patient to tolerate the procedure. Poorly formed noncaseating granulomas are seen on biopsy. The most obvious treatment is avoidance of contact with the offending antigen, although the offending agent is not always known. Immunosuppression with corticosteroids or steroid-sparing agents can be added in select cases.
Classification
HP is classically subdivided into three phases: acute, subacute, and chronic. However, it is often more useful to divide patients into the acute and chronic phases as studies have shown that there is significant clinician variability concerning which patients to classify as subacute HP. In the acute phase, symptoms of dyspnea and sometimes fever occur hours after exposure and usually recur with repeated contacts. These symptoms can wane within twenty-four hours. Unless they repeat over time, acute bouts are not expected to lead to permanent lung damage. In chronic HP, the patient is exposed to the offending agent over a long period of time and has progressive scarring of the lungs. The decline in respiratory function is gradual and not sudden as in acute HP. On CT scan, chronic HP can be difficult to distinguish from other interstitial lung diseases (ILDs) such as idiopathic pulmonary fibrosis or idiopathic nonspecific interstitial pneumonia.
Are you sure your patient has HP? What should you expect to find?
Patients with HP present with shortness of breath and abnormal radiographic findings, as in many other respiratory illnesses. Like all other interstitial lung diseases, patients with HP are often misdiagnosed as having infectious pneumonia, especially as acute HP can present with fever. The key to making the diagnosis is including HP in the differential and taking a thorough history of the subject’s environment to try to establish an offending agent. The diagnosis is supported by a positive HP antibody panel and can be confirmed in some cases with lung biopsies showing non-caseating granulomas.
Beware: there are other diseases that can mimic HP.
Lung infection is by far the most frequent differential diagnosis for subjects with acute bouts of HP. The differential diagnosis for chronic HP must also include most types of interstitial lung disease. Other granulomatous lung diseases include sarcoidosis, berylliosis, and mycobacterial infections. Chronic HP can be very difficult to distinguish from idiopathic pulmonary fibrosis.
How and/or why did the patient develop HP?
HP is an allergic disease most often caused by the inhalation of a variety of organic particles, such as bacteria (Saccharopolyspora rectivirgula) causing farmers’ lung, fungi (Trichosporon cutaneum) causing summer-type HP, mycobacteria (Mycobacterium avium intracellulare) causing hot-tub lung, proteins (altered pigeon serum, probably IgA) causing pigeon breeder’s disease, and chemical products (e.g., Diphenylmethane diisocyanate) causing “MDI” HP.
Any individual who is exposed to significant quantities of these airborne and respirable antigens is at risk of developing HP. For example, farmers develop farmers’ lung because their hay, straw, or grain was harvested without proper drying, allowing molds to flourish, and the subject failed to wear appropriate respiratory protection when manipulating this material. Pigeons, doves, parakeets, and other birds in the home or workplace are another high risk exposure.
The number of environments, clinical settings, and antigens that can cause HP is ever-increasing. Recent publications list such unlikely situations as money counting (a response to ink), colistin aerosolization for gram negative lung infection, and saxophone lung (from molds in wind instruments). A patient develops HP because he or she is exposed to an antigen, and the clinician has the often difficult task of finding what that antigen is, as there are many reported inciting agents for HP. In practice, the offending agent is often unidentifiable.
Which individuals are at greatest risk of developing HP?
The possibility of genetic susceptibility is not clear, as no specific genotypes have been identified. There are reports of familial clusters, but these are probably related to the family’s environment (e.g., dairy farming). Co-factors may play a role in the initiation of HP. The presence of endotoxins with specific antigens could lead to a stronger immune response to the inhaled antigen. The possible role of a concomitant viral infection has also been suggested, in which case a subject would be more likely to develop HP if they are in contact with a causative antigen during a respiratory viral infection than if they are not. Although smoking is often thought of as having a protective effect against the development of HP, studies are not conclusive. Patients with ILD should always be counseled to quit smoking.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
Serum antibodies specific to the causative antigen can help establish the diagnosis and the causative exposure. These tests can be performed by double diffusion or by ELISA (enzyme-linked immunosorbant assay). However, these tests are not available for many of the potential antigens, and the list of antigens included in different laboratories can vary significantly. Further complicating the matter is that many asymptomatic farmers (10%) and pigeon breeders (40%) have positive results, and many cases of HP have negative tests for specific antibodies. Therefore, HP cannot be ruled in solely on the basis of positive antibodies or ruled out solely on the basis of negative antibodies.
Along the same lines, most pigeon breeders have an immune response to their birds, but only a few get pigeon’s breeder’s disease. Almost half of dairy farmers in some regions will have precipitins against Saccharoployspora rectivirgula, the most frequent cause of farmer’s lung, but only three in a thousand in that region will get the disease.
In addition, a study showed fluctuations over four years in the precipitin status of dairy farmers who had repeated measurements of serum antibodies against Saccaropolyspora rectivirgula, Thermoactinomyces vulgaris, and Aspergillus fumigatus. It is currently unclear whether the false negatives result from inappropriate antigens tested or if HP can occur in the absence of specific antibodies to the responsible allergen.
Notwithstanding these limitations, positive serum antibodies were a significant predictor of HP in one study (odds ratio: 5.3; 95% CI: 2.7 – 10.4). The selection of antigens to be tested often needs to be determined locally according to the prevalent antigens.
What imaging studies will be helpful in making or excluding the diagnosis of HP?
Standard PA/lateral CXRs are useful as a first step in establishing the diagnosis of HP. They typically show diffuse interstitial infiltrates, but these images are non-specific. A normal CXR also does not completely rule out HP.
High-resolution CT is the imaging study of choice and should be abnormal in all cases of active HP. Ground glass opacities are the main feature in acute HP. The HRCT in chronic HP is characterized by reticulations. A mid-to-upper lung zone predominance of centrilobular nodular opacities and a mosaic attenuation pattern can help differentiate HP from other ILDs. The mosaicism is more evident on expiratory imaging and indicates air-trapping, which is caused by bronchiolar inflammation and obstruction.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of HP?
Lung function should be measured in all cases of HP. The utility of pulmonary function tests is primarily to describe the physiologic abnormalities and the associated impairment. As with other interstitial lung diseases, the typical physiological profile of HP is a restrictive pattern with low DLCO. However, due to air trapping, expiratory flows can show a mild degree of obstruction, though this is not a common finding. Emphysema can also be present in cases of HP such as farmer’s lung, and these patients can present with mixed obstructive-restrictive pulmonary function tests. Still, the most common pulmonary function profile in HP patients is a pure restrictive pattern.
Pulmonary function tests are important to gauge a trend in lung function and see whether the patient is responding to interventions or declining further. The 6-minute walk test is another useful measure of function. For the 6-minute walk test the distance walked and the patient’s oxygen saturation after exercise are recorded. This is another useful measure of function and can help serially assess disease course and the response to treatment.
What diagnostic procedures will be helpful in making or excluding the diagnosis of HP?
In typical cases, the diagnosis of acute HP can be made with relatively high probability by simple clinical criteria, which include exposure to a known environment/antigen, specific antibodies to that antigen, recurrent symptoms, inspiratory crackles, symptoms four to eight hours after exposure, and weight loss.
In less typical presentations, which is often the case, bronchoscopy with bronchoalveolar lavage may return a large number of recovered cells that are predominately lymphocytes. Bronchoalveolar lymphocytosis is also seen in other diseases, such as sarcoidosis, interstitial pneumonias associated with collagen vascular disease, silicosis, cryptogenic organizing pneumonia, HIV-associated pneumonitis, and drug-induced pneumonitis, so the results should be interpreted with caution. Like the serum antigen panel, it should not be seen as a definitive arbiter to rule the disease in or out. A low CD4/CD8 ratio has classically been associated with HP, but more recent studies suggest high or low ratios can occur with HP.
Transbronchial lung biopsies are difficult to interpret and rarely add sufficient value to the diagnosis to warrant their routine use. If HP is being considered amongst other diffuse parenchymal lung diseases and the diagnosis cannot be made with clinical history and imaging, surgical lung biopsy should be considered. Whereas open lung biopsies were previously the surgical method of choice, now video associated thoracoscopic surgery (VATS) is the preferred, less invasive method of obtaining sufficient lung tissue for diagnosis. However, given the tenuous respiratory status of some patients with ILD and the potential for causing a disease exacerbation, the decision to refer a patient for VATS should be carefully considered.
Surgical lung biopsies reveal features of bronchocentric interstitial lymphocytic infiltrates and small poorly-formed noncaseating granulomas. Macrophages with foamy cytoplasm are also found within the alveolar space. In advanced disease, only isolated multinucleated giant cells, in association with peribronchial fibrosis may be evident. It should be noted that even after surgical lung biopsy, a clear diagnosis is not always established. In fact, in studies that examine the explanted lungs of lung transplant recipients, patients with a diagnosis other than HP prior to transplant occasionally may have their diagnosis changed to HP after tissue examination, and vice versa. This underscores the notion that the diagnosis can be difficult to establish.
If you decide the patient has HP, how should the patient be managed?
Subjects with HP should be removed from contact with the responsible antigen/environment, which may be simple enough if a family pet is the cause. However, when the workplace is the responsible environment or when people cohabitate with pigeons, eliminating the antigenic contact may be difficult. In some developing countries, pigeons are omnipresent in and around human dwellings, and it would be impossible to wear adequate protective respirators in this setting.
In the workplace, it is possible to wear respirators with sufficient filtrating capacity to eliminate almost all respiratory contact with the antigens, although these devices can be uncomfortable. Carbon filter types of respirators, which are placed over the mouth and nose, offer considerable respiratory resistance, while those with battery-operated filters (e.g. AirstreamTM helmet) are more expensive and cannot be worn in cold environments (like those in which hay barns often operate), since the filtered cold air circulates over the head of the subject. In highly dusty environments, respiratory filters are rapidly plugged by the dust, further increasing the resistance to breathing or to the battery-operated pumps.
Oral corticosteroids are the most common form of medical therapy utilized in HP. Two studies have looked at prednisone use prospectively in acute HP, specifically in farmer’s lung. With four weeks of glucocorticoid use, the authors were able to show improvement in some parameters in pulmonary function testing and in radiographic burden of disease. These studies failed to demonstrate a long-term survival benefit with prednisone. Nevertheless, given that prednisone use did improve some parameters in these patients, it is considered the standard of care in acute HP. A typical dosing schedule is prednisone at a dose of 0.5 mg per kilogram of body weight for 2-4 weeks, followed by a taper.
In cases of chronic HP, many expert centers utilize steroid-sparing agents such as mycophenolate mofetil and azathioprine. Often, prednisone is initiated along with the steroid-sparing agents, and then weaned off while the steroid-sparing agent is continued. Chronic low dose prednisone is another treatment option for chronic HP. The evidence for use of these medications is not strong, however, and the decision to initiate long-term immunosuppression should be carefully made. This is especially true given the well-known adverse effects of chronic glucocorticoid use as well as the potential for cytopenias with steroid sparing agents.
What is the prognosis for patients managed in the recommended ways?
The prognosis of HP depends on the stage at which the diagnosis is made and the ability to remove all contact with the antigen as early as possible. One bout or a few bouts of acute attacks are not expected to cause lung damage, but in the chronic phase, residual fibrosis can be severe and can eventually lead to respiratory failure and death.
It is now suspected that, in cases of irreversible lung damage, the lung destruction process can continue even if all contact with the antigen is removed. Still, the disease would likely progress faster with continued exposure, and it is highly advisable to remove the offending agent as possible. Patients that progress despite removal of known antigens and immunosuppressive medications may eventually require referral for lung transplantation.
What other considerations exist for patients with HP?
Patients should be assured that their disease is not contagious. They should be part of the solution in eliminating the cause. Work-related HP may have important psychosocial consequences; for example, more than half of patients with farmer’s lung will quit farming within six years of the diagnosis.
Several interventions have been proposed in order to avoid recurrence of the disease if contacts with the offending antigen cannot be eliminated. There is some evidence that most agricultural workers who develop HP may be able to continue their occupations if appropriate measures are taken.
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