Pulmonary Medicine

Hypersensitivity Pneumonitis

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 is characterized by acute bouts of fever or dyspnea three to eight hours after the exposure or, in more insidious forms, by progressive dyspnea, cough, and weight loss.

The diagnosis of HP can often be made or rejected with confidence, especially in areas of high or low prevalence, using simple diagnostic criteria. Chest X-rays may be normal in active HP; high-resolution-computed tomography is sensitive but not specific for the diagnosis of HP. The utility of pulmonary function tests is to describe the physiologic abnormalities and the associated impairment.

Despite the pitfalls of false positive and false negatives, antigen-specific IgG antibodies analysis can be useful as supportive evidence for HP. Bronchoalveolar lavage plays an important role in the investigation of patients suspected of having HP. A normal number of lymphocytes rules out all but residual disease. Surgical lung biopsy should be reserved for rare cases with puzzling clinical presentation or to verify the clinical diagnosis when the clinical course or response to therapy is unusual. The most obvious treatment is avoidance of contact with the offending antigen. Systemic corticosteroids are the only reliable pharmacologic treatment of HP, but they do not alter long-term outcome.

Classification

HP is classically subdivided into three phases: acute, sub-acute and chronic. In the acute phase, symptoms of fever dyspnea occur hours after exposure and usually recur with repeated contacts. These symptoms wane within twenty-four hours. Unless they repeat over time, acute bouts are not expected to lead to permanent lung damage.

In the sub-acute phase, the febrile reaction is absent, and recurrences are not clearly perceived. Instead, the patients present progressive respiratory (productive cough and dyspnea) and systemic symptoms (fatigue, weight loss). Some degree of permanent functional loss is expected even if the patient is properly treated.

The chronic phase, which is more difficult to define, is usually defined as occurring when the sub-acute phase is prolonged or in the presence of significant lung sequellae. A recent cluster analysis shows that cases of HP fall into two separate clusters, not three, where HP classified as type 1 is comprised of acute cases and most sub-acute cases, and HP classified as type 2 is comprised of longstanding sub-acute cases and subjects with irreversible lung function loss.

Are you sure your patient has HP? What should you expect to find?

The key to making a diagnosis of HP is to think about it. A thorough clinical history is the key element. HP must be considered when in patients with recurrent episodes of fever and dyspnea and in every case of interstitial lung disease. Since HP often presents as a febrile entity with dyspnea and inspiratory crackles on lung auscultation, most cases are initially believed to have an infectious process and are initially treated with antibiotics.

A clinical history of the subject's environment is essential to finding a suspected source of the antigen. Patients often report chills and may document fever, but the febrile episode is usually over when the patient is seen in the clinic, and the patient's temperature will be normal. Inspiratory crackles are often the only finding on physical examination; tachypnea may also be noted, but cyanosis or clubbing is very unusual.

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 must also include most types of interstitial lung disease. More specifically, since HP is a granulomateous lung disease, the differential diagnosis will include sarcoidosis, beryliosis, and mycobacterial infections.

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, it developed molding, and the subject failed to wear appropriate respiratory protection when manipulating this material. People who have pigeons, doves, parakeets, and other birds in their homes or workplace are also at risk.

The number of environments, clinical settings, and antigens that can cause HP is ever-increasing. Recent publications list such unlikely context 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 sometimes difficult task of finding what that antigen is, usually only by questionnaire. In a large cohort of patients with HP, a definite diagnosis was made without any identifiable offending antigen in 1.5 percent of patients.

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 concommitant viral infection has also been suggested, in which case a subject would be more likely to develop HP if he or she is in contact with a causative antigen during a respiratory viral infection than if he or she is not. Although smoking is often thought of as having a protective effect against the development of HP, non-smoking was not identified as an independent predictor of HP in an HP study (see reference list).

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The only laboratory test that can help establish the diagnosis is the finding of serum antibodies specific to the causative antigen. These tests can be done by double diffusion or by ELISA (enzyme-linked immunosorbant assay). However, these tests are not readily accessible and are not available for many of the potential antigens. What's more, HP cannot be ruled in solely on the basis of positive antibodies or ruled out solely on the basis of negative antibodies. Many asymptomatic farmers (10%) and pigeon breeders (40%) have positive results, and many cases of HP have negative specific antibodies.

Along the same line, 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 an HP 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 and lateral chest x-rays are useful as a first step in establishing the diagnosis of HP, but this simple imaging will be abnormal in 80 percent of cases. CXR typically shows diffuse interstitial infiltrates, but these images are non-specific. In about 20 percent of cases, the CXR is normal.

High-resolution computed tomography (HRCT) is the imaging of choice. HRCT will be abnormal in most, if not all, cases of active HP. The interstitial images described as "ground glass opacities" are usually patchy in nature and predominate at the lower parts of the lung. Although not pathogonmonic for HP, such finding should orient the radiologist and the clinician to consider HP as a highly probable diagnosis. Ground glass opacities can be seen in a variety of other diseases, including desquamative interstitial pneumonitis, carinii pneumonia, mycobacterial infection, bronchiolitis obliterans with organizing pneumonia, bronchoalveolar carcinoma, alveolar proteinosis, and alveolar hemorrhage.

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. Pulmonary function tests have no discriminating values in differentiating HP from other interstitial lung diseases.

The typical physiological profile of acute HP is a restrictive pattern with low DLCO. Expiratory flows can show a mild degree of obstruction, and increased airway responsiveness to methacholine has been reported. In chronic disease, the pattern can be restrictive, but at least in farmer's lung, the most frequent profile is an obstructive defect resulting from emphysema. The reason for the difference in outcome is unknown.

The most important use of pulmonary function tests is as reference for follow-up measures and in establishing the degree of functional loss for compensatory purposes when applicable. Their results may also guide therapy by helping the clinician in selecting those for whom a treatment with corticosteroids may be justified.

What diagnostic procedures will be helpful in making or excluding the diagnosis of HP?

In typical cases, the diagnosis of 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 is recommended, as the presence of a large number of recovered cells that are predominately lymphocytes is highly suggestive of the disease. However, bronchoalveolar lymphocytosis is seen in other diseases, such as sarcoidosis, interstitial pneumonia associated with collagen vascular disease, silicosis, bronchiolitis obliterans with organizing pneumonia, HIV-associated pneumonitis, and drug-induced pneumonitis. In these conditions the number of lymphocytes is usually not as high as in HP. Defining the subtypes of these lymphocytes into CD4 and CD8 positive cells has been suggested to help differentiate HP from sarcoidosis, but more recent studies refute the value of these measures.

Another pitfall in interpreting alveolar lymphocytosis is that normal individuals who are exposed to environments that can cause HP can have significant increases in their BAL lymphocyte number but do not have HP and are not at risk of developing it. Therefore, BAL lymphocytosis has to be interpreted in the context of other evidence that supports the diagnosis of HP, although the absence of bronchoalveolar lymphocytosis would rule out active HP.

Transbronchial lung biopsies are difficult to interpret and basically do not add sufficient value to the diagnosis to warrant their routine use. If HP is suspected, surgical lung biopsy is recommended only for rare cases with puzzling clinical presentation or to verify the clinical diagnosis when the clinical course or response to therapy is unusual. In the acute stages, reports on open-lung biopsies reveal features of interstitial lymphocytes infiltrates and fibrosis, edema, noncaseating granulomas, and bronchiolitis obliterans. Macrophages with foamy cytoplasm are also found within the alveolar space.

Widespread fibrotic reaction is a prominent feature, often without predominant involvement of upper lobes with contraction, in chronic cases. Emphysema is recognized as a long-term complication of HP. Patterns of unusual or non-specific interstitial pneumonitis may be the sole histologic expression in chronic cases.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of HP?

Since HP is a lymphocytic lung disease, some have questioned the usefulness of induced sputum to replace the more invasive BAL. However, this technique has not proven helpful, probably because the lymphocytes are predominately in the distal bronchi and alveoli and not in the main airways.

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 are 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., the 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 or systemic corticosteroid administration is the only form of medical treatment available. The short-term use of corticosteroids (e.g., prednisone 50mg daily for four or five days) accelerates recovery in the severe acute phase and helps control symptoms when exposure cannot be avoided immediately (prednisone 20 mg per day). The long-term use of oral corticosteroids is not recommended because of their side effects and because their use does not seem to change the eventual outcome. Evidence on the use of inhaled steroids is anecdotal.

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 sub-acute and chronic phases, residual affection 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, similar to what has been clearly established in emphysema, where the disease progresses after cigarette smoking cessation. Still, the disease would probably progress faster with continued exposure.

The decision to treat with corticosteroids may be guided by the severity of symptoms and physiological abnormalities. Recovery of pulmonary function by patients who do not receive corticosteroids is slower during the initial stages of the disease, but the maximum values for FVC and DLCO are achieved at the same time as those who did not receive coritcosteroids. Corticosteroid therapy should not be prolonged: twelve weeks of steroids had no better outcome than four weeks of steroids did.

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.

What’s the evidence?

Girard, M, Lacasse, Y, Cormier, Y. "Hypersensitivity pneumonitis". Allergy. vol. 64. 2009. pp. 322-34.

An in-depth review of the pathophysiology of HP.

Hodgson, MJ, Parkinson, DK, Karpf, M. "Chest X-rays in hypersensitivity pneumonitis: a meta-analysis of secular trends". Am J Ind Med. vol. 16. 1989. pp. 45-53.

Classical description of the radiological findings in HP.

Kokkarinen, JI, Tukiainen, HO, Terho, EO. "Effect of corticosteroie treatment on the recovery of pulmonary function in farmer's lung". Am Rev Respir Dis. vol. 145. 1992. pp. 3-5.

A unique, randomized, placebo-controlled trial of corticosteroid therapy in HP.

Lacasse, Y, Cormier, Y, Gibson. "Hypersensitivity pneumonitis". Evidence-based respiratory medicine. BMJ Books and Blackwell Publishing. 2005. pp. 509-20.

An updated review of the best evidence regarding the clinical aspects of HP.

Lacasse, Y, Selman, M, Costabel, U, Dalphin, JC, Ando, M, Morell, F. "Clinical diagnosis of hypersensitivity pneumonitis". Am J Respir Crit Care Med. vol. 158. 2003. pp. 952-8.

A large prospective multi-center cohort study designed to develop a clinical prediction rule for the diagnosis of HP.

Lacasse, Y, Selman, M, Costabel, U, Dalphin, JC, Morell, F, Erkinjuntti-Pekkanen, R. "Classification of hypersensitivity pneumonitis: a hypothesis". International Archives of Allergy and Immunology. vol. 149. 2009. pp. 161-6.

The secondary analysis of the HP Study suggested that the classical classification of acute, subacute and chronic HP is obsolete and that "sub-acute" HP is particularly difficult to define.

Lalancette, M, Carrier, G, Ferland, S. "Long-term outcome and predictive value of bronchoalveolar lavage fibrosing factors in farmer's lung". Am Rev Respir Dis. vol. 148. 1993. pp. 216-21.

Emphysema is now recognized as a long-term complication of HP.

Matar, LD, McAdams, PH, Sporn, TA. "Hypersensitivity pneumonitis". AJR. vol. 174. 2000. pp. 1061-6.

An updated and noteworthy pictorial essay of HP.

Richerson, HB, Bernstein, IL, Fink, JN, Hunninghake, GW, Novey, HS, Reed, CE. "Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis". J Allergy Clin Immunol. vol. 84. 1989. pp. 839-84.

This report describes HP divided into the three classical phases: acute, subacute and chronic.
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