Hypersensitivity Pneumonitis Update (Review)

Hypersensitivity Pneumonitis 2012 Review (More PulmCCM Topic Updates)

Hypersensitivity pneumonitis (external intrinsic alveolitis) is an "orphan disease," which means it's uncommon and lacks any likely way to effectively "monetize" the disease with drugs or device therapy, resulting in its being largely ignored from a research funding standpoint. If you think you don't know much about it, don't feel bad: no one does. Expert panels (the 2 majors being the NHLBI and the HP Study Group) can't even agree on a definition for hypersensitivity pneumonitis, but they seem to agree on the following:

Hypersensitivity pneumonitis (HP) is a lung disease caused by inhaling an antigen to which a person has already been sensitized. HP may or may not also have systemic manifestations such as weight loss, myalgias and fever. Importantly, sensitization alone (as evidenced by serum testing) is not diagnostic, because many people with other diseases with respiratory symptoms are sensitized to various environmental antigens.

What Causes Hypersensitivity Pneumonitis? Etiology of HP

Hypersensitivity pneumonitis is caused by ongoing inhalation of an antigen after a person becomes sensitized to it. After an extended period of repeated exposure, irreversible inflammatory processes and lung fibrosis may occur, resulting in progressive HP despite removal of antigen exposure. Therefore, HP is a form of interstitial lung disease that is preventable and "curable" by exposure recognition and avoidance.

Organic antigens (large molecules) from bacteria, birds, and fungi (molds & yeasts) are by far the most common causes of hypersensitivity pneumonitis. Chemicals (small molecules like isocyanates, dyes, and zinc) can also cause HP by acting as haptens. Rather than memorize a list of hundreds of antigens, it makes more sense to remember environmental factors or situations that can result in ongoing antigen exposure. The major ones are:

• Moldy hay or grain (usually, farmers)

• Humidifiers, contaminated forced-air circulation systems, hot tubs

• Birds: direct contact, down comforters or pillows, or sharing a ventilation system with a birder

• Spray paint (auto painters), metalworkers' fluids, and polyurethane foam

In addition to antigen sensitization and subsequent exposure, a separate "trigger factor" may be required in many people who develop hypersensitivity pneumonitis. It's believed that these separate exposures trigger the immune system to begin the inflammatory process in the lungs. Postulated triggers are viruses, anthrax vaccination, and endotoxin, based on reports of patients who were exposed to antigen without symptoms for extended periods, but then developed HP after exposure to a trigger factor.

About one in 100,000 people get hypersensitivity pneumonitis per year; about 0.5 - 3% of farmers will get HP in their working lives. Because HP can represent 4-15% of patients with interstitial lung disease, and is curable/reversible, hypersensitivity pneumonitis is an important consideration in the work-up and evaluation of ILD.

Signs and Symptoms of Hypersensitivity Pneumonitis

The concept that there exist "stages" of hypersensitivity pneumonitis (acute, subacute, chronic) has gone out of favor. Dyspnea and cough are the only consistent symptoms shared by people with hypersensitivity pneumonitis. Like other immunologically mediated illnesses, HP is highly heterogeneous in its manifestations. Patients may experience repeated acute episodes of dyspnea, cough, and fever, or may have few or no defined acute episodes, instead having the insidious progression of breathlessness and cough.

Lacasse et al described 2 "clusters" of HP presentations among 168 patients with hypersensitivity pneumonitis from the HP Study Group:

1. Recurrent systemic symptoms (chills, body aches/myalgias), dyspnea and cough with normal chest X-rays (cluster 1)

2. Clubbing, hypoxemia, fibrosis on chest CT scans, and restrictive pulmonary function tests (cluster 2)

In this analysis, the entity "subacute" hypersensitivity pneumonitis was not identifiable, essentially. This descriptive scheme hasn't been prospectively validated (and neither has the "stages" system).

Patients with chronic or fibrotic HP may also experience superimposed acute exacerbations of hypersensitivity pneumonitis, analogous to the acute exacerbations seen in patients with idiopathic pulmonary fibrosis (an abrupt worsening of dyspnea, with new radiographic changes, in the absence of infection or edema). These occur in the absence of exposure to the antigen responsible for the original development of HP. As in IPF, the cause of these acute exacerbations is unknown, but they portend a very poor prognosis.

Diagnosis of Hypersensitivity Pneumonitis

Diagnosing hypersensitivity pneumonitis is hard, for two main reasons: its clinical presentation and chest X-ray/chest CT findings overlap broadly with other interstitial lung diseases, and because antigen exposures can be surprisingly difficult to identify. Hypersensitivity pneumonitis is therefore a clinical diagnosis made on an analysis of all the available data. There are no accepted diagnostic criteria; however, six factors (antigen exposure, positive precipitating antibodies, recurrent episodes, inspiratory crackles, symptoms 4-8 hours after exposure to antigen, and weight loss) are 98% predictive of HP when all 6 are present, and effectively rule out HP when none are present (Lacasse AJRCCM 2003)

Antigen exposure: This must be present, and must be identified by history, which is probably the most important part of an evaluation for hypersensitivity pneumonitis (or any interstitial lung disease). The ACCP has published a draft questionnaire for interstitial lung disease workup to help guide this meticulous and time consuming process.

Serum antibodies as evidence of antigen exposure are helpful to corroborate the diagnosis of hypersensitivity pneumonitis, but because of their high false positive and false negative rates, they are insufficient by themselves to rule in or rule out HP, and must be considered supporting evidence only. Antigen testing is unreliable for a variety of reasons, which can be summarized as the victory of complexity in nature & the immune system over our testing technology. The ELISA method is preferred, but even this gold standard lacks standardization.

High-resolution CT scan: HRCT findings are highly variable in hypersensitivity pneumonitis. For proof, visit these pictorial atlases of HP from AJR 2007 and AJR 2000 (a fine review article in its own right). 96% of HRCT scans in hypersensitivity pneumonitis are abnormal; findings include ground-glass opacities and centrilobular nodules with mosaic attenuation due to air trapping in expiratory images (in so-called subacute HP), and fibrosis superimposed on the above findings in so-called chronic HP. When radiologists are blinded, the findings are not reliably distinguishable from non-specific interstitial pneumonitis (NSIP) or idiopathic pulmonary fibrosis (IPF). Mediastinal lymphadenopathy can occur in HP; its presence does not rule out HP.

Pulmonary function tests: PFTs cannot distinguish hypersensitivity pneumonitis from other interstitial lung diseases; rather, pulmonary function tests are used to identify the degree of respiratory impairment. A restrictive pattern is common in both acute and chronic HP, but obstructive disease due to emphysema is often seen in farmer's lung. Contrary to medical myth, people with hypersensitivity pneumonitis often have normal DLCO (>20% of the time).

Bronchoscopy and Bronchoalveolar lavage (BAL): Virtually all patients with ongoing hypersensitivity pneumonitis have a lymphocytosis on BAL (patients with inactive, chronic fibrosis or "residual disease" may not). This is nonspecific, though: many normal patients exposed to antigen have BAL lymphocytosis, as do patients with sarcoidosis and some other lung diseases. The CD4/CD8 ratio's usefulness is being challenged: patients with HP can have high or low CD4/CD8 ratios. ATS recently published a statement on their advised use of BAL in the evaluation of ILD.

On histology from transbronchial biopsy, hypersensitivity pneumonitis often shows noncaseating granulomas; this finding is not sensitive or specific enough to use as more than supporting evidence.

Differential Diagnosis / Alternative Diagnoses to HP: Lung infection is the most often-considered alternative diagnosis when people present with acute hypersensitivity pneumonitis, and should be ruled out. Sarcoidosis is most often considered with HP (both have noncaseating granulomas, lymphocytosis on BAL, and nodules on chest CT). Sarcoidosis' inflammation tends to be near granulomas in a lymphangitic distribution; in HP, granulomas follow the airways, and inflammation (interstitial pneumonitis findings) are found far away from granulomas.

In chronic HP (i.e., when fibrosis is present), the differential diagnosis widens to include virtually all diffuse parenchymal lung disease (all ILD), with NSIP and IPF the top alternative diagnoses.

Treatment of Hypersensitivity Pneumonitis

If antigen exposure can be identified at an early stage (before permanent lung damage occurs), and then avoided forever, hypersensitivity pneumonitis is reversible and 100% curable. For this reason, and because of the potentially poor outcomes without treatment, an exceedingly thorough search for an antigen exposure is crucial in patients with signs & symptoms compatible with hypersensitivity pneumonitis.

Experts believe that once emphysema or fibrosis occur, hypersensitivity pneumonitis can progress in the absence of antigen exposure. In these cases, systemic corticosteroids are routinely given, and seem to result in initial improvement in cough and dyspnea, but not to slow the progressive course of the disease. Ultra-fine-particle inhaled steroids worked in one patient, and pentoxifylline shows experimental (in vitro) promise.

Lacasse Y et al. Recent Advances in Hypersensitivity Pneumonitis. Chest 2012; 142:208-217.

Gulati M. Hypersensitivity Pneumonitis: What's New? ACCP website. 

Draft questionnaire for ILD workup, including potential antigen exposures. ACCP website.