Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP), also referred to as extrinsic allergic alveolitis (a misnomer, since type I immunopathology is not evident in this syndrome), results from the inflammatory response to inhalation of environmental antigens. The sequence of events leading to lung disease remains to be fully elucidated, but type II (immune complex) and type III (cell-mediated) responses seem to predominate. HP seems to represent a final common pathway to a variety of antigens, each of which tends to be encountered in a relatively unique niche, and each of which has it's own name based on the source of exposure. Please see the following link to the Merck Manual for a list of common HP syndromes and their associated antigens:

http://www.merckmanuals.com/media/professional/pdf/Table_055-5.pdf

HP generally comes in two flavors, acute and chronic. Acute disease tends to occur within a few hours of antigen exposure, and likely results from inhalation of a large amount of antigen. The clinical presentation is characterized by flu-like symptoms (fever, chills, malaise, arthralgia, myalgia, and headache), shortness of breath, chest tightness, and dry cough. Symptoms usually remit within one to two days of withdrawal of the offending antigen, but recur with repeated exposure. Radiographically, these patients exhibit upper-zone predominant alveolar opacities that may be indistinguishable from a variety of other clinical syndromes such as pulmonary edema, atypical pneumonia, acute eosinophilic pneumonia, diffuse alveolar hemorrhage, or ARDS. Type III immunopathology is thought to be important in the pathogenesis of acute HP.

Subacute and chronic HP result from repeated low-level antigen exposure, and is characterized by the insidious onset of breathlessness, and cough. The cough may be productive of mucoid sputum, and other nonspecific symptoms of chronic illness, such as fatigue, malaise, anorexia, and weight loss. Radiographically, these patients may have completely normal chest X-rays (even in the presence of a markedly abnormal chest CT), or may have lower-zone predominant reticulonodular abnormalities. High resolution CT of the chest reveals ill-defined peribronchovascular and centrilobular nodules, with varying degrees of reticular and honeycomb abnormalities, which reflect fibrosis (scarring) and give an indication as to the severity and chronicity of disease. Expiratory CT imaging reveals diffuse gas trapping. During evaluation for interstitial lung disease, any time that evidence of fibrosis and gas trapping appear simultaneously, a diagnosis of chronic HP must be considered.

Histopathological evaluation of acute HP is problematic, since symptoms usually resolve before lung biopsy can be performed, and since lung biopsy is generally performed relatively late in the evaluation of any lung disease. Chronic HP can occasionally be diagnosed by bronchoscopy and transbronchial biopsy, but in general, the size of transbronchial biopsy specimens (perhaps 1-2 mm in largest dimension) is inadequate to make a firm diagnosis. Open lung biopsy reveals poorly formed, noncaseating granulomas, composed of aggregated lymphocytes with surrounding monocytes and rare multinucleated giant cells. These tend to be located near small airways, corresponding with the location of nodules found on CT scans. This probably also explains why gas trapping is seen on expiratory imaging, since as the patient exhales, small airways that are already extrinsically compressed by nodules tend to collapse before unaffected airways do. Immunohistochemical staining reveals a high CD8+/CD4+ ratio. Mononuclear airway and alveolar infiltrates may also be seen.

Diagnosis is typically made based on the clinical history and radiographic findings, with occasional reliance upon lung biopsy. Identification of the offending antigen can be problematic, as detection of specific antibodies can be inconclusive, and inhalational challenge is investigational (and theoretically dangerous). A meticulous elicitation of exposure history is critical, and sometimes a home or work visit by an industrial hygeinist is required. Physicians should inquire about dust or aerosol exposures in the workplace and at home, as well as any recreational or hobby exposures. Common culprits include molds (musty unfinished basements, water-damaged drywall), indoor hot tubs (cladosporium or mycobacterium avium), woodworking (a variety of antigens depending on the species of wood and its indigenous bacterial and fungal commensals), and pets. Of note, a common mantra in pulmonary medicine is, "Find the bird."

Treatment of HP is centered around identification and removal of the offending antigen, usually coupled with systemic corticosteroid therapy. Inhaled corticosteroids are a theoretical option, but have not been studied rigorously. In a brief survey of the literature, I found two case reports and one abstract describing successful treatment of HP with inhaled steroids. Typical systemic corticosteroid regimens consist of one month of therapy with prednisone at 1 mg/kg/day (or equivalent dose of another agent such as prednisolone, hydrocortisone, or dexamethasone), followed by a gradual taper to 10 mg per day. Cessation of steroid therapy may be attempted once clinical and radiographic resolution have been achieved, but remission is not uncommon, and some patients require prolonged maintenance therapy. Reports of use of steroid sparing drugs in HP are lacking, but I have personally treated one patient, who is a brittle diabetic, with azathioprine monotherapy with some success.

The prognosis of HP depends on a number of factors, including the chemical composition of the antigen, the duration and intensity of exposure, and the nature of the patient's immunologic response to the antigen. Lung fibrosis, in general, is irreversible, but corticosteroid therapy and withdrawal of antigen can attenuate or prevent progression of disease. Disease can, however, progress to end-stage fibrosis. Lung transplantation is an option for these patients. A case series was recently published by a group from the University of Colorado and National Jewish describing four patients with acute exacerbations of HP. This small case series did not identify a cause for these exacerbations. As is typical with acute exacerbations of other interstitial lung diseases, all patients failed to respond to antibiotics and high dose immunosuppression. Three of the four died, and one went on to emergent bilateral lung transplantation.


Selected Bibliography:
1. Olson AL, Huie TJ, Groshong SD, Cosgrove GP, Janssen WJ, Schwarz MI, Brown KK, and Frankel SF. Acute Exacerbations of Fibrotic Hypersensitivity Pneumonitis: A Case Series. Chest 2008; 134(4): 844-850.
2. Selman M. Hypersensitivity Pneumonitis. In: Schwarz MI, King TE, editors. Interstitial Lung Diseases. Hamilton, ON. BC Decker Inc; 2003. pp 452-484.