Nonspecific Interstitial Pneumonitis or Hypersensitivity Pneumonitis?
Case Editor - Victor Kim
Reviewed By Environmental & Occupational Health Assembly
Erica Hughes, MD
Senior Pulmonary Fellow
University of Texas Southwestern Medical Center
Craig Glazer, MD, MSPH, FCCP
Assistant Professor of Medicine
University of Texas Southwestern Medical Center
A 51-year-old man initially presented with dyspnea and dry cough. He denied any constitutional symptoms including fevers, chills, arthralgias, myalgias, night sweats and weight loss. His primary care physician initially treated him with antibiotics without response. The dyspnea on exertion and cough continued to progress over the next several months.
His past medical and surgical history was unremarkable. His family history was positive for sarcoidosis. He was taking no medication and was a nonsmoker. He had no allergies. His occupational history was significant for working in a hospital for many years, and he was not exposed to workplace agents associated with interstitial lung disease.
After several months of symptoms unresponsive to antibiotics, a chest radiograph was performed and revealed interstitial disease. He was subsequently referred to a pulmonologist who performed pulmonary function tests that showed restriction and a severely reduced diffusion capacity.
Although tachypneic, he was not using his accessory muscles. HEENT was unremarkable. Chest examinations indicated symmetric excursions and expansion, resonant to percussion bilaterally. There were bilateral inspiratory crackles halfway up the chest posteriorly. His heart rhythm was regular and he had no murmur or gallop. His abdomen was soft with normal bowel sounds and no organomegaly. His extremities were without cyanosis, clubbing or edema. His skin and joint exams were unremarkable.
Pulmonary function tests
FVC 2.44 (51%)
A high-resolution computed tomography (HRCT) of the chest showed diffuse ground-glass opacities with bibasilar fibrotic changes. A bronchoscopy with bronchoalveolar lavage and transbronchial biopsy revealed 30% lymphocytes and nondiagnostic pathology. An open lung biopsy revealed fibrotic nonspecific interstitial pneumonia (NSIP). Prednisone was started with some initial symptomatic improvement. His symptoms, however, progressed again despite continued prednisone, and he was referred to our institution for a second opinion. At the time we evaluated him, his symptoms were present 1 year and had continued to progress despite the treatment with prednisone. His physical examination revealed diffuse inspiratory crackles and he required continuous supplemental oxygen because of resting hypoxemia.
His connective tissue serologies were negative, but on further questioning, he admitted buying two parakeets for his family 3 months before the onset of symptoms. Precipitins to parakeet droppings were negative. The birds were removed from his home, and his house, including the heating and air conditioning system, was professionally cleaned. The house had no carpet in the area where the birds were housed. Azathioprine was added to his prednisone, starting at 50 mg/day with plans to increase the dose over a 2 month period if needed. One month later, his symptoms were markedly improved and his supplemental oxygen was discontinued. His prednisone and azathioprine were weaned over the next year. He is now stable off all therapy.
The finding of NSIP on a surgical lung biopsy is not specific for idiopathic disease. NSIP was initially described as a pathologic entity by Katzenstein and Fiorelli in 1994 (1). In their series, 24 of the 64 cases had potential causes; 10 cases had a history of underlying connective tissue disease; 2 were taking medications known to cause interstitial pulmonary reactions, and 12 had a history of exposure to agents known to cause hypersensitivity pneumonitis. The diagnosis of hypersensitivity pneumonitis (HP) is based upon compatible historical and objective data. Our patient’s clinical condition satisfied the diagnostic criteria for hypersensitivity pneumonitis proposed by Cormier et al., (2), which are: an appropriate exposure, dyspnea on exertion, inspiratory crackles, and a lymphocytic alveolitis. Historically, HP presents with symptoms of cough, malaise, and dyspnea. Biopsy classically reveals cellular bronchiolitis, lymphocytic interstitial infiltrates, and poorly formed granulomas (3); however, the histologic patterns may vary considerably. Vourlekis, et al., subsequently described 6 cases of hypersensitivity pneumonitis whose sole pathologic finding on biopsy was NSIP, confirming that the pathologic spectrum of hypersensitivity pneumonitis includes isolated NSIP (4). Ohtani, and colleagues recently confirmed that patients with Bird-breeder’s lung can have the cellular or fibrotic form of NSIP (5). In their study, the diagnostic criteria for chronic bird-breeder’s lung included a history of bird exposure, immunologic reactivity to bird antigen, a positive exposure challenge to bird antigen, evidence of interstitial lung disease on biopsy, progressive deterioration on pulmonary function tests over a year and symptoms of greater than 6 months duration. A thorough occupational and exposure history is thus essential before accepting a diagnosis of idiopathic NSIP.
The classic pathologic triad of hypersensitivity pneumonitis includes cellular bronchiolitis, interstitial infiltration with chronic inflammatory cells, and non-necrotizing granulomas. However, there is wide variability and many patients will not have all three components of the triad. Even the granulomas are not always present. (6) Chronic cases are more likely to have fibrotic NSIP changes (5). UIP is also possible. The series of Ohtani et al., had 11 patients with pathology consistent with UIP. (5) Churg ald colleagues also recently reported that chronic HP can present with pathology of UIP. (6) Biopsy features more suggestive of HP than IPF as the cause of UIP include a bronchiolocentric accentuation of disease and the presence of either multinucleated giant cells or poorly formed granulomas (4, 7). Idiopathic UIP is difficult to differentiate from chronic HP by clinical criteria and HRCT often cannot distinguish the two. In a study comparing the radiographic diagnosis of 60 patients with UIP and HP, two radiologists were able to make a confident radiographic diagnosis in 62% of cases, and 10% of the time the confident diagnosis was incorrect (8).
An accelerated decline in lung function with continued antigen exposure has been demonstrated for most forms of HP. (13) For example, symptomatic pigeon breeders, with continued antigen exposure, monitored for 18 years showed a fourfold greater average rate of decline in pulmonary function in comparison with those who were not continuously exposed. (14) Therefore, the cornerstone of HP treatment is cessation of exposure. However, the clinical course of HP is variable even with contact avoidance. Acute HP generally resolves without sequelae. (15) However, progressive impairment may occur with recurrent exposure or with a single significant exposure. (16) In subacute and chronic HP, some patients may progress despite removal while others do not, even with ongoing exposure (17, 18). At present, there is no reliable way to determine who will tolerate ongoing exposure, and removal is thus recommended (13). In the setting of residential bird exposure, simply removing the bird from the home does not guarantee complete exposure removal. One study detected high levels of bird antigen in the home of patients with bird breeder’s lung even 18 months after the bird was removed (19). In this study carpet was a significant antigen reservoir.
Pharmacologic therapy may not prevent progression if the exposure is not eliminated. However, it can be important as a supplement to antigen removal in certain settings. In acute HP its main effect seems to be shortening the duration of symptoms. In patients with acute HP, 2 months of corticosteroids therapy was associated with a more rapid resolution of functional and radiographic abnormalities but long-term follow-up found no difference compared to placebo (20). Controlled trials are lacking for more severe cases. In mild cases of subacute or chronic HP disease resolution or stabilization may occur with exposure removal alone. However, for more severe cases, oral corticosteroids, usually 40 to 60 mg per day are usually used. They are continued until significant symptomatic and objective functional improvement occurs. Pulmonary function should be monitored within the first 4 weeks after initiation of treatment (21). In refractory cases, cytotoxic agents such as cyclophosphamide, azathioprine, and cyclosporine have been used (13).
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