Articles
Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study

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Summary

Background

The clinical features of idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis can be indistinguishable; the need to eliminate occult environmental factors known to cause pulmonary fibrosis in patients suspected to have IPF during diagnostic evaluation is evident. We aimed to investigate occult, putative causes in the environments of patients diagnosed with IPF using tests beyond those conventionally used.

Methods

In this case-cohort study, 60 consecutive patients diagnosed with IPF on the basis of the 2000 American Thoracic Society (ATS) and the European Respiratory Society (ERS) criteria were prospectively followed up every 4 months for 6 years between Jan 1, 2004, and Dec 31, 2009. At each visit a uniformly applied questionnaire was administered to these 60 patients to identify occult antigen exposure known to cause hypersensitivity pneumonitis. Patients underwent specific IgG determination, bronchoalveolar lavage, bronchial challenge testing with suspected antigens, and re-review of histopathological features in existing and subsequently obtained surgical lung biopsy samples and from lung explants. Specimens obtained from suspected sources from the patient's environment were subjected to cultures in microbiology laboratory. These clinical data and discussions among pulmonologists and radiologists familiar with IPF were used to confirm the diagnosis in accordance with 2011 ATS, ERS, Japanese Respiratory Society, and Latin American Thoracic Association guidelines; 46 of the 60 patients had IPF according to the 2011 guidelines, and our analyses in this study were focused on these 46 patients.

Findings

20 of the 46 (43%, 95% CI 29–58) patients with IPF according to 2011 guidelines had a subsequent diagnosis of chronic hypersensitivity pneumonitis: nine patients had positive bronchial challenge testing (eight of whom were also IgG positive and six of these patients also had surgical lung biopsy showing a pattern consistent with chronic hypersensitivity pneumonitis); seven were IgG positive plus had histopathology on surgical lung biopsy that was consistent with hypersensitivity pneumonitis; one was IgG positive plus had greater than 20% lymphocytes in bronchoalveolar lavage fluid; and three had findings on surgical lung biopsy that were consistent with subacute hypersensitivity pneumonitis (and IgG positive). Altogether, 29 of 46 patients diagnosed with IPF who had met the 2011 criteria had lung tissue available for histopathology (surgical lung biopsy in 28 patients and explanted lung in two patients, one of whom also had surgical biopsy) during the study period, and 16 of the 20 patients with chronic hypersensitivity pneumonitis had histopathological features on surgical lung biopsy that were consistent with this diagnosis. 26 of the 46 patients remained with a diagnosis of IPF.

Interpretation

Almost half of patients diagnosed with IPF on the basis of 2011 criteria were subsequently diagnosed with chronic hypersensitivity pneumonitis, and most of these cases were attributed to exposure of occult avian antigens from commonly used feather bedding. Our results reflect findings in one centre with recognised expertise in chronic hypersensitivity pneumonitis, and further research and studies at other centres are warranted.

Funding

Fondo de Investigaciones Sanitarias; Fundació Privada Cellex; SEPAR 2010.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a distinct fibrotic lung disease manifesting in adults, and its diagnosis and clinical features have been well established in evidence-based guidelines.1 The annual incidence in the USA2 between 1996 and 2000 ranged from 1·2 to 76·4 per 100 000 person-years using narrow or broad criteria and is 7·4 per 100 000 person-years in the UK.3 The prognosis of IPF is very poor, with mean survival varying from 3–5 years.1, 4 The 2011 guidelines1 for diagnosis and management of IPF emphasise the need to exclude all known causes associated with interstitial lung diseases or pulmonary fibrosis; however, the burden of this elimination and the clinical index of suspicion for diagnosis of hypersensitivity pneumonitis rests on the individual clinician and their investigation. In this respect, environmental factors at home and at work are very important, not only to aid in the correct diagnosis but also to recommend avoidance of further exposure to the identified antigen or factor because this is prudent to the management of patients with interstitial lung diseases or pulmonary fibrosis. To pursue such preventive measures, proactive efforts are needed to identify potential environmental factors that might cause pulmonary fibrosis.

In the appropriate clinical setting, the presence of radiological or histopathological features of usual interstitial pneumonia is a diagnostic criterion for IPF.4 However, this characteristic pattern of usual interstitial pneumonia is not pathognomonic of IPF because it has been observed in patients with chronic hypersensitivity pneumonitis, collagen vascular diseases, asbestosis, and other contexts.5, 6, 7, 8 Thus, some patients diagnosed with IPF might in fact have chronic hypersensitivity pneumonitis and exposure to the antigen might have been occult or forgotten.9, 10 Exposure to avian antigens by contact with birds is a well recognised common cause of hypersensitivity pneumonitis (so-called bird fancier's lung), but exposure can also occur in circumstances other than by direct contact with live birds. One such situation is exposure through feather bedding use, which in susceptible individuals can lead to development of the hypersensitivity pneumonitis named feather duvet lung.11, 12, 13, 14

We aimed to test the hypothesis that some patients diagnosed with IPF on the basis of the 2011 guidelines actually have chronic hypersensitivity pneumonitis caused by exposure to an occult antigen or antigens known to cause hypersensitivity pneumonitis. We believe that inconspicuous but persistent exposure to such antigens might provoke asymptomatic lung disease that goes unnoticed until it has progressed to stages of pulmonary fibrosis with features of usual interstitial pneumonia and is eventually misdiagnosed or labelled as IPF. Furthermore, such occult factors can only be identified with meticulous protocolised clinical, immunological, and pathological study to allow accurate diagnosis and appropriate treatment intervention.

Section snippets

Study population

In this case-cohort study, from Jan 1, 2004, to Dec 31, 2009, 305 consecutive and previously unreported outpatients were prospectively evaluated within the interstitial lung diseases programme of Hospital Universitari Vall d'Hebron (Barcelona, Catalonia, Spain) in accordance with a research protocol approved by the centre's ethics committee. All patients seen in the interstitial lung diseases clinic during the study period and diagnosed with IPF on the basis of international guidelines

Results

Of the 46 patients who met the 2011 criteria for IPF, 16 (34%) had been exposed to feather duvets or pillows and ten (63%) of these 16 patients were diagnosed with chronic hypersensitivity pneumonitis. Among the 30 of 46 patients who did not have a history of exposure to feather duvets or pillows, ten (33%) were diagnosed with chronic hypersensitivity pneumonitis (figure). Altogether, 20 (43%, 95% CI 29–58) patients were identified as having chronic hypersensitivity pneumonitis during the

Discussion

In this prospective observational study of consecutive patients with well defined IPF in accordance with the current 2011 criteria for diagnosis of IPF,1 a third of patients on further history elicitation and leading questionnaires had occult exposure to feather duvets or pillows and two-thirds of those patients exposed were diagnosed with chronic hypersensitivity pneumonitis (panel 2). Altogether, almost half of patients diagnosed with IPF on the basis of the 2011 criteria had a final

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