Acute exacerbations of idiopathic pulmonary fibrosis

Abstract

The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.

Conflict of interest statement

Conflict of Interest Statement: H.R.C. received $5,000 from InterMune for advisory board activities in 2006. B.B.M. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. K.R.F. received $4,100 in 2005 and $3,000 in 2007 from Boehringer Ingelheim; $2,500 in 2006 from InterMune; and $1,200 in 2005 from Fibrogen for serving on advisory boards related to pulmonary fibrosis. K.K.B. has served as a consultant or spoken to the following companies interested in IPF: Actelion, Amgen, Genzyme, Wyeth, Biogen, Boehringer Ingelheim, Novartis, and Lung Rx. He or his institution have received grants to support the performance of treatment trials in IPF from Actelion, InterMune, Biogen, and Genzyme. R.J.K. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. T.E.K. has served on advisory boards for InterMune and for GlaxoSmithKline (GSK); and served as a consultant for Nektar, Alexza, Astra-Zeneca, Biogen, Centocor, Fibrogen, Genzyme, Human Genome Sciences, Merck, and CoTherix. J.A.L. has been supported by Novartis for an investigator-initiated study, for service on an advisory board by InterMune, and by Actelion for service of advisory and data safety monitoring boards. J.E.L. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. I.N. has participated as a speaker for various pharmaceutical companies (GSK, Pfizer, Boehringer Ingelheim, in 2006 for various amounts). He has also received honoraria for participating in advisory board meetings for Novartis in 2005 and GSK in 2006. I.N.'s institution has received grants and contracts from Actelion, CoTherix, Centocor, Genzyme, InterMune, Novartis, and Roche, all ongoing in 2007. M.A.O. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. G.R. served as a steering committee member for BUILD-1 and serves as a steering committee member for BUILD-3 studies for IPF sponsored by Actelion. J.R. in 2006 received $10,000 for research conducted as part of a multicenter trial sponsored by InterMune. J.H.R. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. D.A.Z. received speaker honoraria and served on advisory board for InterMune ($7,000 in 2006, $6,000 in 2005; $6,000 in 2004). D.A.Z. has received research grants from InterMune, Actelion, and CoTherix for participating in multicenter clinical trials. G.W.H. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. T.V.C. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. J.J.E. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. D.M.H. received $6,000 for giving advice and grading HRCTs for clinical trial run by InterMune in 2005/2006. T.J. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. N.K. received $5,000 for serving on a Biogen Idec advisory board in November 2005. N.K. is also a recipient of an investigator-initiated grant from Biogen Idec in August 2006 ($674,800 for 2 yr). D.S.K. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. Y.K. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. D.A.L. has received less than $5,000 in 2004, 2005, and 2006 from InterMune, for interpretation of CT scans. He has received more than $5,000 from Encysive for consultation on clinical trials. He received $6,000 in 2006 for service on an advisory board for Actelion. J.M.-Q. received a research grant of $180,000 from Boehringer Ingelheim, Germany, in 2003 through 2006 for an in vitro study on fibrogenic mechanisms. J.M.-Q received a research grant of $80,000 from Altana, Germany, in 2003 through 2006 for an in vitro study on alveolar epithelia. J.L.M. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. A.G.N. received $4,000 for reviewing slides for InterMune Ltd in 2004–2006 and £8,600 for reviewing slides for Actelion Ltd in 2006 in relation to entry into drug trials for patients with IPF. M.S. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. G.B.T. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. A.U.W. does not have a financial relationship with a commercial entity that interest in the subject of this manuscript. F.J.M. is a consultant for Altana Pharma and has received compensation greater than $10K. F.J.M has been a member of several advisory boards, CME committees, and the speakers' bureau for Boehringer Ingelheim, Pfizer, and GSK. His total compensation per company was greater than $10K. In addition, F.J.M. is on an advisory board for Novartis and a speaker's bureau for Sepracor and Astra, receiving less than $10K per company. F.J.M. has been an investigator for industry-sponsored studies for GSK, Boehringer Ingelheim, and Actelion.

Figures

Figure 1

High-resolution computed tomography (HRCT) of acute exacerbation of idiopathic pulmonary fibrosis (IPF). (A, B) HRCT images through right upper and lower lung of a patient with stable IPF show typical features of usual interstitial pneumonia pattern: peripheral and basal predominant reticular abnormality with traction bronchiectasis and subpleural honeycombing. A small amount of ground-glass abnormality is present. (C, D) HRCT images through the right upper and lower lung of the same patient during an acute exacerbation of IPF show new, extensive ground-glass abnormality superimposed on the background of lung fibrosis.

Figure 2

Surgical lung biopsy of acute exacerbation of idiopathic pulmonary fibrosis. (A) Low magnification photomicrograph shows chronic interstitial pneumonia with heterogeneous distribution and honeycomb change typical of usual interstitial pneumonia (original magnification, ×20; hematoxylin-and-eosin stain). (B) Higher magnification photomicrograph shows area of acute diffuse alveolar damage in same biopsy specimen characterized by well-developed eosinophilic hyaline membranes (arrows) (original magnification, ×100; hematoxylin-and-eosin stain).