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Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
Re: Acute exacerbations in Idiopathic Pulmonary Fibrosis
understanding the clinical course of an idiopathic disease
Acute exacerbations in Idiopathic Pulmonary Fibrosis
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Fernando J. Martinez, MD, MS University of Michigan
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fmartine{at}umich.edu Fernando J. Martinez
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Crowley, Kelly and Egan raise several important points based on our recent report (1) identifying a high incidence of rapidly progressive pulmonary disease in the placebo arm of a large, multicenter, controlled trial of interferon gamma-1b in idiopathic pulmonary fibrosis (IPF). The identification of patients succumbing to a rapid, fatal deterioration versus those that do not suffer this complication provides important, clinically relevant information. Examination of baseline parameters between patients who experienced an IPF-related acute/abrupt death and those who died following an IPF- related subacute deterioration revealed a similar baseline FVC (64 +/- 12 vs 60 + 12 %predicted, p=0.29) and DLCO (33 +/- 6 vs 31 +/- 7 %predicted, p=0.43) in both groups. The overall incidence of acute/abrupt deterioration leading to death was similar in patients with a baseline DLCO < 40% predicted (10.5%) and those with a baseline DLCO > 40% predicted (11.1%). Interestingly, the incidence was a bit higher in patients with a baseline DLco < 40% predicted (10.5% vs 5.6% in those with baseline DLCO >= 40% predicted) if one examines only the IPF- related acute/abrupt deteriorations that led to death. Using methodology recently published (2) there was a similar distribution of typical, basilar-predominant honeycomb change in those patients who died after acute/abrupt compared with subacute deterioration (87% vs 94%, p=0.60). In addition, the proportion of patients with a mean HRCT extent score > 0 was similar between the two groups (87% in patients with acute/abrupt progression compared with 100% of patients suffering subacute deterioration, p=0.23). In abstract form we have characterized features that predicted the risk of mortality in the placebo-treated cohort (3). In these preliminary analyses a decrease in FVC >= 10%, respiratory hospitalization and an increase in the University of California, San Diego Shortness of Breath Questionnaire score of >= 10 points were associated with an increased risk of mortality in the subsequent three months. Interferon gamma-1b has been explored as a possible novel therapeutic agent in IPF (4, 5). Results of the Phase 3 trial from which the current placebo-treated cohort was drawn suggested a trend to improved survival in the intention-to-treat population favoring interferon gamma-1b (5). At the 2005 European Respiratory Society meeting in Copenhagen, data on the incidence and timing of respiratory serious adverse events (SAEs) after the initiation of interferon gamma-1b was presented. Patients (n=362) from two randomized, double-blind, placebo-controlled trials (RDBPCT) and one extension study (ET) were analyzed. The number of patients with respiratory SAEs throughout the study was similar in the interferon gamma- 1b and placebo groups in both of the RDBPCTs. These data were supported by the open-label ET that failed to show any increased risk of respiratory SAEs after recent initiation of treatment (6). An additional, placebo- controlled study is ongoing to better define the impact of interferon gamma-1b on overall mortality and the timing of death in well characterized patients with mild to moderate IPF. The results of this study should further clarify the natural history and characteristics of mortality in IPF patients and the effect of interferon gamma. Sincerely, Fernando J. Martinez, M.D., M.S. References: 1. Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King Jr TE, Flaherty KR, Schwartz DA, Noble PW, Raghu G, Brown KK, for the IPF Study Group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142:963-7. 2. Lynch DA, Godwin JD, Safrin S, Starko KM, Hormel P, Brown KK, Raghu G, King Jr TE, Bradford WZ, Schwartz DA, Webb RW, for the Idiopathic Pulmonary Fibrosis Study Group. High-resolution computed tomography in idiopathic pulmonary fibrosis. Diagnosis and prognosis. Am J Respir Crit Care Med 2005; 172:488-93. 3. Martinez FJ, Bradford WZ, Safrin S, Starko KM, Brown KK. Rates and characteristics of death in patients with idiopathic pulmonary fibrosis (IPF). Chest 2003; 124:117S-b. 4. Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block L. A preliminary study of long-term treatment with interferon gamma-1b and low- dose prednisone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341:1264-9. 5. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King Jr TE, Idiopathic Pulmonary Fibrosis Study Group. A placebo- controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Eng J Med 2004; 350:125-33. 6. Loutit JS, Safrin S, Suzuki S, Bradford WZ. Serious adverse events (SAEs) of the respiratory tract in patients with idiopathic pulmonary fibrosis (IPF) treated with interferon gamma-1b (IFN-gamma 1b) in three trials. Eur Respir J 2005; 26: Suppl 49:336s. Conflict of Interest:Consultant - Intermune |
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matteo sofia, md fccp dpt respiratory disease university federico II monaldi hospital naples italy
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matsouni{at}libero.it matteo sofia
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To the Editor The article by Martinez et al (1) retrospectively describes the clinical course of the placebo-exposed patients with idiopathic pulmonary fibrosis enrolled in the interferon-gamma study ( 2) with relevant data for monitoring and early lung tranplantation referral of this devastating disease . However their cohort charactheristics and disease severity definitions deserve some comments. Accordingly the study group consisted of 168 patients recruited from 58 centers worldwide, where they have received ipf diagnosis meanly > 1 year before ; furthermore most of the patients had a previous history of long-term steroid treatment before the study . Moreover one of eligibility critheria in the interferon trial was functional tests worsening before study inclusion while actually the Authors conclude that in patients with ipf physiological tests changed minimally during the 72 weeks placebo -period of the study., Thus, comparative data between centers participating to the study should be reported and pooled data from surviving and not-surviving patients during the study should be presented to escape the risk of immortalization of lung function test in survivors of the placebo-exposed cohort. The second point is that despite a mortality rate of 21% the term mild to moderate ipf is used to characterize the patients of the study, likely by translation from staging terminology applied to other chronic disease such as copd (3) but currently not reported in consensus ipf statement (4 ). However a classification of ipf based on simple lung function critheria as recently advocated by the same Author of the present study would be particularly useful for the present analysis if patients could be stratified as having limited,progressive or advanced disease with serial lung function studies of particular value in the first category.(5 ) In conclusion data collected from randomized controlled clinical trial give very important informations to physicians who manage ipf patients ; if this represents a potential tool to evaluate why and when this disease starts and how will be its walking pace in each individual is a challenging issue Kind regards 1Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, Brown KK; IPF Study Group.The clinical course of patients with idiopathic pulmonary fibrosis.Ann Intern Med. 2005 21;142(12 Pt 1):963-7. 2 Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr; Idiopathic Pulmonary Fibrosis Study Group.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004 ;35(2):125-33. 3 Celli BR, MacNee W; ATS/ERS Task Force Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004 Jun;23(6):932-46. 4 American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002 ;165(2):277-304. 5 Egan JJ, Martinez FJ, Wells AU, Williams T. Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification. Thorax. 2005 ;60(4):270-3. Conflict of Interest:None declared |
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Seamus P Crowley, MB BCh BAO, FCARCSI, DIBICM Mater Misericordiae Hospital, P Kelly, JJ Egan
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seamusjcrowley{at}vodafone.ie Seamus P Crowley, et al.
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Acute exacerbations in Idiopathic Pulmonary Fibrosis SP Crowley, P Kelly, JJ Egan Correspondence Dr Jim J Egan MD, FRCP, FRCPI Advanced Lung Disease and Irish National Lung Transplant Program Mater Misericordiae Hospital and St Vincents University Hospital Dublin Molecular Medicine Centre University College Dublin, Ireland Email: jegan@mater.ie Conflict of interest: none To the Editor: The data provided by Martinez et al is a further example of the merits of IPF patients being offered treatment only as part of a therapeutic trial.1 Although the large international interferon gamma study in IPF was largely negative the data gleaned from the placebo group in the context of natural history of IPF is critical to our understanding of this lethal condition.2 Needless to say the information provided raises many additional questions. The emerging recognition of acute exacerbations of IPF is increasingly recognised as an important clinical entity. It would be of interest whether it was possible to identify which patients are most at risk of an exacerbation based on a physiological assessment.3 For instance, do patients with advanced disease (DLco < 40%) have a greater incidence of acute exacerbation than patients with limited disease based on an estimation of their gas transfer. In other words, were patients with advanced disease more predisposed to acute exacerbation. This data would be important in the context of the planning of future studies in IPF. Secondly, data has formally been published suggesting an association between interferon gamma and acute deteriorations.4 The data provided by Martinez et al may refute this by estimating the incidence of acute exacerbations in the treatment group in comparison to the control group. For example, if the incidence of acute exacerbation was the same or less in the treatment group such data would refute this. Therefore, the previous suggested association between a specific drug and the entity of acute exacerbation may in fact be coincidental and the acute exacerbations more related to the degree of physiological impairment of the disease rather than the drug used to treat the condition in this circumstance. Kind regards References 1. Martinez FJ, Safrin S, Weycker D. The clinical course of patients with Idiopathic Pulmonary Fibrosis. Ann Intern Med 2005; 142:963-967 2. Raghu G, Brown KK, Bradford WZ. A placebo controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-33 3. Egan JJ, martinez FJ, Wells AU, Williams T. Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification. Thorax 2005;60:270-273 4. Honore I, Nunes H, Groussard O. Acute respiratory failure after interferon-g therapy of end-stage pulmonary fibrosis. Am J Respir Crit Care Med 2003;167:953-957 Conflict of Interest:None declared |
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