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Original Research: Diffuse Lung Disease |

Outcomes After Hospitalization in Idiopathic Pulmonary FibrosisHospitalization in Idiopathic Pulmonary Fibrosis: A Cohort Study FREE TO VIEW

A. Whitney Brown, MD; Chelsea P. Fischer, BS; Oksana A. Shlobin, MD; Russell G. Buhr, MD; Shahzad Ahmad, MD; Nargues A. Weir, MD, FCCP; Steven D. Nathan, MD, FCCP
Author and Funding Information

From the Advanced Lung Disease and Transplant Program (Drs Brown, Shlobin, Ahmad, Weir, and Nathan and Ms Fischer), Department of Medicine, Inova Fairfax Hospital, Falls Church, VA; and the Department of Medicine (Dr Buhr), University of California at Los Angeles, Los Angeles, CA.

CORRESPONDENCE TO: Steven D. Nathan, MD, FCCP, Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church, VA 22042; e-mail: steven.nathan@inova.org


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(1):173-179. doi:10.1378/chest.13-2424
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OBJECTIVE:  The outcomes of patients with idiopathic pulmonary fibrosis (IPF) who undergo hospitalization have not been well characterized. We sought to determine the frequency of all-cause and respiratory-related hospitalizations and to evaluate their impact on the subsequent course and survival of patients with IPF.

METHODS:  The records of patients with IPF evaluated at a tertiary center were examined for the cause and duration of hospitalization. Data on subsequent patient outcomes were collated.

RESULTS:  The IPF cohort consisted of 592 patients, 25.3% of whom were hospitalized subsequent to their IPF diagnosis. A respiratory-related cause accounted for 77.3% of these hospitalizations. The median transplant-free survival for all patients was 23.3 months (interquartile range [IQR], 7.6-63.6 months) from the time of consultation. Transplant-free survival after hospital admission was much lower for patients with a respiratory hospitalization compared with those with a nonrespiratory hospitalization (median survival, 2.8 months [IQR, 0.63-16.2 months] vs 27.7 months [IQR, 7.4-59.6 months]; P = .0004). Multivariate analyses demonstrated that both all-cause and respiratory-related hospitalizations were strongly associated with mortality after adjusting for baseline demographics. Among patients with a respiratory hospitalization, 22.4% died while in the hospital, whereas 16.4% eventually went on to lung transplantation.

CONCLUSIONS:  Hospitalizations are common events in patients with IPF. Most hospitalizations are respiratory-related and are associated with high in-hospital mortality and limited survival beyond discharge. Both all-cause and respiratory hospitalizations are associated with mortality, and therefore, either could be used as an end point in IPF clinical trials.

Figures in this Article

Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a median survival of only 2.5 to 4 years from diagnosis.14 The disease tends to run an unpredictable course, which precludes assigning a precise prognosis and impacts referral for transplant and stratification of patients in clinical trials.4,5

Hospitalizations, specifically respiratory-related hospitalizations, have prognostic significance in COPD and cystic fibrosis.68 As with patients with these diseases, many patients with IPF will require hospitalization.9 The bleak course for patients with IPF admitted to an ICU has been the subject of a number of small studies, and hospitalization has been linked to short-term mortality in studies of highly select patients with IPF.1015 However, there is a paucity of data on the incidence and long-term outcomes after all-cause and respiratory-related admissions in a broad cohort of patients with IPF. Despite this, hospitalizations have been proposed and have been used as an end point in IPF clinical trials.1619

We sought to analyze the frequency, duration, and subsequent mortality of all-cause and respiratory-related hospitalizations among a cohort of patients with IPF evaluated at a tertiary care center. We also explored whether hospitalization could be regarded as a meaningful end point in IPF clinical trials.

The records of all patients with IPF evaluated at a tertiary referral center were reviewed. Patients were diagnosed based on prior international consensus statements for the diagnosis of IPF.20,21 Most of these same patients were included in a previous publication from our group that provides greater characterization of their diagnosis and treatment.3,4 Hospitalizations of at least 24 h in duration subsequent to the IPF diagnosis were categorized as respiratory or nonrespiratory in nature and were analyzed for length of stay.

Elective hospitalizations for surgical lung biopsies were excluded. Lung allograft recipients were excluded from a subset of the survival analyses because of transplant-related survival bias, but were included in analyses of transplant-free survival and the competing risk analyses, with hospital admission for the transplant surgery itself excluded. The study was approved by the Inova Fairfax institutional review board (Study No. 12.1093).

Demographic and pulmonary function test data were collated, and vital status was ascertained from the clinic database and the Social Security Death Index. The Gender, Age, Physiology Index for IPF (GAP Index) was calculated for each patient.22 Two authors reviewed all hospitalization events, with discordance in categorization adjudicated by a third.

The primary outcome was the association between hospitalization (all-cause and respiratory) and survival in patients with IPF. Other secondary outcomes included agreement on reason for hospitalization (respiratory vs nonrespiratory) between reviewers, relationship between length of hospitalization and subsequent survival, and association between baseline patient characteristics and hospitalization and survival.

Statistical Analysis

The association between patient characteristics and hospitalization type was investigated with bivariate analyses. Survival time was calculated from both the time of initial consultation and the time of initial hospitalization, and was analyzed by medians and interquartile ranges (IQRs). Kaplan-Meier survival curves from the time of hospitalization were generated and compared using the log-rank test, with patients categorized according to respiratory-related or nonrespiratory hospitalization.

Multivariate analyses using Cox proportional hazard modeling were performed to examine the relationship between all-cause and respiratory hospitalization adjusted for baseline patient characteristics. Hospitalization was modeled as a time-varying covariate. Although lung allograft recipients were excluded from the primary analysis, they were included in a competing risk analysis, with transplant as a competing event with death. In the multivariate analyses, a stepwise approach was used to select covariates, although race, BMI, and GAP Index were retained in the models because of their clinical significance. Multiple imputation was used for missing covariate data (BMI, GAP Index, and race).

All statistical analyses were performed using STATA version 12 (StataCorp LP). All tests were two tailed, and P values < .05 were considered significant.

A total of 592 patients with IPF were evaluated between 1997 and 2012. Of these, 151 were listed and 128 underwent lung transplant. Twenty-three patients were listed and died without a transplant, and 441 patients were never listed (Fig 1). The median transplant-free survival for all patients was 23.3 months (IQR, 7.63-63.6 months) from the time of consultation. For those patients who did not receive lung allografts, the median survival was 35.3 months (IQR, 11.1-97.2 months). The demographics of the IPF cohort are shown in Table 1.

Figure Jump LinkFigure 1 –  Flowchart of patient disposition and outcome status for the entire cohort of patients with IPF. IPF = idiopathic pulmonary fibrosis.Grahic Jump Location
Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics of Patients With IPF Stratified by Hospitalization

Significance tests for comparisons between patients with and without respiratory hospitalization were based on two-sample t test or one-way analysis of variance for continuous patient characteristics and Pearson’s χ2 test for categorical patient characteristics. Dlco = diffusing capacity of lung for carbon monoxide; GAP Index = Gender, Age, Physiology Index for Idiopathic Pulmonary Fibrosis; IPF = idiopathic pulmonary fibrosis.

Hospitalization of at least 24 h in duration occurred in 25.3% of patients (n = 150). None of the admissions was purely for end-of-life care. Average hospital length of stay was 8.6 days (range, 1-56 days). ICU admission occurred in 56 of the 150 patients (37.3%) hospitalized. Noninvasive ventilation was required in 26 of the 150 hospitalized patients (17.3%), whereas 27 of the 138 (18%) required mechanical ventilation. The large majority of patients requiring mechanical ventilation (74.1%) died in the hospital. Five patients underwent a lung transplant while waiting in the hospital. Initial consultation from the advanced lung disease program was sought during the index admission in 44 cases. In the remaining 106 patients, hospitalization occurred a mean of 10.7 months after initial evaluation (range, 1 day-81.3 months).

Respiratory Hospitalizations

Most hospitalizations were respiratory in nature (116 of 150 [77.3%]). Interobserver reliability for type of hospitalization was very good (κ = 0.64, P < .0001). There was discordant categorization of respiratory vs nonrespiratory causes for only 16 events (12.1%). Twenty-nine patients with respiratory hospitalizations (25%) required multiple admissions. The mean time from diagnosis to respiratory admission was 6.3 months (range, 0-80.1 months). Initial consultation occurred during the hospital stay in approximately one-third of cases, whereas 62.1% of the patients were evaluated within a 3-month window of the respiratory hospitalization. Patients with a respiratory hospitalization event within 3 months of evaluation had no significant difference in survival after hospitalization compared with those patients not seen within 3 months (median survival, 2.03 months [IQR, 0.7-17 months] vs 3.67 months [IQR, 0.5-22 months]; P = .54). Transplant-free survival beyond the date of initial hospitalization was dramatically reduced in patients hospitalized for a respiratory cause compared with those hospitalized for a nonrespiratory cause (median survival, 2.83 months [IQR, 0.63-16.2 months] vs 27.7 months [IQR, 7.4-59.6 months]; P = .0004) (Fig 2).

Figure Jump LinkFigure 2 –  Transplant-free survival of entire IPF cohort from time of initial hospitalization to death, lung transplant, or last follow-up. Comparison is between patients with respiratory hospitalization and those with nonrespiratory hospitalization (median survival, 2.83 mo vs 27.7 mo; P = .0004). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

We also assessed survival beyond the date of initial hospitalization of nontransplant patients. In patients who were hospitalized for respiratory vs nonrespiratory reasons, there was similarly a marked difference in survival (median survival, 2.83 months [IQR, 0.63-21.7 months] vs 33.3 months [IQR, 24.0-61.5 months]; P = .0004) (Fig 3). Among nontransplant patients who had a respiratory hospitalization, 37.2% died in the hospital. Respiratory hospitalizations of ≥ 1 week showed a greater risk of death compared with those of ≤ 1 week in duration (median survival, 1.5 months [IQR, 0.5-8 months] vs 9.1 months [IQR, 0.8-38 months] from time of hospitalization; P = .0399). A further analysis of the subset of patients who survived to discharge revealed that respiratory hospitalization continued to portend a poor outcome, with a median survival of 9.1 months compared with 43.5 months for those who survived a nonrespiratory admission (P = .02).

Figure Jump LinkFigure 3 –  Survival of patients with IPF who did not undergo lung transplant from time of initial hospitalization to death or last follow-up. Comparison is between patients with respiratory hospitalization and those with nonrespiratory hospitalization (median survival, 2.83 mo vs 33.3 mo; P = .0004). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Multivariate analysis adjusting for patient characteristics confirmed an independent association between both respiratory and all-cause hospitalization and subsequent mortality among patients with IPF (Tables 2, 3). In both the nontransplant cohort and the entire IPF cohort, respiratory hospitalization had a slightly stronger association with risk of death than did all-cause hospitalization. Interestingly, GAP Index, BMI, and race were not significantly associated with mortality in the adjusted analyses.

Table Graphic Jump Location
TABLE 2 ]  Unadjusted and Adjusted Hazard Ratios for Death Among Nontransplant Patients With IPF

Hazard ratios shown for covariates are those from the model evaluating respiratory hospitalizations. See Table 1 legend for expansion of abbreviations.

a 

Based on Cox proportional hazards model, adjusted for GAP Index, race, and BMI.

Table Graphic Jump Location
TABLE 3 ]  Unadjusted and Adjusted Subhazard Ratios for Death for All Patients With IPF and Lung Transplant as a Competing Event

Subhazard ratios shown for covariates are those from the model evaluating respiratory hospitalizations. See Table 1 legend for expansion of abbreviations.

a 

Based on competing risk analysis, adjusted for GAP Index, race, and BMI.

In our analysis of a large cohort of patients with IPF, we demonstrate that hospitalization complicated the disease course in about one-quarter of cases. This is remarkably similar to the prevalence described in other studies, although our cohort represents a broader group of patients with IPF, with longer follow-up.9,14 Our study highlights the important independent prognostic implications of hospitalization events in patients with IPF. This relationship has been demonstrated previously, but only in patients admitted to ICUs or in the context of prospective clinical trials.1015 We further demonstrate that both all-cause and respiratory-related hospitalizations are powerful predictors of subsequent mortality, with the latter having a slightly stronger association. Additionally, our multivariate analyses demonstrate that the association between hospitalization and an increased risk of death is independent of baseline patient characteristics. Our data serve to inform providers and patients about expected outcomes during and after any hospitalization. This information helps frame the discussion for future planning, including consideration of transplant or end-of-life decision-making.

Many factors, primarily physiologic, radiographic, and pathologic, have been explored as prognostic indicators in IPF.5,2226 Despite a greater understanding of the natural history of the disease, the clinical course of patients with IPF remains unpredictable.4 The impact of hospitalization may explain some of the variability in the disease course.

The temporal proximity of the initial consultation and the hospitalization may have introduced possible bias in our analysis, especially if clinical deterioration or hospitalization itself prompted the initial consultation, because these patients may represent a group with an accelerated disease trajectory. However, there was no difference in outcomes subsequent to hospitalization demonstrated between those patients whose initial evaluation was within 3 months of hospitalization and those patients outside of this window. This supports the important prognostic impact of the hospitalization itself, independent of the disease severity or trajectory at the time of the initial consultation.

Although our interobserver agreement for respiratory vs nonrespiratory hospitalization was high, we did not distinguish the specific type of respiratory event. This is notoriously difficult to discern because the progression of disease, superimposed pneumonia, heart failure, or an acute exacerbation can have similar clinical and radiographic appearances. Our exclusion of patients who received lung allografts in the Cox model may have introduced some bias. Therefore, a competing risk analysis inclusive of allograft recipients was undertaken, which confirmed the strong association between hospitalization and subsequent outcomes. Although we conclude that patients requiring hospitalization are at a higher risk of subsequent mortality, we cannot rule out the possibility that the hospitalization itself placed the patient at this greater risk. Specifically, outcomes may have been influenced by inadvertent complications of antibiotics, steroids, high-flow oxygen, and mechanical ventilation, as well as by inactivity and nosocomial infections.

Implications for IPF Study Design

Selection of the best study end points to truly reflect therapeutic efficacy remains a controversial issue in the design of prospective IPF clinical trials.17,2729 Traditionally, physiologic parameters, specifically the FVC, have been used as surrogates for the fibrotic burden of the disease. However, issues have been raised regarding the validity of this approach, and it has been proposed that all-cause hospitalization and mortality may be the best end points for clinical trials in IPF.17 Despite this, all-cause hospitalization remains to be validated as a surrogate for subsequent outcomes.2729 Indeed, our data support the use of hospitalization as a clinical trial end point. Although there may be a slight advantage to using respiratory-related hospitalizations, this has to be balanced against the inherent logistics of adjudicating the reason for admission as well as the advantage of having more events with the broader all-cause categorization.

The added value of a hospitalization end point over other commonly used end points remains uncertain because we were unable to assess for colinearity between hospitalizations and changes in parameters such as the FVC and 6-min walk distance. There is some subjectivity involved in the decision-making with regard to hospitalization, and it is also possible that inherent bias may be introduced in the context of a prospective trial. Our data should not necessarily be interpreted as a validation of hospitalization as a surrogate for mortality, because this will require further study in the context of multiple geographically and culturally diverse centers. Additionally, our cohort represents a broad spectrum of patients with IPF and does not necessarily translate to highly select patients within the context of clinical trials. For example, the relatively poor prognosis subsequent to hospitalization could be related to factors that may be exclusionary to enrollment in any given study.

There are limitations to our study. One issue is the potential for immortal time bias, which we mediated with the use of a time-dependent multivariate model. An inherent difficulty of a retrospective study over a 15-year period is missing data. We used multiple imputation to address missing covariate data for BMI, race, and GAP Index to allow maximum inclusion in our multivariate models. We were limited in our ability to collect complete information on hospitalizations that may have occurred outside of our institution. If the captured and uncaptured hospitalizations were equally predictive of time to death, this would bias our findings toward the null. If, however, the uncaptured hospitalizations were less predictive of time to death than the captured hospitalizations, this would bias our findings in the direction of an association. Therefore, the findings from our study require validation in a cohort of patients in whom all hospitalizations are captured. One advantage of our single-center study is the uniformity of practice habits, even though these patients were admitted by a number of providers. We decided a priori to categorize patients simply as respiratory or nonrespiratory and to avoid attempting to delineate the exact cause of their respiratory decompensation, because these are notoriously difficult to differentiate, even with prospectively collected data. Therefore, we were unable to assess how many of the admissions were for definite or suspected acute exacerbations.30

In conclusion, hospitalization is common in patients with IPF during the course of their disease, and most admissions are respiratory-related. Hospitalization events represent a critical junction in the context of the dynamic prognostic counseling of these patients because there appears to be a strong association between hospitalization and subsequent mortality.4 Our data support hospitalization as a viable end point for clinical trials, but they also underscore the associated potential pitfalls. The association between hospitalization and mortality appears to be driven mostly by respiratory events, and therefore, respiratory hospitalization could represent a powerful study end point. However, all-cause hospitalization may be more pragmatic to implement in the context of large multicenter clinical trials.

Author contributions: S. D. N. is the guarantor of the paper and takes responsibility for the integrity of the work as a whole, from inception to published article. He confirms that the study objectives and procedures were honestly disclosed. Moreover, he has reviewed study execution data and confirms that procedures were followed to an extent that convinced all authors that the results are valid and generalizable to a population similar to that enrolled in this study. A. W. B., C. P. F., and S. D. N. contributed to the inception of the idea, the analysis and interpretation of the data, and the writing of the paper; R. G. B. contributed to the analysis of the data and the writing of the paper; and O. A. S., S. A., and N. A. W. contributed to the acquisition and interpretation of the data.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Nathan is a consultant for Boerhinger-Ingelheim GmbH; Celgene; Genetech; Gilead Sciences, Inc; and Intermune. He has received research funding from Actelion Pharmaceuticals Ltd; Boerhinger-Ingelheim GmbH; FibroGen, Inc; Intermune; Sanofi SA; and Veracyte for IPF studies. Drs Brown, Shlobin, Buhr, Ahmad, and Weir and Ms Fischer have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

GAP Index

Gender, Age, Physiology Index for Idiopathic Pulmonary Fibrosis

IPF

idiopathic pulmonary fibrosis

IQR

interquartile range

Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. 2007;176(3):277-284. [CrossRef] [PubMed]
 
Fernández Pérez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129-137. [CrossRef] [PubMed]
 
Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140(1):221-229. [CrossRef] [PubMed]
 
Brown AW, Shlobin OA, Weir N, et al. Dynamic patient counseling: a novel concept in in idiopathic pulmonary fibrosis. Chest. 2012;142(4):1005-1010. [CrossRef] [PubMed]
 
Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. [CrossRef] [PubMed]
 
Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 pt 1):959-967. [CrossRef] [PubMed]
 
Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest. 2003;124(2):459-467. [CrossRef] [PubMed]
 
Mayer-Hamblett N, Rosenfeld M, Emerson J, Goss CH, Aitken ML. Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir Crit Care Med. 2002;166(12 pt 1):1550-1555. [CrossRef] [PubMed]
 
Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356-363. [CrossRef] [PubMed]
 
Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212. [CrossRef] [PubMed]
 
Stern JB, Mal H, Groussard O, et al. Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest. 2001;120(1):213-219. [CrossRef] [PubMed]
 
Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med. 2002;166(6):839-842. [CrossRef] [PubMed]
 
Mallick S. Outcome of patients with idiopathic pulmonary fibrosis (IPF) ventilated in intensive care unit. Respir Med. 2008;102(10):1355-1359. [CrossRef] [PubMed]
 
Martinez FJ, Safrin S, Weycker D, et al; IPF Study Group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142(12 pt 1):963-967. [CrossRef] [PubMed]
 
du Bois RM, Weycker D, Albera C, et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(4):459-466. [CrossRef] [PubMed]
 
Raghu G, Behr J, Brown KK, et al; ARTEMIS-IPF Investigators*. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158(9):641-649. [CrossRef] [PubMed]
 
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Noth I, Anstrom KJ, Calvert SB, et al; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186(1):88-95. [CrossRef] [PubMed]
 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. [CrossRef] [PubMed]
 
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Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. [CrossRef] [PubMed]
 
Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-691. [CrossRef] [PubMed]
 
Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168(5):538-542. [CrossRef] [PubMed]
 
Flaherty KR, Mumford JA, Murray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168(5):543-548. [CrossRef] [PubMed]
 
Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med. 2003;168(5):531-537. [CrossRef] [PubMed]
 
Wells AU, Desai SR, Rubens MB, et al. Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography. Am J Respir Crit Care Med. 2003;167(7):962-969. [CrossRef] [PubMed]
 
Nathan SD, du Bois RM. Idiopathic pulmonary fibrosis trials: recommendations for the jury. Eur Respir J. 2011;38(5):1002-1004. [CrossRef] [PubMed]
 
du Bois RM, Nathan SD, Richeldi L, Schwarz MI, Noble PW. Idiopathic pulmonary fibrosis: lung function is a clinically meaningful endpoint for phase III trials. Am J Respir Crit Care Med. 2012;186(8):712-715. [CrossRef] [PubMed]
 
Wells AU. Forced vital capacity as a primary end point in idiopathic pulmonary fibrosis treatment trials: making a silk purse from a sow’s ear. Thorax. 2013;68(4):309-310. [CrossRef] [PubMed]
 
Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C; IPFnet investigators. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res. 2013;14:73. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Flowchart of patient disposition and outcome status for the entire cohort of patients with IPF. IPF = idiopathic pulmonary fibrosis.Grahic Jump Location
Figure Jump LinkFigure 2 –  Transplant-free survival of entire IPF cohort from time of initial hospitalization to death, lung transplant, or last follow-up. Comparison is between patients with respiratory hospitalization and those with nonrespiratory hospitalization (median survival, 2.83 mo vs 27.7 mo; P = .0004). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3 –  Survival of patients with IPF who did not undergo lung transplant from time of initial hospitalization to death or last follow-up. Comparison is between patients with respiratory hospitalization and those with nonrespiratory hospitalization (median survival, 2.83 mo vs 33.3 mo; P = .0004). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics of Patients With IPF Stratified by Hospitalization

Significance tests for comparisons between patients with and without respiratory hospitalization were based on two-sample t test or one-way analysis of variance for continuous patient characteristics and Pearson’s χ2 test for categorical patient characteristics. Dlco = diffusing capacity of lung for carbon monoxide; GAP Index = Gender, Age, Physiology Index for Idiopathic Pulmonary Fibrosis; IPF = idiopathic pulmonary fibrosis.

Table Graphic Jump Location
TABLE 2 ]  Unadjusted and Adjusted Hazard Ratios for Death Among Nontransplant Patients With IPF

Hazard ratios shown for covariates are those from the model evaluating respiratory hospitalizations. See Table 1 legend for expansion of abbreviations.

a 

Based on Cox proportional hazards model, adjusted for GAP Index, race, and BMI.

Table Graphic Jump Location
TABLE 3 ]  Unadjusted and Adjusted Subhazard Ratios for Death for All Patients With IPF and Lung Transplant as a Competing Event

Subhazard ratios shown for covariates are those from the model evaluating respiratory hospitalizations. See Table 1 legend for expansion of abbreviations.

a 

Based on competing risk analysis, adjusted for GAP Index, race, and BMI.

References

Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. 2007;176(3):277-284. [CrossRef] [PubMed]
 
Fernández Pérez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129-137. [CrossRef] [PubMed]
 
Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140(1):221-229. [CrossRef] [PubMed]
 
Brown AW, Shlobin OA, Weir N, et al. Dynamic patient counseling: a novel concept in in idiopathic pulmonary fibrosis. Chest. 2012;142(4):1005-1010. [CrossRef] [PubMed]
 
Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. [CrossRef] [PubMed]
 
Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 pt 1):959-967. [CrossRef] [PubMed]
 
Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest. 2003;124(2):459-467. [CrossRef] [PubMed]
 
Mayer-Hamblett N, Rosenfeld M, Emerson J, Goss CH, Aitken ML. Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir Crit Care Med. 2002;166(12 pt 1):1550-1555. [CrossRef] [PubMed]
 
Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356-363. [CrossRef] [PubMed]
 
Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212. [CrossRef] [PubMed]
 
Stern JB, Mal H, Groussard O, et al. Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest. 2001;120(1):213-219. [CrossRef] [PubMed]
 
Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med. 2002;166(6):839-842. [CrossRef] [PubMed]
 
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