The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis

Transcription

1 Er Respir J 2005; 25: DOI: / CopyrightßERS Jornals Ltd 2005 The timed walk test as a measre of severity and srvival in idiopathic plmonary fibrosis T.S. Hallstrand*, L.J. Boitano*, W.C. Johnson #, C.A. Spada*, J.G. Hayes* and G. Ragh* ABSTRACT: Idiopathic plmonary fibrosis (IPF) is a relentlessly progressive disease with a median srvival of,3 yrs. Measrements of airflow and lng volmes at rest are generally sed to monitor the clinical corse in this disorder. This stdy was designed to determine if a modified version of the 6-min walk test, called the timed walk test, accrately characterises disease severity and srvival in IPF. The stdy poplation consisted of 28 patients with well-characterised progressive IPF. The timed walk test and concrrent measres of disease severity were assessed at baseline. Participants were prospectively followed for o4 yrs to determine the relationship between parameters of the timed walk test and srvival. There were strong correlations between the end-exercise satration and walk-velocity parameters of the timed walk test and diffsing capacity, and arterial oxygen tension at rest. In nivariate Cox proportional-hazards models, end-exercise satration, change in satration with exercise, walk distance and walk velocity were associated with srvival. In nadjsted logistic regression models, odds of death at 2 yrs were associated with the same parameters. In conclsion, the timed walk test relates to disease severity and long-term otcome in progressive idiopathic plmonary fibrosis. KEYWORDS: Idiopathic plmonary fibrosis, interstitial lng disease, plmonary fnction, srvival, walk test AFFILIATIONS *Dept of Medicine, Division of Plmonary and Critical Care Medicine, and # Dept of Biostatistics, University of Washington, Seattle, WA, USA. CORRESPONDENCE G. Ragh Chest Clinic Interstitial Lng Disease Sarcoid and Plmonary Fibrosis Program University of Washington Medical Center Box BB-1253 HSC 1959 NE Pacific Street Seattle, WA USA Fax: gragh@.washington.ed Idiopathic plmonary fibrosis (IPF) is a chronic progressive interstitial lng disease (ILD) of nknown case, reslting in severe morbidity and death de to progressive respiratory failre [1], sally within 3 5 yrs [2 5]. Prognostic factors that have been variably associated with srvival inclde age [6], smoking stats [7], sex [8], resting plmonary fnction [9], histopathology score [7], fibrotic score based on high-resoltion compted tomography [10, 11], and initial response to treatment with corticosteroids [10]. A composite score of clinical, radiographical and physiological variables has been associated with srvival in IPF [12]. Srvival is the most important treatment otcome in IPF, bt reqires large nmbers of patients with this rare disease for long periods (i.e. 3 5 yrs) of prospective follow-p. A measrement of disease and fnctional stats that can serve as a srrogate otcome measrement to accrately reflect the risk of progression to death in IPF is needed. A practical and simple measrement of fnctional stats that is widely sed as a clinical tool and otcome measre of patients with heart [13], obstrctive lng disease [14], vasclar [15], and neromsclar disease [16] is the 6-min walk test (6MWT). However, the physiological abnormalities associated with disease severity and progression in IPF are not flly characterised by the distance of the 6MWT [7, 9, 12]. This was illstrated recently in the stdy by LAMA et al. [17], which showed that, in a sbgrop of patients with IPF withot resting hypoxaemia, the 6MWT distance was not associated with srvival [17]. Cardioplmonary exercise tests have shown that changes in arterial satration and exercise performance are related to srvival in IPF, leading to the hypothesis in the crrent stdy that similar parameters assessed dring a self-paced walk test wold be associated with srvival. Therefore, a modified version of the 6MWT, the timed walk test (TWT), was developed as a clinical tool and otcome measrement in IPF. The TWT has three stopping criteria so that continos walk velocity can be assessed and to incorporate change in oxyhaemoglobin satration dring continos exercise. To make the test applicable to patients with a range of disease severity and to redce the inflence of hypoxaemia on walk velocity [18, 19], the TWT was condcted in room air in patients with a baseline satration.88% and on spplemental Received: December Accepted after revision: Agst Eropean Respiratory Jornal Print ISSN Online ISSN VOLUME 25 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

2 T.S. HALLSTRAND ET AL. TIMED WALK TEST IN IPF oxygen if baseline satration was,88%. In this stdy, the relationship between the TWT and concrrent measres of disease severity conventionally sed in IPF was evalated. Participants were prospectively followed for o4 yrs to determine the relationship between parameters of the TWT and srvival. METHODS Stdy poplation A prospective stdy of consective new referrals for frther management of IPF (referred to the Interstitial Lng Disease Clinic, University of Washington Medical Center, Seattle, WA, USA, and for frther evalation and management in the Interstitial Lng Disease/Sarcoid/Plmonary Fibrosis Program at the University of Washington nder the direction of G. Ragh) was initiated between 1996 and Patients were inclded in this stdy if they consented to the stdy and met the diagnostic criteria for IPF. The diagnosis of IPF was ascertained by typical clinical, radiographical, nondiagnostic transbronchial biopsy, and physiological featres consistent with IPF; srgical lng biopsy demonstrating histological featres of sal interstitial pnemonia was accepted for the diagnosis of IPF in patients not meeting the major and minor clinical criteria [1, 20]. Persons with collagen vasclar disease, occpational lng disease, sarcoid, hypersensitivity pnemonitis and other idiopathic interstitial pnemonias were exclded [1, 21]. Patients with concrrent emphysema were exclded based on elevated residal volme of o120% and forced expiratory volme in one second (FEV1)/forced vital capacity (FVC) ratio of f0.60. Patients with IPF who were entered into this stdy had progressive symptomatic and/or physiological deterioration [1], despite treatment with prednisone with or withot immnosppressives. The University of Washington Hman Sbjects Review Committee approved the stdy, and each participant gave written informed consent. Timed walk test A designated respiratory therapist (L.J. Boitano) condcted the TWT on a 30-m-long level corse marked in 1.5-m increments. Oxygen satration was recorded continosly by plse oximetry at rest for 5 min prior to the test, throghot the TWT and immediately after the test. Patients with resting room air satration.88% had an initial walk test in room air and were sbseqently asked to perform a second test on 2 L of oxygen. Patients with resting satration f88% were tested only on 2 L of oxygen after a 5-min period of spplemental oxygen at rest. Dring the TWT, patients were instrcted to walk at a pace comfortable to them ntil they became too fatiged, p to a maximm of 6 min. The respiratory therapist stopped the test if the patient demonstrated signs of overt fatige and/or asked to stop, or the satration dropped to,80%. Althogh the test was stopped when satration reached 80%, the lowest satration was recorded if the satration contined to decline. The distance, time and satration were recorded at the end of the test. The primary parameters of the TWT were the end-exercise satration, change in satration from baseline and walk velocity. Secondary parameters were walk distance and walk time. Plmonary fnction testing Spirometry, plethysmographic lng volmes and diffsing capacity for carbon monoxide (DL,CO) were performed within 24 h of the TWT, according to American Thoracic Society standards [22]. Arterial blood gases were obtained after 5 min of inactivity. The alveolar arterial oxygen tension (PA a,o 2 ) difference was calclated by the alveolar gas eqation [23]. Statistical analysis Relationships between parameters of the TWT and plmonary fnction were assessed with Spearman rank correlation coefficients. Least sqares linear regression was sed to frther delineate the association between DL,CO and the TWT parameters. An intraclass correlation coefficient was sed to assess the repeatability of the TWT. Srvival time was measred in days from enrolment ntil death or censoring. Patients were censored at the end of the follow-p period or if they nderwent lng transplantation. Univariate Cox proportional-hazards models assessed the relative hazard corresponding to overall mortality for each TWT parameter. Cox proportional-hazards models were sbseqently adjsted for spplemental oxygen to assess its effect on each TWT parameter in predicting srvival. The effects of other demographic and baseline variables on TWT parameter estimates of srvival were also explored sing mltivariate Cox proportional-hazards models. Kaplan Meier estimates of srvival were sed to illstrate the findings of the Cox model. Logistic regression models of TWT parameters predicting 2-yr srvival were sed to corroborate findings of the srvival analyses. RESULTS Stdy participants A total of 28 consective patients with IPF [1] were enrolled in the stdy (table 1). Disease severity ranged from FVC o70% pred in eight patients and f40% pred in five. All patients had progressive disease based on symptoms or plmonary fnction tests, despite treatment with prednisone with or withot azathioprine [1]. Characteristics of the timed walk test At entry, nine of the 28 participants had resting oxyhaemoglobin satrations f88% and, therefore, were only tested on 2 L of spplemental oxygen. Six of these nine participants who were tested on spplemental oxygen stopped prior to 6 min becase arterial oxygen satration measred by plse oximetry (SP,O 2 ) reached 80%. Of the 19 patients tested in room air, five were stopped prior to 6 min of walking de to SP,O 2 that reached 80%. Three patients with resting satrations.88% declined the additional test on 2 L of oxygen. For of the five that were stopped prior to 6 min dring the room air test completed 6 min on oxygen withot desatrating to 80%. In the 16 patients tested on both room air and oxygen, walk distance increased from m to m when oxygen was administered dring the test. The impact of spplemental oxygen and the reprodcibility of the TWT were assessed in the sbgrop that was tested both on and off oxygen. Walk distance increased by 27.5%, whilst walk velocity (17.8%) and change in satration (19.3%) were less ssceptible to the effect of spplemental oxygen. The intraclass correlation coefficient was 0.76 (p50.017) for walk distance, 0.96 (p,0.0001) for walk c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 1 97

3 TIMED WALK TEST IN IPF T.S. HALLSTRAND ET AL. TABLE 1 Characteristics Baseline characteristics of the stdy poplation of patients with idiopathic plmonary fibrosis Sbjects n 28 Age yrs 62.7 (57 69) Male 19 (67.9) Smoking history 19 (67.9) Ethnic origin Cacasian 27 (96.4) Other 1 (3.6) FEV1 % pred 61.1 ( ) FVC % pred 59.9 ( ) TLC % pred 60.3 ( ) DL,CO % pred 33.0 ( ) Pa,O 2 mmhg 67.1 ( ) Pa,CO 2 mmhg 40.2 ( ) PA a,o 2 gradient mmhg 34.6 ( ) Time since diagnosis yrs 3.1 ( ) Dration of clinical symptoms yrs 4.3 ( ) Method of diagnosis SLB # 14 (50) Clinical and HRCT featres (withot SLB) 14 (50) Data are presented as n, mean (interqartile range) and n (%). FEV1: forced expiratory volme in one second; % pred: % predicted; FVC: forced vital capacity; TLC: total lng capacity; DL,CO: diffsing capacity for carbon monoxide, corrected to haemoglobin; Pa,O 2 : arterial oxygen tension; Pa,CO 2 : arterial carbon dioxide tension; PA a,o2: alveolar arterial oxygen tension; SLB: srgical lng biopsy; HRCT: high-resoltion compted tomography. # : in addition to clinical and HRCT featres. 1 kpa mmhg. velocity and 0.59 (p50.047) for change in satration, despite the addition of oxygen between the two tests. Association of the timed walk test with plmonary fnction To assess the relationship between the TWT and spirometry, lng volmes, DL,CO and arterial blood-gas parameters, the reslts of the TWT in room air or on 2 L of oxygen (according to the pre-specified criteria) were sed. There were no correlations between the parameters of the TWT and the FVC, FEV1, total lng capacity and arterial carbon dioxide tension. There were strong correlations between DL,CO, resting arterial oxygen tension (Pa,O 2 ) and PA a,o 2 difference, and endexercise satration, walk-distance and walk-velocity parameters of the TWT (table 2). Using a linear regression model, it was fond that the relationship between DL,CO and the endexercise satration parameter of the TWT predicts a decrease of 11.8% pred DL,CO for each 5% decrement in end-exercise satration (95% confidence interval (CI): ), or a 36% difference in DL,CO relative to the mean vale in this poplation (fig. 1a). Addition of the type of test (i.e. room air or oxygen), age, sex, FVC, time from diagnosis and time from onset of symptoms to the regression model did not alter this relationship. A linear regression model showed that the relationship between DL,CO and the walk-velocity parameter of the TWT predicts a decrease of 25.35% pred DL,CO for each 1m?s -1 decrement in walk velocity (95% CI: ; fig. 1b). Association of the timed walk test with srvival Patients were prospectively followed from enrolment for a median (range) of 5.4 yrs ( ). Whilst 19 ot of 28 (67.9%) patients died within 2 yrs from the time of the baseline TWT, 22 ot of 28 (78.6%) died over the entire follow-p period at an average (range) of 1.2 yrs ( ) from enrolment. Dring the stdy period, five patients nderwent single-lng transplant at an average of 1.5 yrs ( ) from enrolment and were censored in the analysis at the time of transplantation. In nivariate Cox proportional-hazards models of srvival, endexercise satration, change in satration with exercise, walk distance and walk velocity were associated with mortality (table 3). The DL,CO, which was highly correlated with parameters of the TWT, was also associated with srvival. Addition of the se of spplemental oxygen dring the TWT to the proportional-hazards model did not inflence the estimate of relative hazard. Mltivariate proportional-hazards models were created for parameters of the TWT (table 3). The addition of the se of spplemental oxygen, age, sex, FVC % pred and dration of symptoms did not appreciably alter the nivariate estimates of the associations between parameters of the TWT and srvival. Kaplan Meier srvival analysis groped according to tertiles of walk velocity showed that the median srvival times were redced according to the strata of walk velocity (fig. 2a; table 4; p50.019, log rank test). Groping according to tertiles of change in satration with exercise demonstrated redced srvival according to strata by Kaplan Meier srvival analysis (fig. 2b; table 5; p50.024, log rank test). TABLE 2 Associations between plmonary fnction and parameters of the timed walk test Variable DL,CO Pa,O2 PA a,o2 difference r p-vale r p-vale r p-vale End-exercise SP,O , Change in SP,O 2 with exercise Walk distance 0.77, , ,0.001 Walk velocity 0.73, , ,0.001 DL,CO: diffsing capacity for carbon monoxide; Pa,O2: arterial oxygen tension; PA a,o2: alveolar arterial oxygen tension; SP,O 2 : arterial oxygen satration measred by plse oximetry. 98 VOLUME 25 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

4 T.S. HALLSTRAND ET AL. TIMED WALK TEST IN IPF a) 70 b) 60 DL,CO % pred End-exercise satration % Walk velocity m s FIGURE 1. Relationships between diffsing capacity for carbon monoxide (DL,CO) and a) end-exercise satration and b) walk-velocity parameters of the timed walk test (TWT) in a poplation (n526) of patients with advanced idiopathic plmonary fibrosis. Least sqares linear regression was sed to describe the relationship between DL,CO and the TWT parameters (a) B52.36, 95% confidence interval (CI): ; b) B525.35, 95% CI: ). To corroborate the findings of the proportional-hazards model, the associations between parameters of the TWT and 2-yr srvival were assessed by logistic regression. According to an nadjsted logistic regression model, odds of death after 2 yrs were redced with incremental improvements in end-exercise satration, change in satration with exercise, walk distance and walk velocity (table 6). DL,CO and resting Pa,O 2 were also associated with death after 2 yrs. DISCUSSION IPF is a fatal disease with no known effective therapy. Clinicians need to provide accrate prognostic information to patients with IPF. In this stdy, the crrent athors describe a modified version of the 6MWT, the TWT, which is designed to captre information abot the physiological limitations of patients with IPF with a broad range of disease severity. The TWT is a simple clinical tool that can be readily applied to clinical practice and incorporates information abot haemoglobin satration at rest and with exertion, characterises continos walk velocity, and has a niform approach to the se of spplemental oxygen dring the test that is based on resting satration. This is the first stdy to characterise the TWT in a well-defined poplation of patients with established IPF, showing that the TWT is associated with disease severity, gas exchange and long-term srvival. The 6MWT is widely sed and provides important prognostic information in several chronic cardioplmonary disease states [13 16]. The primary otcome measrement of the 6MWT is the distance walked dring a period of 6 min, which may inclde periods of rest. In contrast, the TWT assesses the TABLE 3 Reslts of nivariate and mltivariate Cox proportional-hazards models relating parameters of the timed walk test and plmonary fnction to mortality Variables Univariate models Mltivariate # models Relative hazard (95% CI) p-vale Relative hazard (95% CI) p-vale Resting room air SP,O ( ) ( ) End-exercise SP,O 2 2% nits 0.73 ( ) ( ) Change in SP,O 2 with exercise " 0.80 ( ) ( ) Walk distance 30-m nits 0.89 ( ) ( ) Walk velocity 0.1-m?s -1 nits 0.77 ( ) ( ) DL,CO % pred 0.93 ( ) ( ) FVC % pred 1.00 ( ) ( ) Resting Pa,O2 mmhg 0.97 ( ) ( ) Resting PA a,o 2 difference mmhg 1.01 ( ) ( ) CI: confidence interval; SP,O 2 : arterial oxygen satration measred by plse oximetry; DL,CO: diffsing capacity for carbon monoxide; % pred: % predicted; FVC: forced vital capacity; Pa,O2: arterial oxygen tension; PA a,o2: alveolar arterial oxygen tension. # : the mltivariate model inclded age, sex, FVC % pred, time from the onset of symptoms and spplemental oxygen administration dring the test; " : for consistency, change in satration was entered as a negative change sch that a lesser degree of desatration wold be associated with redced mortality; : the mltivariate model exclded FVC as a covariate. 1 kpa mmhg. c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 1 99

5 TIMED WALK TEST IN IPF T.S. HALLSTRAND ET AL. a) 1.0 b) 0.8 Alive % Srvival days Srvival days 2500 FIGURE 2. Kaplan Meier srvival crves according to the tertiles of a) walk velocity ( : highest tertile, median 1.38 m?s -1 ; ----: middle tertile, median 0.76 m?s -1 ;.. : lowest tertile, median 0.45 m?s -1 ; table 4) and b) change in satration ( : lowest tertile, median 5; ----: middle tertile, median 10;.. : highest tertile, median 14.5; table 5) parameters of the timed walk test. Srvival crves were compared with the log rank statistic (a) p50.019; b) p50.024). : censored. TABLE 4 Nmbers at risk according to the tertiles of the walk-velocity parameter at different srvival time points TABLE 5 Nmbers at risk according to the tertiles of the change in satration parameter at different srvival time points Nmber at risk Srvival days Nmber at risk Srvival days Highest tertile Middle tertile Lowest tertile Lowest tertile Middle tertile Highest tertile Data are presented as n. Data are presented as n. change in satration and walk velocity dring continos exertion. The parameters of the TWT are designed to smmarise important information abot gas exchange and exercise performance, which relate to srvival in IPF. For example, end-exercise Pa,O 2 dring maximal exercise [7, 12] and sbmaximal steady-state exercise [12] are important measres of disease severity in IPF, leading to the hypothesis in this stdy that change in satration dring self-paced walking is a meaningfl measre of disease stats and otcome in IPF. This was also recently illstrated by LAMA et al. [17] who showed that, in a sbgrop of patients with IPF withot resting hypoxaemia, desatration to 88% at any point dring the 6MWT was associated with an increased hazard of death; however, the 6MWT distance was not associated with srvival. The TWT has specific criteria to end the test prior to 6 min, with the expectation that many patients with IPF are nable to complete 6 min of continos exertion [17, 24]. A satration of 80% was chosen as one of the stopping criteria in the TWT becase of the potential for cardiac arrhythmias and inaccrate plse oximetry tracings,80%. The data in the crrent stdy confirms that persons with IPF often demonstrate significant desatration dring 6 min of continos walking, especially in TABLE 6 Reslts of nivariate logistic regression models relating parameters of the timed walk test and plmonary fnction to mortality Variables Odds ratio (95% CI) p-vale Resting room air SP,O ( ) End-exercise SP,O 2 2% nits 0.45 ( ) Change in SP,O 2 with exercise # 0.67 ( ) Walk distance 30-m nits 0.80 ( ) Walk velocity 0.1-m?s -1 nits 0.67 ( ) DL,CO % pred 0.83 ( ) FVC % pred 1.00 ( ) Resting Pa,O 2 mmhg 0.90 ( Resting PA a,o2 difference mmhg 1.05 ( ) CI: confidence interval; SP,O 2 : arterial oxygen satration measred by plse oximetry; DL,CO: diffsing capacity for carbon monoxide; % pred: % predicted; FVC: forced vital capacity; Pa,O 2: arterial oxygen tension; PA a,o 2: alveolar arterial oxygen tension. # : for consistency, change in satration was entered as a negative change sch that a lesser degree of desatration wold be associated with redced mortality. 1 kpa mmhg. 100 VOLUME 25 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

6 T.S. HALLSTRAND ET AL. TIMED WALK TEST IN IPF the absence of spplemental oxygen. The standardised approach to the se of spplemental oxygen enabled the assessment of patients with marked differences in disease severity. The walk-distance parameter of the TWT was more ssceptible to the addition of spplemental oxygen than the change in satration parameter in patients with IPF withot resting hypoxaemia. It was fond that the change in satration parameter of the TWT had a better association with srvival than the walk-distance parameter in this diverse grop of patients with IPF. Exercise performance is a measrement of fnctional stats that is assessed by the walk velocity in the TWT. Hypoxaemia impairs exercise performance in ILD [18, 19], sggesting that correction of hypoxaemia is necessary to flly assess this parameter. By sing a two-tiered test based on baseline satration, it was possible to correct hypoxaemia, if necessary, and assess the change in satration parameter within a safe range for each patient. The walk-velocity parameter of the TWT has been sed previosly in chronic obstrctive plmonary disease (COPD) as a measre of fnctional stats [25], and was a highly repeatable measre in the crrent stdy. The reprodcibility of the walk-distance parameter of the TWT was similar to the reprodcibility of 6MWT distance in COPD [26] and heart failre [27], and the walk-velocity parameter was highly reprodcible, despite the addition of oxygen between the two tests in those patients withot resting hypoxaemia. The TWT is a clinically relevant, objective measre of disease severity in IPF. The DL,CO, Pa,O 2 and PA a,o 2 difference, which are strongly associated with the walk velocity and end-exercise satration in this stdy, reflect the severity of parenchymal abnormalities in IPF and have consistently been associated with clinically important endpoints [7, 8, 12, 28 31]. There was no clear association between the TWT and lng volmes in this stdy. However, lng volmes are inconsistently associated with srvival and other otcome measres in IPF [2, 4], and changes in lng volmes are insensitive to the effect of treatment in clinical trials [10, 32]. Srvival is a key otcome measre in IPF. This stdy demonstrates a strong relationship between a nmber of parameters of the TWT and srvival in persons with IPF. The associations between parameters of the TWT and srvival were shown sing a proportional-hazard model and corroborated by logistic regression analysis of 2-yr srvival. De to the modest sample size, the crrent athors were nable to identify additional factors that might alter the associations between parameters of the TWT and mortality. Ftre stdies in larger nmbers of patients may be able to adjst for factors, sch as sex and age, to refine the relationship between parameters of the TWT and srvival. Since the parameters of the TWT are highly interdependent, it is not possible to state which parameter is most predictive. Similar to other recent stdies, DL,CO was also associated with srvival to a greater degree than lng volmes [33]. Longitdinal changes in measrements of resting physiological variables (composite index, FVC, DL,CO) have been demonstrated to predict srvival in IPF [34 36]. In the crrent stdy, the srvival in the patient poplation was predicted by the TWT performed at the baseline visit itself. Additional advantages of the TWT over the DL,CO are that it can be condcted in an amblatory setting and does not involve a breath-holding manoevre reqired for the DL,CO, which may not be tolerated by some patients with advanced IPF. This stdy has a few potential limitations, as follows. 1) The stdy poplation consisted of a small nmber of patients with IPF who had progressed despite conventional therapy. 2) The stdy was condcted at a single tertiary referral centre with expertise in the management of IPF. 3) The TWT was condcted by a single respiratory therapist. 4) The TWT was not condcted at the time of initial diagnosis and was not serially performed dring follow-p. 5) The TWT was not compared with other fnctional measrements, sch as the 6MWT or formal cardioplmonary exercise test. 6) The treatment regimen sbseqent to the TWT was not controlled for in the analysis. Acknowledging that there is no known effective therapy to date, individal therapies are nlikely to have confonded the relationship between the TWT and srvival. In smmary, the timed walk test is a clinical tool that can be performed in the amblatory setting and relates to important aspects of disease severity and long-term otcome in idiopathic plmonary fibrosis. This simple fnctional measrement may have a role in the clinical evalation of persons with idiopathic plmonary fibrosis, and may serve as a reliable otcome measre to assess treatment response, gide timing of lng transplantation and predict long-term srvival in idiopathic plmonary fibrosis. Ftre stdies comparing the timed walk test with the 6-min walk test and/or other exercise tests with continos measrements of arterial oxygen satration measred by plse oximetry in patients with idiopathic plmonary fibrosis are indicated to validate the findings of this stdy in a larger poplation. ACKNOWLEDGEMENTS The athors are greatly indebted to the patients and their families for participating in this stdy, and to commnity physicians for referring their patients to the Interstitial Lng Disease, Sarcoid and Plmonary Fibrosis Program at the University of Washington Medical Center, Seattle, WA, USA, for frther management of idiopathic plmonary fibrosis and related problems. REFERENCES 1 American Thoracic Society. Idiopathic plmonary fibrosis: diagnosis and treatment. International consenss statement. American Thoracic Society (ATS), and the Eropean Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: Mapel DW, Hnt WC, Utton R, Bamgartner KB, Samet JM, Coltas DB. Idiopathic plmonary fibrosis: srvival in poplation based and hospital based cohorts. Thorax 1998; 53: Carrington CB, Gaensler EA, Cot RE, FitzGerald MX, Gpta RG. Natral history and treated corse of sal and desqamative interstitial pnemonia. N Engl J Med 1978; 298: c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 1 101

7 TIMED WALK TEST IN IPF T.S. HALLSTRAND ET AL. 4 Trner-Warwick M, Brrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical featres and their inflence on srvival. Thorax 1980; 35: Hbbard R, Johnston I, Britton J. Srvival in patients with cryptogenic fibrosing alveolitis: a poplation-based cohort stdy. Chest 1998; 113: Tkiainen P, Taskinen E, Holsti P, Korhola O, Valle M. Prognosis of cryptogenic fibrosing alveolitis. Thorax 1983; 38: King TE Jr, Schwarz MI, Brown K, et al. Idiopathic plmonary fibrosis: relationship between histopathologic featres and mortality. Am J Respir Crit Care Med 2001; 164: Schwartz DA, Helmers RA, Galvin JR, et al. Determinants of srvival in idiopathic plmonary fibrosis. Am J Respir Crit Care Med 1994; 149: Erbes R, Schaberg T, Loddenkemper R. Lng fnction tests in patients with idiopathic plmonary fibrosis. Are they helpfl for predicting otcome? Chest 1997; 111: Gay SE, Kazerooni EA, Toews GB, et al. Idiopathic plmonary fibrosis: predicting response to therapy and srvival. Am J Respir Crit Care Med 1998; 157: Nicholson AG, Flford LG, Colby TV, d Bois RM, Hansell DM, Wells AU. The relationship between individal histologic featres and disease progression in idiopathic plmonary fibrosis. Am J Respir Crit Care Med 2002; 166: King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting srvival in idiopathic plmonary fibrosis: scoring system and srvival model. Am J Respir Crit Care Med 2001; 164: Bittner V, Weiner DH, Ysf S, et al. Prediction of mortality and morbidity with a 6-minte walk test in patients with left ventriclar dysfnction. SOLVD Investigators. JAMA 1993; 270: Rejeski WJ, Foley KO, Woodard CM, Zaccaro DJ, Berry MJ. Evalating and nderstanding performance testing in COPD patients. J Cardioplm Rehabil 2000; 20: McDermott MM, Greenland P, Li K, et al. The ankle brachial index is associated with leg fnction and physical activity: the Walking and Leg Circlation Stdy. Ann Intern Med 2002; 136: Brooks D, De Rosie J, Mossea M, Avendano M, Goldstein RS. Long term follow-p of ventilated patients with thoracic restrictive or neromsclar disease. Can Respir J 2002; 9: Lama VN, Flaherty KR, Toews GB, et al. Prognostic vale of desatration dring a 6-minte walk test in idiopathic interstitial pnemonia. Am J Respir Crit Care Med 2003; 168: Harris-Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marcinik DD. Oxygen improves maximal exercise performance in interstitial lng disease. Am J Respir Crit Care Med 1994; 150: Harris-Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, Marcinik DD. Role of hypoxemia and plmonary mechanics in exercise limitation in interstitial lng disease. Am J Respir Crit Care Med 1996; 154: Ragh G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accracy of the clinical diagnosis of newonset idiopathic plmonary fibrosis and other interstitial lng disease: a prospective stdy. Chest 1999; 116: American Thoracic Society, Eropean Respiratory Society. American Thoracic Society/Eropean Respiratory Society International Mltidisciplinary Consenss Classification of the Idiopathic Interstitial Pnemonias. This joint statement of the American Thoracic Society (ATS), and the Eropean Respiratory Society (ERS) was adopted by the ATS board of directors, Jne 2001 and by the ERS Exective Committee, Jne Am J Respir Crit Care Med 2002; 165: Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med 1995; 152: Crapo RO, Jensen RL, Hegewald M, Tashkin DP. Arterial blood gas reference vales for sea level and an altitde of 1,400 meters. Am J Respir Crit Care Med 1999; 160: Chetta A, Aiello M, Foresi A, et al. Relationship between otcome measres of six-minte walk test and baseline lng fnction in patients with interstitial lng disease. Sarcoidosis Vasc Diffse Lng Dis 2001; 18: Menard-Rothe K, Sobsh DC, Bosamra M 2nd, Haasler GB, Lipchik RJ. Self-selected walking velocity for fnctional amblation in patients with end-stage emphysema. J Cardioplm Rehabil 1997; 17: Scirba F, Criner GJ, Lee SM, et al. Six-minte walk distance in chronic obstrctive plmonary disease: reprodcibility and effect of walking corse layot and length. Am J Respir Crit Care Med 2003; 167: Demers C, McKelvie RS, Negassa A, Ysf S. Reliability, validity, and responsiveness of the six-minte walk test in patients with heart failre. Am Heart J 2001; 142: Schwartz DA, Van Fossen DS, Davis CS, et al. Determinants of progression in idiopathic plmonary fibrosis. Am J Respir Crit Care Med 1994; 149: Moglkoc N, Brtsche MH, Bishop PW, Greaves SM, Horrocks AW, Egan JJ. Plmonary fnction in idiopathic plmonary fibrosis and referral for lng transplantation. Am J Respir Crit Care Med 2001; 164: Wells AU, King AD, Rbens MB, Cramer D, d Bois RM, Hansell DM. Lone cryptogenic fibrosing alveolitis: a fnctional-morphologic correlation based on extent of disease on thin-section compted tomography. Am J Respir Crit Care Med 1997; 155: Xabet A, Agsti C, Lbrich P, et al. Plmonary fnction tests and CT scan in the management of idiopathic plmonary fibrosis. Am J Respir Crit Care Med 1998; 158: Hanson D, Winterbaer RH, Kirtland SH, W R. Changes in plmonary fnction test reslts after 1 year of therapy as predictors of srvival in patients with idiopathic plmonary fibrosis. Chest 1995; 108: Moglkoc N, Brtsche MH, Bishop PW, et al. Plmonary (99m)Tc-DTPA aerosol clearance and srvival in sal interstitial pnemonia (UIP). Thorax 2001; 56: Latsi PI, d Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pnemonia: the prognostic vale of longitdinal fnctional trends. Am J Respir Crit Care Med 2003; 168: VOLUME 25 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

8 T.S. HALLSTRAND ET AL. TIMED WALK TEST IN IPF 35 Collard HR, King TE Jr, Bartelson BB, Vorlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict srvival in idiopathic plmonary fibrosis. Am J Respir Crit Care Med 2003; 168: Flaherty KR, Mmford JA, Mrray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pnemonia. Am J Respir Crit Care Med 2003; 168: EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 1 103