Derek Weycker

The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis

Context The natural history of idiopathic pulmonary fibrosis (IPF) is unclear. Contribution A total of 168 participants with mild to moderate IPF assigned to placebo in a randomized trial were followed at 12-week intervals for about 76 weeks. For 32 of 36 patients who died, IPF was a related or main cause of death. Although physiologic variables such as FVC changed little, acute clinical deterioration preceded death in half of the patients who died of IPF. Implications Clinicians may need to rethink referral timing for lung transplantation because many patients with IPF may experience precipitous clinical declines rather than gradual progression of disease. The Editors Idiopathic pulmonary fibrosis (IPF), the most frequent of the idiopathic interstitial pneumonias, is associated with the worst prognosis (1, 2). However, data on the natural history of IPF are sparse. To clearly describe the pace of progression and the cause of death in a well-characterized cohort with mild to moderate IPF, we analyzed data from the placebo group of a randomized, double-blind, controlled clinical trial evaluating therapy with interferon-1b in patients with IPF (3). These data provide important insight into the natural history of IPF and events preceding death in patients with IPF. The data suggest that a gradual, progressive decline does not occur in many patients, thereby supporting the need for early referral for lung transplantation. Methods Overview Using data from a recently completed clinical trial (3), we performed a series of exploratory analyses of physiologic variables, dyspnea measures, hospitalizations, and characteristics of mortality in patients randomly assigned to receive placebo. The prespecified primary end point analysis for the phase III study was to occur after the 306th randomly assigned patient was scheduled to complete 48 weeks of therapy. Patients were enrolled over an approximately 1-year period. Thus, follow-up times for the patients varied, and the numbers of patients available for visits beyond 48 weeks diminished over time. In the published report of the primary analysis of the trial, the median length of observation was 58 weeks (3). In the current report, we summarize data from randomization through the completion of blinded study therapy (the observation period); the median for this period was 76 weeks. Study Participants Study participants were all patients randomly assigned to the placebo group (n= 168) in the trial (3). Criteria for enrollment included a diagnosis of IPF according to American Thoracic Society criteria (4), an FVC of 50% to 90%, diffusing capacity of carbon monoxide (DLco) of 25% or greater, definite or probable IPF on high-resolution computed tomography according to prespecified criteria, and worsening of disease during the preceding year despite a total corticosteroid dose of 1800 mg or greater within the preceding 2 years (3). Patients were permitted to continue taking prednisone (15 mg/d) if the dosage remained stable. Data Collection Data were collected at 12-week intervals and recorded on standardized case report forms by trained research associates at each institution. Information derived from interview and examination of the patient included demographic and clinical data, physiologic assessments, measures of dyspnea, vital status, number of all-cause hospitalizations, and number of hospitalizations for which the primary reason was specified as respiratory. Physiologic measures included FVC, plethysmography, Dlco, and arterial blood gas at room-air ambient temperatures. The transition dyspnea score is derived from an instrument in which the patient assesses the extent of dyspnea in reference to his or her baseline at study entry (5). The transitions or changes in the patients dyspnea in 3 categories (function impairment, magnitude of task needed to evoke dyspnea, and magnitude of effort needed to evoke dyspnea) are rated in 7 grades from 3 (major deterioration) to 0 (unchanged) to 3 (major improvement); the final score ranged from 9 to 9. The lower the total score, the more severe the dyspnea. The validated University of California, San Diego, Shortness of Breath Questionnaire (6) has 24 items: Patients are asked to rate severity of shortness of breath using a 6-point scale (0 = not at all; 5 = maximal severity) during 21 different activities of daily living associated with varying levels of exertion; they are also asked to rate how their daily lives are limited by shortness of breath, fear of harm from overexertion, and fear of shortness of breath. Scores range from 0 to 120, with increasing score indicating worsening quality of life. The physician responsible for any patient who died during the study period completed a retrospective supplemental questionnaire. The investigator-physician, who had full access to all measurements obtained as a part of the study, specified the primary cause of death, whether the cause was respiratory, and whether death was related to IPF. Investigator-physicians were to cite IPF as the primary cause of death only in the absence of a known alternative cause and only if the event was witnessed. For deaths considered to be IPF-related, 1 of 4 categories was assigned on the basis of the interval from the onset of new or worsening symptoms or signs until death: abrupt (occurring within minutes to hours), acute (4 weeks), subacute (progressing over weeks or months), or unknown. In the current report, we combine the abrupt- and acute-onset events within a single category. Statistical Analysis Physiologic variables and measures of dyspnea were compared between baseline and week 72. The frequency of hospitalizations (all-cause and respiratory-related), number of hospital days in patients hospitalized, and mortality were assessed over the entire observation period. Mean values are followed by SDs. The relationships between baseline percentage predicted FVC and the incidence and length of hospitalization were examined by using the Fisher exact test or independent-sample t-test, as appropriate. Missing values were not imputed. The reasons for missing values are as follows: 1) To optimize data integrity, data obtained at visits outside a window of 7 days were not included in the analysis, 2) because trial enrollment was staggered, fewer patients were available for analysis at the latter time points, and 3) the value for a particular variable for a particular patient may be missing, even though all other values for that time point and patient are available. On the basis of the nature of the variations leading to the differences in available data over time, no apparent evidence indicated that the variations are not random. Data analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source InterMune, Inc., funded this study. Authors from InterMune (Drs. Safrin, Starko, and Bradford) participated in the design and analysis of the study, as did the other authors. All authors had full access to the data. The funding source had no role in the decision to publish the results. Results Patients We analyzed 168 patients (mean age, 64 years, SD 9). Most patients were male (66%), white (86%), and nonsmokers (that is, never-smokers or ex-smokers) (91%). Mean time since the diagnosis of IPF was 378 days, SD, 295. The diagnosis of IPF was confirmed by surgical lung biopsy in 58% of patients; in 83%, findings on high-resolution computed tomography met prespecified criteria for definite IPF. At study entry, 31% of patients used supplemental oxygen and 82% were receiving systemic corticosteroids. During the observation period, 2 patients (1.2%) used azathioprine and 1 patient (0.6%) used cyclophosphamide. Physiologic Variables and Measures of Dyspnea For patients who survived to week 72, the mean percentage predicted FVC decreased from 64.5%, SD 11.1%, to 61.0%, SD 14.1%; the mean percentage predicted DLco decreased from 37.8%, SD 11.1%, to 37.0%, SD 19.9%; and the mean alveolararterial gradient increased from 23.2 mm Hg, SD 10.9, to 26.9 mm Hg, SD 13.0. The mean transition dyspnea index score was 1.29, SD 3.6, at week 72, indicating worsening dyspnea, whereas the mean University of California, San Diego, Shortness of Breath Questionnaire score changed minimally (from 45.1, SD 23.4, to 46.8, SD 25.1) (Figure 1). For patients who died during the trial, we observed a general trend toward increases in alveolararterial gradient and dyspnea and toward decreases in FVC and DLco (Figure 2). The spaghetti plots (Figure 2) highlight the finding that although dyspnea or alveolararterial gradient often increased sharply before a patients death, significant intrapatient variability occurs over time. Figure 1. Measures of physiology and dyspnea from study entry through week 72 for patients who survived throughout trial. Figure 2. Measures of physiology and dyspnea for each of the 36 patients who died during the trial; each line represents a single patient. Hospitalizations Fifty-seven (34%) patients had a total of 95 all-cause hospitalizations during the observation period. Among those hospitalized, the mean total number of hospital days was 14.3, SD 13.5. Thirty-eight (23%) patients had 57 hospitalizations for a respiratory disorder, with a mean total number of hospital days of 15.0, SD 14.6. The most commonly reported reason for respiratory hospitalization (33%) was presumed infection. When stratified by the baseline median percentage predicted FVC, patients with more severely impaired lung function (62%) were more likely to be hospitalized for any reason than patients with baseline percentage predicted FVC greater than 62%35 (42%) versus 22 (26%) patients (P= 0.05) and 58 versus 37 hospitalizations overall. Respiratory hospitalizations were similarly more frequent in the subset of patients with baseline FVC of 62% or less: 25 (30%) versus 13 (15%) patients (P= 0.04). In hospitalized patients, the total number

Ascertainment of Individual Risk of Mortality for Patients with Idiopathic Pulmonary Fibrosis

RATIONALE Several predictors of mortality in patients with idiopathic pulmonary fibrosis have been described; however, there is a need for a practical and accurate method of quantifying the prognosis of individual patients. OBJECTIVES Develop a practical mortality risk scoring system for patients with idiopathic pulmonary fibrosis. METHODS We used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with idiopathic pulmonary fibrosis. From the comprehensive model, an abbreviated clinical model comprised of only those predictors that are readily and reliably ascertained by clinicians was derived. Beta coefficients for each predictor were then used to develop a practical mortality risk scoring system. MEASUREMENTS AND MAIN RESULTS Independent predictors of mortality included age, respiratory hospitalization, percent predicted FVC, 24-week change in FVC, percent predicted carbon monoxide diffusing capacity, 24-week change in percent predicted carbon monoxide diffusing capacity, and 24-week change in health-related quality of life. An abbreviated clinical model comprising only four predictors (age, respiratory hospitalization, percent predicted FVC, and 24-wk change in FVC), and the corresponding risk scoring system produced estimates of 1-year mortality risk consistent with observed data (9.9% vs. 9.7%; C statistic = 0.75; 95% confidence interval, 0.71–0.79). CONCLUSIONS The prognosis for patients with idiopathic pulmonary fibrosis may be accurately determined using four readily ascertainable predictors. Our simplified scoring system may be a valuable tool for determining prognosis and guiding clinical management. Additional research is needed to validate the applicability and accuracy of the scoring system.

Prevalence and Economic Burden of Bronchiectasis

We employed a retrospective cohort design to estimate the prevalence and economic burden of bronchiectasis. Data were obtained from the health-care claims processing systems of more than 30 US health plans (with a combined total of 5.6 million covered lives) and spanned the period January 1, 1999, to December 31, 2001. Study subjects consisted of all persons who were aged ≥18 years in 2001 and had diagnoses of bronchiectasis between 1999 and 2001; those with diagnoses of cystic fibrosis were excluded. For purposes of comparison, a cohort of persons without diagnoses of bronchiectasis was randomly selected and matched on age, sex, geographic region, and comorbid conditions. Prevalence of bronchiectasis ranged from 4.2 per 100,000 persons aged 18–34 years to 271.8 per 100,000 among those aged ≥75 years. Prevalence was higher among women than men at all ages. Persons with bronchiectasis averaged 2.0 (95% confidence interval 1.7–2.3) additional days in hospital, 6.1 (6.0–6.1) additional outpatient encounters, and 27.2 (25.0–29.1) more days of antibiotic therapy than those without the disorder in 2001; average total medical-care expenditures were

Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference.

5681 (

Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.

4862–

Long-term mortality and medical care charges in patients with severe sepsis.

6593) higher for bronchiectasis patients. Our findings suggest that over 110,000 persons in the United States may be receiving treatment for bronchiectasis, resulting in additional medical-care expenditures of

Clinical and economic burden of pneumococcal disease in older US adults.

630 million annually.

Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis

RATIONALE The 6-minute-walk test (6MWT) is a practical and clinically meaningful measure of exercise tolerance with favorable performance characteristics in various cardiac and pulmonary diseases. Performance characteristics in patients with idiopathic pulmonary fibrosis (IPF) have not been systematically evaluated. OBJECTIVES To assess the reliability, validity, and responsiveness of the 6MWT and estimate the minimal clinically important difference (MCID) in patients with IPF. METHODS The study population included all subjects completing a 6MWT in a clinical trial evaluating interferon gamma-1b (n = 822). Six-minute walk distance (6MWD) and other parameters were measured at baseline and at 24-week intervals using a standardized protocol. Parametric and distribution-independent correlation coefficients were used to assess the strength of the relationships between 6MWD and measures of pulmonary function, dyspnea, and health-related quality of life. Both distribution-based and anchor-based methods were used to estimate the MCID. MEASUREMENTS AND MAIN RESULTS Comparison of two proximal measures of 6MWD (mean interval, 24 d) demonstrated good reliability (coefficient = 0.83; P < 0.001). 6MWD was weakly correlated with measures of physiologic function and health-related quality of life; however, values were consistently and significantly lower for patients with the poorest functional status, suggesting good construct validity. Importantly, change in 6MWD was highly predictive of mortality; a 24-week decline of greater than 50 m was associated with a fourfold increase in risk of death at 1 year (hazard ratio, 4.27; 95% confidence interval, 2.57- 7.10; P < 0.001). The estimated MCID was 24-45 m. CONCLUSIONS The 6MWT is a reliable, valid, and responsive measure of disease status and a valid endpoint for clinical trials in IPF.

Are Shorter Courses of Filgrastim Prophylaxis Associated with Increased Risk of Hospitalization

RATIONALE Forced vital capacity (FVC) is an established measure of pulmonary function in idiopathic pulmonary fibrosis (IPF). Evidence regarding its measurement properties and minimal clinically important difference (MCID) in this population is limited. OBJECTIVES To assess the reliability, validity, and responsiveness of FVC and estimate the MCID in patients with IPF. METHODS The study population included all 1,156 randomized patients in two clinical trials of IFN-γ1b. FVC and other measures of functional status were measured at screening or baseline and 24-week intervals thereafter. Reliability was assessed based on two proximal measures of FVC, validity was assessed based on correlations between FVC and other measures of functional status, and responsiveness was assessed based on the relationship between 24-week changes in FVC and other measures of functional status. Distribution-based and anchor-based methods were used to estimate the MCID. MEASUREMENTS AND MAIN RESULTS Correlation of percent-predicted FVC between measurements (mean interval, 18 d) was high (r = 0.93; P < 0.001). Correlations between FVC and other parameters were generally weak, with the strongest observed correlation between FVC and carbon monoxide diffusing capacity (r = 0.38; P < 0.001). Correlations between change in FVC and changes in other parameters were slightly stronger (range, r = 0.16-0.37; P < 0.001). Importantly, 1-year risk of death was more than twofold higher (P < 0.001) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%. CONCLUSIONS FVC is a reliable, valid, and responsive measure of clinical status in patients with IPF, and a decline of 2-6%, although small, represents a clinically important difference.

6-minute walk distance is an independent predictor of mortality in patients with idiopathic pulmonary fibrosis

ObjectiveTo estimate long-term mortality and medical care charges among patients with severe sepsis. DesignRetrospective cohort study. SettingLarge, integrated, geographically diverse, U.S. health-insurance claims database covering three million lives annually. PatientsAll persons with bacterial or fungal infections and acute organ dysfunction (severe sepsis) who were hospitalized between January 1, 1991, and August 31, 2000. InterventionsNone. Measurements and Main ResultsAll patients were followed from the date of hospitalization with severe sepsis (index admission) to August 31, 2000, disenrollment from the health plan, or death, whichever occurred first. Measures of interest included mortality and medical care charges and were estimated for the index admission, the 90- and 180-day periods following the index admission, and annually thereafter (up to 5 yrs), using techniques of survival analysis. A total of 16,019 patients were identified who met study entrance criteria. Most patients (81.2%) were ≥65 yrs of age; 53.4% were men. Mortality was 21.2% for the index admission, 51.4% at 1 yr, and 74.2% at 5 yrs. Mean cumulative total medical care charges were