American Journal of Respiratory and Critical Care Medicine

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease associated with a dismal prognosis and a median survival of approximately 3 years. However, in clinical practice the course of the disease in individual patients may vary considerably, and the natural history is only incompletely understood. The recently published evidence-based guidelines for diagnosis and management of IPF differentiate stable disease from slow progression, rapid progression, and acute exacerbation, with slow and steady progression applying to a majority of patients (1). Forced vital capacity (FVC) has been used for decades to assess and describe the functional status of patients with fibrotic lung diseases; a decline of FVC was utilized as a measure of disease progression. Interestingly, independent retrospective and prospective studies have demonstrated that a 10% decline in forced vital capacity (FVC) within 6 to 12 months is associated with a significant increase in mortality (26). A recent publication suggests that even smaller declines of FVC predict worse prognosis (7). However, systematic studies of the reliability and validity of FVC-measurements in large cohorts of patients with pulmonary fibrosis are clearly lacking. Moreover, the minimal clinically important difference (MCID) for FVC has not been defined in IPF so far.

In this issue of the Journal, du Bois and coworkers (pp. 1382–1389) present a systematic evaluation of the measurement properties of FVC based on a large series of 1,156 patients with IPF who had been enrolled in two placebo-controlled trials of interferon-γ 1b (8). Since both trials were negative, patients were included in this analysis irrespective of treatment assignment. The size of this IPF cohort is unprecedented and is one of the strengths of this study. Moreover, the data were collected prospectively in these trials, another strength of this particular dataset, avoiding the selection bias commonly seen in retrospective studies.

The results clearly demonstrate that FVC is a reliable and valid parameter for assessing pulmonary function and disease status in patients with IPF. Data consistency is impressive and reflects the fact that FVC is a very robust measure. Most importantly, the authors could demonstrate that small changes of FVC of only 5 to 10% (i.e., absolute change in % predicted) over a 24-week period are highly predictive of mortality during the subsequent 1-year period. This finding is in good agreement with previously published data (7). The statistical analyses to assess the MCID were performed applying both the distribution-based and the anchor-based methods, resulting in a range of 2.0 to 6.0% change in percent predicted FVC. MCID is a meaningful concept, indicating the smallest change in a measure that would not necessarily be perceived as a change in disease status by patients but which eventually would prompt a doctor to consider a change in therapy. In clinical treatment trials the MCID is helpful to decide whether or not an observed treatment effect would impact on the disease status in a group of patients. In the study by du Bois and colleagues, small changes of FVC (2–6%) were associated with clinically relevant changes of disease status (8). The interpretation of such a “marginal change” for the management of an individual patient is much more challenging. Especially when the range of MCID is close to or overlapping with the variation of the measure itself, as is true for the FVC, a small change may represent a meaningful or a chance finding. Therefore, clinical decisions in individual patients cannot be based on a measure of FVC in isolation, but have to take into account the clinical context of the patient and additional measures like 6-minute-walk distance, diffusion capacity, and oxygenation.

What does this mean for the management of this deleterious disease? To answer this question, three fields of application of these data have to be considered separately:

Since most clinical treatment trials focused on patients with IPF with mild to moderate disease, mortality was low, making studies powered for mortality impracticable, unaffordable, or both (913). In view of its reliability, validity, and responsiveness, FVC is a robust study endpoint that is linked to patient-sensitive outcomes like dyspnea and health status as well as mortality (8). If corroborated with secondary endpoints and at least a positive trend in mortality, change in FVC is a valid primary endpoint in pivotal treatment studies.

Upcoming medical therapies of IPF have already used the “change in FVC” as a primary endpoint in randomized controlled treatment trials (914). In some of these trials, decline of FVC could be ameliorated significantly and was associated with at least a positive trend in mortality (10, 1214). In the context of the data presented by du Bois and coworkers and considering the fact that improvement of FVC was hardly detectable in any of these studies, these data suggest that prevention of a decline in FVC is a desirable treatment goal in patients with IPF. Consequently, available treatments, once approved, should be offered to patients with IPF to preserve pulmonary function and reduce the risk of mortality. This implies a plea for early diagnosis and therapy, since a decline of FVC, once detected, already substantiates an increase in the risk of mortality.

In individual patients physicians have to consider even small changes of FVC more critically as potentially clinically relevant, especially in the context of additional measures and clinical findings indicating disease progression. The data presented here for the FVC measurement are helpful not as an absolute threshold but as an orientation for clinicians.

In conclusion, the study presented by du Bois and coworkers is a landmark study which will have a high impact on study design, treatment strategy and clinical decision making in IPF.

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