In this multicentre study including a heterogeneous group of fibrosing ILDs, 6MWD expressed as percent predicted was found to be only a slightly more significant predictor of LTx-free survival compared to “classic” 6MWD expressed in meters. These results were consistent across 3 different statistical analyses, and reproducible in the validation cohort. There were several significant differences between the 2 cohorts in terms of ILD subtypes, outcomes and treatment strategies. The confirmation of all findings in the validation cohorts suggest a wide applicability of the results across a diverse range of fibrosing ILDs, including both IPF and non-IPF patients. Our findings suggest a potential to use an improved exercise capacity variable in the clinical management of various types and severities of fibrosing ILDs, but also an urgent need for improved reference equation for 6MWD%.

The role of longitudinal changes of 6MWD in following the clinical course of fibrosing ILD has been increasingly recognized [21]. Although reference equations for 6MWD are available and commonly used in reporting the results of the 6MWT [22], no previous studies directly compared the prognostic power of 6MWD-m and 6MWD% across diverse groups of fibrosing ILDs. Using 6MWD% may allow for adjustments based on expected differences in demographic characteristics among patients, making it a potentially more personalized measure of exercise capacity. In a study conducted on IPF and idiopathic pleuroparenchymal fibroelastosis patients, Sato et al. showed that 6MWD is indeed influenced by factors such as age, sex, height, and weight. The authors underlined that these factors need to be considered when evaluating 6MWD outcomes in ILD patients to provide a more accurate prediction of patient prognosis [23].

Our data show a slight superiority of 6MWD% over 6MWD-m as a predictor of LTx-free survival, when used longitudinally, across different statistical approaches and diverse cohorts. Using the cutoffs for lung function (FVC and DLCO) decline recommended by the ATS [8], we were able to confirm that the simultaneous use of 6MWD% provides additional, independent predictive power towards survival. Using 6MWD% as a standardized measure may then further improve risk stratification in patients with fibrosing ILDs, identify high-risk patients, and optimize the timing for LTx. Additionally, it could help monitoring the effectiveness of treatments, informing decisions about continuing or adjusting therapy.

While using a percent predicted 6MWD would make clinical sense, the differences in prognostic power that we observed compared to 6MWD-m were overall modest. This likely due to limitations in the reliability of the reference evaluations themselves. Enright and Sherrill indicated that the predictive equations used to calculate 6MWD% were primarily derived from populations of healthy subjects [17]. It is important to note that these prediction equations only capture 60% of the variance in documented 6MWD, as the authors pointed out in their original publication [17]. The data used to develop these equations were derived from healthy subjects under 80 with a BMI under 35. BMI has an inverse linear relationship with predicted 6MWD [17]. As a result, the formula may not accurately reflect the effects of weight extremes, frailty, and advanced age, which are common characteristics in patients with fibrosing ILDs. Another intriguing and potentially confusing factor is represented by the fact that, in IPF, a higher BMI has been consistently shown to be protective against mortality [24]. Patients with a higher BMI have a lower percent predicted 6MWD. As a result, at least in the IPF subgroup, the protective effect of a higher BMI may somewhat curb the predictive power of a lower 6MWD% against mortality. On the other hand, BMI was not retained as a significant predictor of LTx survival in the multivariate cox proportional hazard regression analysis and, in fact, 6MWD% outperformed 6MWD-m to a greater extent in IPF than in non-IPF ILDs. This finding confirms a previous observation in a prospective IPF cohort [11].

Another study underlined the current limitations of 6MWD%. Balashov et al. highlighted that using the equation developed by Troosters et al. [25], 6MWD% adjusted for confounders had a better correlation with a health-related quality of life questionnaires score than 6MWD [26]. The authors argue that 6MWD often misleads the results in patients with cardiovascular disease compared to healthy subjects, due to comorbidities and demographic differences, as the standard equations for 6MWD were actually validated for healthy subjects [26]. The authors then suggested revising these equations to improve the accuracy of the outcomes’ prediction.

We considered using references other than the ones developed by Enright and Sherrill to calculate predicted 6MWD, but those are even less proficient, accounting for an even smaller portion of the physiological variance in 6MWD [27]. We advocate for the development of new predictive equations based on a wide range of patient characteristics, including old and frail patients, and including an equally wide range of BMIs, in order to improve the accuracy of 6MWD% predictions and, consequently, patient prognostication.

The present study had several strengths, including its comprehensive statistical analysis that took into account the competing risks of death and LTx. The inclusion of large, multicenter cohorts strengthened the reliability of the results. The significant prevalence of death/LTx during the observation period provided ample statistical power to investigate survival predictors. The study’s sufficiently long period of observation allowed for the assessment of both baseline and longitudinal changes in 6MWD and their impact on survival. Finally, the consistency of results among cohorts that were diverse in terms of outcomes and management, and the inclusion of both IPF and non-IPF patients both support the generalizability of the findings in fibrosing ILDs.

On other hand, the present study has also some limitations. The retrospective design carries a risk of selection and confounding bias. For the same reason, the study lacked inter-mediate assessments between baseline and 1-year follow-up. Another limitation is represented by the fact that other comorbidities and confounding factors might need to be fully accounted for, when considering both exercise capacity and outcome. Including another comorbidity score, such as the Charlson comorbidity index or the Elixhauser score, could improve the results, as reported in another study [28]. Finally, we should recognize the likelihood of a learning effect of the 6MWT in ILD patients during consecutive assessments [29].

In conclusion, our multicenter study showed that 6MWD% has a minor, yet detectable advantage over 6MWD-m as an independent predictor of LTx-free survival in a wide range of fibrosing ILDs, when considered in combination with measures of lung function. Our results support the use of a more standardized and personalized approach to the implementation of exercise capacity in the day-to-day management of fibrosing ILDs, but also calls for more accurate reference equations for 6MWD in chronic lung disease. An improved percent prediction of 6MWD will likely enhance the consistency and accuracy of the comprehensive evaluation of fibrosing ILDs across various clinical settings.