*4.3. Limitations*

This systematic review attempted to conduct a comprehensive review of the various types of manual therapies utilized for COPD and to investigate its comparative effectiveness on lung function and exercise capacity of COPD patients using the NMA methodology. However, the results of this review should be interpreted considering the following limitations.

First, given the heterogeneity of interventions investigated, the number of studies that were included in this review (30 in total) was not sufficient to provide strong evidence through quantitative synthesis. In addition, given that most of the included studies had small sample sizes, there is a possibility that the findings of this review were greatly influenced by small-study effects [52]. Second, the quality of the included studies was poor overall. In particular, as aforementioned, the results from these studies may have been influenced by placebo effects or could have been overestimated, as random sequence generation, allocation concealment, and blinding procedures were described unclearly or with a high risk of bias. Third, in our prior protocol, evaluation of publication bias of the included studies was planned using funnel plots and net funnel plots. However, the lack of included studies consequently made it impossible to visually evaluate publication bias using funnel plots. This implies that we cannot rule out the possibility that the results reported in the studies included in this review may be biased. Finally, comparisons between manual therapies performed in this review primarily came from NMA, and the data are lacking in conventional pair-wise meta-analysis. That is, the head-to-head trial comparing the comparative effects of different types of manual therapies for COPD patients in conventional RCTs was insufficient. In particular, head-to-head trials between Western manual therapy and Eastern manual therapy, one of the rationales of this systematic review, did not exist. Although the NMA methodology enables indirect comparison between interventions that have not previously been directly compared with each other [12], the overall poor methodological quality of the included studies suggests that large-scale, highquality head-to-head trials can provide more reliable results. Given that various manual therapies are being used and studied for COPD patients in both East and West, robust clinical trials evaluating the comparative effectiveness of these treatments may be of interest to future researchers.
