Methodological Considerations in Evaluating Recombinant Zoster Vaccine Effectiveness in COPD PatientsDear Editor,We read with great interest the article by Tsai et al. addressing the effectiveness of recombinant zoster vaccine (RZV) in chronic obstructive pulmonary disease (COPD) patients[1]. This study highlights the significantly lower risk of herpes zoster among vaccinated COPD patients (HR, 0.62; 95% CI, 0.51–0.75) and importantly draws attention to the concerningly low vaccination rate (<0.5%) in this high-risk population. While these findings provide valuable evidence supporting RZV vaccination in COPD patients, several methodological considerations warrant discussion to strengthen future research in this area.First, there appears to be a discrepancy regarding the study population selection. While the limitations section suggests the inclusion of predominantly U.S. patients, the flow chart indicates data incorporation from five countries. This inconsistency is critical as zoster vaccine implementation and availability varied substantially across countries[2]. For instance, different countries introduced RZV at varying times following its initial U.S. approval in 2017. Additionally, countries have different histories with the live-attenuated zoster vaccine (ZVL); some countries primarily used ZVL, while others transitioned to or directly implemented RZV as their preferred choice[2]. Recent methodological analyses have demonstrated how differential timing of vaccine availability across regions creates systematic selection bias in vaccine effectiveness studies[3]. The composition of vaccinated and unvaccinated groups becomes intrinsically linked to geographical location and timing of vaccine introduction, potentially confounding the effectiveness estimates[3]. In this study, countries with later RZV implementation would contribute proportionally more patients to the unvaccinated group during their pre-implementation period, while early-adopting countries like the U.S. would contribute more to the vaccinated group. A clear breakdown of the temporal and geographical distribution of both vaccinated and unvaccinated groups, along with country-specific vaccination policies, would help assess the impact of this systematic bias.Second, while propensity score matching was employed, several important confounders were not addressed. The study could have benefited from an active comparator design, such as using influenza vaccine recipients as the reference group. This approach would help control for unmeasured confounding factors related to healthcare access and health-seeking behavior, which are known to affect the validity of observational studies[4]. Additionally, important clinical variables such as COPD exacerbation frequency and healthcare utilization patterns were not included in the matching process.Finally, since COPD severity and medication use could potentially influence vaccine effectiveness, we suggest performing stratification analyses. Previous research has demonstrated that COPD patients have varying risks of herpes zoster depending on disease severity and medication regimens, particularly corticosteroid use[5]. Separating analyses based on GOLD stages and medication use patterns would provide more nuanced insights into vaccine effectiveness across different patient subgroups and help identify those who might benefit most from vaccination.These methodological refinements would strengthen the evidence base for RZV use in COPD patients and better inform clinical decision-making. We commend the authors for addressing this important clinical question and hope these suggestions contribute to future research in this area.Bor-Yun Wang, MD1; James Cheng-Chung Wei, MD, PhD1,2*1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan2 Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan*Corresponding author: James Cheng-Chung Wei, MD, PhD Division of Allergy, Immunology and Rheumatology Chung Shan Medical University Hospital No. 110, Sec. 1, Jianguo N. Rd., South District Taichung City 402, Taiwan. Email: jccwei@gmail.com ORCID: 0000-0002-1235-0679