Methodological considerations for the Lianhua Qingwen capsule influenza prevention trial

We carefully reviewed the recently published study “Preventive effect of Lianhua Qingwen capsule on close contacts of seasonal influenza in residential environments: protocol for a multicenter, randomized, double-blind, placebo-controlled study” (1). This study is commendable for its rigorous design and for addressing a significant evidence gap in traditional Chinese medicine (TCM) for infection prevention. The results are highly anticipated and could offer a valuable public health intervention. However, we wish to raise two pertinent methodological considerations that could strengthen the interpretation of the findings.

First, regarding the primary endpoint, the definition of secondary infection risk (SIR) relies solely on reverse transcription-polymerase chain reaction (RT-PCR) positivity within a short virological follow-up window (up to day 9±1). This may underestimate the true infection burden by missing later seroconversions or infections with low viral loads. The critical importance of systematic surveillance to capture asymptomatic infections is well demonstrated in other settings. A recent prospective cohort study evaluating coronavirus disease 2019 (COVID-19) vaccines successfully employed weekly testing of all participants to provide robust effectiveness estimates against asymptomatic infection (2). We propose that incorporating serological assessment (e.g., hemagglutination inhibition antibody titers) between baseline and a later time point (e.g., days 28–30) as a key secondary endpoint would provide a more comprehensive evaluation of Lianhua Qingwen (LHQW) capsule’s ability to prevent both clinical and subclinical infections, the latter being crucial for interrupting silent transmission chains (3).

Second, while the double-blind design is a strength, the distinctive and potent herbal aroma of LHQW capsules, primarily from ingredients like Guanghuoxiang (Pogostemon cablin) and Dahuang (Rheum palmatum), poses a significant challenge for effective blinding. Even with taste-matched placebos, olfactory cues may unintentionally unmask the group allocation for participants or investigators, potentially introducing performance and detection bias. It would be invaluable to know if the authors plan to formally assess the success of blinding (e.g., by surveying participants’ guesses at the end of the study) to quantify this bias (4).

We congratulate the authors on this ambitious undertaking and believe that addressing these points would further enhance the impact and validity of their important work. We look forward to the publication of the results.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1733/coif). The authors have no conflicts of interest to declare.

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References

1. Zhan Y, Fang Z, Hu Y, et al. Preventive effect of Lianhua Qingwen capsule on close contacts of seasonal influenza in residential environments: protocol for a multicenter, randomized, double-blind, placebo-controlled study. J Thorac Dis 2025;17:2623-33. [Crossref] [PubMed]
2. Tsang NNY, So HC, Cowling BJ, et al. Effectiveness of BNT162b2 and CoronaVac COVID-19 vaccination against asymptomatic and symptomatic infection of SARS-CoV-2 omicron BA.2 in Hong Kong: a prospective cohort study. Lancet Infect Dis 2023;23:421-34. [Crossref] [PubMed]
3. World Health Organization. Manual for the laboratory diagnosis and virological surveillance of influenza. Geneva: World Health Organization; 2011 [cited 2025 Aug 23]. Available online: https://www.who.int/publications/i/item/manual-for-the-laboratory-diagnosis-and-virological-surveillance-of-influenza
4. Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials 2004;25:143-56. [Crossref] [PubMed]