COVID-19 controls causing a kerfuffle

There is little doubt the past 3 years of the COVID-19 pandemic have been some of the most difficult for human physiological research. With systemic, widespread physiologic effects (1) along with postacute sequelae (2), COVID-19 has emerged as a challenging disease to study, let alone how to work around the pandemic to further understanding of human physiology in disease-free cohorts. Before the Omicron wave, the Centers for Disease Control and Prevention (CDC) has reported over 147 million Americans have been infected with SARS-CoV-2 from February 2020 to September 2021, and 123 million of those cases (84%) were symptomatic (3). Although nearly half of all Americans may have been infected with SARS-CoV-2, are we to believe these individuals’ physiology have not been impacted by this disease, and to what extent and duration may these effects last?

Besides the implementation of human challenge trials with SARS-CoV-2 infection, most researchers have relied on cross-sectional analyses to study SARS-CoV-2 in humans. Cross-sectional studies have either utilized healthy control data retrospectively (4) or prospectively (5) for comparison with subjects with SARS-CoV-2. Yet, there is little consensus on how to navigate human physiological research during the active COVID-19 pandemic to prevent the use of subjects with former or asymptomatic SARS-CoV-2 infection in healthy control cohorts, which could confound study results and interpretation.

Indeed, the COVID-19 pandemic is a challenging environment to study human health. Unreliable diagnostic testing (6) and asymptomatic cases (7) along with reliance on self-testing administration and reporting have made it difficult for government agencies to accurately track SARS-CoV-2 infection rates. Additional challenges persist for human physiological researchers to properly discern whether subjects have had SARS-CoV-2 infection and who may qualify as healthy control subjects. With growing evidence of underlying physiological burden from previous SARS-CoV-2 infection or even physiological implications before positive COVID-19 testing (8), what are the ramifications for qualifying subjects as healthy control subjects in research studies during this pandemic? Might we be underestimating the impact of COVID-19 in human health by using poorly controlled comparative subjects? Or may we be contaminating our subject pools by unintentionally including research subjects who may have long-lasting or subclinical yet physiologically relevant alterations from previous SARS-CoV-2 infection?

In addition, what might it mean for subjects with or without previous SARS-CoV-2 infection to be administered a vaccine and the time it may take to physiologically recover from this acute perturbation (9)? Vaccine effectiveness against new variants (10), immunity duration following vaccination or infection, and breakthrough infection potential have left several uncertainties for how to resume human research without worry of the potential impact of SARS-CoV-2 among the research cohorts in physiological and pathophysiological research.

As the Journal of Applied Physiology continues to call for papers on “Long-Term Recovery from SARS-CoV-2 (COVID-19),” how feasible is it to provide comparative “healthy” data, especially within longitudinal investigations during an active pandemic? Should we reconsider what it means to be “healthy” during an active pandemic? And what guidelines should we follow to ensure our “healthy’” control subjects are truly healthy to better understand human physiology?

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

R.E.S. and S.M.R. conceived and designed research; drafted manuscript; edited and revised manuscript; approved final version of manuscript.