Response.

To the Editor:

We thank Dr Khurana et al for their thoughtful response to our letter and for pointing out the value of serum zinc levels. Our study assessed the association between zinc supplementation and survival among hospitalized patients with coronavirus disease 2019 (COVID-19), using a causal inference approach to retrospective data. Our institutions do not routinely measure serum zinc levels. Although our study population consisted of patients admitted to a single hospital, our study assessed the effect of zinc in the contexts in which it was routinely used in the inpatient setting at the peak of the COVID-19 pandemic in the United States. Our findings may inform assessment of zinc’s utility as it was commonly used in the inpatient setting for COVID-19, awaiting the results of randomized controlled trials.

We appreciate the references provided by Dr Khurana et al that demonstrated an association between lower zinc levels and worse pulmonary outcomes in children. , We note, however, that neither of these studies was conducted in adults or among patients with COVID-19. Although our study does not definitively rule out the clinical benefit of zinc among hospitalized patients with COVID-19, our research question looks into the routine use of zinc alone or as an adjunct to other candidate therapies in hospitalized patients with COVID-19––a question similar to those of current randomized trials for COVID-19 that involve zinc. The role of zinc among COVID-19 patients with a deficiency of the trace mineral is unknown. Furthermore, the protective role of zinc against severe acute respiratory syndrome coronavirus 2 infection is another question that is left unanswered. Therefore, we agree with Dr Khurana et al that prospective studies among patients with COVID-19 that take into account serum zinc levels before and after supplementation are needed.

Although our findings are based on retrospective data, thoughtful and thorough analyses of such data in light of the urgency of the ongoing pandemic will likely continue to play a valuable role in paving the way forward. We recognize that prospective randomized controlled trials remain the gold standard of clinical studies. However, situations in which randomized trials are too costly, too slow, or not feasible may necessitate taking into consideration causal inference studies such as ours in informing clinical decisions.

We also must stress that, regardless of the methods employed, efforts must be made to broaden generalizability of the findings by incorporating patients from various clinical and sociodemographic backgrounds. Our hope is that future COVID-19 research ensures inclusion of diverse patient populations and clinical contexts to better identify groups that benefit the most from heterogeneous care strategies.