Structured serological testing is an essential component to investigating SARS-CoV-2 reinfection.

We read with interest Belén Prado-Vivar and colleagues' findings of suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection in a 46-year-old man in Ecuador. As reported elsewhere, Prado-Vivar and colleagues describe a more severe symptomatic course during the second infection than during the first. Understanding factors associated with potential reinfection might enable early decision-making for the clinical management of suspected cases. Reporting of such cases, supported by sequencing, including whole-genome sequencing (WGS), as presented by Prado-Vivar and colleagues, or Sanger sequencing, and preferably viral cell culture, is necessary to identify reinfection rather than prolonged viral shedding. Although a vital step, WGS requires retention of the initial sample and a biosafety 3 laboratory, is resource intensive, and samples with very low viral loads might not be successfully sequenced, limiting its use as a high-throughput tool.

By comparison, serological testing is increasingly widely available, yet in cases of reinfection has so far provided little insight into whether the risk of reinfection correlates in any way with an inability to produce an effective humoral response. Prado-Vivar and colleagues' patient was IgM-reactive, IgG-negative on a lateral flow assay, with presumably an assigned significance of at least an initial response to SARS-CoV-2. Other reported cases of reinfection have likewise described serology at initial presentation as IgM only, negative, or not tested. Our experience with lateral flow assays suggests that early IgM-only positive results should be interpreted with caution: six of 12 health-care workers tested in a delayed case identification programme underwent retesting with both an anti-nucleocapsid (anti-NP) IgG and an anti-receptor binding domain (anti-RBD) IgG assay and had a seronegative result (appendix pp 3–4). Conversely, among patients who had a documented IgG response (both anti-NP and anti-RBD), we found three cases of possible reinfection, albeit they were not substantiated by WGS (appendix pp 3–4).

We therefore strongly advocate use of a structured approach to reporting serological data alongside WGS when exploring reinfection. When high Ct values, as reported by Prado-Vivar and colleagues, are thought to correlate with low viral burden, it is possible that the initial infection could simply lack sufficient stimulation of germinal centre reactions to generate isotype-switching and lasting, detectable antibody production. To delineate any relevance of primary infection viral burden on isotype switch, we must allow for inter-IgG class variability and consider the impact on assay selection; anti-NP IgG assays can identify previous exposure, but it is anti-RBD IgG assays that might provide further information through correlation with neutralising activity, and expression of these antibodies might be discordant. Standardising reporting of serological data for reinfection cases might help characterise the role of the humoral response in cases of reinfection, and it would appear doing so with an anti-RBD IgG assay could have greater utility.

This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on February 15, 2021