Systematic Genomic and Clinical Analysis of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfections and Recurrences Involving the Same Strain

Abstract

Estimates of the burden of severe acute respiratory syndrome coronavirus 2 reinfections are limited by the scarcity of population-level studies incorporating genomic support. We conducted a systematic study of reinfections in Madrid, Spain, supported by genomic viral analysis and host genetic analysis, to cleanse laboratory errors and to discriminate between reinfections and recurrences involving the same strain. Among the 41,195 cases diagnosed (March 2020-March 2021), 93 (0.23%) had 2 positive reverse transcription PCR tests (55-346 days apart). After eliminating cases with specimens not stored, of suboptimal sequence quality, or belonging to different persons, we obtained valid data from 22 cases. Of those, 4 (0.01%) cases were recurrences involving the same strain; case-patients were 39-93 years of age, and 3 were immunosuppressed. Eighteen (0.04%) cases were reinfections; patients were 19-84 years of age, and most had no relevant clinical history. The second episode was more severe in 8 cases.

Keywords: COVID-19; Madrid; SARS-CoV-2; Spain; coronavirus disease; recurrence; reinfection; respiratory infections; severe acute respiratory syndrome coronavirus 2; variant of concern; variant of interest; viruses; zoonoses.

Figure 1

Flow diagram of the analysis and selection criteria for severe acute respiratory syndrome coronavirus 2 re-positive cases, Madrid, Spain, March 2020–March 2021. Re-positive cases were those that had 2 sequential positive RT-PCR tests taken >45 days apart with >1 negative RT-PCRs between the positive tests. C_t, cycle threshold; SNP, single-nucleotide polymorphism; STR, short tandem repeat; VOC, variant of concern; VOI, variant of interest; WGS, whole-genome sequencing.

Figure 2

Global dating of the first emergence of severe acute respiratory syndrome coronavirus 2 variants identified in reinfections, Madrid, Spain, March 2020–March 2021, with available sequences only for the second specimen (patients 11–22). The phylogeny includes the 3,339 genomes from Nextstrain (https://nextstrain.org), extracted from the Europe-focused subsampling, through April 2021. Dates of the first episodes of cases are indicated with vertical lines. Dates for global emergence for the variants involved in their second episodes (B.1.1.7 and B.1.177) are indicated with an arrow and correspond to their first descriptions in Spain (as documented in GISAID, https://www.gisaid.org): for B.1.177, June 16, 2020 (hCoV-19/Spain/IB-IBV-99010764/2020, accession no. EPI_ISL_691664) and for B.1.1.7, November 8, 2020 (hCoV-19/Spain/VC-IBV-98012610/2020, accession no. EPI_ISL_1060510). Only reinfection cases finally validated by short tandem repeat host analysis are included.