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Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers

Our take —

This case series and case-control study set in Brazil examined risk factors for COVID-19 recurrence among 33 cases and 62 controls who were diagnosed and treated at the study hospital. The study found that the vast majority (>90%) of recurrent cases were healthcare workers. While symptom rates did not differ between first and second episode, cases were more likely to be hospitalized during their second episode; other studies have observed mixed results related to infection severity among reinfected cases, though often reinfections have been milder in other reports. The interval range between first and second episodes was 8 to 130 days (mean: 41 days). The major limitation was the challenge in determining if recurrence was actually a second new infection, or just symptoms of the same first infection. The study partially addressed this using next generation sequencing, providing evidence of new infection. It remains to be seen whether these secondary infections reflect new variants and potentially increased severity of disease associated with them.

Study design

Case Series, Case-Control

Study population and setting

The study objective was to determine risk factors for recurrent COVID-19. At the Federal University of Sergipe in Brazil, daily phone monitoring of confirmed COVID-19 cases from the Centro de Doencas Respiratorias (Center for Respiratory Diseases) was conducted. From this patient population, the study recruited 33 cases of recurrent, symptomatic, reverse transcription polymerase chain reaction (RT-PCR) positive infection with SARS-CoV-2. They defined recurrence as symptom recurrence in an individual having developed symptomatic COVID-19, medically isolated for 14 days, and then clinically recovering with at least 7 days without symptoms. They required cases to test positive by RT-PCR in both the first and second episode of COVID-19. They collected sociodemographic and clinical variables from the original 33 cases, and then randomly selected a control group of 62 people with only a single episode of the database. SARS-CoV-2 antibody testing was performed for a subset (51.5%, N=17) of recurrent cases, and the controls (50%, N=31). Next generation sequencing of viral genomes from 2 recurrent cases were also conducted.

Summary of Main Findings

The study found 33 recurrent COVID-19 cases, the majority of whom were female (78.8%, N=26) and were more likely to be healthcare workers (OR: 36.4, 95% CI: 9.7 – 137.2). Healthcare workers in the recurrent group were likely exposed in their work environment (97% reported possible work exposure), 48.5% of whom worked specifically in COVID-19 units. The average interval between recovery and second onset of symptoms was 41 days, with a range of 8 to 130 days. Blood type A+ had the highest prevalence (42%, N=14 cases), followed by O+ (30%, N=10). 45.5% (N=15) had comorbidities which placed them at higher risk for severe COVID-19, with obesity (N=10, 30.3%) being the most prevalent. For clinical symptoms, patients did not have any significant differences between number of symptoms in the first and later episode. Hospitalization was not required for any individuals in the first episode, but 12.1% of patients were hospitalized in the second episode, 2 required ICU admission, and 1 died from COVID-19 in their second episode. Genomic sequencing provided further evidence that these were true reinfections of different viral variants.

Study Strengths

The study had significant case data available for the recurrent cases, which are often understudied. Using next-generation sequencing, they were able to show that a likely second infection did in fact occur among the two participants tested. They also used a case definition that required clinically confirmed recovery before being eligible to be considered a recurrent case, which further added to the robust case definition and likely avoided some misclassification from cases who had a single, long infection as having recurrent infection.


The major limitation was that they were not able to sequence all of the study participants to determine if each had a new infection. There may have been some misclassification of cases who had a single, long infection where symptoms may have abated for a short period, before returning. These individuals would therefore not reflect an actual second infection. Additionally, the study found that individuals were less likely to be hospitalized in the first episode compared to the second episode, however there may have been some survivorship bias due to individuals who were hospitalized and passed from COVID-19 no longer being at risk of second infection, and had they not died they may have gone on to become reinfected. This different survivorship biases their study towards more mild symptoms in the first episode. Finally, there were constraints on the power for the study, given the number of recurrent cases was only 33 and the confidence intervals were very large; adjusting for key confounders thus is difficult and controls were not matched to cases based on underlying characteristics.

Value added

This study has one of the largest sample sizes of recurrent infections included in research. Prior reinfection studies have suffered from very low sample sizes, given that reinfection is unlikely in the majority of COVID-19 patients.

This review was posted on: 22 March 2021