Study explores incidence, severity and long COVID associations of SARS-CoV-2 reinfections

In a recent study published on medRxiv* preprint server, a team of researchers from the United States used electronic health records to characterize the incidence, biomarkers, attributes, and severity of reinfections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ) and assessed the association between reinfections and long-lasting coronavirus disease (COVID).

Study: Re-infection with SARS-CoV-2 is preceded by unique biomarkers and related to the timing and severity of initial infection: a cohort study based on the N3C RECOVER EHR.  Image Credit: Ralf Liebhold/Shutterstock
Study: Re-infection with SARS-CoV-2 is preceded by unique biomarkers and related to the timing and severity of initial infection: a cohort study based on the N3C RECOVER EHR. Image Credit: Ralf Liebhold/Shutterstock


Emerging variants of SARS-CoV-2 are increasing the incidence of breakthrough infections. Mutations in spike protein regions of these variants that increase immune evasion, combined with decreased immunity induced by vaccines against coronavirus disease 2019 (COVID-19) and previous SARS-CoV infections -2 leads to an increase in reinfections. Studies based on whole genome sequences of SARS-CoV-2 variants isolated from reinfected patients have revealed that the variants responsible for the reinfections are distinct from those that caused the previous infections. However, there is a lack of information on whether reinfections differ from the initial infection in their incidence, severity, and attributes, as well as lengthy COVID complications after SARS-CoV- reinfections. 2.

About the study

In the current study, the team used electronic health record data from a cohort of over 1.5 million individuals involved in the National COVID Cohort Collaborative (N3C), part of the COVID Research Initiative from the National Institute of Health to improve recovery (RECOVER). These data were used to assess the incidence, biomarkers and attributes of SARS-CoV-2 reinfections and understand the association between post-acute sequelae of SARS-CoV-2 infection (PASC) and reinfections.

Reinfection was defined based on a positive SARS-CoV-2 antigen or polymerase chain reaction (PCR) test more than 60 days after the index date of initial SARS-CoV infection -2. Long COVID was defined based on the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes.

Reinfections were also examined by SARS-CoV-2 variant epochs, with the wild-type strain epoch spanning March through November 2020, with Alpha, Beta, and Gamma variants dominating December 2020 through May 2021, and the Delta variant epoch covering the period from June 2021 to October 2022. The Omicron epoch has been divided into two parts for the Omicron variant and the Omicron BA variants, corresponding respectively to November 2021-March 2022 and March-August 2022.

Biomarkers such as inflammation, coagulopathies, and organ dysfunction can be used to characterize SARS-CoV-2 infections. A wide range of biomarkers, including laboratory measurements of white blood cell count, erythrocyte sedimentation rates, C-reactive protein, serum creatinine, albumin, and many others, have been used to characterize reinfections.

COVID-associated hospitalization data was used to determine the severity of reinfections. Mild infections included those that did not require an emergency department visit or hospitalization, while those requiring hospitalization were classified as moderately severe, and cases requiring hospitalization, invasive mechanical ventilators, vasopressors, or oxygenation by extracorporeal membrane were considered serious infections.

The period between reinfection and long COVID diagnoses was compared to that between initial infection and long COVID diagnosis to understand the relationship between reinfections and PASC.


The results indicated that most individuals in the cohort had one reinfection, with a small group made up largely of non-Hispanic white males and older individuals who had three or more reinfections. The greatest number of reinfections during the Omicron era were among people who had initial SARS-CoV-2 infections during the wild-type, Alpha, Beta, and Gamma strain eras, followed by reinfections among those who had initial Delta infections.

Biomarker analyzes revealed that compared to the initial SARS-CoV-2 infection, reinfections showed lower elevations in markers of liver inflammation such as alanine transaminase (ALT) and aspartate transaminase (AST). However, albumin levels were consistently low in reinfected patients.

Additionally, the severity of reinfections was found to be associated with the severity of initial SARS-CoV-2 infections. The majority of the cohort had mild symptoms during initial infections and reinfections and did not require hospitalization or emergency room visits. Compared to the initial infection, the percentage of people who required hospitalization or died from infection after reinfection was slightly lower (14.4% versus 12.6%). Nearly half of patients who suffered a severe initial SARS-CoV-2 infection had mild symptoms requiring hospitalization or emergency room visits upon reinfection. In addition, 7.4% of people who had a serious initial infection had serious infections and 5.7% succumbed to reinfection.

Long COVID diagnoses also occurred in a shorter timeframe for infections or reinfections in the Omicron era, compared to infections in the Delta era or those with other variants.


Overall, the results indicated that the severity of SARS-CoV-2 reinfections was similar to that of the initial infection, with people who had mild to moderate symptoms during the first infection showing similar symptoms during of reinfection, while people with a severe initial infection show similar symptoms of reinfection or succumb to disease after reinfection.

Additionally, the study reported that long COVID diagnoses in the Omicron era occurred much closer to the index date of infection or reinfection, and the number of long COVID diagnoses also showed an increase after reinfections with recent variants.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

Journal reference:

  • Emily Hadley, Yun Jae Yoo, Saaya Patel, Andrea Zhou, Bryan Laraway, Rachel Wong, Alexander Preiss, Rob Chew, Hannah Davis, Christopher G Chute, Emily R Pfaff, Johanna Loomba, Melissa Handel, Elaine Hill, Richard Moffitt. (2023). Reinfection with SARS-CoV-2 is preceded by unique biomarkers and linked to the timing and severity of initial infection: a cohort study based on the N3C RECOVER EHR: and the N3C and RECOVER consortia. medRxiv. do I:

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