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

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

Study: SARS-CoV-2 Reinfection is Preceded by Unique Biomarkers and Related to Initial Infection Timing and Severity: an N3C RECOVER EHR-Based Cohort Study. Image Credit: Ralf Liebhold/Shutterstock


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

About the study

In the present study, the team used electronic health record data of a cohort exceeding 1.5 million individuals involved in the National COVID Cohort Collaborative (N3C), which is a part of the National Institute of Health's Researching COVID to Enhance Recovery (RECOVER) initiative. This data was used to evaluate 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 for the initial SARS-CoV-2 infection. Long COVID was defined based on the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes.

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

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 counts, erythrocyte sedimentation rates, C-reactive protein, serum creatinine, albumin, and many more, were used to characterize reinfections.

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

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


The results indicated that most individuals in the cohort had one reinfection, with a small group comprising largely of non-Hispanic White males and older individuals having had three or more reinfections. The largest number of reinfections during the Omicron epoch were among individuals who had initial SARS-CoV-2 infections during the epochs of the wild-type, Alpha, Beta, and Gamma strains, followed by reinfections among those with initial Delta infections.

Analyses of biomarkers revealed that compared to the initial SARS-CoV-2 infection, reinfections showed lower elevation of hepatic inflammation markers such as alanine transaminase (ALT) and aspartate transaminase (AST). However, albumin levels were consistently low in reinfection patients.

Furthermore, the severity of reinfections was found to be associated with the severity of the initial SARS-CoV-2 infections. A majority of the cohort experienced mild symptoms during the initial infections and reinfections and did not require hospitalization or a visit to the emergency department. Compared to the initial infection, the percentage of individuals who required hospitalization or succumbed to the infection after reinfection was marginally lower (14.4% vs. 12.6%). Close to half the patients who experienced a severe initial SARS-CoV-2 infection had moderate symptoms requiring hospitalization or emergency department visits during reinfection. Additionally, 7.4% of the individuals who had a severe initial infection had severe infections, and 5.7% succumbed to the reinfection.

Long COVID diagnoses also occurred in a shorter time frame for infections or reinfections during the Omicron epoch, as compared to infections during the Delta epoch or those with other variants.


Overall, the results indicated that the severity of SARS-CoV-2 reinfections was similar to those of the initial infection, with individuals who experienced mild to moderate symptoms during the first infection having similar symptoms during reinfection, while individuals who experienced a severe initial infection having similar reinfection symptoms or succumbing to the disease after reinfection.

Additionally, the study reported that long COVID diagnoses during the Omicron epoch occurred much closer to the index date of the 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 regarded as conclusive, guide clinical practice/health-related behavior, 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 Haendel, Elaine Hill, Richard Moffitt. (2023). SARS-CoV-2 Reinfection is Preceded by Unique Biomarkers and Related to Initial Infection Timing and Severity: an N3C RECOVER EHR-Based Cohort Study:  and the N3C and RECOVER consortia. medRxiv. doi:

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Alanine, Albumin, Antigen, Blood, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, C-Reactive Protein, Creatinine, Electronic Health Record, Genome, immunity, Inflammation, International Classification of Diseases, Laboratory, Membrane, Omicron, Polymerase, Polymerase Chain Reaction, Protein, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, White Blood Cell

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Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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