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Does COVID Reinfection Increase Risk for Long COVID?

  • Authors: WebMD News Author: Lisa O’Mary; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 12/30/2022
  • Valid for credit through: 12/30/2023
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for primary care physicians, nurses, pharmacists, physician assistants, and all members of the healthcare team who manage patients with COVID-19.

The goal of this activity is for healthcare team members to be better able to analyze the rate of negative outcomes associated with reinfection with COVID-19.

Upon completion of this activity, participants will:

  • Assess a prior study comparing rates of severe outcomes of COVID-19 based on reinfection vs primary infection
  • Analyze the rate of negative health outcomes over time associated with reinfection with COVID-19
  • Outline implications for the healthcare team


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WebMD News Author

  • Lisa O’Mary


    Lisa O’Mary has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Editor/Nurse Planner

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

Compliance Reviewer

  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Yaisanet Oyola, MD, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Does COVID Reinfection Increase Risk for Long COVID?

Authors: WebMD News Author: Lisa O’Mary; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 12/30/2022

Valid for credit through: 12/30/2023


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to the approved COVID-19 vaccines are provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

The pace of reinfection with COVID-19 has increased as the Omicron variant has become the predominant infectious form of SARS-CoV-2. Yet the rate of severe COVID-19 infection has not kept pace, in part as a result of many individuals being more protected from severe symptoms because of previous vaccination against SARS-CoV-2 or prior COVID-19 infection. Abu-Raddad and colleagues compared rates of severe illness associated with primary vs subsequent COVID-19 infections. They used a retrospective case-control analysis of unvaccinated individuals in Qatar to answer their study question, and their results were published in the November 24, 2021, issue of the New England Journal of Medicine.[1]

Nearly 40% of infections in this series featured the B.1.351 or B.1.1.7 variants, and 47.6% of the variant type remained unknown. The relative risk for severe disease with reinfection vs primary infection was 0.12. In fact, there were no cases of critical disease or death at reinfection. The overall risk for severe disease, critical disease, or death with reinfection vs primary infection was 0.10.

Hospitalization and death are not the only complications of COVID-19. Many patients develop organ complications and postacute sequelae of COVID-19 as well. The current study evaluates the broad rate of complications associated with reinfection with COVID-19.

Study Synopsis and Perspective

Contracting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published November 10 in Nature Medicine.[2]

The researchers analyzed Department of Veterans Affairs data:

  • 443,588 people with a first infection of SARS-CoV-2
  • 40,947 people who were infected 2 or more times 
  • 5.3 million people who had not been infected with coronavirus, whose data served as the control group

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr Al-Aly said in a press release from the Washington University School of Medicine in St. Louis, Missouri. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.” Altogether, the findings show that reinfection further increases risks of all-cause mortality and adverse health outcomes in both the acute and postacute phases of reinfection. The findings highlight the clinical consequences of reinfection and emphasize the importance of preventing reinfection by SARS-CoV-2.[2]

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said that a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs (VA) population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medical College in New York, New York.

Dr Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported. Mitigation strategies such as handwashing, social distancing, and masks should also be considered when traveling or spending time in crowded spaces.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

Public health policy should continue to focus on infection prevention messaging to reduce primary and secondary infection-related health risks.

Nat Med. 2022;28(11):2398-2405.

Study Highlights

  • Study data were drawn from the VA Health System database. All study subjects had a positive test for SARS-CoV-2 between March 2020 and April 2022 or no infection with SARS-CoV-2 (control group). Reinfection with COVID-19 was defined by another positive test at least 90 days after the initial positive result for SARS-CoV-2.
  • Researchers compared uninfected controls with persons with one-time infections and reinfections in the following outcomes:
    • All-cause mortality
    • Hospitalization
    • Disorders of major organ systems, including mental health diagnoses and fatigue
  • The study results were adjusted to account for demographic, health habit, and disease variables, as well as COVID-19 vaccination status and previous treatment for COVID-19.
  • 443,588 patients with a single positive test for SARS-CoV-2 were compared with 40,947 people with reinfection and 5,334,729 controls.
  • Among patients with reinfection, 92.8% had 2 infections and 6.3% had 3 infections. The median time between the first and second infection was 191 days.
  • Compared with patients with a single SARS-CoV-2 infection, those with reinfections experienced an additional 19.33 cases of mortality per 1000 persons at 6 months (hazard ratio [HR], 2.17; 95%, 1.93-2.45). The respective rate for hospitalization was 100.19 additional cases per 1000 persons at 6 months (HR, 3.32; 95% CI, 3.13-3.51).
  • The HR for any organ system disorder in comparing reinfection with a single infection was 2.10 (95% CI, 2.04-2.16), an additional burden of 235.91 cases per 1000 persons at 6 months.
  • Compared with a single SARS-CoV-2 infection, reinfection was associated with a higher rate of disorders across multiple organ systems, including gastrointestinal, kidney, mental health, endocrine (diabetes), and musculoskeletal systems. Reinfection was most profoundly associated with higher risks for cardiovascular and pulmonary disorders (HR > 3 for both).
  • The association between reinfection and a higher risk for negative outcomes was present regardless of vaccination status against SARS-CoV-2.
  • The negative consequences of reinfection were most pronounced at the time of the subsequent infection and then waned over time, but were still significant at 6 months.
  • There was a graded increase in the risk for negative outcomes as the number of reinfections increased, but this finding was based on limited data.

Clinical Implications

  • In a previous study, the overall risk for severe disease, critical disease, or death with reinfection with COVID-19 vs primary infection was 0.10.
  • The current study finds that mortality, hospitalization, and organ system dysfunction outcomes are higher with COVID-19 reinfection compared with primary infection, even 6 months after reinfection.
  • Implications for the healthcare team: The healthcare team should continue to promote means to reduce prevention of reinfection with SARS-CoV-2, particularly among patients at high risk for complications.


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