What risk factors are associated with post-acute sequelae of SARS-CoV-2?

In a recent study posted to the medRxiv* preprint server, researchers explored the risk factors correlated with post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC).

Study: Risk Factors Associated with Post-Acute Sequelae of SARS-CoV-2 in an EHR Cohort: A National COVID Cohort Collaborative (N3C) Analysis as part of the NIH RECOVER program. Image Credit: Cryptographer/Shutterstock
Study: Risk Factors Associated with Post-Acute Sequelae of SARS-CoV-2 in an EHR Cohort: A National COVID Cohort Collaborative (N3C) Analysis as part of the NIH RECOVER program. Image Credit: Cryptographer/Shutterstock


Several coronavirus disease 2019 (COVID-19) patients have reported developing long-term complications, also known as PASC or long-COVID. Long-COVID is defined by the World Health Organization (WHO) as the illness manifested in individuals having a history of suspected or confirmed COVID-19, usually within three months since the onset of SARS-CoV-2 infection and related symptoms lasting for a minimum of two months.

Symptoms and complications associated with long-COVID include post-exertional malaise, fatigue, shortness of breath, cognitive dysfunction, depression, and several others. Hence, considerable research effort has been put forward in the identification of PASC risk factors. 

About the study

In the present study, researchers investigated the association of demographic, clinical course, comorbidity, and patient-level social determinants of health (SDoH) factors to PASC risk.

The study cohort included 4,559,795 potentially eligible patients diagnosed with COVID-19 or tested positive for antigen (AG) lab test or polymerase chain reaction (PCR) for COVID-19. Among these, 3,884,477 individuals were aged 18 years and above. The team considered the earliest reported date of a COVID-19 positive diagnosis or test as the COVID-19 index date. The index date was employed to assess the relative timing of SARS-CoV-2 infections and the diagnosis of long-COVID or long-COVID clinic visits.

The primary analyses defined infection cases as those recorded with a U09.0 diagnosis or a long-COVID clinic visit in the National COVID cohort collaborative (N3C). Furthermore, the identification of controls was performed and categorized as: (1) Unrestricted controls- individuals who were not detected as cases, (2) restricted controls- individuals remaining after the exclusion of persons who were highly suspected of experiencing long-COVID and having consulted a long-COVID clinic, and (3) more restricted controls- included individuals who were highly suspected of not experiencing long-COVID and not having visited a long-COVID clinic.

The team utilized data before the COVID-19 diagnosis date to detect a patient’s age, sex, ethnicity, obesity, smoking status, comorbidities, and substance abuse status. The study included 17 common comorbidities employed in the Charlson Comorbidity Index, as well as additional treatments and comorbidities deemed as risk factors for contracting severe acute COVID-19. The team also identified data related to COVID-19 hospitalization, the length of hospital stay, usage of invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), vasopressor, and remdesivir, and the diagnosis of acute kidney injury and sepsis.         


The study findings showed that among 8325 PASC patients diagnosed, 56.6% were aged over 50, 62.8% were women, and 68.6% were non-Hispanic White. Among the comorbidities reported, 56.4% had obesity, 40.4% had hypertension, 28.9% had chronic lung disease, and 20.5% had uncomplicated diabetes. Furthermore, compared to unrestricted controls, PASC patients were older and more likely to be males and non-Hispanic Whites.

Notably, comorbidities were more prevalent among PASC patients than among controls, as hypertension was reported in 40.4% and 26.2% of the patients, chronic lung disease in 28.9% and 13.7%, and uncomplicated diabetes in 20.5% and 13.3% of the patients, respectively. Moreover, the number of hospitalizations associated with COVID-19 was significantly higher among cases than in controls.   

The team identified that age was a significant risk factor for PASC, with a higher risk noted for individuals aged between 40 and 69. Women also had a higher probability of contracting PASC, while non-Hispanic Blacks, Hispanics, and Asians had a lower probability of displaying PASC than non-Hispanic Whites. Furthermore, the most commonly observed comorbidities among PASC patients were tuberculosis, chronic lung disease, rheumatologic disease, peptic ulcer, and obesity. Additionally, severe acute infections were the most robust predictor of PASC along with extended hospital stays, long hospital stays, COVID-associated hospitalizations, and mechanical ventilation.

Among the restricted controls, the magnitude and direction of the odds ratio were comparable to that of the primary analysis. However, obesity ceased to be significant when the team employed less and more restrictive controls. Furthermore, ECMO correlated to PASC when more restrictive controls were employed but did not display statistical significance when restrictive controls were used.

Risk factors associated with hospitalization due to COVID-19 were the probable markers of SARS-CoV-2 infection severity and obesity. Moreover, residing in a community having higher education improved the probability of diagnosis or care sought at a long-COVID clinic. Individuals who were not hospitalized on the index date had the following risk factors that differed from hospitalized patients: coronary artery disease diagnosis, peptic ulcer, systemic corticosteroid use, or depression.        

Overall, the study findings identified the prevalent risk factors associated with PASC, including middle age, comorbidities, and severe SARS-CoV-2 disease.

*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:
Bhavana Kunkalikar

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.


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