In a recent study posted to medRxiv*, researchers presented findings from the second version of a living systematic review (LSR) on long COVID.
Background
New and persistent symptoms and complications following coronavirus disease 2019 (COVID-19), known as long COVID, have been reported globally. The World Health Organization (WHO) has proposed and defined the post-COVID-19 condition as occurring in individuals with a confirmed or probable infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) three months since COVID-19 onset and lasting for a minimum of two months that is unexplainable by alternative diagnoses.
Multiple terms are interchangeably used by clinicians, researchers, and health authorities; however, the present study uses the term ‘long COVID’ and the definition of a syndrome lasting for more than 12 weeks, per the National Institute for Health and Care Excellence. The prevalence of long COVID varies across studies. As per the WHO, approximately 10% to 20% of individuals with COVID-19 experience persistent symptoms much longer than the initial phases of the illness.
About the study
The present study provided findings from the second version of an LSR of long COVID. Unlike the first version, this analysis focused on quantifying the relative risk of developing long COVID. Bibliographic records were obtained from the COVID-19 Living Map Long COVID ‘segment.’ Additionally, the researchers searched Medline and CINAHL, the WHO COVID-19 database, Google Scholar, LitCOVID register’s long COVID segment, and Global Health (Ovid) database.
Eligible manuscripts were peer-reviewed studies with at least 100 participants with clinical or laboratory diagnoses of COVID-19, reporting symptoms for > 12 weeks since COVID-19 onset. Opinion pieces, reviews, and studies with fewer than 100 participants or a follow-up of fewer than 12 weeks were excluded from the analysis.
Two reviewers independently screened studies in two stages (title/abstract screening and full-text review). One systematic reviewer extracted data from selected manuscripts. The extracted data included study design, population characteristics (sample size, gender, age, description), COVID-19 confirmation methods, disease severity, follow-up methods and duration, outcomes, and risk ratios.
The methodological quality of studies was determined using the Newcastle-Ottawa scale. A score from zero to nine was assigned per study; a score of seven or higher indicated a low risk of bias, scores between four and six implied medium risk, and scores below four meant high risk.
Relative risks and corresponding 95% confidence intervals were computed from the number of individuals reporting each outcome. Heterogeneity was assessed using Cochran’s Q test and I2 statistic. The study team also included members affected by long COVID, who actively contributed to the development of the study protocol.
Findings
Of more than 11,000 records for potential screening, 289 articles met the eligibility criteria, and 28 included control populations. Twenty-two studies were included in the meta-analysis. Most studies were cohort studies (89%), followed by cross-sectional studies (11%). Most studies (68%) were set in Europe and Central Asia. Only two studies were from low-middle income countries.
These studies had data on 242,715 individuals with COVID-19 and 276,317 controls across 16 countries. Twenty-three studies focused on adult populations, three included adults and children, and two focused on adolescents. Only nine studies reported the ethnicities of participants. The longest follow-up period was 419.8 mean days after diagnosis. Fourteen studies followed up subjects through outpatient visits, and others used questionnaires.
The methodological quality and risk of bias varied across studies. Five studies had a low risk of bias, 20 had a medium risk, and three were deemed high risk. The focus of each study differed from the others. The prevalence of commonly reported symptoms was also widely variable. The authors performed a meta-analysis of the most common symptoms and signs of long COVID. Symptoms were broadly categorized according to the international consensus-based core outcome set (COS).
Individuals with a history of COVID-19 were 2.5 times more likely to experience cardiovascular functioning conditions/symptoms, twice as likely to experience cognitive symptoms/conditions, and 1.85 times more likely to experience physical symptoms/conditions. Olfactory symptoms, gustatory disturbance, joint pain, and memory impairments were symptoms individually associated with the highest relative risks for those with past COVID-19 compared to controls.
A sub-group analysis was performed based on the setting (community, hospital, or mixed). There were minor differences in the relative risks of the three core outcomes (fatigue, cognitive symptoms, and olfactory disturbances). In contrast, for others (e.g., muscle weakness, gastrointestinal symptoms, and muscle pain), higher relative risks were observed for hospitalized patients compared to those treated in the community.
Conclusions
In summary, the researchers observed that individuals with a previous confirmed COVID-19 diagnosis were 1.5 times more likely to experience symptoms at 12 weeks or later post-onset of COVID-19 compared to controls. The core outcomes with the highest relative risk were cardiovascular, cognitive, and physical functioning, underscoring that long-term COVID-19 symptoms affect multiple organs, despite COVID-19 being a respiratory illness. Future studies should account for the potential role of SARS-CoV-2 variants and vaccination on the risk of developing long COVID.
*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.
