Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19: A Systematic Review

Abstract

Importance: Infection with COVID-19 has been associated with long-term symptoms, but the frequency, variety, and severity of these complications are not well understood. Many published commentaries have proposed plans for pandemic control that are primarily based on mortality rates among older individuals without considering long-term morbidity among individuals of all ages. Reliable estimates of such morbidity are important for patient care, prognosis, and development of public health policy.

Objective: To conduct a systematic review of studies examining the frequency and variety of persistent symptoms after COVID-19 infection.

Evidence review: A search of PubMed and Web of Science was conducted to identify studies published from January 1, 2020, to March 11, 2021, that examined persistent symptoms after COVID-19 infection. Persistent symptoms were defined as those persisting for at least 60 days after diagnosis, symptom onset, or hospitalization or at least 30 days after recovery from the acute illness or hospital discharge. Search terms included COVID-19, SARS-CoV-2, coronavirus, 2019-nCoV, long-term, after recovery, long-haul, persistent, outcome, symptom, follow-up, and longitudinal. All English-language articles that presented primary data from cohort studies that reported the prevalence of persistent symptoms among individuals with SARS-CoV-2 infection and that had clearly defined and sufficient follow-up were included. Case reports, case series, and studies that described symptoms only at the time of infection and/or hospitalization were excluded. A structured framework was applied to appraise study quality.

Findings: A total of 1974 records were identified; of those, 1247 article titles and abstracts were screened. After removal of duplicates and exclusions, 92 full-text articles were assessed for eligibility; 47 studies were deemed eligible, and 45 studies reporting 84 clinical signs or symptoms were included in the systematic review. Of 9751 total participants, 5266 (54.0%) were male; 30 of 45 studies reported mean or median ages younger than 60 years. Among 16 studies, most of which comprised participants who were previously hospitalized, the median proportion of individuals experiencing at least 1 persistent symptom was 72.5% (interquartile range [IQR], 55.0%-80.0%). Individual symptoms occurring most frequently included shortness of breath or dyspnea (26 studies; median frequency, 36.0%; IQR, 27.6%-50.0%), fatigue or exhaustion (25 studies; median frequency, 40.0%; IQR, 31.0%-57.0%), and sleep disorders or insomnia (8 studies; median 29.4%, IQR, 24.4%-33.0%). There were wide variations in the design and quality of the studies, which had implications for interpretation and often limited direct comparability and combinability. Major design differences included patient populations, definitions of time zero (ie, the beginning of the follow-up interval), follow-up lengths, and outcome definitions, including definitions of illness severity.

Conclusions and relevance: This systematic review found that COVID-19 symptoms commonly persisted beyond the acute phase of infection, with implications for health-associated functioning and quality of life. Current studies of symptom persistence are highly heterogeneous, and future studies need longer follow-up, improved quality, and more standardized designs to reliably quantify risks.

Figure 1.. Reported Frequencies of Symptoms Examined by 5 or More Studies

The horizontal bar extends from the first to the third quartile, the interquartile range (IQR). The whiskers extend from the upper and lower quartiles to the largest value within 1.5 IQRs of that quartile. The width of the box represents the IQR. The vertical bar represents the median value for the outcome. The circles represent point estimates from each study. Circles beyond the whiskers are considered outliers. Values for anosmia (loss of smell) and ageusia (loss of taste) represent frequency of loss if that loss began during acute stage of infection among studies with available data. Therefore, 7 studies reporting anosmia and 5 studies reporting ageusia were excluded from the figure.

Figure 2.. Overview of Time Zero Definitions and Follow-up Periods for Each Patient Across Included Studies

The figure depicts heterogeneity in the definitions of time zero (symptom onset, diagnosis, hospital admission, hospital discharge, or recovery from the acute illness), patient care settings, and lengths and types of follow-up across studies. Patients were followed up from time zero until the end of follow-up, which either was consistent for all patients within a study or varied per patient depending on the date of the last medical examination. Summary statistics varied, with some studies reporting the mean (SD) of follow-up time and others reporting the median (IQR) or another nonparametric summary. Error bars indicate the minimum and maximum length of follow-up for individual patients. ^aOutpatients only. ^bInpatients only.