The searches identified 6025 records from electronic databases and five records from hand searching. After removing duplicates, 4123 records were title/abstract screened, of which 86 full-text articles were retrieved and assessed for eligibility. Studies excluded at full-text screening, with reasons for exclusion, are listed in Supplementary Table S3. A total of 33 studies were identified for inclusion in the systematic review (Fig. 1).
Study and patient characteristics
The characteristics of the 33 included studies are summarised in Table 1, with further details available in Supplementary Table S4. Studies were performed in a total of 15 countries, with the majority from Europe and North America. Outcomes reported by the studies were risk of fatigue15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34, shortness of breath/dyspnoea15,16,17, 19, 22,23,24,25, 27,28,29,30,31, 35, 36, cognitive dysfunction15, 17,18,19,20, 22,23,24,25, 27, 29,30,31, 33, 37, 38, and comparisons of quality of life23, 36, 39,40,41,42,43,44,45,46,47.
Participants or records in the studies were retrieved or recruited from healthcare databases or registries, COVID-19 databases, hospitals (including inpatients and outpatients, healthcare workers, and hospital employees), COVID-19 laboratory records, questionnaires, existing study cohorts, and schools. Case populations included people with a positive COVID-19 test, users of healthcare facilities with a positive test, volunteers or survey respondents, and hospitalized patients or outpatients of hospitals. Studies were classed by this review as either those including hospitalized patients, hospital outpatients, or those more representative of the general population (all SARS-CoV2 infections). Two studies included individuals who were tested for SARS-CoV-2 infection in hospital but did not clarify whether these were hospitalized patients24, 26; these were therefore considered representative of a general population by this review. Control populations included those testing negative for SARS-CoV-2 infection (31 studies) or a historical influenza cohort to compare COVID-19 with a well-characterized respiratory viral illness (four studies). Nearly all studies included controls from the same population as the cases; of the 13 studies including outpatients and hospitalized patients, three studies included non-hospitalized individuals as controls38, 41, 42.
Most included studies enrolled adults only. The reported ages of COVID-positive participants in studies that included adults ranged from a median of 39.8 to 70.8 years, and a mean of 35.6 to 60.7 years. Five studies enrolled children or adolescents18, 23, 29, 46, 47. The reported percentage of female participants ranged from 5.4 to 84.3%.
SARS-CoV-2 infection was assessed by PCR (22 studies), antibody test (3 studies) or rapid antigen test (2 studies); the remaining studies did not report the diagnostic test used. Only one study reported details concerning the main circulating variant during the time period for SARS-CoV-2 infection46. The original wild-type COVID-19 strain was estimated to be in circulation during the infection period in most studies.
Risks of fatigue, shortness of breath, and cognitive dysfunction after SARS-CoV-2 infection
Risk of post-COVID symptoms ≥ 4 weeks after infection was reported by 20 studies for fatigue (Supplementary Table S5), 15 studies for shortness of breath (Supplementary Table S6), and 16 studies for cognitive dysfunction (Supplementary Table S7). COVID-19 cases were compared to COVID-19-negative controls in most studies; four studies compared risks in hospitalised COVID-19 patients to hospitalised historical influenza cohorts. While outcome descriptions were similar across fatigue and shortness of breath, cognitive dysfunction outcome descriptions were more varied, and included general cognition outcomes (e.g., cognitive impairment), memory-related problems, concentration-related problems and language disturbances.
At least one significantly higher outcome risk was reported by 15 studies for fatigue, by 11 studies for shortness of breath, and by nine studies for cognitive dysfunction.
Compared to historical hospitalised influenza cohorts, risks of long COVID-19 symptoms ranged from 1.30 (95% CIs not reported) to 2.65 (95% CIs 2.22, 3.08) for fatigue, 1.14 (95% Cis 0.94, 1.40) to 2.28 (95% CIs not reported) for shortness of breath, and from 1.18 (95% Cis 0.89, 1.48) to 1.47 (95% Cis 1.15, 1.87) for cognition.
Meta-analyses of risks of fatigue, shortness of breath, and cognitive dysfunction after SARS-CoV-2 infection
Meta-analyses (random-effects) of risks of fatigue, shortness of breath, and cognitive dysfunction after SARS-CoV-2 infection included all studies of adolescents and/or adults comparing COVID-19-positive cases with COVID-19-negative controls and reporting a comparable risk outcome. Comparisons of historical influenza cohorts were not included as of the four studies, two were additional sub-analyses of hospitalised patients, one did not report a comparable risk ratio, and one did not report 95% CIs. Fourteen studies were eligible for inclusion in the meta-analysis for fatigue and 12 for shortness of breath. Cognitive dysfunction outcomes were classified into those reporting general cognition problems (three studies), memory-related problems (seven studies), and concentration-related problems (six studies).
Compared to non-infected controls, SARS-CoV-2 infection was associated with a significantly higher risk of fatigue (RR 1.72 [95% CIs 1.41, 2.10]) and shortness of breath (RR 2.60 [95% CIs 1.96, 3.44]) ≥ 4 weeks after the infection (Fig. 2). Analyses of studies or subgroups only reporting risks for hospitalised patients/outpatients found a risk ratio of 1.59 (95% CIs 1.20, 2.11) for fatigue (seven studies) and 2.78 (95% CIs 2.31, 3.34) for shortness of breath (five studies).
Both memory and concentration-related problems had a significantly higher risk in COVID-positive participants (memory: RR 2.53 [95% CIs 1.30, 4.93]; concentration: RR 2.14 [95% CIs 1.25, 3.67]) ≥ 4 weeks after infection; while there was an increased risk of cognition problems (RR 1.44 [95% CIs 0.59, 3.56]), this was not statistically significant (Fig. 3).
Sensitivity analyses, heterogeneity, leave-1-out analyses, and publication bias
Sensitivity analyses were performed for all four symptoms, where three or more studies could be included in the analysis (Table 2). All fatigue and shortness of breath sensitivity analyses showed a similar result to the main analyses with no loss of statistical significance, indicating that the results were generally robust. Removal of preprints from the memory and concentration analyses, and removal of post-vaccination studies from the concentration analysis, resulted in a loss of significance, however these analyses included a small number of studies.
Heterogeneity between the studies in all analyses was high, with an I2 value ranging from to 97.1% to 98.8% in the five main analyses. This reflects the highly variable study designs included in the analysis due to the disparate nature of the available data or the heterogeneity of COVID-19 disease and long COVID itself.
Leave-1-out analyses found the main analyses did not lose statistical significance when each study was individually removed, with the exception of the removal of Carazo 202237 from the concentration analysis, indicating that the results were generally robust.
For all analyses, no evidence of publication bias was found when using the Egger’s test (fatigue P-value = 0.53; shortness of breath P-value = 0.99; cognition P-value = 0.58; memory P-value = 0.57; concentration P-value = 0.87), and funnel plots generally showed symmetry, indicating publication bias is unlikely.
Health-related quality of life after SARS-CoV-2 infection
Health-related quality of life was reported in 11 studies (Supplementary Table S8) by validated instruments including the RAND-36, EuroQol-5D (EQ-5D), and 36-Item Short Form Survey (SF-36), and three paediatric instruments: Health Behaviour in School-aged Children (HBSC), Paediatric Quality of Life Inventory (PedsQL), and Children’s Somatic Symptoms Inventory-24 (CSSI-24).
Hospitalised COVID-19 patients’ quality of life was significantly lower in most or all instrument domains when compared to healthy, non-hospitalised uninfected controls40,41,42 but similar to controls hospitalised for pneumonia or other non-COVID-19 reasons39, 43. Quality of life comparisons for all SARS-CoV-2 infections were overall inconclusive; two studies reported no differences between cases and controls for adults using the EQ-5D36, while two studies found that more COVID-19-positive adults self-reported poorer health compared to the previous year at 3 and 8 months post-infection compared to non-infected controls44, 45. In children and/or adolescents, one study reported no significant difference between groups47, one found quality of life and sleep significantly better in the SARS-CoV-2-infected adolescents23, and one study reported that younger teenagers were more likely to report physical concerns while older teenagers more likely to report mental concerns46.
Study quality assessed by the modified Newcastle–Ottawa scale found that 21 studies were of low risk of bias/high quality and 12 of medium risk of bias/medium quality. Scores for each study are presented in Supplementary Table S9.