Prevalence and risk factors of post-COVID-19 condition in adults and children at 6 and 12 months after hospital discharge: a prospective, cohort study in Moscow (StopCOVID)

Although most people fully recover from acute infection with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and coronavirus disease 2019 (COVID-19) disease, some experience ongoing sequelae [1]. This wide range of symptoms occurring in the weeks to months after SARS-CoV-2 infection has been referred to as either long COVID, post-COVID-19 condition, or post-acute sequelae of SARS-CoV-2 infection (PASC), amongst other names [2]. High profile editorials [3, 4] drew attention to an increasing number of people experiencing these ongoing sequelae and called for comprehensive research, including risk factors and clinical features.

Most post-COVID research has focused on adults [5], given the predominance of adult COVID-19 in the first pandemic waves, which appeared to spare children, somewhat. Therefore, there is a more limited number of paediatric studies [6], although the need for research on COVID-19 consequences in children and young people has been previously acknowledged and has grown in importance with emergence of variants that are affecting children [7]. Head-to-head comparison of COVID-19 sequelae in children and adults is still lacking.

Many studies have investigated the prevalence and risk factors of long COVID [5], but heterogeneity in patient assessment and definitions [8] and lack of data regarding symptom duration are challenges to meta-analyses. Notably, in September 2020, the World Health Organization (WHO) Classification and Terminologies unit created International Classification of Diseases 10 (ICD-10) and ICD-11 codes for post-COVID-19 condition, and in October 2021, a clinical case definition of post-COVID-19 condition was announced, following a Delphi consensus process [9]. It was defined as a condition occurring “in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis”. However, this definition was intended for adults, and WHO suggests that a separate definition might be applicable for children.

This prospective study aimed to investigate the prevalence and characteristics of post-COVID-19 condition in previously hospitalised children and adults using standardised follow-up data collection protocols developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Global Adult and Paediatric COVID-19 follow-up working groups.

The study is reported based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort studies (https://​www.​strobe-statement.​org/​), which can be found in the supplementary material.

Out of 2509 eligible adults and 849 eligible children with laboratory confirmed COVID-19 discharged between April and August 2020, 1994 (79%) and 832 (98%) had contact information, and of these, 1013 (40% of discharged, 51% of those with contact information) adults and 360 children (42% of discharged, 43% of those with contact information) participated in both follow-up interviews and were included in the final analysis (Fig. 1). The 6-month follow-up interviews were conducted between November 2020 and March 2021 and the 12-month follow-up between April 2021 and August 2021.

Table 1 shows the demographic and clinical characteristics of the study participants. For adults the median time, after hospital discharge, to the 6- and 12-month assessments was 215 days (IQR 196–235) and 383 days (IQR 376–390). The median age of adult patients was 56.8 years (IQR 47.0–65.8), and 49% (500/1013) were male. The most common pre-existing comorbidity in adults at admission was hypertension (45%, 458/1013), followed by chronic cardiac disease and excessive weight and obesity (20% each, 198/1013) and type II diabetes (15%, 148/1013). Three percent of patients (27/1013) required non-invasive ventilation, invasive ventilation, or ICU care during hospitalisation.

For children, the median time to the 6-month follow-up was 255 days (IQR 223–270) and to the 12-month follow-up 367 days (IQR 351–379). The median paediatric patient age was 9.5 years (IQR 2.4–14.8), and 48% (174/360) were male. Three percent of children (12/360) required non-invasive ventilation, invasive ventilation, or treatment in the ICU during hospitalisation. The most common comorbidities in children were allergic rhinitis (7%, 26/360) and intestinal problems (7%, 25/360).

Figure 2 shows the temporal trend in post-COVID-19 condition manifestations prevalence. Prevalence was significantly higher in adults compared with children at both 6-month and 12-month follow-up (p < 0·001): relative risk of any manifestation 2.51 (2.02 to 3.11) at 6 months and 3.07 (2.26 to 4.16) at 12 months. The difference in prevalence of each specific manifestation between adults and children is shown in tables S2 and S3. The proportion of individuals with at least one post-COVID-19 condition manifestation decreased from 50% (95% CI 47–53) at 6 months to 34% (95% CI 31–37) at 12 months in adults and from 20% (95% CI 16–24) to 11% (95% CI 8–14), respectively, in children. A decline in prevalence was observed across all manifestations.

In adults, the most common post-COVID-19 condition features at 6-month follow-up included fatigue 25% (95% CI 22–28), respiratory 22% (95%CI 20–25), neuro-cognitive 19% (95% CI 17–21), and dermatological 13% (95% CI 11–15) manifestations. At 12 months after the hospital discharge, the prevalence decreased to 12% (95% CI 10–14), 10% (95% CI 8–11), 9% (95% CI 7–11), and 4% (95% CI 3–5) respectively.

In children, the most common post-COVID-19 condition features at 6-month follow-up were fatigue 9% (95% CI 6–13), dermatological 5% (95% CI 3–7), neuro-cognitive 4% (95% CI 2–6), and sleep-related 4% (95% CI 2–6) manifestations. At the 12-month follow-up, these decreased to 4% (95% CI 2–6), 2% (95% CI 1–4), 2% (95% CI 1–3), and 1% (95% CI 0–1) respectively.

We investigated the phenotypes of post-COVID-19 condition in adults and children, defined as a report of two or more different manifestations at 6-month assessment (Figs. 3 and 4). Amongst adults, 28% (287/1013) reported at least two manifestations. We differentiated three prevalent phenotypes at 6 months, namely (a) fatigue/respiratory without neurological manifestations (10%, 29/287); (b) fatigue/respiratory with neurological manifestations (7%, 19/287); and (c) fatigue/neurological without respiratory manifestations (6%, 17/287), regardless of other manifestations reported. By 12 months, 41% (12/29) of people with fatigue/respiratory without neurological manifestations fully recovered, while only 21% (4/19) of fatigue/respiratory with neurological manifestations and 24% (4/17) of fatigue/neurological without respiratory manifestations were symptom-free (Additional file 1: Figure S1).

In children, phenotypes were less feasible to assess due to a smaller case count of post-COVID-19 condition. Seven percent (25/360) of children had a combination of manifestations at 6-month follow-up. The only characteristic phenotype amongst individuals with coexisting manifestations was fatigue/neurological (24%, 6/25), with 50% (3/6) of these having fully resolved by 12 months.

Risk factors association with post-COVID-19 condition 6- and 12-months after hospital discharge were assessed in multivariable regression analysis separately for adults and children (Fig. 5).

In adults, female sex was the only statistically significant risk factor of post-COVID-19 condition at both 6-month (odds ratio of 2.04 (95% CI 1.57 to 2.65) and 12-month (2.04, 1.54 to 2.69) follow-up. Pre-existing hypertension was also (1.42, 1.04 to 1.94) independently associated with post-COVID-19 condition at 12 months only.

In children, pre-existing neurological comorbidities were associated with post-COVID-19 condition at both 6-months (4.38, 1.36 to 15.67) and 12 months (8.96, 2.55 to 34.82). History of allergic respiratory diseases was a risk factor (2.66, 1.04 to 6.47) for post-COVID-19 condition at 12 months only.

This prospective cohort study with 1013 adults and 360 children, who were previously hospitalised with laboratory confirmed SARS-CoV-2 infection, assessed the 6- and 12-month prevalence of post-COVID-19 condition, according to the WHO case definition, along with phenotypes and risk factors. We found that half of adults and one of five children had post-COVID-19 condition at 6 months follow-up, with fatigue being the most common manifestation. Although prevalence of post-COVID-19 condition declined between 6- and 12-month assessment, one in three adults and one in ten children still had sequelae. Post-COVID-19 condition was experienced by both sexes, with a higher risk amongst adult women. Pre-existing hypertension (adults) and pre-existing neurological comorbidities and allergic respiratory diseases (children) were associated with post-COVID-19 condition.

The prevalence of post-COVID-19 condition was significantly higher in adults and the risk of post-COVID-19 condition was 2.5 and 3 times higher in adults relative to children 6 and 12 months post-hospital discharge, respectively. This was true also for individual symptom groups, except gastrointestinal at 6 months, and cardiovascular, dermatological, and gastrointestinal at 12 months. Although persistent symptoms of COVID-19 have been assessed in many studies [5], most published research was performed prior to the WHO post-COVID-19 case definition [9] in absence of agreed terminology and associated data heterogeneity. With differences in methodology, outcome definitions, and absence of symptom duration measurement across cohorts, it is difficult to evaluate the prevalence of post-COVID-19 condition. Another limitation in the existing literature is the inadequate knowledge of COVID-19 sequelae in children [6] and the lack of direct head-to-head comparison of its features and prevalence in adults and children, which do not allow for complete understanding if manifestations behave differently based on age.

Persistence of symptoms is a worrisome issue, with half of the adults in our study reported post-COVID-19 condition at 6 months, and 34% still experiencing one or more manifestations 12 months after discharge. This finding is consistent with data from China, which reported a high rate of single sequelae symptom prevalence and decrease from 68% at 6 months to 49% at 12 months [15]. Difference in prevalence may be related differences in post-COVID condition definitions, as the Chinese study was published before the WHO case definition announcement. We found a twofold decrease in the prevalence of post-COVID-19 condition from 20% between 6 and 12 months in children. To our knowledge, this is the first study reporting consequences of COVID-19 in children 1 year after acute episode, though we did detect persistent symptoms 6 months after hospital discharge in children in a previous study especially in older children and those with allergic disease [11]. Fatigue was the most common manifestation in both children and adults, regardless of the follow-up time point, though proportionally more adults than children reported fatigue. This finding is consistent with prior data [5, 6]. In adults and children, respiratory manifestations were reported in 20% and 2%, respectively. This difference may be related to greater severity of viral pneumonia in adults, as well as greater baseline respiratory comorbidity [20]. More frequent incidental infection rates may also confer some degree of non-specific immunological protection but the association with pre-existing respiratory allergy suggests that allergic hypersensitivity and/or auto-immune responses are involved. More research into pathophysiology and immune mechanisms is required to establish the cause of described association.

One third of individuals with post-COVID-19 condition can be classified by a phenotypes, of combined manifestations. One in five can be characterised by a combination of fatigue and respiratory with or without neurological manifestations. These results are similar to those reported by Taquet and colleagues [21]. We found that people without neurological manifestations become asymptomatic by 12 months more frequently than those reporting neurological manifestations at 6 months. However, due to a limited number of individuals available for phenotyping, it is premature to make any definitive conclusions.

The risk of post-COVID-19 condition was twice as high in female as in male adult patient at both time points, in line with previous studies assessing persistent symptoms [15, 17, 22]. Pre-existing hypertension was associated with post-COVID-19 condition at 12 months in adults. The association between pre-existing hypertension and higher risk of post-COVID-19 condition 12 months after hospital discharge in adults has not been previously reported [23], which may be explained by the difference in outcome definition. Pre-existing neurological comorbidities and allergic respiratory diseases were associated with post-COVID-19 in children. While allergic diseases are felt to be protective of developing COVID-19, this may become a risk factor for the sequelae development and merits further consideration. It was previously hypothesised that allergic conditions may increase the risk of long-term consequences following COVID-19 and that eosinophils, mast cells, or Th-2 responses may be potentially involved in the immunopathology of post-COVID-19 condition [24], but large prospective studies with biological material collection are required to confirm this.

This study has both strengths and limitations. Strengths include the following: (1) using of standardised ISARIC Long-term Follow-up Study CRFs for adults and children; (2) using the WHO post-COVID-19 condition definition; (3) enrolling both adults and children and comparing the two cohorts; and (4) a relatively large sample size of people attending both the 6- and 12-month follow-up visits, one of the longest follow-up assessments of hospitalised patients to-date. Limitations include the following: (1) questions about spectrum composition, as we enrolled only patients from Moscow (which may limit generalisability), a low proportion of whom had severe COVID-19—issues shared with most major COVID-19 cohort studies. This limitation is balanced by their otherwise being a paucity of data from eastern Europe regarding any COVID-19 outcomes, which becomes a novelty; (2) acute data were collected from the electronic medical records with no access to additional information that could be potentially retrieved from the medical notes—we mitigated potential inaccuracies of demographic information reported by the patients/parents/carers at the time of the hospital admission with subsequent verification during follow-up telephone interviews. This is an accepted and common limitation of cohorts assembled using this methodology; (3) a low proportion of patients with severe COVID-19 patients amongst both adults and children in our cohort limits the generalisability of the study findings to hospitalised patients with more mild to moderate COVID-19; (4) parents/caregivers were interviewed in this study and not children themselves, which is an accepted limitation of paediatric research conducted in children of a particular age; (5) a risk of potential selection bias, for instance with those with symptoms more likely to agree to survey and thus overestimating the prevalence of post-COVID-19 condition [25], as only 68% of adults and 62% of children for whom we had contact information agreed to participate in our study, and 51% and 42% respectively completing both visits—although retention of over 40% is generally considered good and rates here are comparable or higher than in the recent similar cohort studies [15, 26]. Any attrition from a cohort may result in a substantial overestimation of the prevalence of post-COVID-19 condition as those who do remain in the cohort may represent a biased sample [25]. However, we did not find significant differences between respondents and non-respondents (Table S4); (6) telephone interviews were used in this study, and we acknowledge that face-to-face interviews and/or objective measurements would deliver more robust results. However, financial and pandemic restrictions did not allow for this; (7) the study used hospitalised patients’ data. Interpretation of the data gathered from such sample may be prone to collider bias, as the sample is non-random as is conditions on hospital admission.

We used the ISARIC/WHO Clinical Characterisation Protocol, a prospective pandemic preparedness protocol which is agnostic to disease and has a pragmatic design to allow recruitment during pandemic conditions. As we already underlined in previous publications, the reality of conducting research in outbreak conditions is such that appropriate co-enrolment of a control group is practically challenging, primarily because COVID-19 has overshadowed other infections which could be used as comparators, and because of the lack of agreement on a commonly accepted control group [10].

This study has shown that half of adults and one of five children have post-COVID-19 condition, as per WHO case definition, 6 months after hospital discharge, with fatigue being the most common manifestation. Respiratory manifestations also were a major problem in adults. Although the prevalence of post-COVID-19 condition declined, one in three adults and one in ten children still had manifestations at 12 months follow-up. Post-COVID-19 condition was more common adult women and amongst adults with pre-existing hypertension. In children, pre-existing neurological comorbidities and allergic respiratory diseases were associated with post-COVID-19 condition. Future studies should define COVID-19 as per the new WHO case definition to allow for a better comparability. Further investigation of risk factors and underlying physiological and immunological mechanisms merit further consideration.