Progress and treatment of "long COVID" in non-hospitalized patients: A single-center retrospective cohort study

Background: "Long COVID" or "post-COVID conditions" describes prolonged symptoms after the acute phase of coronavirus disease 2019 (COVID-19). However, there is a paucity of published reports on its treatment. Method(s): This retrospective cohort study included adult, non-hospitalized patients with COVID-19 symptoms at least one month after the onset who had been examined at the isolation facility in Miyagi prefecture between October 2020 and September 2021. Result(s): In total, 70 patients with a median age of 46 (21-69) years were included, and 37 were women (52.9%). The median time from onset to the end of treatment was 46 (28-396) days. Thirty-eight patients (53.5%) showed improvement in all symptoms, while four (5.7%) did not recover within the study period. The symptoms at six months with high residual rates were dizziness (33.3%), fatigue (14.3%), myalgia (14.3%), abdominal discomfort (14.3%), and taste dysfunction (11.8%). For treatment of prolonged symptoms, formulae of Kampo medicine (Japanese traditional medicine) were used alone or in combination with Western medications in 76%, 66%, 53%, and 66% of patients at 1-2 months, 2-3 months, 3-6 months, and over 6 months respectively. Kampo formulae with anti-inflammatory effects were used in the early period;however, tonifying formulae and blood stasis-resolving formulae were used in the late period. Conclusion(s): Non-hospitalized patients with COVID-19 may suffer from persistent symptoms after the acute phase of infection. For the management of long COVID, a comprehensive and holistic approach is needed. Kampo medicine should be considered as a treatment option for long COVID.Copyright © 2023 The Authors. Traditional & Kampo Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Oriental Medicine and Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine.

Case report: Post-COVID new-onset neurocognitive decline with bilateral mesial-temporal hypometabolism in two previously healthy sisters.

Background: Long coronavirus disease (COVID) is increasingly recognized in adults and children; however, it is still poorly characterized from a clinical and diagnostic perspective, particularly in the younger populations. Case presentation: We described the story of two sisters-with high social and academic performance before their severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-who reported severe neurocognitive problems, initially classified as psychologic pandemic distress and eventually found to have significant brain hypometabolism. Conclusions: We provided a detailed clinical presentation of neurocognitive symptoms in two sisters with long COVID associated with brain hypometabolism documented in both sisters. We believe that the evidence of objective findings in these children further supports the hypothesis that organic events cause persisting symptoms in a cohort of children after SARS-CoV-2 infection. Such findings highlight the importance of discovering diagnostics and therapeutics.

Post-COVID Conditions and Burden of Disease.

Post-COVID condition (PCC), also known as long COVID, is a multi-systemic illness estimated to affect 10% to 20% of those infected, regardless of age, baseline health status, or initial symptom severity. PCC has affected millions of lives, with long-lasting debilitating effects, but unfortunately it remains an underrecognized and therefore poorly documented condition. Defining and disseminating the burden of PCC is essential for developing effective public health strategies to address this issue in the long term.

Long COVID: Clinical characteristics, proposed pathogenesis and potential therapeutic targets.

The emergence of persistent ill-health in the aftermath of SARS-CoV-2 infection has presented significant challenges to patients, healthcare workers and researchers. Termed long COVID, or post-acute sequelae of COVID-19 (PASC), the symptoms of this condition are highly variable and span multiple body systems. The underlying pathophysiology remains poorly understood, with no therapeutic agents proven to be effective. This narrative review describes predominant clinical features and phenotypes of long COVID alongside the data supporting potential pathogenesis of these phenotypes including ongoing immune dysregulation, viral persistence, endotheliopathy, gastrointestinal microbiome disturbance, autoimmunity, and dysautonomia. Finally, we describe current potential therapies under investigation, as well as future potential therapeutic options based on the proposed pathogenesis research.

Characterization of post-COVID syndromes by symptom cluster and time period up to 12 months post-infection: A systematic review and meta-analysis.

OBJECTIVES: The objective of this study was to characterize post-COVID condition symptoms and symptom clusters, their duration, and prevalence. METHODS: We conducted a systematic review and random-effects meta-analysis of studies reporting post-COVID-19 symptoms and clusters, respectively. We searched MEDLINE (via PubMed), Scopus, Web of Science, Science Direct, Google Scholar, EBSCOhost, EMBASE, PsycINFO, Cochrane Library, and Mednar for literature reporting on the post-COVID condition up to August 2022. RESULTS: In the 76 included studies, we found that although most symptoms were reported less frequently 7-12 months after infection compared to earlier, over 20% of patients reported at least one post-COVID condition-compatible symptom. In the seven studies reporting post-COVID symptom clusters, neurological clustering was consistently identified, followed by cardiorespiratory and systemic/inflammatory. CONCLUSION: Post-COVID symptom clustering provides direction for research into the etiology, diagnosis, and management of post-COVID conditions. Studies reporting post-COVID symptom clusters remain rare due to the focus on individual symptom reporting. Studies on post-COVID symptom clusters should replace individual symptom reporting to accelerate our understanding of this emerging public health issue.

Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study.

Background: Adults and children can develop post-Covid-19 condition (PCC) (also referred to as Long Covid). However, existing evidence is scarce, partly due to a lack of a standardised case definition, short follow up duration, and heterogenous study designs, resulting in wide variation of reported outcomes. The primary aim of this study was to characterise risk factors for PCC and longitudinal rates of recovery in a cohort of children and young people using a standardised protocol. Methods: We performed a prospective "disease-based" cohort study between 01/02/2020 to 31/10/2022 including children aged 0-18 years old, with a previous diagnosis of Covid-19. Children with microbiologically confirmed SARS-CoV-2 infection, were invited for an in-clinic follow-up assessment at a paediatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12- and 18-months post-onset). PCC was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection. The statistical association between categorical variables was obtained by Chi-squared tests or Fisher's exact tests. Multivariable logistic regressions are presented using odds ratios (OR) and 95% confidence interval (CI). Survival analysis was conducted using the Kaplan-Meier method. Findings: 1243 children were included, median age: 7.5 (4-10.3) years old; 575 (46.3%) were females. Of these, 23% (294/1243) were diagnosed with PCC at three months post-onset. Among the study population, 143 patients remained symptomatic at six months, 38 at 12 months, and 15 at 18 months follow up evaluation. The following risk factors were associated with PCC: >10 years of age (OR 1.23; 95% CI 1.18-1.28), comorbidities (OR 1.68; 95% CI 1.14-2.50), and hospitalisation during the acute phase (OR 4.80; 95%CI 1.91-12.1). Using multivariable logistic regression, compared to the Omicron variant, all other variants were significantly associated with PCC at 3 and 6 months. At least one dose of vaccine was associated with a reduced, but not statistically significant risk of developing PCC. Interpretation: In our study, acute-phase hospitalisation, pre-existing comorbidity, being infected with pre-Omicron variants and older age were associated with a higher risk of developing PCC. Most children recovered over time, but one-in-twenty of those with PCC at three months reported persistent symptoms 18 months post-Sars-CoV-2 infection. Omicron infection was associated with shorter recovery times. We did not find a strong protective effect of vaccination on PCC development. Although our cohort cannot be translated to all Italian children with PCC as more nationwide studies are needed, our findings highlight the need of new strategies to prevent and treat pediatric PCC are needed. Funding: This study has been funded by Pfizer non-competitive grant, granted to DB (# 65925795).

Trust in sources of information on COVID-19 at the beginning of the pandemic's first wave and incident persistent symptoms in the population-based CONSTANCES cohort: A prospective study.

OBJECTIVE: To examine the association between trust in different sources of information on COVID-19 at the beginning of the pandemic and the burden of incident persistent symptoms. METHODS: This prospective study used data from the SAPRIS and SAPRIS-Sérologie surveys nested in the French CONSTANCES population-based cohort. Trust in different information sources was measured between April 6 and May 4, 2020. Persistent symptoms that emerged afterwards were self-reported between December 2020 and January 2021. The associated psychological burden was measured with the somatic symptom disorder B criteria scale (SSD-12). The analyses were adjusted for gender, age, education, income, self-rated health, SARS-CoV-2 serology tests, and self-reported COVID-19. RESULTS: Among 20,985 participants [mean age (SD), 49.0 years (12.7); 50.2% women], those with higher trust in government/journalists at baseline had fewer incident persistent symptoms at follow-up (estimate (SE) for one IQR increase: -0.21 (0.03), p < 0.001). Participants with higher trust in government/journalists and medical doctors/scientists were less likely to have ≥1 symptom (odds ratio (95% confidence interval) for one IQR increase: 0.87 (0.82-0.91) and 0.91 (0.85-0.98), respectively). Among 3372 participants (16.1%) who reported ≥1 symptom, higher trust in government/journalists and medical doctors/scientists predicted lower SSD-12 scores (-0.39 (0.17), p = 0.02 and - 0.85 (0.24), p < 0.001, respectively), whereas higher trust in social media predicted higher scores in those with lower trust in government/journalists (0.90 (0.34), p = 0.008). These associations did not depend upon surrogate markers of infection with SARS-CoV-2. CONCLUSIONS: Trust in information sources on COVID-19 may be associated with incident persistent symptoms and associated psychological burden, regardless of infection with SARS-CoV-2.

Two-year follow-up of patients with post-COVID-19 condition in Sweden: a prospective cohort study.

Background: Few studies have reported the long-term health effects of COVID-19. The regional population-based Linköping COVID-19 study (LinCoS) included all patients hospitalised due to COVID-19 during the first pandemic wave. Four months post-discharge, over 40% (185/433) experienced persisting symptoms and activity/participation limitations, indicating post-COVID-19 condition (PCC). The present follow-up study aimed to determine the long-term recovery among these patients 24 months post-admission. Methods: This prospective cohort study included all patients from LinCoS with PCC at four months post-discharge. We repeated the same structured interview at a 24-month follow-up to identify persisting symptoms and their impact on daily life. Intercurrent health issues were identified by reviewing medical records. Findings: Of 185 patients with PCC at 4 months post-discharge, 181 were alive at the 24-month assessment and 165 agreed to participate. Of those, 21% (35/165) had been readmitted to hospital for various causes in the interim period. The majority of patients (139/165, 84%) reported persisting problems affecting everyday life at 24 months. Significant improvements were seen in the prevalence and magnitude of some symptoms/limitations compared with four months post-discharge. Cognitive, sensorimotor, and fatigue symptoms were the most common persisting symptoms at 24 months. No clear difference was evident between individuals treated in the intensive care unit (ICU) and non-ICU-treated individuals. Approximately half of those who were on sick leave related to PCC at four months after infection were on sick leave at 24 months. Interpretation: This is one of the first studies to report 2-year outcomes in patients with PCC following COVID-19 hospitalisation. Despite some improvements over time, we found a high prevalence of persisting symptoms and a need for long-term follow-up and rehabilitation post COVID-19 infection. Funding: The study was funded by Region Östergötland.

SARS-CoV-2 infection outcomes associated with the Delta variant: A prospective cohort study.

Background: It is well established that fully vaccinated (≥2 doses) individuals may develop COVID-19. However, little is known about the specific prevalence of post-COVID-19 conditions associated with the Delta variant or the effect of vaccination on post-acute outcomes of COVID-19. In addition, how Delta variant infection severity compares in fully vaccinated individuals versus in those unvaccinated is unknown. Methods: This prospective single-centre observational cohort study assessed adults with SARS-CoV-2 proven infection from August 1 to November 1, 2021. Study participants were enrolled in the Biobanque Québécoise de la COVID-19. Data on demographics, comorbidities, and severity of COVID-19 were collected. Simple and multiple logistic regressions were used to identify risk factors for post-COVID-19 conditions. Results: Among the 395 individuals who were interviewed by phone, 138 (39.4%) agreed to participate. Of the 138 participants, 62.8% were Delta-associated breakthrough infections that occurred in fully vaccinated individuals and 37.1% in unvaccinated individuals. The majority (93.5%) had a history of mild COVID-19 illness. The prevalence of Delta-variant-associated post-COVID-19 conditions was similar in both vaccinated (61.4%) and unvaccinated (51.4%) groups (p = 0.347). The number of symptoms during acute infection was an independent risk factor for post-COVID-19 conditions. Conclusions: This study is the first to describe the incidence of Delta-associated post-COVID-19 condition. In this study, COVID-19 vaccination was not associated with decreased post-COVID-19 conditions in patients with breakthrough Delta infection. These findings have important implications for provincial services planning and underscore the need to develop alternative strategies to prevent post-COVID-19 conditions.

Historique: Il est bien établi que les personnes pleinement vaccinées (au moins deux doses) peuvent contracter la COVID-19. Cependant, on sait peu de choses sur la prévalence exacte des affections post-COVID-19 associées au variant Delta et sur l'effet de la vaccination sur les résultats post-aigus de la COVID-19. Par ailleurs, on ne sait pas quelle est la gravité de l'infection par le variant Delta chez les personnes pleinement vaccinées par rapport à celles qui ne le sont pas. Méthodologie: La présente étude de cohorte observationnelle unicentrique et prospective visait à évaluer des adultes atteints d'une infection démontrée par le SRAS-CoV-2 entre le 1er aoÛt et le 1er novembre 2021. Les participants à l'étude étaient inscrits à la Biobanque québécoise de la COVID-19. Les chercheurs ont recueilli les données sur les caractéristiques démographiques, les affections connexes et la gravité de la COVID-19. Ils ont utilisé la régression logistique simple et multiple pour déterminer les facteurs de risque d'affections post-COVID-19. Résultats: Des 395 personnes interviewées par téléphone, 138 (39,4%) ont accepté de participer. De ce nombre, 62,8% étaient des personnes pleinement vaccinées qui avaient souffert d'une infection postvaccinale par le variant Delta et 37,1%, des personnes non vaccinées. La majorité (93,5%) avait une histoire de COVID-19 légère. La prévalence d'affections post-COVID-19 liées au variant Delta était semblable dans les groupes vaccinés (61,4% [48,4%­73%]) et non vaccinés (51,4% [35,6%­67%]; p = 0,347. Le nombre de symptômes pendant l'infection aiguë était un facteur de risque indépendant d'affections post-COVID-19. Conclusions: La présente étude est la première à décrire l'incidence d'affections post-COVID-19 liées au variant Delta. La vaccination contre la COVID-19 n'était pas liée à une diminution d'affections post-COVID-19 chez les patients atteints d'une infection postvaccinale par le variant Delta. Ces observations ont des conséquences importantes pour la planification des services provinciaux et font ressortir la nécessité de trouver d'autres stratégies pour éviter les affections post-COVID-19.

Post-COVID-19 condition is not only a question of persistent symptoms: structured screening including health-related quality of life reveals two separate clusters of post-COVID.

PURPOSE: Some patients experience long-term sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, despite a present post-COVID condition, defined as "any symptom lasting longer than 12 weeks," only a subset of patients search for medical help and therapy. METHOD: We invited all adults with a positive real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 between March 2020 and September 2021 (n = 4091) in the city of Jena to answer a standardized questionnaire including demographic information, the course of the acute infection and current health status. K-means-clustering of quality of life (QoL) was used to explore post-COVID subgroups. RESULTS: A total of 909 participants at a median interval of 367 (IQR 291/403) days after acute infection were included in the analysis. Of those, 643 (70.7%) complained of having experienced persistent symptoms at the time of the survey. Cluster analysis based on QoL revealed two subgroups of people with persistent post-COVID symptoms. Whereas 189/643 participants (29.4%) showed markedly diminished QoL, normal QoL was detected in 454/643 individuals (70.6%). CONCLUSION: Despite persistent symptoms being reported by nearly three quarters of participants, only one-third of these described a significant reduction in QoL (cluster 1), whereas the other two-thirds reported a near-normal QoL (cluster 2), thus indicating a differentiation between "post-COVID disease" and "post-COVID condition". The prevalence of clinically relevant post-COVID disease was at least 20.7%. Health policies should focus on this subset.

Epidemiology of post-COVID conditions beyond 1 year: a cross-sectional study.

OBJECTIVE: The aim of this study was to investigate the epidemiology of post-COVID conditions beyond 12 months and identify factors associated with the persistence of each condition. STUDY DESIGN: This was a cross-sectional questionnaire-based survey. METHODS: We conducted the survey among patients who had recovered from COVID-19 and visited our institute between February 2020 and November 2021. Demographic and clinical data and data regarding the presence and duration of post-COVID conditions were obtained. We identified factors associated with the persistence of post-COVID conditions using multivariable linear regression analyses. RESULTS: Of 1148 surveyed patients, 502 completed the survey (response rate, 43.7%). Of these, 393 patients (86.4%) had mild disease in the acute phase. The proportion of participants with at least one symptom at 6, 12, 18, and 24 months after symptom onset or COVID-19 diagnosis was 32.3% (124/384), 30.5% (71/233), 25.8% (24/93), and 33.3% (2/6), respectively. The observed associations were as follows: fatigue persistence with moderate or severe COVID-19 (ß = 0.53, 95% confidence interval [CI] = 0.06-0.99); shortness of breath with moderate or severe COVID-19 (ß = 1.39, 95% CI = 0.91-1.87); cough with moderate or severe COVID-19 (ß = 0.84, 95% CI = 0.40-1.29); dysosmia with being female (ß = -0.57, 95% CI = -0.97 to -0.18) and absence of underlying medical conditions (ß = -0.43, 95% CI = -0.82 to -0.05); hair loss with being female (ß = -0.61, 95% CI = -1.00 to -0.22), absence of underlying medical conditions (ß = -0.42, 95% CI = -0.80 to 0.04), and moderate or severe COVID-19 (ß = 0.97, 95% CI = 0.41-1.54); depressed mood with younger age (ß = -0.02, 95% CI = -0.04 to -0.004); and loss of concentration with being female (ß = -0.51, 95% CI = -0.94 to -0.09). CONCLUSIONS: More than one-fourth of patients after recovery from COVID-19, most of whom had had mild disease in the acute phase, had at least one symptom at 6, 12, 18, and 24 months after onset of COVID-19, indicating that not a few patients with COVID-19 suffer from long-term residual symptoms, even in mild cases.

Risk of New-Onset Diabetes Mellitus as a Post-COVID-19 Condition and Possible Mechanisms: A Scoping Review.

Long-term effects of COVID-19 are becoming more apparent even as the severity of acute infection is decreasing due to vaccinations and treatment. In this scoping review, we explored the current literature for the relationship between COVID-19 infection and new-onset diabetes mellitus four weeks after acute infection. We systematically searched the peer-reviewed literature published in English between 1 January 2020 and 31 August 2022 to study the risk of new-onset diabetes mellitus post-COVID-19 infection. This scoping review yielded 11 articles based on our inclusion and exclusion criteria. Except for one, all studies suggested an increased risk of new-onset diabetes mellitus 4 weeks after acute infection. This risk appears most in the first six months after the acute COVID-19 infection and seems to increase in a graded fashion based on the severity of the initial COVID-19 infection. Our review suggests a possible association of new-onset diabetes mellitus 4 weeks after acute COVID-19 infection. Since the severity of COVID-19 infection is associated with the development of post-infectious diabetes, vaccination that reduces the severity of acute COVID-19 infection might help to reduce the risk of post-COVID-19 diabetes mellitus. More studies are needed to better understand and quantify the association of post-COVID-19 conditions with diabetes and the role of vaccination in influencing it.

Long COVID-19/post-COVID condition in children: do we all speak the same language?

Post-COVID condition is a new and highly debated entity that is still to be outlined in its complexity, especially in the pediatric population. In response to the article by Trapani and colleagues, we report the results of a long-term follow-up conducted in the outpatient clinic of the Pediatric Infectious Diseases Unit on children admitted to our hospital with SARS-CoV-2 infection.

Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial.

BACKGROUND: With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug. METHODS: The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. RESULTS: Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60-40.90) vs 83.5 (23.9) p < 0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442 (180) (95% CI 358-525) vs 662 (18) meters p < 0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort. CONCLUSIONS: An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials. Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 . EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE.

Persistent physical symptoms after COVID-19 infection and the risk of Somatic Symptom Disorder.

OBJECTIVE: Evidence shows that many patients with COVID-19 present persistent symptoms after the acute infection. Some patients may be at a high risk of developing Somatic Symptom Disorder (SSD), in which persistent symptoms are accompanied by excessive and disproportionate health-related thoughts, feelings and behaviors regarding these symptoms. This study assessed the frequency of persistent physical symptoms and SSD and their associated factors in patients with confirmed COVID-19. METHODS: We conducted a longitudinal retrospective study after the first two French lockdowns at the Lille University Hospital (France), including all patients with confirmed COVID-19. Persistent physical symptoms and excessive preoccupations for these symptoms were measured 8 to 10 months after the onset of COVID-19. The combination of the Patient Health Questionnaire-15 and the Somatic Symptom Disorder-B Criteria Scale was used to identify the individuals likely to present with SSD. Two linear regression models were performed to identify sociodemographic and medical risk factors of SSD. RESULTS: Among the 377 patients with a laboratory-confirmed diagnosis, 220 (58.4%) completed the questionnaires. Sixty-five percent of the 220 included patients required hospitalization, 53.6% presented at least one persistent physical symptom and 10.4% were considered to present SSD. Female sex, older age, infection during the second wave and having probable PTSD were significantly associated with the severity of SSD and SSD was associated with a significantly higher healthcare use. CONCLUSIONS: The identification of SSD should encourage clinicians to move beyond the artificial somatic/psychiatric dualism and contribute to a better alliance based on multi-disciplinary care.

Response to commentary 'long COVID-19/post-COVID condition in children: do we all speak the same language?

Here we present the Authors' answer to the Letter written by Dr. Garazzino and Colleagues with reference to our article "Long COVID-19 in children: an Italian cohort study".

[Post-Covid Affection, an adapted management is necessary]. / Affection post-Covid, une prise en charge adaptée est nécessaire.

Covid-19 is a polymorphic disease, characterized in some patients by persistent symptoms several weeks or even months after the initial manifestations of SARS-CoV-2 infection. This is referred to as "long Covid" or post-Covid-19 disease. The polysymptomatic and fluctuating nature of these clinical manifestations generates questions and concerns for patients. To meet their care needs, the regional health agencies have worked with local health care providers to develop appropriate care pathways.

The Prevalence, Characteristics and Risk Factors of Persistent Symptoms in Non-Hospitalized and Hospitalized Children with SARS-CoV-2 Infection Followed-Up for up to 12 Months: A Prospective, Cohort Study in Rome, Italy.

Previous studies assessing the prevalence of COVID-19 sequelae in children have included either a small number of children or a short follow-up period, or have only focused on hospitalized children. We investigated the prevalence of persistent symptoms amongst children and assessed the risk factors, including the impact of variants. A prospective cohort study included children (≤18 years old) with PCR-confirmed SARS-CoV-2 infection. The participants were assessed via telephone and face-to-face visits at 1-5, 6-9 and 12 or more months post-SARS-CoV-2 diagnosis using the ISARIC COVID-19 follow-up survey. Of the 679 children enrolled, 51% were female; 488 were infected during the wild virus wave, and 29 were infected with the Alpha, 42 with the Delta and 120 with the Omicron variants. Fatigue (19%), headache (12%), insomnia (7.5%), muscle pain (6.9%) and confusion with concentration issues (6.8%) were the most common persistent symptoms. Families reported an overall improvement over time, with 0.7% of parents interviewed at 12 months or more of the follow-up period reporting a poor recovery. Patients that had not recovered by 6-9 months had a lower probability of recovering during the next follow-up period. Children infected with a variant or the wild virus had an overall similar rate of persistent symptoms (although the pattern of reported symptoms differed significantly) and recovery rates. Conclusions: Recovery rates after SARS-CoV-2 infection improved as time passed from the initial infection, ranging from 4% of children having poor recovery at 1-5 months' follow-up to 1.3% at 6-9 months and 0.7% at 12 months. The patterns of persistence changed according to the variants involved at the time of infection. This study reinforces that a subgroup of children develop long-lasting persistent symptoms and highlights the need for further studies investigating the reasons behind the development of PCC.