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ImportanceWhile much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID. ObjectiveTo estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recovery DesignWe jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study. ResultsAnalyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8-312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38-7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9-92.4), 60.4% (18.9-89.1), and 35.4% (9.4-75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84-4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10-9.78]). At twelve months, 15.1% (10.3-21.1) continued to experience long COVID symptoms. Conclusions and relevanceThe occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the extent and nature of the most common long COVID symptoms by country in 2020 and 2021? FindingsGlobally, 144.7 million people experienced one or more of three symptom clusters (fatigue; cognitive problems; and ongoing respiratory problems) of long COVID three months after infection, in 2020 and 2021. Most cases arose from milder infections. At 12 months after infection, 15.1% of these cases had not yet recovered. MeaningThe substantial number of people with long COVID are in need of rehabilitative care and support to transition back into the workplace or education when symptoms start to wane.
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Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Comprehensively capturing the host physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index and APACHE II score were poor predictors of survival. Plasma proteomics instead identified 14 proteins that showed concentration trajectories different between survivors and non-survivors. A proteomic predictor trained on single samples obtained at the first time point at maximum treatment level (i.e. WHO grade 7) and weeks before the outcome, achieved accurate classification of survivors in an exploratory (AUROC 0.81) as well as in the independent validation cohort (AUROC of 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that predictors derived from plasma protein levels have the potential to substantially outperform current prognostic markers in intensive care. Trial registrationGerman Clinical Trials Register DRKS00021688
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BackgroundThe long-term sequelae of coronavirus disease 2019 (Covid-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with Covid-19 and associated risk factors. MethodsThis is a prospective cohort study of children ([≤]18 years old) admitted with confirmed Covid-19 to Z.A. Bashlyaeva Childrens Municipal Clinical Hospital in Moscow, Russia. Children admitted to the hospital during the first wave of the pandemic, between April 2, 2020 and August 26, 2020, were included. Telephone interview using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Covid-19 Health and Wellbeing paediatric follow up survey. Persistent symptoms (>5 months) were further categorised by system(s) involved. FindingsOverall, 518 of 853 (61%) of eligible children were available for the follow-up assessment and included in the study. Median age was 10.4 years (IQR, 3-15.2) and 270 (52.1%) were girls; median follow-up since hospital discharge was 256 (223-271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%,) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: age "6-11 years" (odds ratio 2.74 (95% confidence interval 1.37 to 5.75) and "12-18 years" (2.68, 1.41 to 5.4), and a history of allergic diseases (1.67, 1.04 to 2.67). InterpretationA quarter of children experienced persistent symptoms months after hospitalization with acute covid-19 infection, with almost one in ten experiencing multi-system involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up. Our findings highlight the need for replication and further investigation of potential mechanisms as well as clinical support to improve long term outcomes in children. FundingNone. O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that Covid-19 may result in short- and long-term consequences to health. Studies in children and adolescents are limited and available evidence is scarce. We searched Embase for publications from inception to April, 25, 2021, using the following phrases or combinations of phrases "post-covid condition" or "post-covid syndrome" or "covid sequalae" or "post-acute covid" or "long covid" or "long hauler" with "pediatric*" or "paediatric*" or "child*" or "infant*" or "newborn*" or "toddler*" or "neonate*" or "neonatal" or "adolescent*" or "teen*". We found small case series and small cohort studies looking at Covid-19 consequences in children. No large cohort studies of previously hospitalised children, assessing symptom duration, categorisation or attempting multivariable analyses to identify independent risk factors for long Covid development were identified. Added value of this studyTo our knowledge, this is the largest cohort study with the longest follow-up since hospital discharge of previously hospitalised children. We found that even months after discharge from the hospital, approximately a quarter of children experience persistent symptoms with one in ten having multi-system involvement. Older age and allergic diseases are associated with Covid-19 consequences. Parents of some children report emotional and behavioural changes in their children after Covid-19. Implications of all the available evidenceOur findings highlight the need for continued global research of Covid-19 consequences in the paediatric population. Older children admitted to the hospital should be carefully monitored upon discharge. Large, controlled studies aiming to identify risk groups and potential intervention strategies are required to fill knowledge gaps. C_TEXTBOX
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BackgroundThe long-term sequalae of COVID-19 remain poorly characterised. In this study, we aimed to assess long-standing symptoms (LS) (symptoms lasting from the time of discharge) in previously hospitalised patients with COVID-19 and assess associated risk factors. MethodsThis is a longitudinal cohort study of adults ([≥]18 years of age) with clinically diagnosed or laboratory-confirmed COVID-19 admitted to Sechenov University Hospital Network in Moscow, Russia. Data were collected from patients discharged between April 8 and July 10, 2020. Participants were interviewed via telephone using Tier 1 ISARIC Long-term Follow-up Study CRF and the WHO CRF for Post COVID conditions. Reported symptoms were further categorised based on the system(s) involved. Additional information on dyspnoea, quality of life and fatigue was collected using validated instruments. Multivariable logistic regressions were performed to investigate risk factors for development of LS categories. FindingsOverall, 2,649 of 4,755 patients discharged from the hospitals were available for the follow-up and included in the study. The median age of the patients was 56 years (IQR, 46-66) and 1,353 (51.1%) were women. The median follow-up time since hospital discharge was 217.5 (200.4-235.5) days. At the time of the follow-up interview 1247 (47.1%) participants reported LS. Fatigue (21.2%, 551/2599), shortness of breath (14.5%, 378/2614) and forgetfulness (9.1%, 237/2597) were the most common LS reported. Chronic fatigue (25%, 658/2593) and respiratory (17.2% 451/2616) were the most common LS categories. with reporting of multi-system involvement (MSI) less common (11.3%; 299). Female sex was associated with LS categories of chronic fatigue with an odds ratio of 1.67 (95% confidence interval 1.39 to 2.02), neurological (2.03, 1.60 to 2.58), mood and behaviour (1.83, 1.41 to 2.40), dermatological (3.26, 2.36 to 4.57), gastrointestinal (2.50, 1.64 to 3.89), sensory (1.73, 2.06 to 2.89) and respiratory (1.31, 1.06 to 1.62). Pre-existing asthma was associated with neurological (1.95, 1.25 to 2.98) and mood and behavioural changes (2.02, 1.24 to 3.18) and chronic pulmonary disease was associated with chronic fatigue (1.68, 1.21 to 2.32). Interpretation6 to 8 months after acute infection episode almost a half of patients experience symptoms lasting since hospital discharge. One in ten individuals experiences MSI. Female sex is the main risk factor for majority of the LS categories. chronic pulmonary disease is associated with a higher risk of chronic fatigue development, and asthma with neurological and mood and behaviour changes. Individuals with LS and MSI should be the main target for future research and intervention strategies. FundingThis study is supported by Russian Fund for Basic Research and UK Embassy in Moscow. The ISARIC work is supported by grants from: the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], and the Bill and Melinda Gates Foundation [OPP1209135], EU Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) [FP7 project 602525] This research was funded in part, by the Wellcome Trust. The views expressed are those of the authors and not necessarily those of the DID, NIHR, Wellcome Trust or PHE. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that COVID-19 may result in short- and long-term consequences to health. Most studies do not provide definitive answers due to a combination of short follow-up (2-3 months), small sample size, and use of non-standardised tools. There is a need to study the longer-term health consequences of previously hospitalised patients with COVID-19 infection and to identify risk factors for sequalae. Added value of this studyTo our knowledge, this is the largest cohort study (n=2,649) with the longest follow-up since hospital discharge (6-8 months) of previously hospitalised adult patients. We found that 6-8 months after discharge from the hospital, around a half (47.1%) of patients reported at least one long-standing symptom since discharge. Once categories of symptoms were assessed, chronic fatigue and respiratory problems were the most frequent clusters of long-standing symptoms in our patients. Of those patients having long-term symptoms, a smaller proportion (11.3%) had multisystem involvement, with three or more categories of long-standing symptoms present. Although most patients developed symptoms since discharge, a smaller number of individuals experienced symptom beginning symptom appearing weeks or months after the acute phase. Female sex was a predictor for most of the symptom categories at the time of the follow-up interview, with chronic pulmonary disease associated with chronic fatigue-related symptoms, and asthma with a higher risk of neurological symptoms, mood and behaviour problems. Implications of all the available evidenceThe majority of patients experienced long-lasting symptoms 6 to 8 months after hospital discharge and almost half reported at least one long-standing symptom, with chronic fatigue and respiratory problems being the most frequent. A smaller number reported multisystem impacts with three or more long-standing categories present at follow-up. A higher risk was found for women, for chronic pulmonary disease with chronic fatigue, and neurological symptoms and mood and behaviour problems with asthma. Patterns of the symptom development following COVID-19 should be further investigated in future research.
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COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. There is an urgent need for predictive markers that can guide clinical decision-making, inform about the effect of experimental therapies, and point to novel therapeutic targets. Here, we characterize the time-dependent progression of COVID-19 through different stages of the disease, by measuring 86 accredited diagnostic parameters and plasma proteomes at 687 sampling points, in a cohort of 139 patients during hospitalization. We report that the time-resolved patient molecular phenotypes reflect an initial spike in the systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution and immunomodulation. Further, we show that the early host response is predictive for the disease trajectory and gives rise to proteomic and diagnostic marker signatures that classify the need for supplemental oxygen therapy and mechanical ventilation, and that predict the time to recovery of mildly ill patients. In severely ill patients, the molecular phenotype of the early host response predicts survival, in two independent cohorts and weeks before outcome. We also identify age-specific molecular response to COVID-19, which involves increased inflammation and lipoprotein dysregulation in older patients. Our study provides a deep and time resolved molecular characterization of COVID-19 disease progression, and reports biomarkers for risk-adapted treatment strategies and molecular disease monitoring. Our study demonstrates accurate prognosis of COVID-19 outcome from proteomic signatures recorded weeks earlier.
