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      COVID-19 Sequelae in adults aged less than 50 years: A Systematic Review

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          Abstract

          Background

          There is emerging evidence of long-term sequelae in a considerable proportion of COVID-19 patients after recovery and the spectrum and severity of such sequelae should be systematically reviewed. This review aims to evaluate the available evidence of all intermediate and long-term COVID-19 sequelae affecting formerly healthy adults.

          Methods

          A systematic literature search of Embase, WHO, Scopus, Pubmed, Litcovid, bioRxiv and medRxiv was conducted with a cutoff date of the 17th September 2020 according to PRISMA guidelines and registered in PROSPERO (CRD42020208725). Search terms included “COVID-19”, “coronavirus disease 2019”, “SARS-CoV-2”, “sequelae” and “consequence*”. Publications on adult participants, with a confirmed SARS-CoV-2 infection were included. Elderly (>50 years old) and children (<18 years old) were excluded. Bias assessment was performed using a modified Newcastle-Ottawa Scale.

          Results

          A total of 31 papers were included. Study types included prospective and retrospective cohort studies, cross-sectional studies and case reports. Sequelae persistence since infection spanned 14 days to three months. Sequelae included persistent fatigue (39-73% of assessed persons), breathlessness (39-74%), decrease in quality of life (44-69%), impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39-83%), evidence of peri-/perimyo-/myocarditis (3-26%), changes in microstructural and functional brain integrity with persistent neurological symptoms (55%), increased incidence of psychiatric diagnoses (5.8% versus 2.5-3.4% in controls), incomplete recovery of olfactory and gustatory dysfunction (33-36% of evaluated persons).

          Conclusions

          A variety of organ systems are affected by COVID-19 in the intermediate and longer-term after recovery. Main sequelae include post-infectious fatigue, persistent reduced lung function and carditis. Careful follow-up post COVID 19 is indicated to assess and mitigate possible organ damage and preserve life quality.

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          Most cited references43

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          Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

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            Persistent Symptoms in Patients After Acute COVID-19

            This case series describes COVID-19 symptoms persisting a mean of 60 days after onset among Italian patients previously discharged from COVID-19 hospitalization.
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              Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

              Summary Background Before the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19. Methods In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I 2 statistics, and assessment of study quality. Findings 1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5–36·0] of 129 patients), depressed mood (42 [32·6%; 24·7–40·9] of 129), anxiety (46 [35·7%; 27·6–44·2] of 129), impaired memory (44 [34·1%; 26·2–42·5] of 129), and insomnia (54 [41·9%; 22·5–50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5–14·1] of 332 patients), insomnia (34 [12·1%; 8·6–16·3] of 280), anxiety (21 [12·3%; 7·7–17·7] of 171), irritability (28 [12·8%; 8·7–17·6] of 218), memory impairment (44 [18·9%; 14·1–24·2] of 233), fatigue (61 [19·3%; 15·1–23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9–37·3] of 181) and sleep disorder (14 [100·0%; 88·0–100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7–42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1–18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1–19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1–84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality. Interpretation If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term. Funding Wellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.
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                Author and article information

                Journal
                Travel Med Infect Dis
                Travel Med Infect Dis
                Travel Medicine and Infectious Disease
                The Author(s). Published by Elsevier Ltd.
                1477-8939
                1873-0442
                22 February 2021
                22 February 2021
                : 101995
                Affiliations
                [a ]University of Zurich, Epidemiology, Biostatistics and Prevention Institute, WHO Collaborating Centre for Travel Medicine, Competence Centre for Military Medicine and Biology, Hirschengraben 84, 8001, Zurich, Switzerland
                [b ]Institute of Evolutionary Medicine, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland
                [c ]Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland
                Author notes
                []Corresponding author. , Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, 8001 Zürich, Switzerland. , +41 79 783 82 42
                [1]

                These authors contributed equally: Shared last authorship

                Article
                S1477-8939(21)00036-3 101995
                10.1016/j.tmaid.2021.101995
                7898978
                33631340
                65df0727-e161-4a64-b809-5a3084faf075
                © 2021 The Author(s)

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 26 October 2020
                : 3 February 2021
                : 9 February 2021
                Categories
                Review

                Infectious disease & Microbiology
                covid-19,sars-cov-2,coronavirus,sequelae,consequences,long-term
                Infectious disease & Microbiology
                covid-19, sars-cov-2, coronavirus, sequelae, consequences, long-term

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