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      The autonomic aspects of the post-COVID19 syndrome

      review-article
      a , b , c , * , b , d , b , c , a , b , e
      Autoimmunity Reviews
      Published by Elsevier B.V.
      COVID-19, Post-COVID19 syndrome, Long COVID-19, Dysautonomia, Autonomic nervous system dysfunction, Fibromyalgia, Chronic fatigue syndrome, Autoimmunity, Autoimmune disease, AGTR1, Angiotensin II Receptor Type 1, AGTR2, Angiotensin II Receptor Type 2, BDKRB1, Bradykinin Receptor B1, MAS1, MAS1 Proto-Oncogene, CXCR3, C-X-C Motif Chemokine Receptor 3, CHRM2, Cholinergic Receptor Muscarinic 2, CHRM3, Cholinergic Receptor Muscarinic 3, CHRM5, Cholinergic Receptor Muscarinic 5, F2R, Coagulation Factor II Thrombin Receptor, NOR, nociception-like opioid receptor, ADRB1, Adrenergic receptor beta-1, ADRB2, Adrenergic receptor beta-2, ADRA1, Adrenoceptor Alpha 1A, NRP1, Neuropilin 1, STAB1, Stabilin 1, ETA, Selective endothelin-A

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          Abstract

          The SARS-CoV-2 outbreak, responsible for the widespread COVID-19, led to one of the most rogue pandemics in modern time, yet the major effects of the pandemic may still be ahead of us. SARS-CoV-2 had been found to possess autoimmune properties. Close to 20 distinct functionally active autoantibodies which target GPCR of the nervous system and renin-angiotensin system-related molecules were found significantly associated with the clinical severity of COVID-19. The new on-set of more than 10 various autoimmune disorders were documented as well. Additionally, clinical presentations of persisted symptoms were triggered in numerous recently recovered COVID-19 patients, which led to the formulation of the novel term “post-COVID19 syndrome”. Manifestations related to post-COVID-19 syndrome exist among approximately 50–80% of symptomatic COVID-19 patients who recovered, and among patients reported more than 50 different long-term effects of the SARS-CoV-2 infection. Many of the common symptoms of the post-COVID19 syndrome are not explained by the virus-related injury alone. Similarly to chronic fatigue syndrome and fibromyalgia, autoimmune-mediated autonomic nervous system dysfunction may play a significant part in the pathogenesis of such symptoms, including chronic fatigue, cognitive impairment, mood related disorders, and numerous more. Importantly, therapeutic options such as immunomodulatory and immunosuppressive therapy may favor some post-COVID19 patients, while plasmapheresis and IVIG could be considered in severe cases. Nevertheless, as physical exercise has been found to stabilize the autonomic nervous system, exercise therapy might be a safer and more effective remedy for the post-COVID19 syndrome.

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          6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

          Background The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. Methods We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. Findings In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0–65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0–199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5–6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5–6, and median CT scores were 3·0 (IQR 2·0–5·0) for severity scale 3, 4·0 (3·0–5·0) for scale 4, and 5·0 (4·0–6·0) for scale 5–6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80–3·25) for scale 4 versus scale 3 and 4·60 (1·85–11·48) for scale 5–6 versus scale 3 for diffusion impairment; OR 0·88 (0·66–1·17) for scale 4 versus scale 3 and OR 1·77 (1·05–2·97) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58–0·96) for scale 4 versus scale 3 and 2·69 (1·46–4·96) for scale 5–6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. Interpretation At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.
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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
                Autoimmun Rev
                Autoimmun Rev
                Autoimmunity Reviews
                Published by Elsevier B.V.
                1568-9972
                1873-0183
                16 February 2022
                16 February 2022
                : 103071
                Affiliations
                [a ]Ariel University, Israel
                [b ]Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat-Gan 52621, Israel
                [c ]Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                [d ]Department of Medicine B, Sheba Medical Center, Tel Hashomer, Israel
                [e ]Laboratory of the Mosaics of Autoimmunity, Saint Petersburg University, 199034, Russia
                Author notes
                [* ]Corresponding author at: Ariel University, Israel.
                Article
                S1568-9972(22)00041-6 103071
                10.1016/j.autrev.2022.103071
                8848724
                35182777
                a9d4322f-ba8d-479f-ad6c-6c473d3e7d73
                © 2022 Published by Elsevier B.V.

                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
                : 7 February 2022
                : 14 February 2022
                Categories
                Review

                Immunology
                covid-19,post-covid19 syndrome,long covid-19,dysautonomia,autonomic nervous system dysfunction,fibromyalgia,chronic fatigue syndrome,autoimmunity,autoimmune disease,agtr1, angiotensin ii receptor type 1,agtr2, angiotensin ii receptor type 2,bdkrb1, bradykinin receptor b1,mas1, mas1 proto-oncogene,cxcr3, c-x-c motif chemokine receptor 3,chrm2, cholinergic receptor muscarinic 2,chrm3, cholinergic receptor muscarinic 3,chrm5, cholinergic receptor muscarinic 5,f2r, coagulation factor ii thrombin receptor,nor, nociception-like opioid receptor,adrb1, adrenergic receptor beta-1,adrb2, adrenergic receptor beta-2,adra1, adrenoceptor alpha 1a,nrp1, neuropilin 1,stab1, stabilin 1,eta, selective endothelin-a

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