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      Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up

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          Abstract

          COVID-19 outbreak is associated with mental health implications during viral infection and at short-term follow-up. Data on psychiatric and cognitive sequelae at medium-term follow-up are still lacking. During an ongoing prospective cohort study, the psychopathological and cognitive status of 226 COVID-19 pneumonia survivors (149 male, mean age 58) were prospectively evaluated one and three months after hospital discharge. Psychiatric clinical interview, self-report questionnaires, and neuropsychological profiling of verbal memory, working memory, psychomotor coordination, executive functions, attention and information processing, and verbal fluency were performed.

          Three months after discharge from the hospital, 35.8% still self-rated symptoms in the clinical range in at least one psychopathological dimension. We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up. Sex, previous psychiatric history, and the presence of depression at one month affected the depressive symptomatology at three months. Regardless of clinical physical severity, 78% of the sample showed poor performances in at least one cognitive domain, with executive functions and psychomotor coordination being impaired in 50% and 57% of the sample.

          Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, predicted self-rated depressive symptomatology and cognitive impairment at three-months follow-up; and changes of SII predicted changes of depression during follow-up. Neurocognitive impairments associated with severity of depressive psychopathology, and processing speed, verbal memory and fluency, and psychomotor coordination were predicted by baseline SII.

          We hypothesize that COVID-19 could result in prolonged systemic inflammation that predisposes patients to persistent depression and associated neurocognitive dysfunction. The linkage between inflammation, depression, and neurocognition in patients with COVID-19 should be investigated in long-term longitudinal studies, to better personalize treatment options for COVID-19 survivors.

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          Most cited references69

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Mental Health and the Covid-19 Pandemic

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              Timely mental health care for the 2019 novel coronavirus outbreak is urgently needed

              The 2019 novel coronavirus (2019-nCoV) pneumonia, believed to have originated in a wet market in Wuhan, Hubei province, China at the end of 2019, has gained intense attention nationwide and globally. To lower the risk of further disease transmission, the authority in Wuhan suspended public transport indefinitely from Jan 23, 2020; similar measures were adopted soon in many other cities in China. As of Jan 25, 2020, 30 Chinese provinces, municipalities, and autonomous regions covering over 1·3 billion people have initiated first-level responses to major public health emergencies. A range of measures has been urgently adopted,1, 2 such as early identification and isolation of suspected and diagnosed cases, contact tracing and monitoring, collection of clinical data and biological samples from patients, dissemination of regional and national diagnostic criteria and expert treatment consensus, establishment of isolation units and hospitals, and prompt provision of medical supplies and external expert teams to Hubei province. The emergence of the 2019-nCoV pneumonia has parallels with the 2003 outbreak of severe acute respiratory syndrome (SARS), which was caused by another coronavirus that killed 349 of 5327 patients with confirmed infection in China. 3 Although the diseases have different clinical presentations,1, 4 the infectious cause, epidemiological features, fast transmission pattern, and insufficient preparedness of health authorities to address the outbreaks are similar. So far, mental health care for the patients and health professionals directly affected by the 2019-nCoV epidemic has been under-addressed, although the National Health Commission of China released the notification of basic principles for emergency psychological crisis interventions for the 2019-nCoV pneumonia on Jan 26, 2020. 5 This notification contained a reference to mental health problems and interventions that occurred during the 2003 SARS outbreak, and mentioned that mental health care should be provided for patients with 2019-nCoV pneumonitis, close contacts, suspected cases who are isolated at home, patients in fever clinics, families and friends of affected people, health professionals caring for infected patients, and the public who are in need. To date, epidemiological data on the mental health problems and psychiatric morbidity of those suspected or diagnosed with the 2019-nCoV and their treating health professionals have not been available; therefore how best to respond to challenges during the outbreak is unknown. The observations of mental health consequences and measures taken during the 2003 SARS outbreak could help inform health authorities and the public to provide mental health interventions to those who are in need. Patients with confirmed or suspected 2019-nCoV may experience fear of the consequences of infection with a potentially fatal new virus, and those in quarantine might experience boredom, loneliness, and anger. Furthermore, symptoms of the infection, such as fever, hypoxia, and cough, as well as adverse effects of treatment, such as insomnia caused by corticosteroids, could lead to worsening anxiety and mental distress. 2019-nCoV has been repeatedly described as a killer virus, for example on WeChat, which has perpetuated the sense of danger and uncertainty among health workers and the public. In the early phase of the SARS outbreak, a range of psychiatric morbidities, including persistent depression, anxiety, panic attacks, psychomotor excitement, psychotic symptoms, delirium, and even suicidality, were reported.6, 7 Mandatory contact tracing and 14 days quarantine, which form part of the public health responses to the 2019-nCoV pneumonia outbreak, could increase patients' anxiety and guilt about the effects of contagion, quarantine, and stigma on their families and friends. Health professionals, especially those working in hospitals caring for people with confirmed or suspected 2019-nCoV pneumonia, are vulnerable to both high risk of infection and mental health problems. They may also experience fear of contagion and spreading the virus to their families, friends, or colleagues. Health workers in a Beijing hospital who were quarantined, worked in high-risk clinical settings such as SARS units, or had family or friends who were infected with SARS, had substantially more post-traumatic stress symptoms than those without these experiences. 8 Health professionals who worked in SARS units and hospitals during the SARS outbreak also reported depression, anxiety, fear, and frustration.6, 9 Despite the common mental health problems and disorders found among patients and health workers in such settings, most health professionals working in isolation units and hospitals do not receive any training in providing mental health care. Timely mental health care needs to be developed urgently. Some methods used in the SARS outbreak could be helpful for the response to the 2019-nCoV outbreak. First, multidisciplinary mental health teams established by health authorities at regional and national levels (including psychiatrists, psychiatric nurses, clinical psychologists, and other mental health workers) should deliver mental health support to patients and health workers. Specialised psychiatric treatments and appropriate mental health services and facilities should be provided for patients with comorbid mental disorders. Second, clear communication with regular and accurate updates about the 2019-nCoV outbreak should be provided to both health workers and patients in order to address their sense of uncertainty and fear. Treatment plans, progress reports, and health status updates should be given to both patients and their families. Third, secure services should be set up to provide psychological counselling using electronic devices and applications (such as smartphones and WeChat) for affected patients, as well as their families and members of the public. Using safe communication channels between patients and families, such as smartphone communication and WeChat, should be encouraged to decrease isolation. Fourth, suspected and diagnosed patients with 2019-nCoV pneumonia as well as health professionals working in hospitals caring for infected patients should receive regular clinical screening for depression, anxiety, and suicidality by mental health workers. Timely psychiatric treatments should be provided for those presenting with more severe mental health problems. For most patients and health workers, emotional and behavioural responses are part of an adaptive response to extraordinary stress, and psychotherapy techniques such as those based on the stress-adaptation model might be helpful.7, 10 If psychotropic medications are used, such as those prescribed by psychiatrists for severe psychiatric comorbidities, 6 basic pharmacological treatment principles of ensuring minimum harm should be followed to reduce harmful effects of any interactions with 2019-nCoV and its treatments. In any biological disaster, themes of fear, uncertainty, and stigmatisation are common and may act as barriers to appropriate medical and mental health interventions. Based on experience from past serious novel pneumonia outbreaks globally and the psychosocial impact of viral epidemics, the development and implementation of mental health assessment, support, treatment, and services are crucial and pressing goals for the health response to the 2019-nCoV outbreak. © 2020 VW Pics/Science Photo Library 2020 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.
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                Author and article information

                Journal
                Brain Behav Immun
                Brain Behav Immun
                Brain, Behavior, and Immunity
                Published by Elsevier Inc.
                0889-1591
                1090-2139
                24 February 2021
                24 February 2021
                Affiliations
                [a ]Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
                [b ]Vita-Salute San Raffaele University, Milano, Italy
                [c ]Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
                [d ]Clinical Neuroimmunology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
                Author notes
                [* ]Corresponding author at: Istituto Scientifico Ospedale San Raffaele, Department of Clinical Neurosciences, San Raffaele Turro, Via Stamira d’Ancona 20, Milano, Italy
                [1]

                The COVID-19 BioB Outpatient Clinic Study group

                Article
                S0889-1591(21)00086-6
                10.1016/j.bbi.2021.02.021
                7903920
                33639239
                f36b8e5a-e515-49f9-a841-943718811aff
                © 2021 Published by Elsevier Inc.

                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
                : 23 December 2020
                : 28 January 2021
                : 22 February 2021
                Categories
                Full-length Article

                Neurosciences
                covid-19,depression,follow-up,mental health,psychiatry,inflammation
                Neurosciences
                covid-19, depression, follow-up, mental health, psychiatry, inflammation

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