key: cord-0723794-iq5bn820 authors: Mendez, R.; Balanza-Martinez, V.; Luperdi, S. C.; Estrada, I.; Latorre, A.; Gonzalez-Jimenez, P.; Feced, L.; Bouzas, L.; Yepez, K.; Ferrando, A.; Hervas, D.; Zaldivar, E.; Reyes, S.; Berk, M.; Menendez, R. title: Short-term Neuropsychiatric Outcomes and Quality of Life in COVID-19 Survivors date: 2020-09-23 journal: nan DOI: 10.1101/2020.09.23.20190090 sha: e3b70d084049ca4d97db1b990382250b64889674 doc_id: 723794 cord_uid: iq5bn820 Background: The general medical impacts of coronavirus (COVID-19) are increasingly appreciated. However, its impact on neurocognitive, psychiatric health and quality of life (QoL) in survivors after the acute phase is poorly understood. We aimed to evaluate neurocognitive function, psychiatric symptoms, and QoL in COVID-19 survivors shortly after hospital discharge. Methods: This was a cross-sectional analysis of a prospective study of hospitalized COVID-19 survivors followed-up for 2 months after discharge. A battery of standardized instruments evaluating neurocognitive function, psychiatric morbidity, and QoL (mental and physical components) was administered by telephone. Findings: Of the 229 screened patients, 179 were included in the final analysis. Among survivors, the prevalence of moderately impaired immediate verbal memory and learning was 38%, delayed verbal memory (11.8%), verbal fluency (34.6%), and working memory (executive function) (6.1%), respectively. Moreover, 58.7% of patients had neurocognitive impairment in at least one function. Rates of positive screening for anxiety were 29.6%, depression (26.8%), and post-traumatic stress disorder (25.1%) respectively. In addition, 39.1% of the patients had psychiatric morbidity. Low QoL for physical and mental components was detected in 44.1% and 39.1% of patients, respectively. Delirium and stress-related symptoms increased approximately 4-fold the odds of developing neurocognitive impairment. Female gender and neurocognitive impairment diagnosis were related with an increase of 2.5 and 4.56-fold odds respectively of psychiatric morbidity. Interpretation: Hospitalized COVID-19 survivors showed a high prevalence of neurocognitive impairment, psychiatric morbidity, and poor QoL in the short-term. It is uncertain if these impacts persist over the long-term. Keywords: COVID-19; sequelae; neurocognitive; psychiatric morbidity; quality of life. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09. 23.20190090 doi: medRxiv preprint The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019 (1) . As of September 22, SARS-CoV-2 caused more than 31 million cases of coronavirus disease and over 965.000 deaths worldwide (2) . Efforts by the international community are focusing on decreasing the virus transmission as well as reducing its mortality. Despite the considerable mortality rate, the vast majority of patients survive COVID-19, however potential systemic sequelae are poorly understood and may be an additional global public health issue (3) . Pulmonary fibrosis, cardiovascular damage, and neurological impairment are among the potential sequelae of COVID-19 in survivors. It is known that many human coronaviruses display neurotropism, such as HCoV-OC43, SARS-CoV-1, and the Middle East respiratory syndrome CoV (MERS-CoV) (4) . Psychiatric and neurological presentations have been found in the acute and post-illness stage in other severe coronavirus infections (5) . Nevertheless, most of the studies were of either low or medium quality and focused on the acute phase of infection (5) . During hospitalization more than a half of COVID-19 patients have neurological symptoms, and their persistence after the acute phase is currently under study (6) (7) (8) . The most frequently observed neurological symptoms are headache, dizziness, fatigue, anorexia, ageusia, and anosmia (9) . Of note, neurocognitive deficits in the post-acute stage of COVID-19 and other coronavirus infections are insufficiently described (10) . Only preliminary data support the neurological and neuropsychiatric impact in COVID-19 patients. In a national surveillance study with voluntary case notification, Varatharaj et al reported that 31% of patients had an altered mental status including neuropsychiatric and neurocognitive symptoms in the acute phase (11) . To the authors' knowledge, there are no previous studies in COVID-19 simultaneously evaluating . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 6 neurocognitive function, psychiatric symptoms (such as stress-related symptoms, including depression, anxiety, and post-traumatic stress disorder [PTSD] ), and quality of life (QoL) following the acute phase in survivors. We hypothesized that COVID-19 survivors may present with persistent impaired cognition, psychiatric symptoms, and poorer QoL. Severity at admission, hypoxemia, systemic inflammation, and respiratory support during hospitalization may be associated with neuropsychiatric and QoL impairment in COVID-19. We thus conducted a cross-sectional cohort study in COVID-19 survivors post hospitalization to assess the neuropsychiatric and QoL consequences 2 months after hospital discharge. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. We conducted a cross-sectional analysis of a prospective cohort study in a large tertiary care hospital in Valencia, Spain. All hospitalized patients with COVID-19 were diagnosed with reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swab or sputum samples. Exclusion criteria included patients aged ≥ 85 or <18 years, non-Spanish speaking subjects, nursing-home residents, pre-existing dementia, pre-existing or cognitive decline under evaluation, previous brain injury with cognitive sequelae, current alcohol/substance use disorder (except for nicotine), and previously diagnosed major psychiatric disorders. All screened patients required hospitalization between March 8 and April 25 2020 in the Department of Pneumology and/or the Intensive Care Unit (ICU). Survivors were referred to the COVID-19 outpatient clinic in the Pneumology Department for clinical control where they were invited to participate in the study. All patients provided written informed consent to participate in the study. The Biomedical Research Ethics Committee of La Fe University and Polytechnic Hospital reviewed and approved the study (2020-280-1). The hospital discharge dates were between March 23 to July 7 and outpatient clinic visits were from May 18 to July 24. All recruited patients were contacted by telephone 2 (±1) months from the date of hospital discharge. A battery of standardized instruments evaluating neurocognitive function, psychiatric morbidity, and QoL was administered by telephone (eTable 1). The neuropsychiatric evaluation included immediate verbal memory and learning, delayed verbal memory, verbal fluency, and working memory (executive function) for the . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 8 neurocognitive domain; anxiety, depression, and PTSD were evaluated for the psychiatric domain (stress-related symptoms). The telephone battery was designed by two psychiatrists experienced in neurocognition (12) . An independent researcher, blind to clinical data and the study hypothesis, conducted pilot interviews under monitoring of her supervisors before enrolment. The duration of the interview was approximately 20 minutes. Three telephone contact attempts were made with the patients at different times before desisting. The data obtained from the interview were attached to the database with clinical data collected by an independent researcher. Relevant variables such as demographics, comorbidities, chronic treatments, laboratory parameters, and radiographic data were recorded. Initial severity was . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. During follow-up visits, a checklist of enduring symptoms was administered. All the symptoms were dichotomized as present or absent. This checklist included: fatigue, dyspnoea (if grade ≥ 2 on the MRC scale), cough, sputum production, chest pain, dysgeusia/ageusia, anosmia, headache, arthralgia, myalgia, paraesthesia, hypoesthesia, tremors, and memory complaints. Blood extraction for routine analysis and future studies was obtained. Vital signs and anthropometric data were also recorded. Neurocognitive domain impairment was pre-defined as moderate/severe impairment of any of the four neuropsychological tests. In the same way, psychiatric morbidity was pre-defined as positive screening in any of the three questionnaires assessing stress-related symptoms. This definition was used in previous studies of acute lung injury and neurocognitive evaluation (13) . The reference values and cut-off points for the QoL questionnaire and for each variable in the neurocognitive and psychiatric domains are detailed in the Supplemental File. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 1 1 A total of 229 patients discharged after COVID-19 hospitalization were followed in the outpatient clinic of the Pneumology Department. Of those, 197 were contacted by telephone, and 179 completed the test battery ( Figure 1 ). The final data analysis was performed in this cohort. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 1 3 The eTable 4 shows clinical data regarding neurocognitive impairment and psychiatric morbidity. Logistic regression models were performed to identify potential predictors for neurocognitive impairment and a positive screening for psychiatric morbidity ( Table 2) The PCS and MCS scores for QoL appear on Figure 3A . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In the acute phase, several studies reported neurological problems like stroke, encephalitis, or delirium (6, 24) . In a small study of COVID-19, one third of ICU survivors were found to have a dysexecutive syndrome (25) . In this regard, follow-up studies in other coronaviruses outbreaks in the post-acute stage may be informative. In a . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 23, 2020. (17) . In our study, delirium and having concurrent stress-related symptoms were linked to the odds of developing neurocognitive impairment. Delirium is a recognized risk factor for cognitive decline and reveals acute neurological damage that can persist over time (14, 15, 19) . Furthermore, psychiatric disorders with coexisting stress-related symptoms such as PTSD and depression are associated with neurocognitive impairment (26) . Screening for delirium and psychiatric morbidity may be useful to identify vulnerable subjects. No other convincing associations were found in the analysis, such as severity, levels of systemic inflammation, thrombosis related biomarkers, metabolic disorders, respiratory support, or oxygenation. There was also no association with age, although it should be noted that the neurocognitive tests were age-adjusted. Additional factors or mechanisms not explored in this study may further explain neurocognitive decline, such as neuroinvasion of SARS-CoV-2, endothelial injury, blood brain barrier disruption, or neuroinflammation (27) . In ICU survivors, similar rates of stress-related symptoms have been identified 3 and 12 months after discharge compared to our much less severe cohort (28, 29) . In other coronavirus infections substantial rates of persistent depressed mood and anxiety have been reported (5) . Recently, a study of COVID-19 survivors analyzed the presence of PTSD, depression, anxiety, obsessive-compulsive, and insomnia symptomatology (30) . The authors reported very similar frequencies to those found in this study and . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 1 6 showed that the female gender along with previous psychiatric diagnoses, but not systemic inflammation were associated with a higher prevalence of psychiatric symptoms. Indeed, women are two to three times more at risk to develop stress-related disorders (31) . However, neurocognition and clinical data such as comorbidities, severity, or clinical outcomes (ICU admission, mechanical ventilation, delirium) were not characterized in that study. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 1 7 with survivors of other acute diseases since most studies have focused on ICU survivors. Study strengths not previously mentioned include the methodologically rigorous assessment of the outcomes. In previous studies, cognitive deficits were based on selfreport (5) . Therefore, no study has used neuropsychological tests to objectively establish cognitive deficits. All the selected tests were previously validated in the Spanish general population and included cut-off points for cognitive impairment or psychiatric screening. Moreover, confounding variables such as age and educational level were controlled in the case of cognitive performance. The study was performed in a wellcharacterized cohort and the high percentage of eligible patients who completed the assessment adds internal validation. Finally, very elderly patients and those with previous cognitive impairment or major psychiatric disorders were excluded. Further research on these more vulnerable patients are needed on the post-acute phase and in the long-term. In summary, our findings reveal a high prevalence of neurocognitive impairment, psychiatric comorbidity, and QoL in COVID-19 survivors after the acute phase, even in non-critically ill patients. These data have important clinical consequences and hence implications for health policies aimed to mitigate a wave of mental ill health following the current pandemic. Public health prevention, early detection, neurocognitive remediation, and treatment of psychiatric symptoms should be prioritized in COVID-19 survivors which may ultimately lead to an improvement in QoL and daily functioning. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 1 8 This study was approved by the Ethics Committee of the Hospital Universitario y Politécnico La Fe (2020-280-1). All authors have accepted the publication of the manuscript. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Dr There was non-specific funding for this study. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Conceptualization . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. We are indebted to all patients and colleagues for their cooperation and assistance in this study. Always in our memory those who are no longer among us due to this pandemic. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint RB, Bernard GR, Dittus RS, Ely EW. Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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(%) Nadir lymphocyte count, cells/mL, median %) 18 (10.1) O2 Venturi mask, no. (%) 38 (21.2) Median length of MV, days . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09. 23 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. MV denotes mechanical ventilation, OR odds ratio, SpO2/FiO2 peripheral blood oxygen saturation/fraction of inspired oxygen.. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted September 23, 2020. . https://doi.org/10.1101/2020.09.23.20190090 doi: medRxiv preprint 3 1 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted September 23, 2020.