COVID-19 and Risk for Mental Disorders Among Adults in Denmark.

Importance: Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking. Objective: To estimate the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections. Design, Setting, and Participants: This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021. Exposures: Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization. Main Outcomes and Measures: Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status. Results: A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean [SD] age, 41.18 [17.06] years), while 3 124 933 had negative test results (50.6% women; mean [SD] age, 49.36 [19.00] years), and 501 110 had no tests performed (54.6% men; mean [SD] age, 60.71 [19.78] years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 [95% CI, 1.17-1.31]) and negative (HRR, 1.42 [95% CI, 1.38-1.46]) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 [95% CI, 0.69-0.81]), whereas individuals 70 years or older had an increased risk (HRR, 1.25 [95% CI, 1.05-1.50]). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 [95% CI, 0.76-0.85]) and elevated risk in those 70 years or older (HRR, 1.57 [95% CI, 1.45-1.70]). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 [95% CI, 2.06-3.14]); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 [95% CI, 0.82-1.29]). Conclusion and Relevance: In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.

COVID-19 and the subsequent risk of mental disorders: A nationwide study of all SARS-CoV-2 PCR test results in Denmark

Importance Psychiatric outcomes after COVID-19 have been of high concern during the pandemic, however, studies on a nation-wide level are lacking. Objective To examine the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared to individuals not tested, individuals tested SARS-CoV-2 negative and those hospitalized for non-COVID infections. Design, setting and participants Nation-wide cohort study using Danish registries to identify all individuals alive, ≥18 years and resident in Denmark between January-March-2020 (N=4,152,792), excluding everyone with a previous history of a mental disorder (N=616,546). Exposures SARS-CoV-2 PCR testing (negative, positive, and never tested) and COVID-19 hospitalization. Main outcomes and measures Risk of new-onset mental disorders and redeemed psychotropic medication was estimated through survival analysis using a Cox proportional hazard model reporting hazard rate ratios (HRR) with 95% confidence intervals (CI) as measures of relative risk. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson-Comorbidity-Index, education-level, income, and job-status. Results A total of 526,749 individuals tested positive for SARS-CoV-2, while 3,124,933 tested negative and 501,110 had no tests performed. The risk of mental disorders was increased in individuals tested positive, respectively, negative for SARS-CoV-2 (HRR, 1.24;95%CI, 1.17-1.31, respectively, HRR, 1.42;95%CI, 1.38-1.46), compared to those never tested. Compared to individuals tested negative, the risk of new-onset mental disorders in SARS-CoV-2 positive individuals was lower in the 18-29yrs age-group (HRR, 0.75;95%CI, 0.69-0.81), whereas individuals >70-years had increased risk (HRR, 1.25;95%CI, 1.05-1.50). A similar pattern was seen regarding psychotropic medication use with a decreased risk in the 18-29 years age-group (HRR, 0.81;95%CI, 10.76-0.85) and elevated risk in those >70yrs (HRR, 1.57;95%CI, 1.45-1.70). The risk for new-onset mental disorders were substantially elevated in hospitalized COVID-19 patients compared to the general population (HRR, 2.52;95%CI, 2.34-2.72);however, no difference in risk was seen when compared to hospitalization for non-COVID respiratory infections (HRR, 1.03;95%CI, 0.82-1.29). Conclusion and relevance In this nation-wide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2 positive did not exceed the risk among individuals tested negative (except for those >70yrs). However, when hospitalized, COVID-19 patients had markedly increased risk compared to the general population, but comparable to those hospitalized for non-COVID infections.

Influence of vaccination on adverse health outcomes after SARS-CoV-2 infection among individuals with alcohol use disorder: a population-based study.

BACKGROUND AND AIMS: Alcohol use disorders (AUD) have not been included in the priority groups for early vaccine against SARS-CoV-2. We aimed to determine adverse outcomes after SARS-CoV-2 infection among individuals with AUD and how this is modified by vaccination. DESIGN, SETTING AND PARTICIPANTS: This was a registry-based cohort study carried out in Denmark, 27 February 2020 to 15 October 2021, comprising 2157 individuals with AUD and 237 541 without AUD who had had a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection during the study period. MEASUREMENTS: The association of AUD with the absolute and relative risk of hospitalization, intensive care and 60-day mortality after SARS-CoV-2 infection and of all-cause mortality throughout the follow-up period were measured. Potential interactions with SARS-CoV-2 vaccination, education and sex were explored in stratified analyses and tested by including interaction terms and using likelihood ratio tests. FINDINGS: Individuals with AUD had an increased absolute and relative risk of adverse outcomes, including hospitalization [incidence rate ratio (IRR) = 1.72, 95% confidence interval (CI) = 1.51-1.95], intensive care (IRR = 1.47, 95% CI = 1.07-2.02) and 60-day mortality [mortality rate ratio (MRR) = 2.35, 95% CI = 1.94-2.85] compared with SARS-CoV-2-positive individuals without AUD. Irrespective of AUD, highest risks of these adverse health outcomes were observed for individuals not vaccinated against SARS-CoV-2 infection, for individuals of low educational level and in males. However, for all-cause mortality throughout the follow-up period, SARS-CoV-2 infection showed a lower relative mortality risk increase, whereas being unvaccinated showed a higher relative mortality risk increase, in individuals with AUD than in the reference population without AUD (P of interaction tests < 0.0001). CONCLUSIONS: Both alcohol use disorder and being unvaccinated for SARS-CoV-2 appear to be independent risk factors for adverse health outcomes following SARS-CoV-2 infection.

Association between SARS-CoV-2 infection and self-harm: Danish nationwide register-based cohort study.

BACKGROUND: Case studies have linked SARS-CoV-2 infection to suicidal behaviour. However, conclusive evidence is lacking. AIMS: To examine whether a history of SARS-CoV-2 infection or SARS-CoV-2-related hospital admission was associated with self-harm in the general population and in high-risk groups. METHOD: A cohort design was applied to nationwide data on all people aged ≥15 years and living in Denmark between 27 February 2020 and 15 October 2021. Exposure was identified as having had a positive SARS-CoV-2 PCR test, and further assessed as SARS-CoV-2-related hospital admission. Rates of probable self-harm were examined using adjusted incidence rate ratios (aIRRs). The following subgroups were identified: (a) lower educational level, (b) chronic medical conditions, (c) disability pension, (d) mental disorders, (e) substance use disorders, and history of (f) homelessness and (g) imprisonment. RESULTS: Among 4 412 248 included individuals, 260 663 (5.9%) had tested positive for SARS-CoV-2. Out of 5453 individuals presenting with self-harm, 131 (2.4%) had been infected. Individuals with a history of a positive SARS-CoV-2 test result had an aIRR for self-harm of 0.86 (95% CI 0.72-1.03) compared with those without. High rates were found after a SARS-CoV-2-related hospital admission (aIRR = 7.68; 95% CI 5.61-10.51) or a non-SARS-CoV-2-related admission (aIRR = 10.27; 95% CI 9.65-10.93) versus non-infected and not admitted. In sensitivity analyses with a more restrictive definition of self-harm, a positive PCR test was associated with lower rates of self-harm. CONCLUSIONS: Individuals with a PCR-confirmed SARS-CoV-2 infection did not have higher rates of self-harm than those without. Hospital admission in general, rather than being SARS-CoV-2 positive. seemed to be linked to elevated rates of self-harm.

How COVID-19 shaped mental health: from infection to pandemic effects.

The Coronavirus Disease 2019 (COVID-19) pandemic has threatened global mental health, both indirectly via disruptive societal changes and directly via neuropsychiatric sequelae after SARS-CoV-2 infection. Despite a small increase in self-reported mental health problems, this has (so far) not translated into objectively measurable increased rates of mental disorders, self-harm or suicide rates at the population level. This could suggest effective resilience and adaptation, but there is substantial heterogeneity among subgroups, and time-lag effects may also exist. With regard to COVID-19 itself, both acute and post-acute neuropsychiatric sequelae have become apparent, with high prevalence of fatigue, cognitive impairments and anxiety and depressive symptoms, even months after infection. To understand how COVID-19 continues to shape mental health in the longer term, fine-grained, well-controlled longitudinal data at the (neuro)biological, individual and societal levels remain essential. For future pandemics, policymakers and clinicians should prioritize mental health from the outset to identify and protect those at risk and promote long-term resilience.

Frequency of Neurological Diseases After COVID-19, Influenza A/B and Bacterial Pneumonia.

Introduction: COVID-19 might affect the incidence of specific neurological diseases, but it is unknown if this differs from the risk following other infections. Here, we characterized the frequency of neurodegenerative, cerebrovascular, and immune-mediated neurological diseases after COVID-19 compared to individuals without COVID-19 and those with other respiratory tract infections. Methods: This population-based cohort study utilized electronic health records covering ~50% of Denmark's population (n = 2,972,192). Between 02/2020 and 11/2021, we included individuals tested for COVID-19 or diagnosed with community-acquired bacterial pneumonia in hospital-based facilities. Additionally, we included individuals tested for influenza in the corresponding pre-pandemic period between 02/ 2018 and 11/2019. We stratified cohorts for in- and outpatient status, age, sex, and comorbidities. Results: In total, 919,731 individuals were tested for COVID-19, of whom 43,375 tested positive (35,362 outpatients, 8,013 inpatients). Compared to COVID-negative outpatients, COVID-19 positive outpatients had an increased RR of Alzheimer's disease (RR = 3.5; 95%CI: 2.2-5.5) and Parkinson's disease (RR = 2.6; 95%CI: 1.7-4.0), ischemic stroke (RR = 2.7; 95%CI: 2.3-3.2) and intracerebral hemorrhage (RR = 4.8; 95%CI: 1.8-12.9). However, when comparing to other respiratory tract infections, only the RR for ischemic stroke was increased among inpatients with COVID-19 when comparing to inpatients with influenza (RR = 1.7; 95%CI: 1.2-2.4) and only for those >80 years of age when comparing to inpatients with bacterial pneumonia (RR = 2.7; 95%CI: 1.2-6.2). Frequencies of multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome and narcolepsy did not differ after COVID-19, influenza and bacterial pneumonia. Conclusion: The risk of neurodegenerative and cerebrovascular, but not neuroimmune, disorders was increased among COVID-19 positive outpatients compared to COVID-negative outpatients. However, except for ischemic stroke, most neurological disorders were not more frequent after COVID-19 than after other respiratory infections.

Adverse SARS-CoV-2-associated outcomes among people experiencing social marginalisation and psychiatric vulnerability: A population-based cohort study among 4,4 million people.

Background: Knowledge of the adverse problems related to SARS-CoV-2 infection in marginalised and deprived groups may help to prioritise more preventive efforts in these groups. We examined adverse outcomes associated with SARS-CoV-2 infection among vulnerable segments of society. Methods: Using health and administrative registers, a population-based cohort study of 4.4 million Danes aged at least 15 years from 27 February 2020 to 15 October 2021 was performed. People with 1) low educational level, 2) homelessness, 3) imprisonment, 4) substance abuse, 5) supported psychiatric housing, 6) psychiatric admission, and 7) severe mental illness were main exposure groups. Chronic medical conditions were included for comparison. COVID-19-related outcomes were: 1) hospitalisation, 2) intensive care, 3) 60-day mortality, and 4) overall mortality. PCR-confirmed SARS-CoV-2 infection and PCR-testing were also studied. Poisson regression analysis was used to compute adjusted incidence and mortality rate ratios (IRRs, MRRs). Findings: Using health and administrative registers, we performed a population-based cohort study of 4,412,382 individuals (mean age 48 years; 51% females). In all, 257,450 (5·8%) individuals had a PCR-confirmed SARS-CoV-2 infection. After adjustment for age, calendar time, and sex, we found that especially people experiencing homelessness had high risk of hospitalisation (IRR 4·36, 95% CI, 3·09-6·14), intensive care (IRR 3·12, 95% CI 1·29-7·52), and death (MRR 8·17, 95% CI, 3·66-18·25) compared with people without such experiences, but increased risk was found for all studied groups. Furthermore, after full adjustment, including for status of vaccination against SARS-CoV-2 infection, individuals with experiences of homelessness and a PCR-confirmed SARS-CoV-2 infection had 41-times (95% CI, 24·84-68·44) higher risk of all-cause death during the study period compared with individuals without. Supported psychiatric housing was linked to almost 3-times higher risk of hospitalisation and 60-day mortality following SARS-CoV-2 infection compared with the general population with other living circumstances. Interpretation: Socially marginalised and psychiatrically vulnerable individuals had substantially elevated risks of adverse health outcomes following SARS-CoV-2 infection. The results highlight that pandemic preparedness should address inequalities in health, including infection prevention and vaccination of vulnerable groups. Funding: Novo Nordisk Foundation.

Vaccination against SARS-CoV-2 infection among vulnerable and marginalised population groups in Denmark: A nationwide population-based study.

Background: Social deprivation, psychiatric and medical disorders have been associated with increased risk of infection and severe COVID-19-related health problems. We aimed to study the rates of SARS-CoV-2 vaccination in these high-risk groups. Methods: Using health, vaccination, and administrative registers, we performed a population-based cohort study including all Danish residents aged at least 15 years, December 27, 2020, to October 15, 2021. Population groups were people experiencing: (1) homelessness, (2) imprisonment, (3) substance abuse, (4) severe mental illness, (5) supported psychiatric housing, (6) psychiatric admission, and (7) chronic medical condition. The outcome was vaccine uptake of two doses against SARS-CoV-2 infection. We calculated cumulative vaccine uptake and adjusted vaccination incidence rate ratios (IRRs) relative to the general population by sex and population group. Findings: The cohort included 4,935,344 individuals, of whom 4,277,380 (86·7%) received two doses of vaccine. Lower cumulative vaccine uptake was found for all socially deprived and psychiatrically vulnerable population groups compared with the general population. Lowest uptake was found for people below 65 years experiencing homelessness (54·6%, 95% confidence interval (CI) 53·4-55·8, p<0·0001). After adjustment for age and calendar time, homelessness was associated with markedly lower rates of vaccine uptake (IRR 0·5, 95% CI 0·5-0·6 in males and 0·4, 0·4-0·5 in females) with similar results for imprisonment. Lower vaccine uptake was also found for most of the psychiatric groups with the lower IRR for substance abuse (IRR 0·7, 0·7-0·7 in males and 0·8, 0·8-0·8 in females). Individuals with new-onset severe mental illness and, especially, those in supported psychiatric housing and with chronic medical conditions had the highest vaccine uptake among the studied population groups. Interpretation: Especially, socially deprived population groups, but also individuals with psychiatric vulnerability need higher priority in the implementation of the vaccination strategy to increase equity in immunization uptake. Funding: Novo Nordisk Foundation.

Neuropsychiatric and Cognitive Outcomes in Patients 6 Months After COVID-19 Requiring Hospitalization Compared With Matched Control Patients Hospitalized for Non-COVID-19 Illness.

Importance: Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking. Objective: To investigate cognitive impairment, neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness. Design, Setting, and Participants: This prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset. Exposures: Hospitalization for COVID-19. Main Outcomes and Measures: Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing. Results: A total of 85 COVID-19 survivors (36 [42%] women; mean [SD] age 56.8 [14] years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 [44%] women, mean age 59.4 years [SD, 13]) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among COVID-19 survivors (26.7; 95% CI, 26.2-27.1) than control patients (27.5; 95% CI, 27.0-27.9). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing. Conclusions and Relevance: In this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.

Biological and Psychological Factors Determining Neuropsychiatric Outcomes in COVID-19.

PURPOSE OF REVIEW: We present biological and psychological factors implicated in psychiatric manifestations of SARS-CoV-2, as well as its neuroinvasive capability and immune pathophysiology. RECENT FINDINGS: Preexisting mental illness leads to worse clinical outcomes in COVID-19. The presence of the virus was reported in the cerebrospinal fluid (CSF) and brain tissue post-mortem. Most common psychiatric manifestations include delirium, mood disorders, anxiety disorders, and posttraumatic stress disorder. "Long-COVID" non-syndromal presentations include "brain-fogginess," autonomic instability, fatigue, and insomnia. SARS-CoV-2 infection can trigger prior vulnerabilities based on the priming of microglia and other cells, induced or perpetuated by aging and mental and physical illnesses. COVID-19 could further induce priming of neuroimmunological substrates leading to exacerbated immune response and autoimmunity targeting structures in the central nervous system (CNS), in response to minor immune activating environmental exposures, including stress, minor infections, allergens, pollutants, and traumatic brain injury.

Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis.

BACKGROUND: Mental disorders might be a risk factor for severe COVID-19. We aimed to assess the specific risks of COVID-19-related mortality, hospitalisation, and intensive care unit (ICU) admission associated with any pre-existing mental disorder, and specific diagnostic categories of mental disorders, and exposure to psychopharmacological drug classes. METHODS: In this systematic review and meta-analysis, we searched Web of Science, Cochrane, PubMed, and PsycINFO databases between Jan 1, 2020, and March 5, 2021, for original studies reporting data on COVID-19 outcomes in patients with psychiatric disorders compared with controls. We excluded studies with overlapping samples, studies that were not peer-reviewed, and studies written in languages other than English, Danish, Dutch, French, German, Italian, and Portuguese. We modelled random-effects meta-analyses to estimate crude odds ratios (OR) for mortality after SARS-CoV-2 infection as the primary outcome, and hospitalisation and ICU admission as secondary outcomes. We calculated adjusted ORs for available data. Heterogeneity was assessed using the I2 statistic, and publication bias was tested with Egger regression and visual inspection of funnel plots. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle Ottawa Scale to assess study quality. We also did subgroup analyses and meta-regressions to assess the effects of baseline COVID-19 treatment setting, patient age, country, pandemic phase, quality assessment score, sample sizes, and adjustment for confounders. This study is registered with PROSPERO, CRD42021233984. FINDINGS: 841 studies were identified by the systematic search, of which 33 studies were included in the systematic review and 23 studies in the meta-analysis, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. The sample included 130 807 females (8·9% of the whole sample) and 130 373 males (8·8%). Nine studies provided data on patient race and ethnicity, and 22 studies were rated as high quality. The presence of any mental disorder was associated with an increased risk of COVID-19 mortality (OR 2·00 [95% CI 1·58-2·54]; I2=92·66%). This association was also observed for psychotic disorders (2·05 [1·37-3·06]; I2=80·81%), mood disorders (1·99 [1·46-2·71]; I2=68·32%), substance use disorders (1·76 [1·27-2·44]; I2=47·90%), and intellectual disabilities and developmental disorders (1·73 [1·29-2·31]; I2=90·15%) but not for anxiety disorders (1·07 [0·73-1·56]; I2=11·05%). COVID-19 mortality was associated with exposure to antipsychotics (3·71 [1·74-7·91]; I2=90·31%), anxiolytics (2·58 [1·22-5·44]; I2=96·42%), and antidepressants (2·23 [1·06-4·71]; I2=95·45%). For psychotic disorders, mood disorders, antipsychotics, and anxiolytics, the association remained significant after adjustment for age, sex, and other confounders. Mental disorders were associated with increased risk of hospitalisation (2·24 [1·70-2·94]; I2=88·80%). No significant associations with mortality were identified for ICU admission. Subgroup analyses and meta-regressions showed significant associations of baseline COVID-19 treatment setting (p=0·013) and country (p<0·0001) with mortality. No significant associations with mortality were identified for other covariates. No evidence of publication bias was found. GRADE assessment indicated high certainty for crude mortality and hospitalisation, and moderate certainty for crude ICU admission. INTERPRETATION: Pre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiolytics were associated with COVID-19 mortality in both crude and adjusted models. Although further research is required to determine the underlying mechanisms, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in at-risk patient groups identified in this study. FUNDING: None. TRANSLATIONS: For the Italian, French and Portuguese translations of the abstract see Supplementary Materials section.

A large-scale investigation into the role of classical HLA loci in multiple types of severe infections, with a focus on overlaps with autoimmune and mental disorders.

BACKGROUND: Infections are a major disease burden worldwide. While they are caused by external pathogens, host genetics also plays a part in susceptibility to infections. Past studies have reported diverse associations between human leukocyte antigen (HLA) alleles and infections, but many were limited by small sample sizes and/or focused on only one infection. METHODS: We performed an immunogenetic association study examining 13 categories of severe infection (bacterial, viral, central nervous system, gastrointestinal, genital, hepatitis, otitis, pregnancy-related, respiratory, sepsis, skin infection, urological and other infections), as well as a phenotype for having any infection, and seven classical HLA loci (HLA-A, B, C, DPB1, DQA1, DQB1 and DRB1). Additionally, we examined associations between infections and specific alleles highlighted in our previous studies of psychiatric disorders and autoimmune disease, as these conditions are known to be linked to infections. RESULTS: Associations between HLA loci and infections were generally not strong. Highlighted associations included associations between DQB1*0302 and DQB1*0604 and viral infections (P = 0.002835 and P = 0.014332, respectively), DQB1*0503 and sepsis (P = 0.006053), and DQA1*0301 with "other" infections (a category which includes infections not included in our main categories e.g. protozoan infections) (P = 0.000369). Some HLA alleles implicated in autoimmune diseases showed association with susceptibility to infections, but the latter associations were generally weaker, or with opposite trends (in the case of HLA-C alleles, but not with alleles of HLA class II genes). HLA alleles associated with psychiatric disorders did not show association with susceptibility to infections. CONCLUSIONS: Our results suggest that classical HLA alleles do not play a large role in the etiology of severe infections. The discordant association trends with autoimmune disease for some alleles could contribute to mechanistic theories of disease etiology.

Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up.

OBJECTIVE: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. METHODS: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. RESULTS: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. CONCLUSION: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

Thirty-Day Mortality and Morbidity in COVID-19 Positive vs. COVID-19 Negative Individuals and vs. Individuals Tested for Influenza A/B: A Population-Based Study.

Background: As of October 2020, COVID-19 has caused 1,000,000 deaths worldwide. However, large-scale studies of COVID-19 mortality and new-onset comorbidity compared to individuals tested negative for COVID-19 and individuals tested for influenza A/B are lacking. We investigated COVID-19 30-day mortality and new-onset comorbidity compared to individuals with negative COVID-19 test results and individuals tested for influenza A/B. Methods and findings: This population-based cohort study utilized electronic health records covering roughly half (n = 2,647,229) of Denmark's population, with nationwide linkage of microbiology test results and death records. All individuals ≥18 years tested for COVID-19 and individuals tested for influenza A/B were followed from 11/2017 to 06/2020. Main outcome was 30-day mortality after a test for either COVID-19 or influenza. Secondary outcomes were major comorbidity diagnoses 30-days after the test for either COVID-19 or influenza A/B. In total, 224,639 individuals were tested for COVID-19. To enhance comparability, we stratified the population for in- and outpatient status at the time of testing. Among inpatients positive for COVID-19, 356 of 1,657 (21%) died within 30 days, which was a 3.0 to 3.1-fold increased 30-day mortality rate, when compared to influenza and COVID-19-negative inpatients (all p < 0.001). For outpatients, 128 of 6,263 (2%) COVID-19-positive patients died within 30 days, which was a 5.5 to 6.9-fold increased mortality rate compared to individuals tested negative for COVID-19 or individuals tested positive or negative for influenza, respectively (all p < 0.001). Compared to hospitalized patients with influenza A/B, new-onset ischemic stroke, diabetes and nephropathy occurred more frequently in inpatients with COVID-19 (all p < 0.05). Conclusions: In this population-based study comparing COVID-19 positive with COVID-19 negative individuals and individuals tested for influenza, COVID-19 was associated with increased rates of major systemic and vascular comorbidity and substantially higher mortality. Results should be interpreted with caution because of differences in test strategies for COVID-19 and influenza, use of aggregated data, the limited 30-day follow-up and the possibility for changing mortality rates as the pandemic unfolds. However, the true COVID-19 mortality may even be higher than the stated 3.0 to 5.5-fold increase, owing to more extensive testing for COVID-19.