COVID-19 hospitalization outcomes in adults by HIV status; a nation-wide register-based study.

OBJECTIVES: To assess the outcome of patients hospitalized with COVID-19 by HIV status and risk factors for severe COVID-19 in people living with HIV (PWH), we performed a nationwide cohort study using register data. METHODS: All people aged ≥18 years hospitalized with a primary COVID-19 diagnosis (U07.1 or U07.2) in Sweden between February 2020 and October 2021 were included. The primary outcome was severe COVID-19 [intensive care unit (ICU) admission or 90-day mortality]. Secondary outcomes were days in hospital and ICU, complications in hospital, and risk factors for severe COVID-19 in PWH. Regression analyses were performed to assess severe COVID-19 by HIV status and risk factors. RESULTS: Data from 64 815 hospitalized patients were collected, of whom 121 were PWH (0.18%). PWH were younger (p < 0.001), and larger proportions were men (p = 0.014) and migrants (p < 0.001). Almost all PWH had undetectable HIV-RNA (93%) and high CD4 T-cell counts (median = 560 cells/µL, interquartile range: 376-780). In an unadjusted model, PWH had statistically significant lower odds of severe COVID-19 compared with patients without HIV [odds ratio (OR) = 0.6, 95% confidence interval (CI): 0.34-0.94], but there was no significant difference after adjusting for age and comorbidity (adjusted OR = 0.7, 95% CI: 0.43-1.26). A statistically significant lower proportion of PWH (8%, 95% CI: 5-15%) died within 90 days compared with those without HIV (16%, 95% CI: 15-16%, p = 0.024). There was no statistically significant difference in days in hospital and complications during the hospital stay between PWH and patients without HIV. CONCLUSIONS: In this nationwide study including well-treated PWH, HIV was not a risk factor in hospitalized patients for developing severe COVID-19.

A novel precision-serology assay for SARS-CoV-2 infection based on linear B-cell epitopes of Spike protein.

Introduction: The COVID-19 pandemic illustrates the need for serology diagnostics with improved accuracy. While conventional serology based on recognition of entire proteins or subunits thereof has made significant contribution to the antibody assessment space, it often suffers from sub-optimal specificity. Epitope-based, high-precision, serology assays hold potential to capture the high specificity and diversity of the immune system, hence circumventing the cross-reactivity with closely related microbial antigens. Methods: We herein report mapping of linear IgG and IgA antibody epitopes of the SARS-CoV-2 Spike (S) protein in samples from SARS-CoV-2 exposed individuals along with certified SARS-CoV-2 verification plasma samples using peptide arrays. Results: We identified 21 distinct linear epitopes. Importantly, we showed that pre-pandemic serum samples contain IgG antibodies reacting to the majority of protein S epitopes, most likely as a result of prior infection with seasonal coronaviruses. Only 4 of the identified SARS-CoV-2 protein S linear epitopes were specific for SARS-CoV-2 infection. These epitopes are located at positions 278-298 and 550-586, just proximal and distal to the RBD, as well as at position 1134-1156 in the HR2 subdomain and at 1248-1271 in the C-terminal subdomain of protein S. To substantiate the applicability of our findings, we tested three of the high-accuracy protein S epitopes in a Luminex assay, using a certified validation plasma sample set from SARS-CoV-2 infected individuals. The Luminex results were well aligned with the peptide array results, and correlated very well with in-house and commercial immune assays for RBD, S1 and S1/S2 domains of protein S. Conclusion: We present a comprehensive mapping of linear B-cell epitopes of SARS-CoV-2 protein S, that identifies peptides suitable for a precision serology assay devoid of cross-reactivity. These results have implications for development of highly specific serology test for exposure to SARS-CoV-2 and other members of the coronaviridae family, as well as for rapid development of serology tests for future emerging pandemic threats.

Cohort profile: a longitudinal study of HIV infection in the central nervous system with focus on cerebrospinal fluid - the Gothenburg HIV CSF Study Cohort.

PURPOSE: In order to enable long-term follow-up of the natural course of HIV infection in the central nervous system, a longitudinal cohort study with repeated cerebrospinal fluid (CSF) analyses at intervals over time was initiated in 1985. When antiretrovirals against HIV were introduced in the late 1980s, short-term and long-term effects of various antiretroviral treatment (ART) regimens were added to the study. PARTICIPANTS: All adult people living with HIV (PLWH) who were diagnosed at or referred to the Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden were asked to participate in the Gothenburg HIV CSF Study Cohort. PLWH with neurological symptoms or other clinical symptoms of HIV, as well as those with no symptoms of HIV infection, were included. Most participants were asymptomatic, which distinguishes this cohort from most other international HIV CSF studies. In addition, HIV-negative controls were recruited. These included people on HIV pre-exposure prophylaxis who served as lifestyle-matched controls to HIV-infected men who have sex with men. Since lumbar puncture (LP) is an invasive procedure, some PLHW only consented to participate in one examination. Furthermore, at the beginning of the study, several participants were lost to follow-up having died from AIDS. Of 662 PLWH where an initial LP was done, 415 agreed to continue with follow-up. Among the 415, 56 only gave permission to be followed with LP for less than 1 year, mainly to analyse the short-term effect of ART. The remaining 359 PLWH were followed up with repeated LP for periods ranging from >1 to 30 years. This group was defined as the 'longitudinal cohort'. So far, on 7 April 2022, 2650 LP and samplings of paired CSF/blood had been performed, providing a unique biobank. FINDINGS TO DATE: A general finding during the 37-year study period was that HIV infection in the central nervous system, as mirrored by CSF findings, appears early in the infectious course of the disease and progresses slowly in the vast majority of untreated PLWH. Combination ART has been highly effective in reducing CSF viral counts, inflammation and markers of neural damage. Minor CSF signs of long-term sequels or residual inflammatory activity and CSF escape (viral CSF blips) have been observed during follow-up. The future course of these changes and their clinical impact require further studies. FUTURE PLANS: PLWH today have a life expectancy close to that of non-infected people. Therefore, our cohort provides a unique opportunity to study the long-term effects of HIV infection in the central nervous system and the impact of ART and is an ongoing study.

Association between SARS-CoV-2 vaccination and healthcare contacts for menstrual disturbance and bleeding in women before and after menopause: nationwide, register based cohort study.

OBJECTIVES: To evaluate the risks of any menstrual disturbance and bleeding following SARS-CoV-2 vaccination in women who are premenopausal or postmenopausal. DESIGN: A nationwide, register based cohort study. SETTING: All inpatient and specialised outpatient care in Sweden from 27 December 2020 to 28 February 2022. A subset covering primary care for 40% of the Swedish female population was also included. PARTICIPANTS: 2 946 448 Swedish women aged 12-74 years were included. Pregnant women, women living in nursing homes, and women with history of any menstruation or bleeding disorders, breast cancer, cancer of female genital organs, or who underwent a hysterectomy between 1 January 2015 and 26 December 2020 were excluded. INTERVENTIONS: SARS-CoV-2 vaccination, by vaccine product (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 (AZD1222)) and dose (unvaccinated and first, second, and third dose) over two time windows (one to seven days, considered the control period, and 8-90 days). MAIN OUTCOME MEASURES: Healthcare contact (admission to hospital or visit) for menstrual disturbance or bleeding before or after menopause (diagnosed with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes N91, N92, N93, N95). RESULTS: 2 580 007 (87.6%) of 2 946 448 women received at least one SARS-CoV-2 vaccination and 1 652 472 (64.0%) 2 580 007 of vaccinated women received three doses before the end of follow-up. The highest risks for bleeding in women who were postmenopausal were observed after the third dose, in the one to seven days risk window (hazard ratio 1.28 (95% confidence interval 1.01 to 1.62)) and in the 8-90 days risk window (1.25 (1.04 to 1.50)). The impact of adjustment for covariates was modest. Risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with BNT162b2 and mRNA-1273 after the third dose, but the association with ChAdOx1 nCoV-19 was less clear. For menstrual disturbance or bleeding in women who were premenopausal, adjustment for covariates almost completely removed the weak associations noted in the crude analyses. CONCLUSIONS: Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal. These findings do not provide substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.

Plasmablasts in previously immunologically naïve COVID-19 patients express markers indicating mucosal homing and secrete antibodies cross-reacting with SARS-CoV-2 variants and other beta-coronaviruses.

Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. The phenotype and specificity of plasmablasts can reveal information about early B cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1 and IgM, and that most express CCR10 and integrin ß1, only some integrin ß7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the Spike (S) and Nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, but that that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in serum of COVID-19 patients.

A comprehensive characterisation of patients diagnosed with post-COVID-19 condition in Sweden 16 months after the introduction of the ICD-10 diagnosis code (U09.9): a population-based cohort study.

BACKGROUND: The objective of this study was to provide a comprehensive characterisation of patients diagnosed with post-COVID-19 condition (PCC) during the first 16 months of usage of the International Classification of Diseases revision 10 (ICD-10) diagnosis code U09.9 in Sweden. METHODS: We used data from national registers and primary healthcare databases for all adult inhabitants of the two largest regions in Sweden, comprising 4.1 million inhabitants (approximately 40% of the Swedish population). We present the cumulative incidence and incidence rate of PCC overall and among subgroups and describe COVID-19 patients with or without PCC regarding sociodemographic characteristics, comorbidities, subsequent diseases, COVID-19 severity, and virus variants. FINDINGS: Of all registered COVID-19 cases available for PCC diagnosis (n=506,107), 2.0% (n=10,196) had been diagnosed with PCC using ICD-10 code U09.9 as of 15 February 2022 in the two largest regions in Sweden. The cumulative incidence was higher among women compared to men (2.3% vs 1.6%, p<0.001). The majority of PCC cases (n=7,162, 70.2%) had not been hospitalised for COVID-19. This group was more commonly female (69.9% vs 52.9%, p<0.001), had a tertiary education (51.0% vs 44.1%, p<0.001), and was older (median age difference 5.7 years, p<0.001) compared to non-hospitalised COVID-19 patients without PCC. INTERPRETATION: This characterisation furthers the understanding of patients diagnosed with PCC and could support policymakers with appropriate societal and healthcare resource allocation.

Longitudinal single-cell analysis of SARS-CoV-2-reactive B cells uncovers persistence of early-formed, antigen specific clones.

Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from severe COVID-19 patients every third to seventh day during hospitalization and every third month after recovery. We profiled the antigen-specific immune cell dynamics by combining single cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-Seq, B cell receptor (BCR)-Seq with oligo-tagged antigen baits. While the proportion of Spike Receptor Binding Domain-specific memory B cells (MBC) increased from 3 months after infection, the other Spike- and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen specific cells, which was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to one year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen specific B cell responses in longitudinally sampled COVID-19 infected patients.

COVID-19 is associated with bystander polyclonal autoreactive B cell activation as reflected by a broad autoantibody production, but none is linked to disease severity.

Coronavirus disease 2019 (COVID-19) is associated with autoimmune features and autoantibody production in a small subset of the population. Pre-existing neutralizing antitype I interferons (IFNs) autoantibodies are related to the severity of COVID-19. Plasma levels of IgG and IgM against 12 viral antigens and 103 self-antigens were evaluated using an antibody protein array in patients with severe/critical or mild/moderate COVID-19 disease and uninfected controls. Patients exhibited increased IgGs against Severe acute respiratory syndrome coronavirus-2 proteins compared to controls, but no difference was observed in the two patient groups. 78% autoreactive IgGs and 93% autoreactive IgMs were increased in patients versus controls. There was no difference in the plasma levels of anti-type I IFN autoantibodies or neutralizing anti-type I IFN activity of plasma samples from the two patient groups. Increased anti-type I IFN IgGs were correlated with higher lymphocyte accounts, suggesting a role of nonpathogenic autoantibodies. Notably, among the 115 antibodies tested, only plasma levels of IgGs against human coronavirus (HCOV)-229E and HCOV-NL63 spike proteins were associated with mild disease outcome. COVID-19 was associated with a bystander polyclonal autoreactive B cell activation, but none of the autoantibody levels were linked to disease severity. Long-term humoral immunity against HCOV-22E and HCOV-NL63 spike protein was associated with mild disease outcome. Understanding the mechanism of life-threatening COVID-19 is critical to reducing mortality and morbidity.

Sex difference in circulating soluble form of ACE2 protein in moderate and severe COVID-19 and healthy controls.

Introduction: Membrane-bound angiotensin-converting enzyme-2 (ACE2) in epithelial cells is the main receptor for SARS-CoV-2. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (a disintegrin and metalloproteinase 17) is important. Results on the relationship between circulating levels of the soluble form of ACE2 (sACE2) and disease severity are inconclusive. This study investigates if sACE2 concentration correlates with COVID-19 severity, and whether this is affected by sex. Materials and methods: Soluble form of ACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n = 19, 4 women and 15 men), and age and sex matched healthy controls (n = 20, 4 women and 16 men). Blood samples were collected at hospital admission between 18 March 2020, and 3 May 2021, and at follow-up between 27 October 2020, and 19 October 2021. Circulating sACE2 (µg/L) was measured in EDTA plasma with a sensitive enzyme-linked immunosorbent assay. Additionally, CRP, ferritin, and lymphocyte count were analyzed during hospital stay. Results: In total, 23 patients (22%) died in the ICU. When comparing healthy controls [mean age 58.1 (SD 11.4) years] and patients with moderate COVID-19 [mean age 61.0 (SD 13.2) years] with patients in the ICU [mean age 63.6 (SD 11.6) years], we found that sACE2 concentration decreased (70% reduction) with disease severity in men (p = 0.002) but increased 3.7-fold with severity in women (p = 0.043), suggesting a sex-related difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP and higher ferritin concentration correlated with lower sACE2 concentration in men. Conclusion: The decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in severe disease. Our findings imply that sACE2 is a possible biomarker of disease severity in a sex-specific manner.

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men.

BACKGROUND: The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription. METHODS: Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs. RESULTS: Reanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p=0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p=0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p=0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93-143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p=6e-11). CONCLUSIONS: We present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.

Effectiveness of COVID-19 Vaccines over 13 Months Covering the Period of the Emergence of the Omicron Variant in the Swedish Population.

BACKGROUND: We estimated real-world vaccine effectiveness (VE) against COVID-19 infection, hospitalization, ICU admission, and death up to 13 months after vaccination. VE before and after the emergence of Omicron was investigated. METHODS: We used registered data from the entire Swedish population above age 12 (n = 9,153,456). Cox regression with time-varying exposure was used to estimate weekly/monthly VE against COVID-19 outcomes from 27 December 2020 to 31 January 2022. The analyses were stratified by age, sex, and vaccine type (BNT162b2, mRNA-1273, and AZD1222). RESULTS: Two vaccine doses offered good long-lasting protection against infection before Omicron (VE were above 85% for all time intervals) but limited protection against Omicron infection (dropped to 43% by week four and no protection by week 14). For severe COVID-19 outcomes, higher VE was observed during the entire follow-up period. Among individuals above age 65, the mRNA vaccines showed better VE against infection than AZD1222 but similar high VE against hospitalization. CONCLUSIONS: Our findings provide strong evidence for long-term maintained protection against severe COVID-19 by the basic two-dose schedule, supporting more efforts to encourage unvaccinated persons to get the basic two doses, and encourage vaccinated persons to get a booster to ensure better population-level protection.

COVID-19 in people aged 18-64 in Sweden in the first year of the pandemic: Key factors for severe disease and death.

Background: Studies on risk factors for severe COVID-19 in people of working age have generally not included non-working persons or established population attributable fractions (PAFs) for occupational and other factors. Objectives: We describe the effect of job-related, sociodemographic, and other exposures on the incidence, relative risks and PAFs of severe COVID-19 in individuals aged 18-64. Methods: We conducted a registry-based study in Swedish citizens aged 18-64 from 1 January 2020 to 1 February 2021 with respect to COVID-19-related hospitalizations and death. Results: Of 6,205,459 persons, 272,043 (7.5%) were registered as infected, 3399 (0.05%) needed intensive care, and 620 (0.01%) died, with an estimated case fatality rate of 0.06% over the last 4-month period when testing was adequate. Non-Nordic origin was associated with a RR for need of intensive care of 3·32, 95%CI 2·19-3·36, and a PAF of 33·1% after adjustment for age, sex, work, region and comorbidities. In a second model with occupation as main exposure, and adjusted for age, sex, region, comorbidities and origin, essential workers had an RR of 1·51, 95%CI, 1·35-1·6, blue-collar workers 1·18, 95%CI 1·06-1·31, school staff 1·21, 95%CI 1·01-1·46, and health and social care workers 1·89, 95%CI 1·67-2·135) compared with people able to work from home, with altogether about 14% of the PAF associated with these occupations. Essential workers and blue-collar workers, but no other job categories had higher risk of death, adjusted RRs of 1·66, 95%CI 1·24-2·23 and 1·37, 95%CI 1·04-1·81, with adjusted PAFs of altogether 9%. Conclusion: Among people of working age in Sweden, overall mortality and case fatality were low. Occupations that require physical presence at work were associated with elevated risk of needing intensive care for COVID-19, with 14% cases attributable to this factor, and 9% of deaths.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Comparison of SARS-CoV-2 spike RNA sequences in feces and nasopharynx indicates intestinal replication.

BACKGROUND: Little is known of possible selection and replication of SARS-CoV-2 in the intestines and if viral load in feces is associated with severity of disease. Therefore, sequence variations of the spike region in strains collected from feces and nasopharynx (NPH) from the same patients were compared. It was also investigated whether viral load in feces related to severity of COVID-19 in hospitalized patients. RESULTS: SARS-CoV-2 RNA was found in 88 (79%) fecal samples from 112 patients. The complete spike region could be sequenced in 15 fecal and 14 NPH samples. Fourteen Alpha-variants and one Beta-variant of SARS-CoV-2 were identified. The majority of the viral genetic variants (viral populations) in two fecal samples, but none in NPH, had a reversion of the H69/V70 amino acid deletion normally seen in the Alpha variants. Nine fecal samples contained up to nine minority variants, each which may constitute a separate viral population. Five NPH samples had one genetic variant each, and one NPH sample contained nine minority populations of SARS-CoV-2 spike genes. CONCLUSIONS: The higher genomic diversity of SARS-CoV-2 in feces compared to NPH, and the reversion of the H69/V70 deletion in Alpha variants from feces indicate a selection of viral strains and replication of SARS-CoV-2 in the gastrointestinal tract.

TTCOV19: timing of tracheotomy in SARS-CoV-2-infected patients: a multicentre, single-blinded, randomized, controlled trial.

BACKGROUND: Critically ill COVID-19 patients may develop acute respiratory distress syndrome and the need for respiratory support, including mechanical ventilation in the intensive care unit. Previous observational studies have suggested early tracheotomy to be advantageous. The aim of this parallel, multicentre, single-blinded, randomized controlled trial was to evaluate the optimal timing of tracheotomy. METHODS: SARS-CoV-2-infected patients within the Region Västra Götaland of Sweden who needed intubation and mechanical respiratory support were included and randomly assigned to early tracheotomy (≤ 7 days after intubation) or late tracheotomy (≥ 10 days after intubation). The primary objective was to compare the total number of mechanical ventilation days between the groups. RESULTS: One hundred fifty patients (mean age 65 years, 79% males) were included. Seventy-two patients were assigned to early tracheotomy, and 78 were assigned to late tracheotomy. One hundred two patients (68%) underwent tracheotomy of whom sixty-one underwent tracheotomy according to the protocol. The overall median number of days in mechanical ventilation was 18 (IQR 9; 28), but no significant difference was found between the two treatment regimens in the intention-to-treat analysis (between-group difference: - 1.5 days (95% CI - 5.7 to 2.8); p = 0.5). A significantly reduced number of mechanical ventilation days was found in the early tracheotomy group during the per-protocol analysis (between-group difference: - 8.0 days (95% CI - 13.8 to - 2.27); p = 0.0064). The overall correlation between the timing of tracheotomy and days of mechanical ventilation was significant (Spearman's correlation: 0.39, p < 0.0001). The total death rate during intensive care was 32.7%, but no significant differences were found between the groups regarding survival, complications or adverse events. CONCLUSIONS: The potential superiority of early tracheotomy when compared to late tracheotomy in critically ill patients with COVID-19 was not confirmed by the present randomized controlled trial but is a strategy that should be considered in selected cases where the need for MV for more than 14 days cannot be ruled out. Trial registration NCT04412356 , registered 05/24/2020.

No effect of remdesivir or betamethasone on upper respiratory tract SARS-CoV-2 RNA kinetics in hospitalised COVID-19 patients: a retrospective observational study.

BACKGROUND: The viral kinetics of SARS-CoV-2 has been considered clinically important. While remdesivir and corticosteroids are recommended for COVID-19 patients requiring oxygen support, there is a limited number of published reports on viral kinetics in hospitalised patients with COVID-19 treated with remdesivir or corticosteroids. METHODS: We conducted a retrospective study by collecting longitudinal samples from the nasopharynx/throat of 123 hospitalised patients (median age 55 years, 74% male) with COVID-19, to evaluate the effects of remdesivir and corticosteroid treatment on viral RNA levels. The subjects were divided into four groups: those receiving remdesivir (n = 25), betamethasone (n = 41), both (n = 15), or neither (n = 42). Time to viral RNA clearance was analysed using Kaplan-Meier plots, categorical data were analysed using Fisher's exact test, and Kruskal-Wallis for continuous data. Viral RNA decline rate was analysed using a mixed effect model. RESULTS: We found no significant difference in SARS-CoV-2 RNA decline rate or time to SARS-CoV-2 RNA clearance between the groups. Moreover, clinical status at baseline was not correlated with time to viral clearance. CONCLUSIONS: Since SARS-CoV-2 RNA kinetics was not affected by treatment, repeated sampling from the upper respiratory tract cannot be used to evaluate treatment response.

Severe COVID-19 in people 55 and older during the first year of the pandemic in Sweden.

BACKGROUND: Exposure to many contacts is the main risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while risk of serious disease and death is chiefly determined by old age and comorbidities. Relative and population-attributable fractions (PAFs) of multiple medical and social exposures for COVID-19 outcomes have not been evaluated among older adults. OBJECTIVES: We describe the effect of multiple exposures on the odds of testing positive for the virus and of severe disease (hospital care or death) and PAFs in Swedish citizens aged 55 years and above. METHODS: We used national registers to follow all citizens aged 55 years and above with respect to (1) testing positive, (2) hospitalization, and (3) death between 31 January 2020 and 1 February 2021. RESULTS: Of 3,410,241 persons, 156,017 (4.6%, mean age 68.3 years) tested positive for SARS-CoV-2, while 35,999 (1.1%, mean age 76.7 years) were hospitalized or died (12,384 deaths, 0.4%, mean age 84.0 years). Among the total cohort, the proportion living without home care or long-term care was 98.8% among persons aged 55-64 and 22.1% of those aged 95 and above. After multiple adjustment, home care and long-term care were associated with odds ratios of 7.9 (95% confidence interval [CI] 6.8-9.1) and 22.5 (95% CI 19.6-25.7) for mortality, with PAFs of 21.9% (95% CI 20.9-22.9) and 33.3% (95% CI 32.4-34.3), respectively. CONCLUSION: Among Swedish residents aged 55 years and above, those with home care or long-term care had markedly increased risk for COVID-19 death during the first year of the pandemic, with over 50% of deaths attributable to these factors.

Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms.

Importance: Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). Objective: To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. Design, Setting, and Participants: This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, ß2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). Results: Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, ß2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. Conclusions and Relevance: In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.

Association of cardiometabolic risk factors with hospitalisation or death due to COVID-19: population-based cohort study in Sweden (SCAPIS)

ObjectiveTo assess the association of cardiometabolic risk factors with hospitalisation or death due to COVID-19 in the general population.Design, setting and participantsSwedish population-based cohort including 29 955 participants.ExposuresCardiometabolic risk factors assessed between 2014 and 2018.Main outcome measuresHospitalisation or death due to COVID-19, as registered in nationwide registers from 31 January 2020 through 12 September 2020. Associations of cardiometabolic risk factors with the outcome were assessed using logistic regression adjusted for age, sex, birthplace and education.ResultsMean (SD) age was 61.2 (4.5) and 51.5% were women. 69 participants experienced hospitalisation or death due to COVID-19. Examples of statistically significant associations between baseline factors and subsequent hospitalisation or death due to COVID-19 included overweight (adjusted OR (aOR) vs normal weight 2.73 (95% CI 1.25 to 5.94)), obesity (aOR vs normal weight 4.09 (95% CI 1.82 to 9.18)), pre-diabetes (aOR vs normoglycaemia 2.56 (95% CI 1.44 to 4.55)), diabetes (aOR vs normoglycaemia 3.96 (95% CI 2.13 to 7.36)), sedentary time (aOR per hour/day increase 1.10 (95% CI 1.02 to 1.17)), grade 2 hypertension (aOR vs normotension 2.44 (95% CI 1.10 to 5.44)) and high density lipoprotein cholesterol (aOR per mmol/L increase 0.33 (95% CI 0.17 to 0.65)). Statistically significant associations were not observed for grade 1 hypertension (aOR vs normotension 1.03 (95% CI 0.55 to 1.96)), current smoking (aOR 0.56 (95% CI 0.24 to 1.30)), total cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.71 to 1.13)), low density lipoprotein cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.69 to 1.15)) and coronary artery calcium score (aOR per 10 units increase 1.00 (95% CI 0.99 to 1.01)).ConclusionsIn a large population-based sample from the general population, several cardiometabolic risk factors were associated with hospitalisation or death due to COVID-19.