Antiviral Effectiveness, Clinical Outcomes, and Artificial Intelligence Imaging Analysis for Hospitalized COVID-19 Patients Receiving Antivirals.

INTRODUCTION: There is still a lack of clinical evidence comprehensively evaluating the effectiveness of antiviral treatments for COVID-19 hospitalized patients. METHODS: A retrospective cohort study was conducted at Beijing You'An Hospital, focusing on patients treated with nirmatrelvir/ritonavir or azvudine. The study employed a tripartite analysis-viral dynamics, survival curve analysis, and AI-based radiological analysis of pulmonary CT images-aiming to assess the severity of pneumonia. RESULTS: Of 370 patients treated with either nirmatrelvir/ritonavir or azvudine as monotherapy, those in the nirmatrelvir/ritonavir group experienced faster viral clearance than those treated with azvudine (5.4 days vs. 8.4 days, p < 0.001). No significant differences were observed in the survival curves between the two drug groups. AI-based radiological analysis revealed that patients in the nirmatrelvir group had more severe pneumonia conditions (infection ratio is 11.1 vs. 5.35, p = 0.007). Patients with an infection ratio higher than 9.2 had nearly three times the mortality rate compared to those with an infection ratio lower than 9.2. CONCLUSIONS: Our study suggests that in real-world studies regarding hospitalized patients with COVID-19 pneumonia, the antiviral effect of nirmatrelvir/ritonavir is significantly superior to azvudine, but the choice of antiviral agents is not necessarily linked to clinical outcomes; the severity of pneumonia at admission is the most important factor to determine prognosis. Additionally, our findings indicate that pulmonary AI imaging analysis can be a powerful tool for predicting patient prognosis and guiding clinical decision-making.

Characterization of hospitalized patients with acute kidney injury associated with COVID-19 in Spain: renal replacement therapy and mortality. FRA-COVID SEN Registry Data.

BACKGROUND: Acute kidney injury (AKI) is common among hospitalized patients with COVID-19 and associated with worse prognosis. The Spanish Society of Nephrology created the AKI- COVID Registry to characterize the population admitted for COVID-19 that developed AKI in Spanish hospitals. The need of renal replacement therapy (RRT) therapeutic modalities, and mortality in these patients were assessed MATERIAL AND METHOD: In a retrospective study, we analyzed data from the AKI-COVID Registry, which included patients hospitalized in 30 Spanish hospitals from May 2020 to November 2021. Clinical and demographic variables, factors related to the severity of COVID-19 and AKI, and survival data were recorded. A multivariate regression analysis was performed to study factors related to RRT and mortality. RESULTS: Data from 730 patients were recorded. A total of 71.9% were men, with a mean age of 70 years (60-78), 70.1% were hypertensive, 32.9% diabetic, 33.3% with cardiovascular disease and 23.9% had some degree of chronic kidney disease (CKD). Pneumonia was diagnosed in 94.6%, requiring ventilatory support in 54.2% and admission to the ICU in 44.1% of cases. The median time from the onset of COVID-19 symptoms to the appearance of AKI (37.1% KDIGO I, 18.3% KDIGO II, 44.6% KDIGO III) was 6 days (4-10). A total of 235 (33.9%) patients required RRT: 155 patients with continuous renal replacement therapy, 89 alternate-day dialysis, 36 daily dialysis, 24 extended hemodialysis and 17 patients with hemodiafiltration. Smoking habit (OR 3.41), ventilatory support (OR 20.2), maximum creatinine value (OR 2.41), and time to AKI onset (OR 1.13) were predictors of the need for RRT; age was a protective factor (0.95). The group without RRT was characterized by older age, less severe AKI, and shorter kidney injury onset and recovery time (p < 0.05). 38.6% of patients died during hospitalization; serious AKI and RRT were more frequent in the death group. In the multivariate analysis, age (OR 1.03), previous chronic kidney disease (OR 2.21), development of pneumonia (OR 2.89), ventilatory support (OR 3.34) and RRT (OR 2.28) were predictors of mortality while chronic treatment with ARBs was identified as a protective factor (OR 0.55). CONCLUSIONS: Patients with AKI during hospitalization for COVID-19 had a high mean age, comorbidities and severe infection. We defined two different clinical patterns: an AKI of early onset, in older patients that resolves in a few days without the need for RRT; and another more severe pattern, with greater need for RRT, and late onset, which was related to greater severity of the infectious disease. The severity of the infection, age and the presence of CKD prior to admission were identified as a risk factors for mortality in these patients. In addition chronic treatment with ARBs was identified as a protective factor for mortality.

Clinical findings and electrocardiography predicted mortality among COVID-19 patients with pre-existing hypertension: A cross-sectional study of East Java Province, Indonesia.

OBJECTIVE: To evaluate the factors associated with mortality among coronavirus disease-2019 patients with preexisting hypertension. METHODS: The retrospective, cross-sectional study was conducted from June 15 to July 7, 2021, after approval from Dr Soetomo General Province Hospital, Indonesia, and comprised data from the coronavirus disease-2019 registry in the East Java province of Indonesia from March 2020 to June 2021. Data was collected for adult patients infected by coronavirus disease-2019 with pre-existing hypertension Data was analysed using SPSS 23. RESULTS: Of the 2,732 patients in the registry, 425(15.6%) with median age 56.5 years (interquartile range: 50-64 years) had pre-existing hypertension. Of them, 251(59.06%) were males, and 110(25.9%) had died while in hospital. Mortality was associated with older age; higher white blood cell counts at admission and lower platelet count (p<0.05). In addition, electrocardiogram parameters associated with mortality were faster heart rate and ST abnormality (p<0.05). CONCLUSIONS: Older age, high white blood cell level, lower platelet count, faster heart rate, and ST abnormality at admission were found to be the predictors of mortality among hospitalised coronavirus disease-2019 patients with pre-existing hypertension.

Deaths with COVID-19 and from all-causes following first-ever SARS-CoV-2 infection in individuals with preexisting mental disorders: A national cohort study from Czechia.

BACKGROUND: Evidence suggests reduced survival rates following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in people with preexisting mental disorders, especially psychotic disorders, before the broad introduction of vaccines. It remains unknown whether this elevated mortality risk persisted at later phases of the pandemic and when accounting for the confounding effect of vaccination uptake and clinically recorded physical comorbidities. METHODS AND FINDINGS: We used data from Czech national health registers to identify first-ever serologically confirmed SARS-CoV-2 infections in 5 epochs related to different phases of the pandemic: 1st March 2020 to 30th September 2020, 1st October 2020 to 26th December 2020, 27th December 2020 to 31st March 2021, 1st April 2021 to 31st October 2021, and 1st November 2021 to 29th February 2022. In these people, we ascertained cases of mental disorders using 2 approaches: (1) per the International Classification of Diseases 10th Revision (ICD-10) diagnostic codes for substance use, psychotic, affective, and anxiety disorders; and (2) per ICD-10 diagnostic codes for the above mental disorders coupled with a prescription for anxiolytics/hypnotics/sedatives, antidepressants, antipsychotics, or stimulants per the Anatomical Therapeutic Chemical (ATC) classification codes. We matched individuals with preexisting mental disorders with counterparts who had no recorded mental disorders on age, sex, month and year of infection, vaccination status, and the Charlson Comorbidity Index (CCI). We assessed deaths with Coronavirus Disease 2019 (COVID-19) and from all-causes in the time period of 28 and 60 days following the infection using stratified Cox proportional hazards models, adjusting for matching variables and additional confounders. The number of individuals in matched-cohorts ranged from 1,328 in epoch 1 to 854,079 in epoch 5. The proportion of females ranged from 34.98% in people diagnosed with substance use disorders in epoch 3 to 71.16% in individuals diagnosed and treated with anxiety disorders in epoch 5. The mean age ranged from 40.97 years (standard deviation [SD] = 15.69 years) in individuals diagnosed with substance use disorders in epoch 5 to 56.04 years (SD = 18.37 years) in people diagnosed with psychotic disorders in epoch 2. People diagnosed with or diagnosed and treated for psychotic disorders had a consistently elevated risk of dying with COVID-19 in epochs 2, 3, 4, and 5, with adjusted hazard ratios (aHRs) ranging from 1.46 [95% confidence intervals (CIs), 1.18, 1.79] to 1.93 [95% CIs, 1.12, 3.32]. This patient group demonstrated also a consistently elevated risk of all-cause mortality in epochs 2, 3, 4, and 5 (aHR from 1.43 [95% CIs, 1.23, 1.66] to 1.99 [95% CIs, 1.25, 3.16]). The models could not be reliably fit for psychotic disorders in epoch 1. People diagnosed with substance use disorders had an increased risk of all-cause mortality 28 days postinfection in epoch 3, 4, and 5 (aHR from 1.30 [95% CIs, 1.14, 1.47] to 1.59 [95% CIs, 1.19, 2.12]) and 60 days postinfection in epoch 2, 3, 4, and 5 (aHR from 1.22 [95% CIs, 1.08, 1.38] to 1.52 [95% CIs, 1.16, 1.98]). Cases ascertained based on diagnosis of substance use disorders and treatment had increased risk of all-cause mortality in epoch 2, 3, 4, and 5 (aHR from 1.22 [95% CIs, 1.03, 1.43] to 1.91 [95% CIs, 1.25, 2.91]). The models could not be reliably fit for substance use disorders in epoch 1. In contrast to these, people diagnosed with anxiety disorders had a decreased risk of death with COVID-19 in epoch 2, 3, and 5 (aHR from 0.78 [95% CIs, 0.69, 0.88] to 0.89 [95% CIs, 0.81, 0.98]) and all-cause mortality in epoch 2, 3, 4, and 5 (aHR from 0.83 [95% CIs, 0.77, 0.90] to 0.88 [95% CIs, 0.83, 0.93]). People diagnosed and treated for affective disorders had a decreased risk of both death with COVID-19 and from all-causes in epoch 3 (aHR from 0.87 [95% CIs, 0.79, 0.96] to 0.90 [95% CIs, 0.83, 0.99]), but demonstrated broadly null effects in other epochs. Given the unavailability of data on a number of potentially influential confounders, particularly body mass index, tobacco smoking status, and socioeconomic status, part of the detected associations might be due to residual confounding. CONCLUSIONS: People with preexisting psychotic, and, less robustly, substance use disorders demonstrated a persistently elevated risk of death following SARS-CoV-2 infection throughout the pandemic. While it cannot be ruled out that part of the detected associations is due to residual confounding, this excess mortality cannot be fully explained by lower vaccination uptake and more clinically recorded physical comorbidities in these patient groups.

Determining the frequency of thyroid involvement in chest CT scans of COVID-19 patients and its correlation with the severity of lung involvement and survival of patients in 2020.

Introduction: This study aimed to determine the frequency of thyroid gland involvement in chest CT scans of patients with COVID-19 admitted to university-affiliated hospitals and assess its relationship with the severity of lung involvement and patient survival in 2020. Material and methods: In this retrospective cross-sectional study, 1000 PCR-positive patients with COVID-19 who were referred to University-affiliated Hospital in 2020 and had chest CT performed within 72 hours of admission to the hospital were examined. The data was collected by patient file information and CT findings recorded in the PACS system, including thyroid involvement, the severity of lung involvement, and findings related to the death and recovery of patients. Results: The mean age of the examined patients was 56 years. 525 people (52.5%) were men, and 475 (47.5%) were women. 14% had severe pulmonary involvement, and 9.3% had very severe involvement. Moreover, 15.9 percent of them had deceased. 19.7% had focal thyroid involvement, 14% had diffuse involvement, and 66.3% were healthy subjects. Male gender and older age showed a significant relationship with thyroid gland involvement. The severity of lung involvement, the death rate in patients, and hospitalization in ICU were also significantly related to thyroid gland involvement in patients with COVID. Discussion and conclusion: This study highlights the importance of considering thyroid-gland involvement in the comprehensive management of COVID-19 patients. Routine screening and monitoring of thyroid-function may facilitate earlier detection and appropriate management of thyroid-related complications, potentially improving clinical outcomes. This study suggests that in COVID-19 infection the monitoring of thyroid function is prudent, particularly in cases of more serious disease.

Nirmatrelvir/ritonavir or Molnupiravir for treatment of non-hospitalized patients with COVID-19 at risk of disease progression.

BACKGROUND: In randomized controlled trials, Nirmatrelvir/ritonavir (NMV/r) and Molnupiravir (MPV) reduced the risk of severe/fatal COVID-19 disease. Real-world data are limited, particularly studies directly comparing the two agents. METHODS: Using the VA National COVID-19 database, we identified previously uninfected, non-hospitalized individuals with COVID-19 with ≥1 risk factor for disease progression who were prescribed either NMV/r or MPV within 3 days of a positive test. We used inverse probability of treatment weights (IPTW) to account for providers' preferences for a specific treatment. Absolute risk difference (ARD) with 95% confidence intervals were determined for those treated with NMV/r vs. MPV. The primary outcome was hospitalization or death within 30 days of treatment prescription using the IPTW approach. Analyses were repeated using propensity-score matched groups. RESULTS: Between January 1 and November 30, 2022, 9,180 individuals were eligible for inclusion (6,592 prescribed NMV/r; 2,454 prescribed MPV). The ARD for hospitalization/death for NMV/r vs MPV was -0.25 (95% CI -0.79 to 0.28). There was no statistically significant difference in ARD among strata by age, race, comorbidities, or symptoms at baseline. Kaplan-Meier curves did not demonstrate a difference between the two groups (p-value = 0.6). Analysis of the propensity-score matched cohort yielded similar results (ARD for NMV/r vs. MPV -0.9, 95% CI -2.02 to 0.23). Additional analyses showed no difference for development of severe/critical/fatal disease by treatment group. CONCLUSION: We found no significant difference in short term risk of hospitalization or death among at-risk individuals with COVID-19 treated with either NMV/r or MPV.

Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.

BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.

Pronounced benefits of JAK inhibition with baricitinib in COVID-19 pneumonia in obese but not lean subjects.

OBJECTIVE: Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19. METHODS: A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m2, 25-30 kg/m2 and >30 kg/m2) and age <65 years and ≥65 years. RESULTS: In the high BMI group (>25 kg/m2), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m2, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05). CONCLUSION: The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.

Survival of Critically Ill COVID-19 Patients in Sweden During the First Two and a Half Years of the Pandemic.

OBJECTIVES: Some studies have examined survival trends among critically ill COVID-19 patients, but most were case reports, small cohorts, and had relatively short follow-up periods. We aimed to examine the survival trend among critically ill COVID-19 patients during the first two and a half years of the pandemic and investigate potential predictors across different variants of concern periods. DESIGN: Prospective cohort study. SETTING: Swedish ICUs, between March 6, 2020, and December 31, 2022. PATIENTS: Adult COVID-19 ICU patients of 18 years old or older from the Swedish Intensive Care Register (SIR) that were linked to multiple other national registers. MEASUREMENT AND MAIN RESULTS: Survival probability and predictors of COVID-19 death were estimated using Kaplan-Meier and Cox regression analysis. Of 8975 patients, 2927 (32.6%) died. The survival rate among COVID-19 critically ill patients appears to have changed over time, with a worse survival in the Omicron period overall. The adjusted hazard ratios (aHRs) comparing older and younger ages were consistently strong but slightly attenuated in the Omicron period. After adjustment, the aHR of death was significantly higher for men, older age (40+ yr), low income, and with comorbid chronic heart disease, chronic lung disease, impaired immune disease, chronic renal disease, stroke, and cancer, and for those requiring invasive or noninvasive respiratory supports, who developed septic shock or had organ failures ( p < 0.05). In contrast, foreign-born patients, those with booster vaccine, and those who had taken steroids had better survival (aHR = 0.87; 95% CI, 0.80-0.95; 0.74, 0.65-0.84, and 0.91, 0.84-0.98, respectively). Observed associations were similar across different variant periods. CONCLUSIONS: In this nationwide Swedish cohort covering over two and a half years of the pandemic, ICU survival rates changed over time. Older age was a strong predictor across all periods. Furthermore, most other mortality predictors remained consistent across different variant periods.

Case fatality rates of COVID-19 during epidemic periods of variants of concern: A meta-analysis by continents.

OBJECTIVES: To calculate the case fatality rates (CFR) of COVID-19 during epidemic periods of different variants of concern (VOC) by continents. METHODS: We systematically searched five authoritative databases (Web of Science, PubMed, Embase, Cochrane Library, and MedRxiv) for epidemiological studies on the CFR of COVID-19 published between January 1, 2020, and March 31, 2023. After identifying the epidemic trends of variants, we used a random-effects model to calculate the pooled CFRs during periods of different VOCs. This meta-analysis was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered with PROSPERO (CRD42023431572). RESULTS: There were variations in the CFRs among different variants of COVID-19 (Alpha: 2.62%, Beta: 4.19%, Gamma: 3.60%, Delta: 2.01%, Omicron: 0.70%), and disparities in CFRs also existed among continents. On the whole, the CFRs of COVID-19 in Europe and Oceania were slightly lower than in other continents. There was a statistically significant association between the variant, HDI value, age distribution, coverage of full vaccination of cases, and the CFR. CONCLUSIONS: The CFRs of COVID-19 varied across the epidemic periods of different VOCs, and disparities existed among continents. The CFR value reflected combined effects of various factors within a certain context. Caution should be exercised when comparing CFRs due to disparities in testing capabilities and age distribution among countries, etc.

Mortality risk in patients with obesity and COVID-19 infection: a systematic review and meta-analysis.

Obesity is a risk factor for severe respiratory diseases, including COVID-19 infection. Meta-analyses on mortality risk were inconsistent. We systematically searched 3 databases (Medline, Embase, CINAHL) and assessed the quality of studies using the Newcastle-Ottawa tool (CRD42020220140). We included 199 studies from US and Europe, with a mean age of participants 41.8-78.2 years, and a variable prevalence of metabolic co-morbidities of 20-80 %. Exceptionally, one third of the studies had a low prevalence of obesity of <20 %. Compared to patients with normal weight, those with obesity had a 34 % relative increase in the odds of mortality (p-value 0.002), with a dose-dependent relationship. Subgroup analyses showed an interaction with the country income. There was a high heterogeneity in the results, explained by clinical and methodologic variability across studies. We identified one trial only comparing mortality rate in vaccinated compared to unvaccinated patients with obesity; there was a trend for a lower mortality in the former group. Mortality risk in COVID-19 infection increases in parallel to an increase in BMI. BMI should be included in the predictive models and stratification scores used when considering mortality as an outcome in patients with COVID-19 infections. Furthermore, patients with obesity might need to be prioritized for COVID-19 vaccination.

Therapeutic high-dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double-blind, placebo-controlled study (SHADE-S).

BACKGROUND: efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied. OBJECTIVE: effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19. METHODS: participants with moderate to severe COVID-19 with PaO2/FiO2 ratio < 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo. OUTCOMES: primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality. RESULTS: in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10-16) and 13 (12-18) ng/ml (P = 0.06) at baseline; and 60 (55-65) ng/ml and 4 (1-7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2-5) versus 5 (95% CI, 3-7), P = 0.01, intergroup difference - 2 (95% CI, -4 to -0.01); r = 0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P = 0.046)] was observed with vitamin D. CONCLUSIONS: single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19. ClinicalTrials.gov  id: NCT04952857 registered dated 7 July 2021. What is already known on this topic-vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs. What this study adds-high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D > 50 ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19. How this study might affect research, practice or policy-vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced.

Síndrome inflamatória multissistêmica em crianças infectadas por coronavírus: uma revisão integrativa / Multisystemic inflamatory syndrome in children infected by coronavirus: an integrative review / Síndrome inflamatorio multisistémico en niños infectados por coronavirus: una revisión integradora

Durante a pandemia de COVID-19, foram observadas manifestações atípicas em pacientes pediátricos em diversas regiões do mundo, e o conjunto desses sintomas caracterizou uma nova patologia denominada Síndrome Inflamatória Multissistêmica em Crianças (MIS-C), ou Síndrome Inflamatória Multissistêmica Pediátrica Temporariamente associada ao COVID-19 (PIMS- TS). O objetivo desta revisão foi analisar as manifestações clínicas e as possíveis complicações relacionadas a tal quadro inflamatório. Foi realizada uma busca por artigos científicos nas bases de dados Embase, PubMed e Web of Science, por meio da combinação dos descritores "MIS-C", "PIMS- TS" e "COVID-19". Após a análise dos artigos encontrados, e considerando critérios de inclusão e exclusão, foram selecionados 15 estudos para compor esta revisão. A maioria dos estudos mencionaram complicações gastrointestinais, cardiovasculares, respiratórias e mucocutâneas. Ademais, foram encontrados marcadores que indicavam estado inflamatório generalizado e coagulopatia. Assim, concluiu-se que MIS-C provavelmente é uma síndrome manifestada após a infecção por SARS-CoV-2, podendo ocasionar quadros mais graves, mas com baixas taxas de mortalidade.

During the COVID-19 pandemic, atypical manifestations were observed in pediatric patients in different regions of the world, and the set of these symptoms characterized a new pathology called Multisystemic Inflammatory Syndrome in Children (MIS-C), or Pediatric Multisystemic Inflammatory Syndrome Temporarily associated with COVID-19 (PIMS-TS). The purpose of this review was to analyze the clinical manifestations and possible complications related to such an inflammatory condition. A search for scientific articles was carried out in the databases Embase, PubMed and Web of Science, by combining the descriptors "MIS-C", "PIMS-TS" and "COVID-19". After analyzing the articles found, and considering inclusion and exclusion criteria, 15 studies were selected to compose this review. Most studies mentioned gastrointestinal, cardiovascular, respiratory and mucocutaneous complications. In addition, markers were found that indicated generalized inflammatory status and coagulopathy. Thus, it was concluded that MIS-C is probably a syndrome manifested after infection by SARS-CoV-2, which can cause more severe conditions, but with low mortality rates.

Durante la pandemia de COVID-19 se observaron manifestaciones atípicas en pacientes pediátricos de diferentes regiones del mundo, y el conjunto de estos síntomas caracterizó una nueva patología denominada Síndrome Inflamatorio Multisistémico en Niños (SMI-C), o Síndrome Inflamatorio Multisistémico Pediátrico Asociado Temporalmente a COVID-19 (SIPM-TS). El propósito de esta revisión fue analizar las manifestaciones clínicas y las posibles complicaciones relacionadas con dicha condición inflamatoria. Se realizó una búsqueda de artículos científicos en las bases de datos Embase, PubMed y Web of Science, combinando los descriptores "MIS-C", "PIMS- TS" y "COVID-19". Tras analizar los artículos encontrados, y teniendo en cuenta los criterios de inclusión y exclusión, se seleccionaron 15 estudios para componer esta revisión. La mayoría de los estudios mencionaron complicaciones gastrointestinales, cardiovasculares, respiratorias y mucocutáneas. Además, se encontraron marcadores que indicaban un estado inflamatorio generalizado y coagulopatía. Así pues, se concluyó que el SMI-C es probablemente un síndrome que se manifiesta tras la infección por el SARS-CoV-2, que puede causar cuadros más graves, pero con bajas tasas de mortalidad.

Perfil epidemiológico de óbitos decorrentes da Covid-19 em um município do sudoeste do Paraná / Epidemiological profile of death resulting from Covid-19 in a municipality in southwest of Paraná / Perfil epidemiológico de las muertes por Covid-19 en un municipio del suroeste de Paraná

Introdução: No final do ano de 2019 surgiu na China uma doença infectocontagiosa de característica respiratória e alto grau de disseminação até então desconhecida. No Brasil o primeiro caso de Covid-19 foi confirmado no final de fevereiro de 2020 e a primeira morte em meados de março. Segundo dados da plataforma Coronavírus Brasil, em 17 de março de 2021, houve registro de 11.603.535 casos confirmados e 282.127 óbitos. Objetivo: Descrever o perfil de pessoas que morreram tendo como causa básica do óbito a Covid-19, em um município do Sudoeste do Paraná, entre os anos de 2020 e 2021. Metodologia: Trata-se de um estudo transversal, descritivo, documental de caráter quantitativo que foi realizado na prefeitura municipal de Francisco Beltrão. Resultados: Houve prevalência de óbitos em pacientes do sexo masculino, idosos, com presença de alguma comorbidade associada, sendo hipertensão a mais citada (50,8%). Os sintomas mais prevalentes foram tosse (74,4%), dispneia (56,3%) e saturação < 95% (48,3%), necessitando ainda de hospitalização em algum período da doença (94,1%), sendo os leitos de Sistema Único de Saúde os mais procurados (74,4%). Quanto à taxa de ocupação 49,6% dos casos necessitou apenas de leitos de enfermaria e 42% unidades de terapia intensiva. Discussão: Diversas pesquisas apontam que o sexo masculino é o mais acometido por condições graves de saúde, devido à demora na busca de assistência médica. No que se refere à idade, neste estudo, a prevalência de óbitos se deu entre 71 e 75 anos (15,1%) o que justifica que o envelhecimento é um fator de risco elevado para complicações da doença. Durante a análise dos dados, notou- se que grande parte dos pacientes que tiveram como desfecho o óbito, possuíam algum fator associado, dentre os mais citados, verificou-se a Hipertensão Arterial Sistêmica (50,8%) Diabetes Mellitus (24,8%), doenças cardiovasculares (23,9%) e obesidade (14,7%). No que diz respeito à hospitalização, nesse estudo notou-se que 74,4% da amostra foram hospitalizadas em leitos de SUS, 18,5% em hospitais particulares e 7,1% não possuíam essa informação. Conclusão: É possível observar a importância do estudo epidemiológico para identificar o perfil da população em risco, podendo auxiliar no planejamento do atendimento, rastreamento e controle da doença, além de conhecer a evolução da patologia, a fim de buscar ações adequadas para seu enfrentamento.

Introduction: At the end of 2019, a previously unknown infectious disease with respiratory characteristics and a high degree of dissemination emerged in China. In Brazil the first case of Covid-19 was confirmed in late February 2020 and the first death in mid-March. According to data from the Coronavirus Brazil platform, as of March 17, 2021, 11,603,535 confirmed cases and 282,127 deaths were recorded. Objective: To describe the profile of people who died with Covid-19 as the underlying cause of death in a city in southwestern Paraná between the years 2020 and 2021. Methodology: This is a cross-sectional, descriptive, documental, quantitative study carried out at the Francisco Beltrão City Hall. Results: There was a prevalence of deaths in male patients, elderly, with the presence of some associated comorbidity, hypertension being the most cited (50.8%). The most prevalent symptoms were cough (74.4%), dyspnea (56.3%) and saturation < 95% (48.3%), requiring hospitalization in some period of the disease (94.1%), and the Unified Health System beds were the most sought (74.4%). As for the occupancy rate, 49.6% of the cases required only ward beds and 42% intensive care units. Discussion: Several studies show that men are the most affected by serious health conditions, due to the delay in seeking medical assistance. Regarding age, in this study, the prevalence of deaths was between 71 and 75 years (15.1%), which justifies that aging is a high risk factor for disease complications. During data analysis, it was noted that most patients who died had some associated factor, among the most cited were systemic arterial hypertension (50.8%), diabetes mellitus (24.8%), cardiovascular diseases (23.9%) and obesity (14.7%). Regarding hospitalization, in this study it was noted that 74.4% of the sample were hospitalized in SUS beds, 18.5% in private hospitals, and 7.1% did not have this information. Conclusion: It is possible to observe the importance of the epidemiological study to identify the profile of the population at risk, which can help in planning care, tracking and control of the disease, besides knowing the evolution of the pathology in order to seek appropriate actions for its confrontation

Introducción: A finales del año 2019 apareció en China una enfermedad infecto- contagiosa de característica respiratoria y alto grado de diseminación desconocida hasta entonces. En Brasil se confirmó el primer caso de Covid-19 a finales de febrero de 2020 y la primera muerte a mediados de marzo. Según los datos de la plataforma Coronavirus Brasil, hasta el 17 de marzo de 2021, había 11.603.535 casos confirmados y 282.127 muertes. Objetivo: Describir el perfil de las personas fallecidas con Covid-19 como causa subyacente de muerte en una ciudad del sudoeste de Paraná entre los años 2020 y 2021. Metodología: Se trata de un estudio transversal, descriptivo, documental de carácter cuantitativo que se realizó en la prefectura municipal de Francisco Beltrão. Resultados: Hubo una prevalencia de muertes en pacientes masculinos, de edad avanzada, con presencia de alguna comorbilidad asociada, siendo la hipertensión la más citada (50,8%). Los síntomas más prevalentes fueron la tos (74,4%), la disnea (56,3%) y la saturación < 95% (48,3%), requiriendo hospitalización en algún periodo de la enfermedad (94,1%), siendo las camas del Sistema Único de Salud las más solicitadas (74,4%). En cuanto a la tasa de ocupación, el 49,6% de los casos sólo necesitaban camas de sala y el 42% unidades de cuidados intensivos. Discusión: Varias investigaciones señalan que el género masculino es el más afectado por las condiciones de salud graves, debido al retraso en la búsqueda de asistencia médica. En cuanto a la edad, en este estudio, la prevalencia de muertes se produjo entre los 71 y los 75 años (15,1%), lo que justifica que el envejecimiento sea un factor de riesgo elevado para las complicaciones de la enfermedad. Durante el análisis de los datos, se observó que la mayoría de los pacientes que fallecieron tenían algún factor asociado, entre los más citados estaban la Hipertensión Arterial Sistémica (50,8%), la Diabetes Mellitus (24,8%), las enfermedades cardiovasculares (23,9%) y la obesidad (14,7%). En lo que respecta a la hospitalización, en este estudio se observó que el 74,4% de la muestra estaba hospitalizada en camas del SUS, el 18,5% en hospitales privados y el 7,1% no tenía esta información. Conclusión: Es posible observar la importancia del estudio epidemiológico para identificar el perfil de la población en riesgo, pudiendo ayudar en la planificación de la atención, el rastreo y el control de la enfermedad, además de conocer la evolución de la patología, con el fin de buscar las acciones adecuadas para su enfrentamiento.

Systemic administration of glucocorticoids, cardiovascular complications and mortality in patients hospitalised with COVID-19, SARS, MERS or influenza: A systematic review and meta-analysis of randomised trials.

BACKGROUND: Administration of glucocorticoids might reduce mortality in patients with severe COVID-19 but have adverse cardiometabolic effects. OBJECTIVES: to investigate the effect of systemic administration of glucocorticoids on cardiovascular complications and all-cause mortality in patients hospitalised with respiratory viral infections, including COVID-19, SARS, MERS and influenza. METHODS: We identified randomised trials published prior to July 28th, 2021. The Mantel-Haenszel random effects method and the Hartung and Knapp adjustment were used to obtain pooled estimates of treatment effect with 95% confidence intervals. RESULTS: No randomised trials of glucocorticoids for SARS, MERS or influenza reported relevant outcomes. We included eleven COVID-19 randomised trials (8109 patients). Overall, compared to placebo or standard care, glucocorticoids were not associated with a reduction of in-hospital mortality (p = 0.09). In a pre-specified sub-analysis, in-hospital mortality was reduced by 19% when follow-up was restricted to 14 days from randomisation (5/11 trials, 1329 patients, p = 0.02). With longer follow-up (9/11 trials, 7874 patients), administration of glucocorticoids was associated with a trend to benefit for those requiring mechanical ventilation (RR 0.86; 95% CI 0.57-1.27) but possible harm for those not receiving oxygen at randomisation (RR 1.27; 95% CI 1.00 - 1.61), an effect that was significantly different amongst subgroups (p = 0.0359). Glucocorticoids reduced the risk of worsening renal function by 37% (4/11 trials); reported rate of other cardiovascular complications was low. CONCLUSIONS: Administration of systemic glucocorticoids to patients hospitalised with COVID-19 does not lower mortality overall but may reduce it in those requiring respiratory support and increase it in those who do not.

Viral burden and diversity in acute respiratory tract infections in hospitalized children in wet and dry zones of Sri Lanka.

The present study was done to identify the viral diversity, seasonality and burden associated with childhood acute respiratory tract infection (ARTI) in Sri Lanka. Nasopharyngeal aspirates (NPA) of hospitalized children (1 month-5 years) with ARTI were collected in 2 centers (wet and dry zones) from March 2013 to August 2014. Respiratory viral antigen detection by immunofluorescence assay (IFA) was used to identify the infecting viruses. IFA negative 100 NPA samples were tested for human metapeumovirus (hMPV), human bocavirus and corona viruses by polymerase chain reaction. Of the 443 and 418 NPAs, 37.2% and 39.4% were positive for any of the 8 different respiratory viruses tested from two centers studied. Viral co-infection was detected with respiratory syncytial virus (RSV) in both centers. Peak viral detection was noted in the wet zone from May-July 2013 and 2014 and in the dry zone from December-January 2014 suggesting a local seasonality for viral ARTI. RSV showed a clear seasonality with a direct correlation of monthly RSV infections with rainy days in the wet zone and an inverse correlation with temperature in both centers. The case fatality rate was 2.7% for RSV associated ARTI. The overall disability adjusted life years was 335.9 and for RSV associated ARTI it was 241.8. RSV was the commonly detected respiratory virus with an annual seasonality and distribution in rainy seasons in the dry and wet zones of Sri Lanka. Identifying the virus and seasonality will contribute to employ preventive measures and reduce the empirical use of antibiotics in resource limited settings.

Kinetics of antibody response in critically ill patients with Middle East respiratory syndrome and association with mortality and viral clearance.

The objective of this study is to examine the IgG antibody response in critically ill patients with the Middle East respiratory syndrome (MERS) and to examine the association of early antibody response with mortality and viral clearance. We collected blood samples from 40 consecutive real-time reverse transcription-polymerase chain reaction (rRT-PCR) confirmed critically ill MERS patients on ICU days 1, 3, 7, 14 and 28. MERS-CoV antibodies were detected by enzyme-linked immunosorbent assay (ELISA), using wells coated with MERS-CoV S1 antigen. Patients were admitted to ICU after a median (Q1, Q3) of 9 (4, 13) days from onset of symptoms with an admission Sequential Organ Failure Assessment (SOFA) score of 11 (6.5, 12). Among the study cohort, 38 patients (95%) received invasive ventilation, 35 (88%) vasopressors, 21 (53%) renal replacement therapy and 17 (43%) corticosteroids. Median (Q1,Q3) ELISA optical density (OD) ratio significantly increased with time (p < 0.001) from 0.11 (0.07, 1.43) on day 1; to 0.69 (0.11, 2.08) on day 3, 2.72 (1.84, 3.54) on day 7, 2.51 (0.35, 3.35) on day 14 and 3.77 (3.70, 3.84) on day 28. Early antibody response (day 1-3) was observed in 13/39 patients (33%) and was associated with lower mortality (hazard ratio: 0.31, 95% CI 0.10, 0.96, p = 0.04) but was not associated with faster clearance of MERS-CoV RNA. In conclusion, among critically ill patients with MERS, early antibody response was associated with lower mortality but not with faster clearance of MERS-CoV RNA. These findings have important implications for understanding pathogenesis and potential immunotherapy.

25-Hydroxycholesterol-Conjugated EK1 Peptide with Potent and Broad-Spectrum Inhibitory Activity against SARS-CoV-2, Its Variants of Concern, and Other Human Coronaviruses.

The COVID-19 pandemic caused by SARS-CoV-2 infection poses a serious threat to global public health and the economy. The enzymatic product of cholesterol 25-hydroxylase (CH25H), 25-Hydroxycholesterol (25-HC), was reported to have potent anti-SARS-CoV-2 activity. Here, we found that the combination of 25-HC with EK1 peptide, a pan-coronavirus (CoV) fusion inhibitor, showed a synergistic antiviral activity. We then used the method of 25-HC modification to design and synthesize a series of 25-HC-modified peptides and found that a 25-HC-modified EK1 peptide (EK1P4HC) was highly effective against infections caused by SARS-CoV-2, its variants of concern (VOCs), and other human CoVs, such as HCoV-OC43 and HCoV-229E. EK1P4HC could protect newborn mice from lethal HCoV-OC43 infection, suggesting that conjugation of 25-HC with a peptide-based viral inhibitor was a feasible and universal strategy to improve its antiviral activity.

Multi-Organ Histopathological Changes in a Mouse Hepatitis Virus Model of COVID-19.

Infection with SARS-CoV-2, the virus responsible for the global COVID-19 pandemic, causes a respiratory illness that can severely impact other organ systems and is possibly precipitated by cytokine storm, septic shock, thrombosis, and oxidative stress. SARS-CoV-2 infected individuals may be asymptomatic or may experience mild, moderate, or severe symptoms with or without pneumonia. The mechanisms by which SARS-CoV-2 infects humans are largely unknown. Mouse hepatitis virus 1 (MHV-1)-induced infection was used as a highly relevant surrogate animal model for this study. We further characterized this animal model and compared it with SARS-CoV-2 infection in humans. MHV-1 inoculated mice displayed death as well as weight loss, as reported earlier. We showed that MHV-1-infected mice at days 7-8 exhibit severe lung inflammation, peribronchiolar interstitial infiltration, bronchiolar epithelial cell necrosis and intra-alveolar necrotic debris, alveolar exudation (surrounding alveolar walls have capillaries that are dilated and filled with red blood cells), mononuclear cell infiltration, hyaline membrane formation, the presence of hemosiderin-laden macrophages, and interstitial edema. When compared to uninfected mice, the infected mice showed severe liver vascular congestion, luminal thrombosis of portal and sinusoidal vessels, hepatocyte degeneration, cell necrosis, and hemorrhagic changes. Proximal and distal tubular necrosis, hemorrhage in interstitial tissue, and the vacuolation of renal tubules were observed. The heart showed severe interstitial edema, vascular congestion, and dilation, as well as red blood cell extravasation into the interstitium. Upon examination of the MHV-1 infected mice brain, we observed congested blood vessels, perivascular cavitation, cortical pericellular halos, vacuolation of neuropils, darkly stained nuclei, pyknotic nuclei, and associated vacuolation of the neuropil in the cortex, as well as acute eosinophilic necrosis and necrotic neurons with fragmented nuclei and vacuolation in the hippocampus. Our findings suggest that the widespread thrombotic events observed in the surrogate animal model for SARS-CoV-2 mimic the reported findings in SARS-CoV-2 infected humans, representing a highly relevant and safe animal model for the study of the pathophysiologic mechanisms of SARS-CoV-2 for potential therapeutic interventions.

Elevated Expression Levels of Lung Complement Anaphylatoxin, Neutrophil Chemoattractant Chemokine IL-8, and RANTES in MERS-CoV-Infected Patients: Predictive Biomarkers for Disease Severity and Mortality.

The complement system, a network of highly-regulated proteins, represents a vital part of the innate immune response. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement-modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including seven complement proteins, complement regulatory factors, IL-8, and RANTES in MERS-CoV infected patients without underlying chronic medical conditions. Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a, and C3a was positively correlated with IL-8, RANTES, and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P, suggesting positive regulation of the complement during MERS-CoV infection. High levels of lung C5a, C3a, factor P, IL-8, and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8, and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the prediction of functional partners (proteins) of highly expressed proteins (C5a, C3a, factor P, IL-8, and RANTES), the computational protein-protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.