Risk factors and early preventive measures for long COVID in non-hospitalized patients: analysis of a large cohort in the United Arab Emirates.

OBJECTIVES: Long COVID is characterized by persistent symptoms lasting for 4 weeks or more following the acute infection with SARS-CoV-2. Risk factors for long COVID and the impact of pre-COVID vaccination and treatment during acute COVID-19 remain uncertain. This study aimed to investigate patient-specific factors associated with long COVID in a large cohort of non-hospitalized adult patients with mild to moderate COVID-19 in Dubai. STUDY DESIGN: Cohort study. METHODS: The study included 28,375 non-hospitalized adult patients diagnosed with mild to moderate COVID-19 between January 1, 2021, and September 31, 2022, in Dubai, who were followed up for 90 days. The presence of long COVID symptoms was documented by physicians during patient visits to the family medicine department. Furthermore, long COVID-related risk factors were collected and analyzed, including patient demographics, comorbidities, pre-COVID vaccination status, and the COVID-related treatments received during the acute phase of the illness. Cox proportional hazard models were applied for the statistical analysis. RESULTS: Among the cohort, 2.8% of patients experienced long COVID symptoms during the 90-day follow-up. Patients with long COVID tended to be younger, female, and of Caucasian race. Common symptoms included fatigue, muscle pain, respiratory symptoms, abdominal and neurological symptoms, allergic reactions, skin rashes, and hair loss. Risk factors for long COVID were identified as diabetes mellitus, asthma, and Vitamin D deficiency. Females and Caucasians had a higher risk of long COVID during the pre-Omicron period compared to the Omicron period. Pre-COVID vaccination was associated with a reduced risk of long COVID in all patient subgroups. Treatment with favipiravir or sotrovimab during the acute phase of COVID-19 was linked to a decreased risk of long COVID, although favipiravir showed limited effectiveness in the high-risk group. CONCLUSION: This study contributes to the existing knowledge by identifying risk factors for long COVID among non-hospitalized patients and emphasizing the potential benefits of pre-COVID vaccination and timely treatment.

Multiple inborn errors of type I IFN immunity in a 33-year-old male with a fatal case of COVID-19.

The host genetic inborn errors of immunity (IEIs) have been shown to contribute to susceptibility to life-threatening coronavirus disease 2019 (COVID-19), as it had been associated previously with other viral infections. Most genetic association studies have described IEIs as a monogenic defect, while there have been no reports of patients with multiple inherited immune deficiencies. This is a complex case of IEIs predisposing to severe viral infections in an unvaccinated 33-year-old male patient. The patient was admitted with no respiratory symptoms, showed a SARS-CoV-2 PCR positive test on the second day of admission, started developing progressive lung consolidation within three days of hospitalization, and was moved from non-invasive to mechanical ventilation within 12 days of hospitalization. Impaired production of type I IFN was detected in patient PBMCs treated with poly(I:C), at both mRNA and protein levels. Whole exome sequencing revealed three mutations across type I IFN production pathway, which were predicted to be loss-of-function (pLOF). The three mutations were predicted to predispose to severe viral infections: monoallelic R488X TLR3, monoallelic His684Arg TLR3, and biallelic Val363Met IRF3. Functional analysis confirmed that all these mutations dysregulated the type I IFN pathway. Evaluation of TLR3 and IRF3 IFN-ß1 luciferase reporter activity showed a hypomorphic suppression of function. TOPO TA cloning was used to ascertain the positioning of both TLR3 variants, indicating that both variants were on the same allele. We have described a unique complex IEI patient with multiple mutations, particularly along type I IFN production pathway.

Salivary autoantibodies to type I IFNs: Mirror plasma levels, predispose to severe COVID-19, and enhance feasibility for clinical screening.

BACKGROUND: Autoantibodies have been demonstrated to dampen the interferon (IFN) response in viral infections. Elevated levels of these preexisting autoantibodies (aAbs) decrease basal interferon levels, increasing susceptibility to severe infections. OBJECTIVES: This study aimed to evaluate the prevalence of type I IFN aAbs in both plasma and saliva from COVID-19 patients, analyze their neutralizing activity, and examine their associations with clinical outcomes, including the need for mechanical ventilation and in-hospital mortality. METHODS: Prospective analyses of patients admitted to intensive care units in three UAE hospitals from June 2020 to March 2021 were performed to measure aAbs using enzyme-linked immunosorbent assay (ELISA), assess aAbs activity via neutralization assays, and correlate aAbs with clinical outcomes. RESULTS: Type I IFN aAbs (α2 and/or ω) were measured in plasma samples from 213 ICU patients, and positive results were obtained for 20 % (n = 42) of the patients, with half exhibiting neutralizing activity. Saliva samples from a subgroup of 24 patients reflected plasma levels. In multivariate regression analyses, presence of type I IFN aAbs was associated with a higher need for mechanical ventilation (OR 2.58; 95 % CI 1.07-6.22) and greater in-hospital mortality (OR 2.40; 95 % CI 1.13 - 5.07; P = 0.022). Similarly, positive neutralizing aAbs (naAbs) were associated with a greater need for mechanical ventilation (OR 4.96; 95 % CI 1.12-22.07; P = 0.035) and greater odds of in-hospital mortality (OR 2.87; 95 % CI 1.05-7.89; P = 0.041). CONCLUSIONS: Type I IFN autoantibodies can be detected in noninvasive saliva samples, alongside conventional plasma samples, from COVID-19 patients and are associated with worse outcomes, such as greater mechanical ventilation needs and in-hospital mortality.

Clinical pharmacist interventions in an intensive care unit reduces ICU mortality at a tertiary hospital in Dubai, United Arab Emirates.

Background: Drug-related problems (DRPs) are prevalent in critical care settings and can be life-threatening. Involving clinical pharmacists (CP) within the critical care team is recommended to optimize therapy and improve patient survival. Objective: To classify DRPs identified by a CP in the Intensive Care Unit (ICU) and to assess the impact of CP interventions accepted by physicians on the length of ICU stay and in-hospital survival. Methods: This study was conducted prospectively at the Medical ICU of Rashid Hospital, a tertiary hospital in Dubai, over a 16-month period from September 2021 to December 2022. The study included patients admitted to ICU during the study period. CP interventions were documented, and DRPs were classified using the modified Pharmaceutical Care Network Europe V.9.1. Results: During the study period, 1004 interventions were recommended for 200 patients. The majority of these interventions, 92% (n = 922), received physician acceptance, and 82% (n = 820) were fully implemented by the physician. In total, 1033 drug-related problems (DRPs) were identified, with a median of 3 DRPs per patient. The most common DRPs was drug selection (61%), followed by dose selection (22%). There were 337 DRPs related to antimicrobial agents. Interestingly, we noted that when we adjusted for patients' demographic data and the Glasgow Coma Scale severity score, patients who received >4 implemented interventions exhibited lower cumulative hazard of death within 90 days of their ICU stay in comparison to their counterparts (adjusted Hazard Ratio: 0.10, 95% CI of 0.02-0.41; P = 0.027). Conclusion: The study emphasizes the critical role of CP in the ICU, addressing DRPs, and enhancing overall patient care. Furthermore, it highlights the potential impact of pharmacist interventions in improving patient survival outcomes. This underscores the importance of implementing CP services in ICUs across the UAE.

Unraveling the gut-Lung axis: Exploring complex mechanisms in disease interplay.

The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung diseases via multifaceted mechanisms. Advancements in omics and metagenomics technologies revealed a potential link between gut and lung microbiota, adding further complexity to GLA. Despite substantial studies on GLA in various disease models, mechanisms beyond microbial dysbiosis regulating the interplay between gut and lung tissues during disease conditions are not thoroughly reviewed. This review outlines disease specific GLA mechanisms, emphasizing research gaps with a focus on gut-to-lung direction based on current GLA literature. Moreover, the review discusses potential gut microbiota and their products like metabolites, immune modulators, and non-bacterial contributions as a basis for developing treatment strategies for lung diseases. Advanced experimental methods, modern diagnostic tools, and technological advancements are also highlighted as crucial areas for improvement in developing novel therapeutic approaches for GLA-related diseases. In conclusion, this review underscores the importance of exploring additional mechanisms within the GLA to gain a deeper understanding that could aid in preventing and treating a wide spectrum of lung diseases.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population.

BACKGROUND: Prostate cancer (PCa) is a prevalent disease worldwide. However, the incidence and patient-specific risk factors of PCa in the Middle East, specifically in the United Arab Emirates, have not been previously reported. METHODS: We conducted a retrospective cohort study on 2377 men diagnosed with either benign prostatic hyperplasia (BPH) or PCa in the Northern and Eastern regions of the United Arab Emirates, excluding the Western part, which includes Abu Dhabi. The study spanned from January 2012 and December 2021. To calculate the PCa incidence rate, we utilized the world age-standardized incidence rates (W-ASIR) categorized by age groups. Patient-specific risk factors of PCa were identified through a multivariate logistic regression analysis of clinical data. RESULTS: A total of 247 cases of PCa and 2130 cases of BPH were included in the study. In our cohort, the W-ASIR for PCa was 21.3 per 100,000 men. The incidence of PCa showed an increasing trend with age, with the highest incidence observed among men aged 70 years and older. Accordingly, multivariate analysis revealed that age over 70 was associated with an increased risk of PCa (OR: 2.546, 95% confidence interval [CI]: 1.892-3.425, p < 0.01). On the other hand, preexisting conditions such as hypertension and diabetes mellitus were found to lower the risk of PCa (OR: 0.222, 95% CI: 0.163-0.302, p < 0.001) and (OR: 0.364, 95% CI: 0.205-0.648, p < 0.001), respectively. Additionally, metformin intake was associated with a reduced risk of PCa (OR: 0.385, 95% CI: 0.190-0.782, p = 0.008); while insulin usage increased the risk of PCa (OR: 2.586, 95% CI: 1.539-4.344, p < 0.001). Anti-BPH medications such as phosphodiesterase inhibitors (OR: 0.223, 95% CI: 0.069-0.723, p = 0.012) or 5-α reductase (OR: 0.206, 95% CI: 0.110-0.389, p < 0.000), were found to lower the risk of PCa. CONCLUSION: The findings underscore the high incidence of PCa in the United Arab Emirates, with age being a significant factor. Furthermore, the study highlights the influence of certain comorbidities and medications on the risk of developing PCa within the United Arab Emirates population.

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons.

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. While regulatory T (Treg) and B (Breg) cells, as the main elements of immune homeostasis, contribute to the control of hyperinflammation during COVID-19 infection, we hypothesized change in their levels in relation to disease severity and the presence of autoantibodies (auto-Abs) to type I IFNs. Cytometric analysis of blood of 62 COVID-19 patients with different severities revealed an increased proportion of conventional (cTreg; CD25+FoxP3+) and unconventional (uTreg; CD25-FoxP3+) Tregs, as well as the LAG3+ immune suppressive form of cTreg/uTreg, in the blood of severe COVID-19 cases compared to the milder, non-hospitalized cases. The increase in blood levels of cTreg/uTreg, but not LAG3+ cTreg/uTreg subtypes, was even higher among patients with severe COVID-19 and auto-Abs to type I IFNs. Regarding Bregs, compared to the milder, non-hospitalized cases, the proportion of IL-35+ and IL-10+ Bregs was elevated in the blood of severe COVID-19 patients, and to a higher extent in those with auto-Abs to type I IFNs. Moreover, blood levels of cTreg, LAG3+ cTreg/uTreg, and IL-35+ and IL-10+ Breg subtypes were associated with lower blood levels of proinflammatory cytokines such as IL-6, IL-17, TNFα, and IL-1ß. Interestingly, patients who were treated with either tocilizumab and/or a high dose of Vitamin D had higher blood levels of these regulatory cells and better control of the proinflammatory cytokines. These observations suggest that perturbations in the levels of immunomodulatory Tregs and Bregs occur in COVID-19, especially in the presence of auto-Abs to type I IFNs.

Nucleic acid sensor STING drives remodeling and its inhibition enhances steroid responsiveness in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is progressive and irreversible chronic lung inflammatory disease. Cigarette smoke, the main cause of COPD, is often associated with double-stranded DNA release which potentially activates DNA-sensing pathways, such as STING. This study, therefore, analyzed the role of STING pathway in inducing pulmonary inflammation, steroid resistance, and remodeling in COPD. METHODS: Primary cultured lung fibroblasts were isolated from healthy non-smoker, healthy smoker, and smoker COPD individuals. The expression of STING pathway, remodeling, and steroid resistance signatures were investigated in these fibroblasts upon LPS stimulation and treatment with dexamethasone and/or STING inhibitor, at both mRNA and protein levels using qRT-PCR, western blot, and ELISA. RESULTS: At baseline, STING was elevated in healthy smoker fibroblasts and to a higher extent in smoker COPD fibroblasts when compared to healthy non-smoker fibroblasts. Upon using dexamethasone as monotherapy, STING activity was significantly inhibited in healthy non-smoker fibroblasts but showed resistance in COPD fibroblasts. Treating both healthy and COPD fibroblasts with STING inhibitor in combination with dexamethasone additively inhibited STING pathway in both groups. Moreover, STING stimulation triggered a significant increase in remodeling markers and a reduction in HDAC2 expression. Interestingly, treating COPD fibroblasts with the combination of STING inhibitor and dexamethasone alleviated remodeling and reversed steroid hyporesponsiveness through an upregulation of HDAC2. CONCLUSION: These findings support that STING pathway plays an important role in COPD pathogenesis, via inducing pulmonary inflammation, steroid resistance, and remodeling. This raises the possibility of using STING inhibitor as a potential therapeutic adjuvant in combination with common steroid treatment.

Risks of prostate cancer and mortality in the city of Sharjah, United Arab Emirates.

Background: Prostatic hyperplasia (BPH) and prostate cancer (PCa) are common age-related diseases in men. According to World Health Organization (WHO), PCa is the second most common cancer among Emirati men. This study aimed to identify the risk factors associated with PCa and mortality in a cohort diagnosed with PCa between 2012 and 2021 in Sharjah, United Arab Emirates (UAE). Methods: The data collected in this retrospective case-control study included patient demographics and comorbidities, as well as PCa markers such as prostate-specific antigen (PSA), prostate volume, prostate-specific antigen density (PSAD), and Gleason scores. Risk factors for PCa were assessed using multivariate logistic regression analysis, and factors associated with all-cause mortality in PCa patients were evaluated using Cox-proportional hazard analysis. Results: Of the 192 cases analyzed in this study, 88 were diagnosed with PCa and 104 were diagnosed with BPH. Regarding risk factors for PCa, a higher risk of PCa was associated with age 65 or older (OR=2.76, 95% confidence interval (CI): 1.04-7.30; P=0.038) and serum PSAD greater than 0.1 ng/mL2 (OR=3.48, 95% CI:1.66-7.32; P=0.001), whereas being of UAE nationals (OR=0.40, 95% CI:0.18-0.88; P=0.029) were associated with lower risk of PCa, after adjusting for patient demographics and comorbidities. Moreover, regarding cancer markers, higher serum PSA level (P=0.003) and smaller prostate volume (P=0.028) were associated with a higher risk of PCa, after adjusting with patients' age and BMI. Additionally, a high-grade Gleason score was associated with an increased risk of all-cause mortality after adjusting for patient's age and BMI (hazard ratio, aHR= 2.3, 95% CI:1.3-4.1; P= 0.016). Conclusion: This study found that age 65 or older and serum PSAD greater than 0.1 ng/mL2 are risk factors for PCa, while UAE nationality is associated with a lower risk. PSAD may be a better screening marker for PCa compared to traditional markers such as PSA and prostate volume.

Simvastatin reduced infiltration of memory subsets of T lymphocytes in the lung tissue during Th2 allergic inflammation.

Lymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.

Airways tissue expression of type I interferons and their stimulated genes is higher in children than adults.

There is emerging evidence that age-dependent differences in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with stronger innate immune response in the upper respiratory tract in children compared to adults. The efficient induction of interferon (IFN) alpha and beta (α and ß) signaling, and interferon-stimulated genes (ISGs) is fundamental to the host antiviral response. In-silico transcriptomic analyses was conducted to determine the expression levels of IFN α/ß pathway genes as well as 524 human ISGs in upper and lower airways of children and adults at baseline and post respiratory infections including coronavirus disease 2019 (COVID-19). To validate our in-silico analysis, we conducted qRT-PCR to measure ISGs levels in children and adult's nasal epithelial samples. At baseline, children had significantly higher levels of IFN α/ß and ISGs genes compared to adults. More distinction was also seen in bronchial compared to nasal basal levels. Children nasal epithelial cells exhibited superior antiviral IFN α/ß and associated ISGs response following ex-vivo poly (I:C) treatment model, and in clinical samples of SARS-CoV-2 infected patients. This was also confirmed in nasal epithelial samples using qRT-PCR validation. No gender-based difference in type I IFN levels across both age groups were observed. Understanding the biological basis for children resistance against severe COVID-19 is a challenge that has substantial clinical importance. More mechanistic studies are needed to carefully quantify how much of early IFN levels is needed to bypass the viral evasion mechanism and prevent its further replication and dissemination to lower airways and the rest of the body.

Saliva metabolomic profile of COVID-19 patients associates with disease severity.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is strongly linked to dysregulation of various molecular, cellular, and physiological processes that change abundance of different biomolecules including metabolites that may be ultimately used as biomarkers for disease progression and severity. It is important at early stage to readily distinguish those patients that are likely to progress to moderate and severe stages. OBJECTIVES: This study aimed to investigate the utility of saliva and plasma metabolomic profiles as a potential parameter for risk stratifying COVID-19 patients. METHOD: LC-MS/MS-based untargeted metabolomics were used to profile the changes in saliva and plasma metabolomic profiles of COVID-19 patients with different severities. RESULTS: Saliva and plasma metabolites were screened in 62 COVID-19 patients and 18 non-infected controls. The COVID-19 group included 16 severe, 15 moderate, 16 mild, and 15 asymptomatic cases. Thirty-six differential metabolites were detected in COVID-19 versus control comparisons. SARS-CoV-2 induced metabolic derangement differed with infection severity. The metabolic changes were identified in saliva and plasma, however, saliva showed higher intensity of metabolic changes. Levels of saliva metabolites such as sphingosine and kynurenine were significantly different between COVID-19 infected and non-infected individuals; while linoleic acid and Alpha-ketoisovaleric acid were specifically increased in severe compared to non-severe patients. As expected, the two prognostic biomarkers of C-reactive protein and D-dimer were negatively correlated with sphingosine and 5-Aminolevulinic acid, and positively correlated with L-Tryptophan and L-Kynurenine. CONCLUSION: Saliva disease-specific and severity-specific metabolite could be employed as potential COVID-19 diagnostic and prognostic biomarkers.

Vitamin D enhances type I IFN signaling in COVID-19 patients.

The ability of Vitamin D (VitD) to modulate antiviral responses through induction of antimicrobial peptide is well established. However, the effect of VitD on host responses to SARS-CoV-2 is not well investigated. We here report the ability of VitD to enhance host IFN-alpha/beta (a/ß) signaling both in vitro and among severe COVID-19 patients treated with VitD. Blood and saliva specimens were obtained from severe COVID-19 patients treated (43 patients), or not (37 patients), with vitD, during their stay in intensive care unit. Patients were followed up to 29 days following admission, and patient survival outcomes were collected. Higher activity levels of RIG-1/MDA-5 and JAK-STAT signaling pathways were observed with significantly higher gene and protein levels of antiviral interferon stimulating genes (ISGs) such as MX-1 and ISG-15; both in vitro, following treatment of PBMCs with vitD, and in whole blood and saliva specimens of VitD treated patients. Moreover, VitD treated patients had lower risk of all-cause mortality by day 29 compared to untreated patients (adjusted hazard ratio, 0.37, 95% confidence interval of 0.14-0.94; P = 0.038). The herein uncovered regulatory role of VitD on type I IFNs suggests the importance of insuring a normal level of VitD for the prevention and probably treatment of SARS-CoV-2 infection. Additional mechanistic studies, however, are needed to fully elucidate the antiviral effects of VitD particularly in the setting of COVID-19 infection.

Upregulation of interleukin-19 in saliva of patients with COVID-19.

Cytokines are major players in orchestrating inflammation, disease pathogenesis and severity during COVID-19 disease. However, the role of IL-19 in COVID-19 pathogenesis remains elusive. Herein, through the analysis of transcriptomic datasets of SARS-CoV-2 infected lung cells, nasopharyngeal swabs, and lung autopsies of COVID-19 patients, we report that expression levels of IL-19 and its receptor, IL-20R2, were upregulated following SARS-CoV-2 infection. Of 202 adult COVID-19 patients, IL-19 protein level was significantly higher in blood and saliva of asymptomatic patients compared to healthy controls when adjusted for patients' demographics (P < 0.001). Interestingly, high saliva IL-19 level was also associated with COVID-19 severity (P < 0.0001), need for mechanical ventilation (P = 0.002), and/or death (P = 0.010) within 29 days of admission, after adjusting for patients' demographics, diabetes mellitus comorbidity, and COVID-19 serum markers of severity such as D-dimer, C-reactive protein, and ferritin. Moreover, patients who received interferon beta during their hospital stay had lower plasma IL-19 concentrations (24 pg mL-1) than those who received tocilizumab (39.2 pg mL-1) or corticosteroids (42.5 pg mL-1). Our findings indicate that high saliva IL-19 level was associated with COVID-19 infectivity and disease severity.

Sotrovimab Lowers the Risk of COVID-19 Related Hospitalization or Death in a Large Population Cohort in the United Arab Emirates.

Sotrovimab, an anti-severe acute respiratory syndrome-coronavirus 2 monoclonal antibody is being utilized to prevent progression of coronavirus disease 2019 (COVID-19). Therefore, to understand its benefits, we have conducted a retrospective analysis of all non-hospitalized patients with symptomatic COVID-19 who received a single infusion of sotrovimab and/or oral favipiravir at any Dubai COVID-19 related healthcare center between July 1, 2021, and October 31, 2021. The main outcome was to evaluate the risk of hospitalization for patients with COVID-19 or all-cause death within 28 days of treatment initiation. In this analysis, which included 10,882 patients (1,135 in the sotrovimab group, 2,653 in the sotrovimab/favipiravir group, and 7,094 in the favipiravir group), sotrovimab or sotrovimab/favipiravir reduced the risk of hospitalization (13 patients (1.5%) in the sotrovimab group and 71 patients (2.9%) in the sotrovimab/favipiravir group vs. 251 patients (4%) in the favipiravir group; hazard ratio (HR) for sotrovimab: 0.16, 95% confidence interval (CI): 0.09-0.28, P < 0.001; and for sotrovimab/favipiravir, HR: 0.42, 95% CI: 0.32-0.56, P < 0.001), or death by day 28 from the start of treatment (no death in the sotrovimab group and 2 deaths in the the sotrovimab/favipiravir group vs. 10 deaths in the favipiravir group; odds ratio: 0.18, 95% CI: 0.04 to 0.81, P = 026). Safety was assessed in all the 3,788 patients in the sotrovimab and sotrovimab/favipiravir groups, and the reported adverse events were by 34 patients (<1%). In conclusion, sotrovimab was found to reduce the risk of progression of COVID-19 when administrated early to non-hospitalized patients with symptomatic COVID-19. No safety concern was detected.

Favipiravir Effectiveness and Safety in Hospitalized Moderate-Severe COVID-19 Patients: Observational Prospective Multicenter Investigation in Saudi Arabia.

Objectives: There are limited data on the efficacy and safety of favipiravir antiviral in coronavirus disease 2019 (COVID-19), particularly in the more progressed disease phase. This study aims to evaluate the favipiravir effect on reducing the length of hospital stay and in-hospital mortality among moderate and severe hospitalized COVID-19 patients. Methods: A prospective, multicenter observational study was conducted that included moderate and severe hospitalized adult COVID-19 patients in four major regions (Riyadh (Riyadh), Eastern (Dammam), Al-Qassem (Buraydah), and Macca (Jeddah) of Saudi Arabia. For the primary outcome of all-cause mortality, a Cox proportional hazard analysis was performed. While the association between favipiravir use and length of hospital stay was determined using adjusted generalized linear model. This study was approved by the Central Institutional Review Board in The Saudi Ministry of Health (MoH) with the approval number IRB # 20-85-M. Results: This study included 598 moderate and severe COVID-19 patients, of whom 156 (26%) received favipiravir. Favipiravir treatment was associated with more extended hospital stays (14 vs. 10 median days, P = 0.034) and higher mortality rate (aHR 3.63; 95% CI 1.06-12.45) compared to no favipiravir regimen. Despite lack of effectiveness, favipiravir use was only associated with higher diarrhea adverse effects (12 vs. 5%, P = 0.002), but it did not affect the renal and liver profiles of patients. Conclusion: Favipiravir was ineffective in reducing the length of hospital stay and in-hospital mortality in patients with moderate and severe COVID-19.

Enhanced Infiltration of Central Memory T Cells to the Lung Tissue during Allergic Lung Inflammation.

Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (TEM) and central memory (TCM) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent TCM phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of TCM cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of TCM cells to lung tissues during allergic airway inflammation. Expression levels of TCM homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased TCM infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of TCM profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for TEM cells during lung inflammation, suggesting a shift for TEM into the TCM state. To our knowledge, this is the first study to report an increased infiltration of TCM cells into inflamed lung tissues and to suggest differentiation of TEM to TCM cells in these tissues. Therapeutic interference at TCM infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.

Psychological Distress and Anxiety Levels Among Health Care Workers at the Height of the COVID-19 Pandemic in the United Arab Emirates.

Objectives: Providing medical care during a global pandemic exposes healthcare workers (HCW) to a high level of risk, causing anxiety and stress. This study aimed to assess the prevalence of anxiety and psychological distress among HCWs during COVID-19. Methods: We invited HCWs from 3 hospitals across the United Arab Emirates (UAE) to participate in an anonymous online survey between April 19-May 3, 2020. The GAD-7 and K10 measures were used to assess anxiety and psychological distress. Logistic regression models assessed associations between knowledge, attitude, worry, and levels of anxiety and psychological distress. Results: A total of 481 HCWs participated in this study. The majority of HCWs were female (73.6%) and aged 25-34 years (52.6%). More than half were nurses (55.7%) and had good knowledge of COVID-19 (86.3%). Over a third (37%) of HCWs reported moderate/severe psychological distress in the K10 measure and moderate/severe anxiety (32.3%) in the GAD-7, with frontline workers significantly reporting higher levels of anxiety (36%). Knowledge of COVID-19 did not predict anxiety and psychological distress, however, HCWs who believed COVID-19 was difficult to treat and those who perceived they were at high risk of infection had worse mental health outcomes. Worry about spreading COVID-19 to family, being isolated, contracting COVID-19 and feeling stigmatized had 1.8- to 2.5-fold increased odds of symptoms of mental health problems. Additionally, HCWs who felt the need for psychological support through their workplace showed increased odds of psychological distress. Conclusion: HCWs in the UAE reported a high prevalence of psychological distress and anxiety while responding to the challenges of COVID-19. The findings from this study emphasize the public, emotional and mental health burden of COVID-19 and highlight the importance for health systems to implement, monitor, and update preventive policies to protect HCWs from contracting the virus while also providing psychological support in the workplace.

Early administration of remdesivir to COVID-19 patients associates with higher recovery rate and lower need for ICU admission: A retrospective cohort study.

OBJECTIVES: Remdesivir is one of the most widely recommended and used medications for COVID-19 treatment. However, different outcomes have been reported for hospitalized patients with COVID-19 treated with remdesivir. Specifically, the effect of the timing of remdesivir initiation (from patient's symptom onset) on clinical outcomes in COVID-19 patients has not been investigated. METHODS: This is a retrospective cohort study of patients hospitalized with COVID-19 and treated with or without remdisivir. The primary outcome was patient's recovery rate, defined as clinical improvement and patient's discharge by day 14 of symptom onset. The secondary outcome was the need for intensive care unit (ICU) admission, mechanical ventilation, and mortality within 28 days of patient's symptom onset. RESULTS: Out of 323 hospitalized adults with COVID-19, 107 (33.1%) received no remdesivir during their hospital stay, 107 (33.1%) received remdesivir early within 7 days of the symptom onset, and 109 (33.7%) received it at 8 days or later of symptom onset. At day 14 following symptom onset, higher proportion of patients recovered in the early remdesivir compared to the late remdesivir cohort, or patients who did not receive remdesivir (adjusted odds ratio, aOR, 2.65; 95% confidence interval [CI], 1.31 to 5.35). Moreover, early administration of remdesivir was associated with lower admission to intensive care unit (adjusted hazard ratio [aHR], 0.31; 95% CI, 0.15 to 0.64), less need for mechanical ventilation (aHR, 0.22; 95% CI, 0.10 to 0.51), and lower mortality at 28 days (aHR, 0.15; 95% CI, 0.04 to 0.53), as compared to the late remdesivir cohort or patients who did not receive remdesivir. CONCLUSION: Early administration of remdesivir within 7 days of symptom onset is associated with less need for mechanical ventilation and lower 28-days mortality.