Longevity of Middle East Respiratory Syndrome Coronavirus Antibody Responses in Humans, Saudi Arabia.

Understanding the immune response to Middle East respiratory syndrome coronavirus (MERS-CoV) is crucial for disease prevention and vaccine development. We studied the antibody responses in 48 human MERS-CoV infection survivors who had variable disease severity in Saudi Arabia. MERS-CoV-specific neutralizing antibodies were detected for 6 years postinfection.

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.

Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case-control study.

OBJECTIVES: Vitamin D status in patients with COVID-19 is an on-going controversial issue. This study aims to determine differences in the serum 25(OH)D concentrations of Arab Gulf adult residents screened for SARS-CoV-2 and its association with risk of COVID-19 infection together with other comorbidities. METHODS: In this multi-center, case-control study, a total of 220 male and female adults presenting with none to mild symptoms were screened for COVID-19 (n = 138 RT-PCR-confirmed SARS-CoV-2 positive and 82 negative controls). Medical history was noted. Anthropometrics were measured and non-fasting blood samples were collected for the assessment of glucose, lipids, inflammatory markers and serum 25(OH)D concentrations. RESULTS: Serum 25(OH)D levels were significantly lower in the SARS-CoV-2 positive group compared to the negative group after adjustment for age and BMI (52.8 nmol/l ± 11.0 versus 64.5 nmol/l ± 11.1; p = 0.009). Being elderly (> 60 years) [Odds ratio 6 (95% Confidence Interval, CI 2-18; p = 0.001) as well as having type 2 diabetes (T2D) [OR 6 (95% CI 3-14); p < 0.001)] and low HDL cholesterol (HDL-c) [OR 6 (95% CI 3-14); p < 0.001)] were significant risk factors for COVID-19 infection independent of age, sex and obesity. CONCLUSIONS: Among Arab Gulf residents screened for SARS-CoV-2, serum 25(OH) D levels were observed to be lower in those who tested positive than negative individuals, but it was the presence of old age, diabetes mellitus and low-HDL-c that were significantly associated with risk of COVID-19 infection. Large population-based randomized controlled trials should be conducted to assess the protective effects of vitamin D supplementation against COVID-19.

Antigenic drift of hemagglutinin and neuraminidase in seasonal H1N1 influenza viruses from Saudi Arabia in 2014 to 2015.

Antigenic drift of the hemagglutinin (HA) and neuraminidase (NA) proteins of the influenza virus cause a decrease in vaccine efficacy. Since the information about the evolution of these viruses in Saudi is deficient so we investigated the genetic diversity of circulating H1N1 viruses. Nasopharyngeal aspirates/swabs collected from 149 patients hospitalized with flu-like symptoms during 2014 and 2015 were analyzed. Viral RNA extraction was followed by a reverse transcription-polymerase chain reaction and genetic sequencing. We analyzed complete gene sequences of HA and NA from 80 positive isolates. Phylogenetic analysis of HA and NA genes of 80 isolates showed similar topologies and co-circulation of clades 6b. Genetic diversity was observed among circulating viruses belonging to clade 6B.1A. The amino acid residues in the HA epitope domain were under purifying selection. Amino acid changes at key antigenic sites, such as position S101N, S179N (antigenic site-Sa), I233T (antigenic site-Sb) in the head domain might have resulted in antigenic drift and emergence of variant viruses. For NA protein, 36% isolates showed the presence of amino acid changes such as V13I (n = 29), I314M (n = 29) and 12% had I34V (n = 10). However, H257Y mutation responsible for resistance to neuraminidase inhibitors was missing. The presence of amino acid changes at key antigenic sites and their topologies with structural mapping of residues under purifying selection highlights the importance of antigenic drift and warrants further characterization of recently circulating viruses in view of vaccine effectiveness. The co-circulation of several clades and the predominance of clade 6B.1 suggest multiple introductions in Saudi.

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract.

MERS-CoV, a highly pathogenic virus in humans, is associated with high morbidity and case fatality. Inflammatory responses have a significant impact on MERS-CoV pathogenesis and disease outcome. However, CD4+ T-cell induced immune responses during acute MERS-CoV infection are barely detectable, with potent inhibition of effector T cells and downregulation of antigen presentation. The local pulmonary immune response, particularly the Th1 and Th2-related immune response during acute severe MERS-CoV infection is not fully understood. In this study, we offer the first insights into the pulmonary gene expression profile of Th1 and Th2-related cytokines/chemokines (Th1 & Th2 responses) during acute MERS-CoV infection using RT2 Profiler PCR Arrays. We also quantified the expression level of primary inflammatory cytokines/chemokines. Our results showed a downregulation of Th2, inadequate (partial) Th1 immune response and high expression levels of inflammatory cytokines IL-1α and IL-1ß and the neutrophil chemoattractant chemokine IL-8 (CXCL8) in the lower respiratory tract of MERS-CoV infected patients. Moreover, we identified a high viral load in all included patients. We also observed a correlation between inflammatory cytokines, Th1, and Th2 downregulation and the case fatality rate. Th1 and Th2 response downregulation, high expression of inflammatory cytokines, and high viral load may contribute to lung inflammation, severe infection, the evolution of pneumonia and ARDS, and a higher case fatality rate. Further study of the molecular mechanisms underlying the Th1 and Th2 regulatory pathways will be vital for active vaccine development and the identification of novel therapeutic strategies.

Lysozyme's lectin-like characteristics facilitates its immune defense function.

Interactions between human lysozyme (HL) and the lipopolysaccharide (LPS) of Klebsiella pneumoniae O1, a causative agent of lung infection, were identified by surface plasmon resonance. To characterize the molecular mechanism of this interaction, HL binding to synthetic disaccharides and tetrasaccharides representing one and two repeating units, respectively, of the O-chain of this LPS were studied. pH-dependent structural rearrangements of HL after interaction with the disaccharide were observed through nuclear magnetic resonance. The crystal structure of the HL-tetrasaccharide complex revealed carbohydrate chain packing into the A, B, C, and D binding sites of HL, which primarily occurred through residue-specific, direct or water-mediated hydrogen bonds and hydrophobic contacts. Overall, these results support a crucial role of the Glu35/Asp53/Trp63/Asp102 residues in HL binding to the tetrasaccharide. These observations suggest an unknown glycan-guided mechanism that underlies recognition of the bacterial cell wall by lysozyme and may complement the HL immune defense function.

Impact of Mycobacterium tuberculosis complex lineages as a determinant of disease phenotypes from an immigrant rich moderate tuberculosis burden country.

BACKGROUND: Growing evidences suggested that the Mycobacterium tuberculosis complex (MTBC) lineages can determine the clinical outcome of pulmonary and extra-pulmonary tuberculosis. However, limited data only available revealing such association of bacterial genotypes and clinical phenotypes from immigrant rich countries. METHODS: A multicenter study has been carried out on a collection of 2092 (1003 extrapulmonary and 1089 pulmonary) MTBC isolates. Genotyping of all the isolates were carried out by spoligotyping and 24 loci based MIRU-VNTR typing. RESULTS: Demographically domination of young Saudi nationals (61.4%) and men (61.2%) were found in this cohort. Lymph nodes (62.4%) and gastrointestinal sites (16.7%) were the most common anatomical sites of infection. The predominant lineages were Delhi/CAS (26.9%), EAI (14.2%) and Ghana (9.9%). Mycobacterium africanum type I and II were reported for the first time in the country among extrapulmonary cases. 'Ancestral' lineages M.bovis (OR-5.22; 95% CI-2.23-8.22, p- < 0.001) and Delhi/CAS (OR-0.57; 95% CI-0.411-0.734, p- < 0.001) were directly associated with lymph node tuberculosis and gastrointestinal tuberculosis (M. bovis-OR-0.33; 95% CI-0.085-0.567, p-0.001 and Delhi/CAS-OR-1.87; 95% CI-1.22-2.53, p- < 0.001) respectively. Among the 'Modern' lineages, EAI showed significant association to central nervous system tuberculosis (OR-1.98; 95% CI-0.76-3.19, p-0.04) and Uganda-I to gastrointestinal tuberculosis (OR-2.41; 95% CI-0.77-4.06, p-0.02). CONCLUSIONS: The findings substantially contribute to the emerging evidences that MTBC lineages influence disease phenotypes and epidemiological consequences.

Impact of carbapenem versus non-carbapenem treatment on the rates of superinfection: A meta-analysis of randomized controlled trials.

Imipenem and meropenem are the recommended antipseudomonal carbapenems for nosocomial pneumonia per clinical practice guidelines. However, these agents have a relatively broader spectrum of activity than other antibiotics and need to be reserved. Carbapenems might cause higher rate of superinfection. The aim of this study was to compare the rate of superinfection between patients who received imipenem or meropenem versus those who received non-carbapenem treatment. PubMed, EMBASE, Cochrane Library databases and two trial registries were searched for relevant randomized controlled trials of hospitalized adults with pneumonia through February 24, 2017 without date or language restrictions. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using random-effects models. The primary outcome was based on the intention-to-treat analysis while clinically evaluable patients were analyzed as secondary outcome. Eight RCTs were included in this meta-analysis. A statistically higher risk of superinfection with low heterogeneity (RR = 1.690, 95% CI 1.247-2.291, p = 0.001, I2 = 0%) was associated with the two carbapenems compared to non-carbapenems. However, in comparison with non-carbapenems, superinfection with imipenem was significantly higher (RR = 1.694, 95% CI 1.234-2.325, p = 0.001, I2 = 0%), while it was non-significant with meropenem (RR = 1.647, 95% CI 0.552-4.919, p = 0.371, I2 = 0%). Superinfection was statistically higher in both double-blind and open-label studies and when carbapenems were compared to other antipseudomonal beta-lactams. This meta-analysis identified significantly higher superinfection with imipenem compared to non-carbapenems. The findings confirm the theory of higher superinfections with broader spectrum agents and provide additional support for reserving carbapenems for the treatment of infections caused by multidrug-resistant organisms.

Acute Middle East Respiratory Syndrome Coronavirus: Temporal Lung Changes Observed on the Chest Radiographs of 55 Patients.

OBJECTIVE: The objective of our study was to describe lung changes on serial chest radiographs from patients infected with the acute Middle East respiratory syndrome corona-virus (MERS-CoV) and to compare the chest radiographic findings and final outcomes with those of health care workers (HCWs) infected with the same virus. Chest radiographic scores and comorbidities were also examined as indicators of a fatal outcome to determine their potential prognostic value. MATERIALS AND METHODS: Chest radiographs of 33 patients and 22 HCWs infected with MERS-CoV were examined for radiologic features indicative of disease and for evidence of radiographic deterioration and progression. Chest radiographic scores were estimated after dividing each lung into three zones. The scores (1 [mild] to 4 [severe]) for all six zones per chest radiographic examination were summed to provide a cumulative chest radiographic score (range, 0-24). Serial radiographs were also examined to assess for radiographic deterioration and progression from type 1 (mild) to type 4 (severe) disease. Multivariate logistic regression analysis, Kaplan-Meier survival curve analysis, and the Mann-Whitney U test were used to compare data of deceased patients with those of individuals who recovered to identify prognostic radiographic features. RESULTS: Ground-glass opacity was the most common abnormality (66%) followed by consolidation (18%). Overall mortality was 35% (19/55). Mortality was higher in the patient group (55%, 18/33) than in the HCW group (5%, 1/22). The mean chest radiographic score for deceased patients was significantly higher than that for those who recovered (13 ± 2.6 [SD] vs 5.8 ± 5.6, respectively; p = 0.001); in addition, higher rates of pneumothorax (deceased patients vs patients who recovered, 47% vs 0%; p = 0.001), pleural effusion (63% vs 14%; p = 0.001), and type 4 radiographic progression (63% vs 6%; p = 0.001) were seen in the deceased patients compared with those who recovered. Univariate and logistic regression analyses identified the chest radiographic score as an independent predictor of mortality (odds ratio [OR], 1.38; 95% CI, 1.07-1.77; p = 0.01). The number of comorbidities in the patient group (n = 33) was significantly higher than that in the HCW group (n = 22) (mean number of comorbidities, 1.90 ± 1.27 vs 0.17 ± 0.65, respectively; p = 0.001). The Kaplan-Meier analysis revealed a median survival time of 15 days (95% CI, 4-26 days). CONCLUSION: Ground-glass opacity in a peripheral location was the most common abnormality noted on chest radiographs. A higher chest radiographic score coupled with a high number of medical comorbidities was associated with a poor prognosis and higher mortality in those infected with MERS-CoV. Younger HCWs with few or no comorbidities had a higher survival rate.

CT correlation with outcomes in 15 patients with acute Middle East respiratory syndrome coronavirus.

OBJECTIVE: The purpose of this article is to retrospectively analyze chest CT findings for 15 patients with Middle East respiratory syndrome coronavirus and to identify features associated with survival. MATERIALS AND METHODS: Patients were assigned to group 1 if they died (n=9) and to group 2 if they made a full recovery (n=6). Two reviewers scored chest radiographs and CT examinations for segmental involvement, ground-glass opacities, consolidation, and interstitial thickening. RESULTS: Eight patients had ground-glass opacity (53%), five had ground-glass and consolidation in combination (33%), five had pleural effusion (33%), and four patients had interlobular thickening (27%). Of 281 CT findings, 151 (54%) were peripheral, 68 (24%) were central, and 62 (22%) had a mixed location. The number of involved lung segments was higher in group 1. The lower lobe was more commonly involved (mean, 12.2 segments) than in the upper and middle lobes combined (mean, 6.3 segments). The mean number of lung segments involved was 12.3 segments in group 1 and 3.4 segments in group 2. The CT lung score (mean±SD, 15.78±7.9 vs 7.3±5.7, p=0.003), chest radiographic score (20.8±1.7 vs 5.6±5.4; p=0.001), and mechanical ventilation duration (13.11±8.3 vs 0.5±1.2 days; p=0.002) were higher in group 1. All nine group 1 patients and three of six group 2 patients had pleural effusion (p=0.52). CONCLUSION: CT of patients with Middle East respiratory syndrome coronavirus predominantly showed ground-glass opacities, with peripheral lower lobe preference. Pleural effusion and higher CT lung and chest radiographic scores correlate with poor prognosis and short-term mortality.

Moderately Low Effectiveness of the Influenza Quadrivalent Vaccine: Potential Mismatch between Circulating Strains and Vaccine Strains.

The annual seasonal influenza vaccination is the most effective way of preventing influenza illness and hospitalization. However, the effectiveness of influenza vaccines has always been controversial. Therefore, we investigated the ability of the quadrivalent influenza vaccine to induce effective protection. Here we report strain-specific influenza vaccine effectiveness (VE) against laboratory-confirmed influenza cases during the 2019/2020 season, characterized by the co-circulation of four different influenza strains. During 2019-2020, 778 influenza-like illness (ILI) samples were collected from 302 (39%) vaccinated ILI patients and 476 (61%) unvaccinated ILI patients in Riyadh, Saudi Arabia. VE was found to be 28% and 22% for influenza A and B, respectively. VE for preventing A(H3N2) and A(H1N1)pdm09 illness was 37.4% (95% CI: 43.7-54.3) and 39.2% (95% CI: 21.1-28.9), respectively. The VE for preventing influenza B Victoria lineage illness was 71.7% (95% CI: -0.9-3), while the VE for the Yamagata lineage could not be estimated due to the limited number of positive cases. The overall vaccine effectiveness was moderately low at 39.7%. Phylogenetic analysis revealed that most of the Flu A genotypes in our dataset clustered together, indicating their close genetic relatedness. In the post-COVID-19 pandemic, flu B-positive cases have reached three-quarters of the total number of influenza-positive cases, indicating a nationwide flu B surge. The reasons for this phenomenon, if related to the quadrivalent flu VE, need to be explored. Annual monitoring and genetic characterization of circulating influenza viruses are important to support Influenza surveillance systems and to improve influenza vaccine effectiveness.

Evaluation of 34 Cytokines and Vitamin D Status Reveal A Sexually-Dimorphic Active Immune Response to SARS-CoV-2.

Background: Several observational studies have inconsistently demonstrated that vitamin D deficiency is a risk factor for coronavirus disease-19 (COVID-19) infection and severity. Discrepancies in results may partially be explained by the individuals' immune profiles, which are modulated, in varying degrees, by vitamin D status and sex hormones. Methods: In this study we evaluated the differences and associations of serum levels of 25(OH)D with 34 cytokines in 220 adults (82 controls (41 males; 41 females) and 138 SARS-CoV-2 patients (79 males and 59 females)) with and without COVID-19. Results: Serum 25(OH)D levels were significantly lower in the SARS-CoV-2 group than in the controls. Serum IP-10, MCP-1, CRP, IFNγ, IL-10, IL-13, IL-17α, IL-23, and IL-6 were significantly higher in COVID-19 patients compared to controls. Serum levels of VEGF, IFNγ, IL-13, and IL-5 were significantly higher in male patients than in females. 25(OH)D was significantly correlated with EFG (R = 0.39, p < 0.05) and IL-15 (R = 0.39, p < 0.05) in male patients, while it was inversely correlated with CRP (R = −0.51, p < 0.05) in female patients. Conclusions: Altered levels of cytokines, chemokines, and vitamin D were observed in SARS-CoV-2 adult patients. These expressions were sexually dimorphic and thus highlight the sex-specific nature of the active immune response following SARS-CoV-2 infection.

The Saudi Critical Care Society practice guidelines on the management of COVID-19 in the ICU: Therapy section.

BACKGROUND: The rapid increase in coronavirus disease 2019 (COVID-19) cases during the subsequent waves in Saudi Arabia and other countries prompted the Saudi Critical Care Society (SCCS) to put together a panel of experts to issue evidence-based recommendations for the management of COVID-19 in the intensive care unit (ICU). METHODS: The SCCS COVID-19 panel included 51 experts with expertise in critical care, respirology, infectious disease, epidemiology, emergency medicine, clinical pharmacy, nursing, respiratory therapy, methodology, and health policy. All members completed an electronic conflict of interest disclosure form. The panel addressed 9 questions that are related to the therapy of COVID-19 in the ICU. We identified relevant systematic reviews and clinical trials, then used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach as well as the evidence-to-decision framework (EtD) to assess the quality of evidence and generate recommendations. RESULTS: The SCCS COVID-19 panel issued 12 recommendations on pharmacotherapeutic interventions (immunomodulators, antiviral agents, and anticoagulants) for severe and critical COVID-19, of which 3 were strong recommendations and 9 were weak recommendations. CONCLUSION: The SCCS COVID-19 panel used the GRADE approach to formulate recommendations on therapy for COVID-19 in the ICU. The EtD framework allows adaptation of these recommendations in different contexts. The SCCS guideline committee will update recommendations as new evidence becomes available.

Structural Mapping of Mutations in Spike, RdRp and Orf3a Genes of SARS-CoV-2 in Influenza Like Illness (ILI) Patients.

In December 2019, the emergence of SARS-CoV-2 virus in China led to a pandemic. Since both Influenza Like Illness (ILI) and COVID-19 case definitions overlap, we re-investigated the ILI cases using PCR for the presence of SARS-CoV-2 in 739 nasopharyngeal swabs collected from November 2019 to March 2020. SARS-CoV-2 RNA was found in 37 samples (5%) collected mostly during February 2020. It was followed by confirmation of evolutionary and spatial relationships using next generation sequencing (NGS). We observed that the overall incidence of ILI cases during 2019-2020 influenza season was considerably higher than previous years and was gradually replaced with SARS-CoV-2, which indicated a silent transmission among ambulatory patients. Sequencing of representative isolates confirmed independent introductions and silent transmission earlier than previously thought. Evolutionary and spatial analyses revealed clustering in the GH clade, characterized by three amino acid substitutions in spike gene (D614G), RdRp (P323L) and NS3 (Q57H). P323L causes conformational change near nsp8 binding site that might affect virus replication and transcription. In conclusion, assessment of the community transmission among patients with mild COVID-19 illness, particularly those without epidemiological link for acquiring the virus, is of utmost importance to guide policy makers to optimize public health interventions. The detection of SARS-CoV-2 in ILI cases shows the importance of ILI surveillance systems and warrants its further strengthening to mitigate the ongoing transmission of SARS-CoV-2. The effect of NS3 substitutions on oligomerization or membrane channel function (intra- and extracellular) needs functional validation.

Complement Anaphylatoxins and Inflammatory Cytokines as Prognostic Markers for COVID-19 Severity and In-Hospital Mortality.

COVID-19 severity due to innate immunity dysregulation accounts for prolonged hospitalization, critical complications, and mortality. Severe SARS-CoV-2 infections involve the complement pathway activation for cytokine storm development. Nevertheless, the role of complement in COVID-19 immunopathology, complement-modulating treatment strategies against COVID-19, and the complement and SARS-CoV-2 interaction with clinical disease outcomes remain elusive. This study investigated the potential changes in complement signaling, and the associated inflammatory mediators, in mild-to-critical COVID-19 patients and their clinical outcomes. A total of 53 patients infected with SARS-CoV-2 were enrolled in the study (26 critical and 27 mild cases), and additional 18 healthy control patients were also included. Complement proteins and inflammatory cytokines and chemokines were measured in the sera of patients with COVID-19 as well as healthy controls by specific enzyme-linked immunosorbent assay. C3a, C5a, and factor P (properdin), as well as interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IgM antibody levels, were higher in critical COVID-19 patients compared to mild COVID-19 patients. Additionally, compared to the mild COVID-19 patients, factor I and C4-BP levels were significantly decreased in the critical COVID-19 patients. Meanwhile, RANTES levels were significantly higher in the mild patients compared to critical patients. Furthermore, the critical COVID-19 intra-group analysis showed significantly higher C5a, C3a, and factor P levels in the critical COVID-19 non-survival group than in the survival group. Additionally, IL-1ß, IL-6, and IL-8 were significantly upregulated in the critical COVID-19 non-survival group compared to the survival group. Finally, C5a, C3a, factor P, and serum IL-1ß, IL-6, and IL-8 levels positively correlated with critical COVID-19 in-hospital deaths. These findings highlight the potential prognostic utility of the complement system for predicting COVID-19 severity and mortality while suggesting that complement anaphylatoxins and inflammatory cytokines are potential treatment targets against COVID-19.

Colistin Nephrotoxicity: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Nephrotoxicity is a known adverse effect of polymyxin antibiotics, including colistin. Although previous meta-analyses have aimed to characterize colistin-associated nephrotoxicity risk relative to other antibiotics, included studies were observational in nature with high risk of confounding and heterogeneity. We conducted this systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to evaluate the incidence of nephrotoxicity associated with colistin versus minimally nephrotoxic antibiotics. METHODS: We searched PubMed, EMBASE, Cochrane Library, and 3 trial registries for RCTs comparing the nephrotoxicity of colistin to nonpolymyxin antibiotics. Randomized controlled trials that used aminoglycosides were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. The study outcome was the rate of nephrotoxicity. RESULTS: Five RCTs with a total of 377 patients were included. Most patients received colistin for pneumonia in the intensive care unit, and the comparators were ß-lactam-based regimens. Colistimethate sodium was dosed at 9 million units/day (300 mg/day of colistin base activity), with administration of a loading dose in 4 studies. The nephrotoxicity incidence in patients who received colistin was 36.2% (95% CI, 23.3% to 51.3%). The nephrotoxicity rate was significantly higher in the colistin arm than comparators (RR, 2.40; 95% CI, 1.47 to 3.91; P ≤ .001; I2 = 0%), and the number needed to harm was 5. Findings persisted upon one-study-removed-analysis. CONCLUSIONS: This meta-analysis of RCTs found a colistin-associated nephrotoxicity rate of 36.2% and an increase in this risk compared with ß-lactam-based regimens by 140%. Colistin should be regarded as a last-line agent and safer alternatives should be considered when possible.

Dual catastrophe of COVID-19: Massive pulmonary embolism and stroke in a previously healthy young patient: A case report.

We are reporting a 45-year-old woman with COVID-19 who presented to the Emergency Department with a transient loss of consciousness and was found to have a massive pulmonary embolism and an acute stroke. To our knowledge, this is the first reported case that calls for attention to the importance of vigilance for such a catastrophic presentation of COVID-19.

Promoting cross-regional collaboration in antimicrobial stewardship: Findings of an infectious diseases working group survey in Arab countries of the Middle East.

BACKGROUND: Antimicrobial resistance is a significant global issue that presents an increasing threat to patients' wellbeing. Although a global concern, the emergence of multi-drug resistant organisms is of particular significance in the Middle East. In recent years, this region has seen an alarming increase in antimicrobial resistance presenting a major challenge to physicians managing various infectious diseases. METHODS: A Working Group comprising experts in infectious diseases from Arab countries of Middle East assembled to review similarities and differences in antimicrobial practices and management of multi-drug resistant organisms across the region and assess the barriers to achieving cross-regional collaboration. The Working Group conducted an anonymous online survey to evaluate current practice and understanding of management of multi-drug resistant organisms across the region. RESULTS: A total of 122 physicians from Arab countries of the Middle East responded to the survey. Their responses demonstrated heterogeneity between countries in awareness of local epidemiology, management of multi-drug resistant organisms and antimicrobial stewardship practices. The Working Group recognized similarities and differences in the management of multi-drug resistant organisms across the region, and these were validated by the data collected in the survey. Overall, the similarities across the region reflect several key issues that can have an impact on the management of multi-drug resistant organisms and the prevention of antimicrobial resistance. CONCLUSIONS: This paper highlights the urgency of addressing antimicrobial resistance in Arab countries of the Middle East. The Working Group identified key barriers to effective management which may guide the development of future coherent strategies to promote effective antimicrobial stewardship in the region. Here, we outline a call to action for the region, with a need to focus on training and education, capacity building, infrastructure, regional research, and regional surveillance.

Combination of (interferon beta-1b, lopinavir/ritonavir and ribavirin) versus favipiravir in hospitalized patients with non-critical COVID-19: A cohort study.

OBJECTIVES: Our study aims at comparing the efficacy and safety of IFN-based therapy (lopinavir/ritonavir, ribavirin, and interferon ß-1b) vs. favipiravir (FPV) in a cohort of hospitalized patients with non-critical COVID-19. METHODS: Single center observational study comparing IFN-based therapy (interferon ß-1b, ribavirin, and lopinavir/ritonavir) vs. FPV in non-critical hospitalized COVID-19 patients. Allocation to either treatment group was non-random but based on changes to national treatment protocols rather than physicians' selection (quasi-experimental). We examined the association between IFN-based therapy and 28-day mortality using Cox regression model with treatment as a time-dependent covariate. RESULTS: The study cohort included 222 patients, of whom 68 (28%) received IFN-based therapy. Antiviral therapy was started at a median of 5 days (3-6 days) from symptoms onset in the IFN group vs. 6 days (4-7 days) for the FPV group, P <0.0001. IFN-based therapy was associated with a lower 28-day mortality as compared to FPV (6 (9%) vs. 18 (12%)), adjusted hazard ratio [aHR] (95% Cl) = 0.27 (0.08-0.88)). No difference in hospitalization duration between the 2 groups, 9 (7-14) days vs. 9 (7-13) days, P = 0.732 was found. IFN treated group required less use of systemic corticosteroids (57%) as compared to FPV (77%), P = 0.005 after adjusting for disease severity and other confounders. Patients in the IFN treated group were more likely to have nausea and diarrhea as compared to FPV group (13%) vs. (3%), P = 0.013 and (18%) vs. (3%), P<0.0001, respectively. CONCLUSION: Early IFN-based triple therapy was associated with lower 28-days mortality as compared to FPV.

Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial.

OBJECTIVE: Vitamin D deficiency has been associated with an increased risk of COVID-19 severity. This multi-center randomized clinical trial aims to determine the effects of 5000 IU versus 1000 IU daily oral vitamin D3 supplementation in the recovery of symptoms and other clinical parameters among mild to moderate COVID-19 patients with sub-optimal vitamin D status. STUDY DESIGN AND SETTING: A total of 69 reverse transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 positive adults who were hospitalized for mild to moderate COVID-19 disease were allocated to receive once daily for 2 weeks either 5000 IU oral vitamin D3 (n = 36, 21 males; 15 females) or 1000 IU oral vitamin D3 (standard control) (n = 33, 13 males; 20 females). Anthropometrics were measured and blood samples were taken pre- and post-supplementation. Fasting blood glucose, lipids, serum 25(OH)D, and inflammatory markers were measured. COVID-19 symptoms were noted on admission and monitored until full recovery. RESULTS: Vitamin D supplementation for 2 weeks caused a significant increase in serum 25(OH)D levels in the 5000 IU group only (adjusted p = 0.003). Within-group comparisons also showed a significant decrease in BMI and IL-6 levels overtime in both groups (p-values < 0.05) but was not clinically significant in between-group comparisons. Kaplan-Meier survival analysis revealed that the 5000 IU group had a significantly shorter time to recovery (days) than the 1000 IU group in resolving cough, even after adjusting for age, sex, baseline BMI, and D-dimer (6.2 ± 0.8 versus 9.1 ± 0.8; p = 0.039), and ageusia (loss of taste) (11.4 ± 1.0 versus 16.9 ± 1.7; p = 0.035). CONCLUSION: A 5000 IU daily oral vitamin D3 supplementation for 2 weeks reduces the time to recovery for cough and gustatory sensory loss among patients with sub-optimal vitamin D status and mild to moderate COVID-19 symptoms. The use of 5000 IU vitamin D3 as an adjuvant therapy for COVID-19 patients with suboptimal vitamin D status, even for a short duration, is recommended.