The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes.

Introduction: Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes. Methods: To evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity). Results: According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02). Discussion: Our data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.

Implication of myddosome complex genetic variants in outcome severity of COVID-19 patients.

BACKGROUND/PURPOSE(S): During a viral infection, the immune response is mediated by the toll-like receptors and myeloid differentiation Factor 88 (MyD88) that play an important role sensing infections such as SARS-CoV-2 which has claimed the lives of more than 6.8 million people around the world. METHODS: We carried out a cross-sectional with a population of 618 SARS-CoV-2-positive unvaccinated subjects and further classified based on severity: 22% were mild, 34% were severe, 26% were critical, and 18% were deceased. Toll Like Receptor 7 (TLR7) single-nucleotide polymorphisms (rs3853839, rs179008, rs179009, and rs2302267) and MyD88 (rs7744) were genotyped using TaqMan OpenArray. The association of polymorphisms with disease outcomes was performed by logistic regression analysis adjusted by covariates. RESULTS: A significant association of rs3853839 and rs7744 of the TLR7 and MyD88 genes, respectively, was found with COVID-19 severity. The G/G genotype of the rs3853839 TLR7 was associated with the critical outcome showing an Odd Ratio = 1.98 (95% IC = 1.04-3.77). The results highlighted an association of the G allele of MyD88 gene with severe, critical and deceased outcomes. Furthermore, in the dominant model (AG + GG vs. AA), we observed an Odd Ratio = 1.70 (95% CI = 1.02-2.86) with severe, Odd Ratio = 1.82 (95% CI = 1.04-3.21) with critical, and Odd Ratio = 2.44 (95% CI = 1.21-4.9) with deceased outcomes. CONCLUSION: To our knowledge this work represents an innovative report that highlights the significant association of TLR7 and MyD88 gene polymorphisms with COVID-19 outcomes and the possible implication of the MyD88 variant with D-dimer and IFN-α concentrations.

Metabolic Reprogramming in SARS-CoV-2 Infection Impacts the Outcome of COVID-19 Patients.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection triggers inflammatory clinical stages that affect the outcome of patients with coronavirus disease 2019 (COVID-19). Disease severity may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. The aim of this study was to characterize the profile of amino acids and acylcarnitines in COVID-19 patients. A multicenter, cross-sectional study was carried out. A total of 453 individuals were classified by disease severity. Levels of 11 amino acids, 31 acylcarnitines, and succinylacetone in serum samples were analyzed by electrospray ionization-triple quadrupole tandem mass spectrometry. Different clusters were observed in partial least squares discriminant analysis, with phenylalanine, alanine, citrulline, proline, and succinylacetone providing the major contribution to the variability in each cluster (variable importance in the projection >1.5). In logistic models adjusted by age, sex, type 2 diabetes mellitus, hypertension, and nutritional status, phenylalanine was associated with critical outcomes (odds ratio=5.3 (95% CI 3.16-9.2) in the severe vs. critical model, with an area under the curve of 0.84 (95% CI 0.77-0.90). In conclusion the metabolic imbalance in COVID-19 patients might affect disease progression. This work shows an association of phenylalanine with critical outcomes in COVID-19 patients, highlighting phenylalanine as a potential metabolic biomarker of disease severity.

ACE and ACE2 Gene Variants Are Associated With Severe Outcomes of COVID-19 in Men.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, affecting more than 219 countries and causing the death of more than 5 million people worldwide. The genetic background represents a factor that predisposes the way the host responds to SARS-CoV-2 infection. In this sense, genetic variants of ACE and ACE2 could explain the observed interindividual variability to COVID-19 outcomes. In order to improve the understanding of how genetic variants of ACE and ACE2 are involved in the severity of COVID-19, we included a total of 481 individuals who showed clinical manifestations of COVID-19 and were diagnosed by reverse transcription PCR (RT-PCR). Genomic DNA was extracted from peripheral blood and saliva samples. ACE insertion/deletion polymorphism was evaluated by the high-resolution melting method; ACE single-nucleotide polymorphism (SNP) (rs4344) and ACE2 SNPs (rs2285666 and rs2074192) were genotyped using TaqMan probes. We assessed the association of ACE and ACE2 polymorphisms with disease severity using logistic regression analysis adjusted by age, sex, hypertension, type 2 diabetes, and obesity. The severity of the illness in our study population was divided as 31% mild, 26% severe, and 43% critical illness; additionally, 18% of individuals died, of whom 54% were male. Our results showed in the codominant model a contribution of ACE2 gene rs2285666 T/T genotype to critical outcome [odds ratio (OR) = 1.83; 95%CI = 1.01-3.29; p = 0.04] and to require oxygen supplementation (OR = 1.76; 95%CI = 1.01-3.04; p = 0.04), in addition to a strong association of the T allele of this variant to develop critical illness in male individuals (OR = 1.81; 95%CI = 1.10-2.98; p = 0.02). We suggest that the T allele of rs2285666 represents a risk factor for severe and critical outcomes of COVID-19, especially for men, regardless of age, hypertension, obesity, and type 2 diabetes.

Outpatient prescription patterns of COVID-19 drugs in the metropolitan area of Mexico City.

BACKGROUND: We aimed to describe the use of drugs with apparent efficacy in ambulatory patients with confirmed COVID-19 and the relationship of Google Trends searches with prescriptions and the total number of COVID-19 cases in Mexico City. METHODS: Between March 2020 and February 2021, we surveyed 350 patients confirmed to have COVID-19 across 3 hospitals in Mexico City for their ambulatory prescriptions. We analysed the correlation between prescription patterns of 4 drugs with apparent efficacy against COVID-19, Google Trends searches for these drugs, and the overall number of confirmed COVID-19 cases in Mexico City. RESULTS: We included 350 patients, of whom 59% were women with a median age of 38 years (interquartile range, 29-51), and 72% had a bachelor's degree or higher. There were ambulatory medical prescriptions in 172 (49%) patients, and self-prescriptions were reported in 99 (28%) patients. The prescription rate was high for hydroxychloroquine/azithromycin (19%) and dexamethasone (25%). There was a decrease in the prescription of hydroxychloroquine (P < 0.001) and a strong positive correlation between hydroxychloroquine (r = 0.66; 95% confidence interval, 0.11-0.90; P = 0.02) prescription and online searches for hydroxychloroquine. There was a strong positive correlation between online searches for azithromycin, dexamethasone, ivermectin, and vitamin D and the number of confirmed COVID-19 cases. CONCLUSIONS: During the COVID-19 pandemic, there was a high proportion of prescriptions for hydroxychloroquine/azithromycin and dexamethasone despite their unproven efficacy. Analysis of Google Trends showed a strong correlation between the overall number of confirmed COVID-19 cases and searches for such drugs, suggesting a higher rate of prescriptions. Analysis of online searches could thus help to actively survey public health behaviours in the future.

Noma and Noma-like disease in HIV/AIDS patients, a comorbid interaction: A systematic review.

INTRODUCTION: Noma is an opportunistic polymicrobial infection that cause necrosis of the mouth and face, with high morbidity and mortality, predominantly affecting malnourished children and persons with debilitating diseases. Cases of noma-like disease in adults, although rare, have been increasingly reported in HIV/AIDS patients particularly in developing countries but also in more developed countries. METHODOLOGY: A systematic review of the literature to assess the occurrence and clinical impact of noma and noma-like disease in HIV/AIDS patients was performed on PubMed, Virtual Health Library, Cochrane Library and Google Scholar using the keywords "HIV"[ All Fields] AND "Noma"[All Fields] in December 2016 (years includead for the search: 1985 to 2016). RESULTS: Twenty-four published studies were identified that document the occurrence of noma or noma-like disease in a total of 133 HIV/AIDS children and adult patients in the last 22 years. Although HIV infection is not the principal risk factor for noma, in some regions may play a substantial role in its pathogenesis. The mortality rate for noma-like disease in HIV/AIDS patients was 54.3%, compared to the 15% mortality rate of treated noma patients without HIV/AIDS. Most of the cases have never been on antiretroviral therapy, and their HIV infection was discovered because of the noma-like disease. CONCLUSIONS: The syndemic interaction between HIV/AIDS and noma-like disease adversely impacts the severity of the disease and the mortality rate. Noma-like disease, although not yet considered a specific or frequent disease associated with HIV infection, should be considered as an opportunistic infection for AIDS.

Primary Cutaneous Mucormycosis Caused by Rhizopus oryzae: A Case Report and Review of Literature.

Mucormycosis is an invasive infection caused by opportunistic fungi. Rhizopus, Lichtheimia, Mucor and Rhizomucor are the most common isolated genera. Primary cutaneous mucormycosis is usually related to traumatic injuries, but immunocompromised cases are associated with underlying conditions such as diabetes mellitus and malignancies. The treatment of choice is surgical debridement and liposomal amphotericin B. We present a 40-year-old male with fever and a painful necrotic lesion on the middle back and history of poorly controlled diabetes mellitus. Rhizopus oryzae was isolated and identified using an internal transcribed spacer regions ITS1 and ITS2. An initial good response to treatment was observed; however, 7 days later a diabetic ketoacidosis due to poor adherence to treatment caused a lethal outcome.