We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.
Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org)
Dog bites may result in serious bacterial infections because of various microorganisms, including gram-negative rod Capnocytophaga canimorsus, whose disease can be complicated by acute development of sepsis and/or meningitis. In this review, we report a case of C. canimorsus meningitis in a patient with major risk factors and subsequently analyze 48 other cases described in literature. Approximately a little less than 50% of reported cases had a major predisposing condition such as splenectomy, alcoholism, or immunosuppressive treatment. In almost all of the cases, recent animal exposure was reported. Sensorineural hearing loss, which has been described as a permanent complication of C. canimorsus meningitis, was present in a minority of cases (18%), and a possible association with alcoholism was observed. In conclusion, C. canimorsus should be considered as a possible cause of sporadic meningitis in adults, particularly if presenting with a subacute course or deafness and in concomitance of major predisposing conditions, such as alcoholism.
PURPOSE. To assess and compare the serum 25OH-vitamin D levels in three cohorts of patients hospitalized due to acute illness, either related or not to a SARS-COV-2 infection. To investigate, in the patients group with SARS-COV-2 pneumonia, the possible relationship between the serum vit- amin D levels and both disease severity and mortality risk.METHODS. This is a retrospective case-control study. Serum 25OH-vitamin D levels were compared between patients with SARS-COV-2 pneumonia (COVID-19 group, 52 patients), and two control groups, including patients with pneumonia not related to SARS-CoV-2 (NO COVID1 group, 52 patients) and patients with a non-respiratory acute disease (NO COVID2 group, 52 pa- tients).RESULTS. No differences were found in the serum 25 OH-Vitamin D levels among the three groups. In the COVID-19 group, serum 25 OH-Vitamin D levels did not show significant associa- tion with mortality risk (p=0.12), Intensive Care Unit admission risk (p=0.36), inpatients duration (p=0.40) and remission time (p=0.33). Similar results were found for parameters estimating the dis- ease severity, such as basal PO2/FiO2 (p=0.77), worse PO2/FiO2 (p=0.41), basal D-dimer (p=0.46) and basal LDH (p=0.52).CONCLUSIONS. Our data do not show lower 25OH-vitamin D levels in the patients with SARS- COV-2 pneumonia compared to patients hospitalized for other acute illnesses. In the COVID-19 group the 25OH-vitamin D levels did not show significant correlation with a worse outcome.
The use of antivirals, corticosteroids, and IL-6 inhibitors has been recommended by the WHO to treat COVID-19. CP has also been considered for severe and critical cases. Clinical trials on CP have shown contradictory results, but an increasing number of patients, including immunocompromised ones, have shown benefits from this treatment. We reported two clinical cases of patients with prolonged COVID-19 infection and B-cell depletion who showed rapid clinical and virological recovery after the administration of CP. The first patient in this study was a 73-year-old female with a history of follicular non-Hodgkin lymphoma previously treated with bendamustine followed by maintenance therapy with rituximab. The second patient was a 68-year-old male with chronic obstructive pulmonary disease, bipolar disorder, alcoholic liver disease, and a history of mantellar non-Hodgkin lymphoma treated with rituximab and radiotherapy. After the administration of CP, both patients showed a resolution of symptoms, improvement of their clinical conditions, and a negative result of the nasopharyngeal swab test. The administration of CP might be effective in resolving symptoms and improving clinical and virological outcomes in patients with B-cell depletion and prolonged SARS-CoV2 infections.
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