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Advanced age, male sex and chronic comorbidities are associated with severe COVID-19. However, these general risk factors cannot explain why critical illness occurs in young and apparently healthy individuals. In the past months, several publications have identified susceptibility loci and genes using comprehensive GWAS studies or genome, exome or candidate genes analysis. A recent study reported rare, loss-of-function TLR7 variants in otherwise healthy young brother pairs from two families with severe COVID-19. We aimed to prospectively study the prevalence of rare X-chromosomal TLR7 genetic variants in our cohort of young male patients with severe COVID-19. We recruited 13 patients [≤]50 years who had no risk factors known to be associated with severe disease. We studied the entire TLR7 coding region and identified two missense variants (p.Asn215Ser, c.644A>G and p.Trp933Arg, c.2797T>C) in two out of 13 cases (15.4%). These variants were not previously reported in population control databases (gnomAD) and were predicted to be damaging by all in silico predictors. The male index patients were between 25 and 30 years old and had no apparent comorbidities. The TLR7 p.Asn215Ser co-segregated in 2 first-degree relatives severely affected by COVID-19, in a younger previously healthy the variant was found in hemizygous state, and in an older than 60 was in heterozygous state. No family members were available for testing the segregation of the p.Trp933Arg variant. These results further support that susceptibility to severe COVID-19 could be determined by inherited rare genetic variants in TLR7. Understanding the causes and mechanisms of life-threatening COVID-19 is crucial and could lead to novel preventive and therapeutic options. This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but it also enables for pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.
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Background: A higher incidence of thrombotic events, mainly pulmonary embolism (PE), has been reported in hospitalized patients with COVID-19. Objectives: To assess clinical and weekly laboratory differences in hospitalized COVID-19 patients according to occurrence of PE. Methods: This retrospective study included all consecutive patients hospitalized with COVID-19 who underwent a computed tomography (CT) angiography for PE clinical suspicion. Clinical data and median blood test results distributed into weekly periods from COVID-19 symptoms onset were compared between PE and non-PE patients. Results: Ninety-two patients were included, 29 (32%) had PE. PE patients were younger (63.9 (SD13.7) vs 69.9 (SD12.5) years). Clinical symptoms and COVID-19 CT features were similar in both groups. PE was diagnosed after a mean of 20.0 (SD8.6) days from the onset of COVID-19 symptoms. Corticosteroid boluses were more frequently used in PE patients (62% vs. 43%). Median values [IQR] of D-dimer in PE vs non-PE patients were: week 2 (2010.7 [770.1-11208.9] vs 626.0 [374.0-2382.2]; p=0.04); 3 (3893.1 [1388.2-6694.0] vs 1184.4 [461.8-2447.8]; p=0.03); and 4 (2736.3 [1202.1-8514.1] vs 1129.1 [542.5-2834.6]; p=0.01). Median fold-increase of D-dimer between week 1 and 2 differed between groups (6.64 [3.02-23.05] vs 1.57 [0.64-2.71], p=0.003); ROC curve AUC was 0.879 (p=0.003) with a sensitivity and specificity for PE of 86% and 80%, respectively. Conclusions: Among hospitalized COVID-19 patients, D-dimer levels are higher at weeks 2, 3 and 4 after COVID-19 symptom onset in patients who develop PE. This difference is more pronounced when the fold increase between weeks 1 and 2 is compared.
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IntroductionOn the basis of the preliminary report from the RECOVERY trial, the use of dexamethasone or alternative corticosteroids (CS) is currently recommended in severe COVID-19 patients requiring supplemental oxygen. However, last updated recommendations have not taken a position either for or against the use of other immunomodulators such as tocilizumab (TCZ), with or without CS, since results are still limited. MethodsFrom March 17 to April 7, 2020, a real-world observational retrospective analysis was conducted at our 750-bed university hospital to study the characteristics and risk factors for mortality in patients with severe COVID-19 treated with TCZ +/-CS, in addition to standard of care (SOC). Data were obtained from routine clinical practice, stored in electronic medical records. The main outcome was all-cause in-hospital mortality. ResultsA total of 1,092 COVID-19 patients were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186, 155 (83.3 %) patients were receiving non-invasive ventilation when TCZ +/-CS was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 ({+/-} 4.3) and 4.3 days ({+/-} 3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR=1.09, p<0.001), chronic heart failure (HR=4.4, p=0.003), and chronic liver disease (HR=4.69, p=0.004). The use of CS, in combination with TCZ, was the main protective factor against mortality (HR=0.26, p<0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up. ConclusionsIn severe COVID-19 patients receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed beneficial effect in preventing in-hospital mortality.
