Cerebral venous sinus thrombosis in the setting of COVID-19 vaccination: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Cerebral venous sinus thrombosis (CVST) has been reported as a rare adverse event in association with thrombosis-thrombocytopenia syndrome (TTS) following COVID-19 vaccination. METHODS:  We performed a systematic review and meta-analysis of investigator-initiated registries including confirmed CVST cases, with the aim to calculate (1) the odds ratio of TTS-CVST versus non-TTS-CVST after vector-based vaccines and (2) after non-vector-based vaccines, (3) the in-hospital mortality ratio of TTS-CVST compared to non-TTS-CVST; and (4) the dependency or death at discharge among TTS-CVST compared to non-TTS-CVST cases. RESULTS: Two eligible studies were included in the meta-analysis, comprising a total of 211 patients with CVST associated with COVID-19 vaccination. Vector-based COVID-19 vaccination was associated with a higher likelihood of TTS-associated CVST than with non-TTS-CVST (OR: 52.34, 95% CI 9.58-285.98). TTS-CVST was also associated with higher likelihood of in-hospital mortality (OR: 13.29; 95% CI 3.96-44.60) and death or dependency at discharge compared to non-TTS-CVST (OR: 6.70; 95% CI 3.15-14.26). TTS-CVST was recorded with a shorter interval between vaccination and symptom onset [Mean Difference (MD):-6.54 days; 95% CI - 12.64 to - 0.45], affecting younger patients (MD:-9.00 years; 95% CI - 14.02 to - 3.99) without risk factors for thromboses (OR:2.34; 95% CI 1.26-4.33), and was complicated more frequently with intracerebral hemorrhage (OR:3.60; 95% CI 1.31-9.87) and concomitant thromboses in other sites (OR:11.85; 95% CI 3.51-39.98) compared to non-TTS-CVST cases. CONCLUSIONS: TTS-CVST following COVID-19 vaccination has distinct risk factor profile, clinical phenotype and prognosis compared to non-TTS-CVST. Further epidemiological data are required to evaluate the impact of different treatment strategies on outcome of TTS-CVST cases following COVID-19 vaccination.

Cerebral Venous Sinus Thrombosis and Thrombotic Events After Vector-Based COVID-19 Vaccines: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: There is accumulating evidence supporting an association between the thrombosis and thrombocytopenia syndrome (TTS) and adenovirus vector-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yet TTS and TTS-associated cerebral venous sinus thrombosis (CVST) remain poorly characterized. We aim to systematically evaluate the proportion of CVST among TTS cases and assess its characteristics and outcomes. METHODS: We performed a systematic review and meta-analysis of clinical trials, cohorts, case series, and registry-based studies with the aim to assess (1) the pooled mortality rate of CVST, TTS-associated CVST, and TTS and (2) the pooled proportion of patients with CVST among patients with any thrombotic event and TTS. Secondary outcomes comprised clinical characteristics of patients with postvaccination thrombotic event. This meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology proposal. RESULTS: Sixty-nine studies were included in the qualitative analysis comprising 370 patients with CVST out of 4,182 patients with any thrombotic event associated with SARS-CoV-2 vector-based vaccine administration. Twenty-three studies were included further in quantitative meta-analysis. Among TTS cases, the pooled proportion of CVST was 51% (95% confidence interval [CI] 36%-66%; I 2 = 61%). TTS was independently associated with a higher likelihood of CVST when compared to patients without TTS with thrombotic events after vaccination (odds ratio 13.8; 95% CI 2.0-97.3; I 2 = 78%). The pooled mortality rates of TTS and TTS-associated CVST were 28% (95% CI 21%-36%) and 38% (95% CI 27%-49%), respectively. Thrombotic complications developed within 2 weeks of exposure to vector-based SARS-CoV-2 vaccines (mean interval 10 days; 95% CI 8-12) and affected predominantly women (69%; 95% CI 60%-77%) under age 45, even in the absence of prothrombotic risk factors. DISCUSSION: Approximately half of patients with TTS present with CVST; almost one-third of patients with TTS do not survive. Further research is required to identify independent predictors of TTS following adenovirus vector-based vaccination. REGISTRATION INFORMATION: The prespecified study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (CRD42021250709).

Angiotensin-converting-enzyme insertion/deletion polymorphism, ACE activity, and COVID-19: A rather controversial hypothesis. A case-control study.

Accumulating data has shown a contribution of the renin-angiotensin system in COVID-19 pathogenesis. The role of angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism as a risk factor in developing COVID-19 disease comes from epidemiological data and is controversially discussed. We conducted a retrospective case-control study and assessed the impact of ACE I/D genotype in COVID-19 disease prevalence and severity. In 81 COVID-19 patients explicitly characterized and 316 controls, recruited during the first wave of COVID-19 pandemic, ACE I/D genotype, and ACE activity were determined. A generalized linear model was used and Poisson regression analysis estimated the risk ratios (RRs) of alleles and genotypes for disease severity. DD patients had almost 2.0-fold increased risk (RR: 1.886, confidence limit [CL] 95%: 1.266-2.810, p = 0.0018) of developing a more severe disease when contrasted to ID and II individuals, as did D allele carriers compared to I carriers (RR: 1.372; CL 95%: 1.051-1.791; p = 0.0201). ACE activity (expressed as arbitrary units, AU/L) was lower in patients (3.62 ± 0.26) than in controls (4.65 ± 0.13) (p < 0.0001), and this reduction was observed mainly among DD patients compared to DD controls (3.97 ± 0.29 vs. 5.38 ± 0.21; p = 0.0014). Our results demonstrate that ACE DD genotype may predispose to COVID-19 increased disease severity via a mechanism associated, at least in part, with the significant fall in their ACE activity. Our findings suggest a more complex pattern of synergy between this polymorphism and ACE activity in COVID-19 patients compared to healthy individuals and set the grounds for large-scale studies assessing ACE genotype-based optimized therapies with ACE inhibitors and angiotensin receptor blockers.

Children and Adolescents With SARS-CoV-2 Infection: Epidemiology, Clinical Course and Viral Loads.

BACKGROUND: There is limited information on severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection in children. METHODS: We retrieved data from the national database on SARS-CoV-2 infections. We studied in-family transmission. The level of viral load was categorized as high, moderate, or low based on the cycle threshold values. RESULTS: We studied 203 SARS-CoV-2-infected children (median age: 11 years; range: 6 days to 18.4 years); 111 (54.7%) had an asymptomatic infection. Among the 92 children (45.3%) with coronavirus disease 2019 (COVID-19), 24 (26.1%) were hospitalized. Infants <1 year were more likely to develop COVID-19 (19.5% of all COVID-19 cases) (P-value = 0.001). There was no significant difference between viral load and age, sex, underlying condition, fever and hospitalization, as well as between type of SARS-CoV-2 infection and age, sex, underlying condition and viral load. Transmission from a household member accounted for 132 of 178 (74.2%) children for whom the source of infection was identified. An adult member with COVID-19 was the first case in 125 (66.8%) family clusters. Child-to-adult transmission was found in one occasion only. CONCLUSIONS: SARS-CoV-2 infection is mainly asymptomatic or mild during childhood. Adults appear to play a key role in spread of the virus in families. Most children have moderate or high viral loads regardless of age, symptoms or severity of infection. Further studies are needed to elucidate the role of children in the ongoing pandemic and particularly in light of schools reopening and the need to prioritize groups for vaccination, when COVID-19 vaccines will be available.