In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

Data availabilitySummary statistics generated by COVID-19 Host Genetics Initiative are available online (https://www.covid19hg.org/results/r6/). The analyses described here use the freeze 6 data. The COVID-19 Host Genetics Initiative continues to regularly release new data freezes. Summary statistics for samples from individuals of non-European ancestry are not currently available owing to the small individual sample sizes of these groups, but the results for 23 loci lead variants are reported in Supplementary Table 3. Individual-level data can be requested directly from the authors of the contributing studies, listed in Supplementary Table 1.

Triple therapy with steroids, vitamin C and thiamine has been recently proposed as a safe and beneficial in patients with sepsis. In 2017, we added the use of intravenous vitamin C and thiamine in septic shock patients receiving low dose hydrocortisone because poorly responsive to vasopressors. Aim of this study is to verify whether triple therapy rather than steroids alone can improve outcome in patients with refractory shock. Materials and methods: In this before-after retrospective analysis, we compared septic shock patients admitted to our intensive care unit (ICU) who received triple therapy from June 2017 to November 2019 to septic shock patients who received only hydrocortisone from January 2015 to June 2017. Patients of the two study periods were matched 1:1 using a propensity score model. Results: A final cohort of 56 patients treated with triple therapy were matched to 56 patients treated only with steroids. Triple therapy reduced the length of mechanical ventilation (p = 0,01) and showed a trend in lowering the 30-day and hospital mortality compared to therapy with only hydrocortisone. Conclusions: Although with significant limitations, our experience indicated that triple therapy seems to provide an improvement of clinical outcomes in patients with refractory septic shock.

The reviews of this paper are available via the supplemental material section.

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