Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study.

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene. Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses. Conclusions: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19. Funding: Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative. Clinical trial number: NCT04549831.

Unique immunological profile in patients with COVID-19.

The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included. Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes, with an increased proportion of mature natural killer (NK) cells and low T-cell numbers. NK cells and CD8+ T cells overexpressed T-cell immunoglobulin and mucin domain-3 (TIM-3) and CD69. NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1 (PD-1) positive cells and reduced frequencies of natural killer group 2 member D (NKG2D)-, DNAX accessory molecule-1 (DNAM-1)- and sialic acid-binding Ig-like lectin 7 (Siglec-7)-expressing NK cells, associated with a reduced ability to secrete interferon (IFN)γ. Patients with poor outcome showed a contraction of immature CD56bright and an expansion of mature CD57+ FcεRIγneg adaptive NK cells compared to survivors. Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors. Of note, monocytes secreted abundant quantities of IL-6, IL-8, and IL-1ß which persisted at lower levels several weeks after recovery with concomitant normalization of CD69, PD-1 and TIM-3 expression and restoration of CD8+ T cell numbers. A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection, probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes. These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.

The obesity paradox: Analysis from the SMAtteo COvid-19 REgistry (SMACORE) cohort.

BACKGROUND AND AIMS: Obesity has been suggested as a possible risk factor for a more severe course of COVID-19; however, conclusive evidence is lacking and few studies have investigated the role of BMI as a risk factor for admission to intensive care unit (ICU) and mortality. We retrospectively analyzed a COVID-19 cohort recruited during the first 40 days of the epidemic in Italy. We examined the association between obesity and 30-day mortality, admission to ICU, mortality and length of hospital stay in patients with COVID-19. METHODS AND RESULTS: Demographic, clinical and outcome data were retrospectively analyzed in 331 patients with COVID-19 admitted to hospital between 21 February and 31 March 2020. The predictive effect of obesity on mortality was assessed using a Cox proportional-hazard regression model, its effect on ICU admission and mortality in the ICU using logistic regressions, and its effect on length of hospital stay using a linear regression. Seventy-four of 331 patients had a BMI ≥30 kg/m2. Among obese patients, 21 (28.4%) required admission in ICU and 25 died (33.8%). After controlling for sex, age, comorbidities and clinical data, obesity was not significantly associated with mortality, mortality in ICU and length of hospital stay. The effect of obesity on ICU admission remained significant after controlling for sex, age, interstitial lung disease, heart disease and serum C-reactive protein. CONCLUSIONS: Obese patients with COVID-19 were more likely to be admitted to ICU than non-obese patients. However, there were no significant differences in mortality between the two groups.

Running out of bullets: The challenging management of acute hepatitis and SARS-COV-2 from the SMatteo COvid19 Registry (SMACORE).

Liver impairment is frequent in patients with novel coronavirus disease (COVID-19) and direct viral tropism for the liver has been proven. Since several of the currently administered drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are possibly hepatotoxic, the management of patients with COVID-19 and liver failure is still an almost unexplored field. Taking this challenging case of acute HBV with persistent hyperbilirubinemia and SARS-COV-2 infection with respiratory distress as a starting point, we here loop through this condition. Where the available therapeutic options are scarce, we here propose hemoperfusion (HP) as an attractive alternative to both delay any late-stage progression of hyper inflammation process in COVID-19 and remove the toxins involved in acute liver failure.

Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol.

OBJECTIVES: Beginning in December 2019, the 2019 novel coronavirus disease (COVID-19) has caused a pneumonia epidemic that began in Wuhan, China, and is rapidly spreading throughout the whole world. Italy is the hardest hit country after China. Considering the deleterious consequences of malnutrition, which certainly can affect patients with COVID-19, the aim of this article is to present a pragmatic protocol for early nutritional supplementation of non-critically ill patients hospitalized for COVID-19 disease. It is based on the observation that most patients present at admission with severe inflammation and anorexia leading to a drastic reduction of food intake, and that a substantial percentage develops respiratory failure requiring non-invasive ventilation or even continuous positive airway pressure. METHODS: High-calorie dense diets in a variety of different consistencies with highly digestible foods and snacks are available for all patients. Oral supplementation of whey proteins as well as intravenous infusion of multivitamin, multimineral trace elements solutions are implemented at admission. In the presence of 25-hydroxyvitamin D deficit, cholecalciferol is promptly supplied. If nutritional risk is detected, two to three bottles of protein-calorie oral nutritional supplements (ONS) are provided. If <2 bottles/d of ONS are consumed for 2 consecutive days and/or respiratory conditions are worsening, supplemental/total parenteral nutrition is prescribed. CONCLUSION: We are aware that our straight approach may be debatable. However, to cope with the current emergency crisis, its aim is to promptly and pragmatically implement nutritional care in patients with COVID-19, which might be overlooked despite being potentially beneficial to clinical outcomes and effective in preventing the consequences of malnutrition in this patient population.