New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations (preprint)

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.

Therapeutic strategies for COVID-19 lung disease in children (preprint)

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has milder presentation in children than adults, mostly requiring only supportive therapy. The immunopathogenic course of COVID-19 can be divided in two distinct but overlapping phases: the first triggered by the virus itself and the second one by the host immune response. Cytokine storm induces Acute Respiratory Distress Syndrome (ARDS) in 20-30% of adults while less than 1% of children develops severe pulmonary or systemic involvement as Multisystem Inflammatory Syndrome in Children (MIS-C), requiring intensive care. Less severe lung injury in children could be explained by qualitative and quantitative differences in age-related immune response. Evidence on the best therapeutic approach for COVID-19 lung disease in children is lacking. Currently, the approach is mainly conservative and based on supportive therapy. However, in hospitalized children with critical illness and worsening lung function, antiviral therapy with remdesivir and immunomodulant treatment with systemic steroids could be considered the “therapeutic pillars”. In addition, optimal disease control of allergic and asthmatic children and, in the near future, vaccinations are expected to be important as preventive strategies to reduce the COVID-19 burden.

A distinct metabolic profile associated with a fatal outcome in COVID-19 patients during early epidemic in Italy (preprint)

Leveraging the unique biological resource based upon the initial COVID-19 patients in Policlinico di Milano (Italy), our study provides the first metabolic profile associated with a fatal outcome. The identification of potential predictive biomarkers offers a vital opportunity to employ metabolomics in a clinical setting as diagnostic tool of disease prognosis upon hospital admission.

The efficacy of mineral corticoid receptor antagonist, canrenone, in COVID-19 patients (preprint)

Purpose: Despite the spread of SARS-CoV-2 global pandemic and the volume of clinical trials launched, no specific therapeutic drug approaches improving outcomes have been so far approved. In COVID-19 patients, aldosterone via ACE2 deregulation may be responsible for systemic and pulmonary vasoconstriction, inflammation and oxidative organ damage.Aim: To verify retrospectively the impact of the mineral corticoid receptor antagonist canrerone i.v. on the need of invasive ventilatory support and/or all-cause in-hospital mortality.Study design: In this retrospective study (CARDIOVID-19, ID-107162), COVID-19 patients hospitalized for severe respiratory failure were taken care by pneumologists or cardiologists and received two different therapeutic approaches according to personal skill of referral medical team on pharmacological management. Group 1 (n=39) were given vasodilator agents or RAAS-inhibitors and group 2 (n=30) were given canrenone i.v.Results: Among 69 consecutive COVID-19 patients, enrolled in COVID-19 NETWORK registry, the group given canrenone (200 mg/q.d. for a median of 14±11) showed a free event rate of 83% with a survival percentage of 90%. In group 1, not receiving canrenone, free event rate was 51% and survival 64%. Kaplan-Meier analysis for composite outcomes showed a Log Rank of 0.0004 and for mortality, Log Rank was 0.005.Conclusions: The novelty of our observation relies on the independent positive impact of the canrenone, a mineral corticoid receptor antagonist, on all-cause mortality and clinical improvement in COVID-19 patients.

Early Detection Of Deep Vein Thrombosis In Patients With Coronavirus Disease 2019: Who to Screen and Who not to with Doppler Ultrasound? (preprint)

BACKGROUND. Aim of the study is to evaluate the incidence of DVT in COVID-19 patients and its correlation with the severity of the disease and with clinical and laboratory findings.METHODS. 234 symptomatic patients with COVID-19, diagnosed according to the World Health Organization guidelines, were included in the study. The severity of the disease was classified as moderate, severe and critical. Doppler ultrasound (DUS) was performed in all patients. DUS findings, clinical, laboratory’s and therapeutic variables were investigated by contingency tables, Pearson chi square test and by Student T test and Fisher's exact test. ROC curve analysis was applied to study significant continuous variables.RESULTS. Overall incidence of DVT was 10.7% (25/234): 1.6% (1/60) among moderate cases, 13.8% (24/174) in severely and critically ill patients. Prolonged bedrest and intensive care unit admission were significantly associated with the presence of DVT (19.7%). Fraction of inspired oxygen, P/F ratio, respiratory rate, heparin administration, D-dimer, IL-6, ferritin and CRP showed correlation with DVT. CONCLUSIONS. DUS may be considered a useful and valid tool for early identification of DVT. In less severely affected patients, DUS as screening of DVT might be unnecessary. High rate of DVT found in severe patients and its correlation with respiratory parameters and some significant laboratory findings suggests that these can be used as a screening tool for patients who should be getting DUS.

Analysis of the role of Chest X-Ray in a large cohort of 1117 patients with SARS-CoV-2 infection: an Italian multicenter study (preprint)

Objective. To describe the radiographic key patterns on CXR in patients with SARS-CoV-2 infection, assessing the prevalence of radiographic signs of interstitial pneumonia. To evaluate pattern variation between a baseline and a follow-up CXR.Materials and methods. 1117 patients tested positive for SARS-CoV-2 infection were retrospectively enrolled from four centers in Lombardy region. All patients underwent a CXR at presentation. Follow-up CXR was performed when clinically indicated.Two radiologists in each center reviewed CXR images and classified them as suggestive or not for interstitial pneumonia, recording the presence of ground-glass opacity (GGO), reticular pattern or consolidation and their distribution.Pearson’s chi-square test for categorical variables and McNemar test (chi-square for paired data) were performed.Results. Patients mean age 63.3 years, 767 were males (65.5%). The main result is the large proportion of positive CXR in COVID-19 patients.Baseline CXR was positive in 940 patients (80.3%), with significant differences in age and sex distribution between patients with positive and negative CXR. 382 patients underwent a follow-up CXR. The most frequent pattern on baseline CXR was the GGO (66.1%), on follow-up was consolidation (53.4%). The most common distributions were peripheral and middle-lower lung zone.Conclusions. We described key-patterns and their distribution on CXR in a large cohort of COVID-19 patients: GGO was the most frequent finding on baseline CXR, while we found an increase in the proportion of lung consolidation on follow-up CXR. CXR proved to be a reliable tool in our cohort obtaining positive results in 80.3% of the baseline cases.

Early phases of COVID-19 are characterized by a reduction of lymphocyte populations and the presence of atypical monocytes (preprint)

Background Severe acute respiratory syndrome coronavirus 2 is a recently discovered pathogen responsible of coronavirus disease 2019 (COVID-19). The immunological changes associated with this infection are largely unknown. Methods We evaluated the peripheral blood mononuclear cells profile of 63 patients with COVID-19 at diagnosis and the presence of association with inflammatory biomarkers and 28-days mortality. Results Lymphocytopenia was present in 51 of 63 (80.9%) patients. This reduction was mirrored also on CD8+ lymphocytes (128 cells/uL), natural killer cells (67 cells/uL) and natural killer T cells (31 cells/uL). Monocytes were preserved in total number but displayed a subpopulation composed mainly of cells with a reduced expression of both CD14 and HLA-DR. A direct correlation was found between serum values of IL-6 and the frequency of Th2 lymphocytes (R=0.17; p=0.04) but not with the monocytes count (R=0.01; p=0.60). Patients who died in the 28 days from admission (N=10, 15.9%), when compared to those who did not, displayed lower mean values of CD3+ (p=0.028) and CD4+ cells (p=0.042) and higher mean percentages of CD8+/CD38+/HLA-DR+ lymphocytes (p=0.026). Conclusions The early phases of COVID-19 are characterized by lymphocytopenia, predominance of Th2 lymphocytes and less immunocompetent monocytes, which include atypical mononuclear cells.