Preliminary Evidence of Good Safety Profile and Outcomes of Early Treatment With Tixagevimab/Cilgavimab Compared to Previously Employed Monoclonal Antibodies for COVID-19 in Immunocompromised Patients (preprint)

Objectives: Monoclonal antibodies (mAbs) have proven to be a valuable tool against COVID-19, mostly among subjects with risk factors for progression to severe illness. Tixagevimab/cilgavimab (TIX/CIL), a combination of two Fc-modified human monoclonal antibodies, has been recently approved to be employed as early treatment. Methods: Two groups of immunocompromised patients exposed to different early treatments (i.e., TIX/CIL vs. other mAbs [casirivimab/imdevimab, bamlanivimab/etesevimab, sotrovimab]) were compared in terms of clinical outcomes (hospitalization and mortality within 14 days from administration) and time to the negativity of nasal swabs. We used either Pearson’s chi-square or Fisher’s exact test for categorical variables, whereas the Wilcoxon rank–sum test was employed for continuous ones. Kaplan–Meier curves were produced to compare the time to nasopharyngeal swab negativity. Results: Early treatment with TIX/CIL was administered to 19 immunocompromised patients, while 89 patients received other mAbs. Most of them were solid organ transplant recipients or suffering from hematologic or solid malignancies. Overall, no significant difference was observed between the two groups in terms of clinical outcomes. In the TIX/CIL group, one patient (1/19, 5.3%), who was admitted to the emergency room within the first 14 days from treatment and was hospitalised due to COVID-19 progression, died. Regarding the time to nasal swab negativity, no significant difference (p=0.088) emerged. Conclusions: Early treatment of SARS-CoV-2 infection with TIX/CIL shows favourable outcomes in a small group of immunocompromised patients, reporting no significant difference when compared to similar patients treated with other mAbs.

Long term longitudinal follow up of AD-HIES cohort: impact of early diagnosis and enrolment to IPINet centres on natural history of Job's Syndrome (preprint)

BackgroundJob’s Syndrome or Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES) is a very rare inborn error of immunity disorder with multi-organ involvement and long-life post-infective damages. Longitudinal registries are of main importance to improve knowledge on natural history and management of these rare disorders. This study aims to describe the natural history of 30 Italian patients recorded in the IPINet registry with dominat negative AD-HIES. MethodsThe study shows the incidence of manifestations presented at the time of diagnosis versus the ones arose during follow up at a referral centre for inborn errors of immunity (IEI). ResultsThe mean time of diagnostic delay was 13.7 years, while age at disease onset was <12 months in the 66.7% of patients. Respiratory complications such as bronchiectasis and pneumatoceles were present at diagnosis in the 46.7% and 43.3% respectively. Antimicrobial prophylaxis resulted in decrease of pneumonia incidence from 76.7% to 46.7%. At diagnosis skin involvement was present in 93.3% of patients: eczema 80.8%, abscess 66.7%. At the follow up, under therapy the prevalence of complications decreased: eczema reduced to 63.3% and skin abscess to 56.7%. Antifungal prophylaxis decreased the mucocutaneous candidiasis occurrence from 70% to 56.7%. In the course of SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients are still alive, while three patients died at age of 28, 39 and 46 as consequence of lungs bleeding, lymphoma and sepsis, respectively. ConclusionsAnalysis of a cumulative follow-up of 278.7 patient-years has shown that early diagnosis, adequate management at expertise centres for IEI, prophylactic antibiotic and antifungal therapy improve outcome and can positively influence patients’ life expectancy. 

Long Term Longitudinal Follow up of AD-HIES Cohort: Impact of Early Diagnosis and Enrolment to IPINet Centres on Natural History of Job Syndrome (preprint)

The Job Syndrome or Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES, LOF-STAT3 gene) is a very rare inborn error of immunity disorder with multi-organ involvement and long-life post-infective damages. Longitudinal registries are of main importance to improve knowledge on natural history and management of these rare disorders. This study aims to describe the natural history of 30 Italian patients recorded in the IPINet registry with AD-HIES, with a cumulative observational-time of 721.1 patient-years. Age at disease onset was < 12 months in the 66.7% of patients, but the mean time of diagnostic delay was 13.7 years. At diagnosis skin involvement was present in 93.3% of patients (eczema 80.8%, abscess 66.7%). At the follow up eczema was still present in 63.3% and abscess in 56.7%. Respiratory complications such as bronchiectasis and pneumatoceles were present at diagnosis in the 46.7% and 43.3% respectively. Antimicrobial prophylaxis resulted in decrease of pneumonia from 76.7–46.7%. Antifungal prophylaxis decreased mucocutaneous candidiasis occurrence from 70–56.7%. In the course of SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients are still alive, while three patients died at age of 28, 39 and 46 as consequence of lungs bleeding, lymphoma and sepsis, respectively. Our study shows that many severe complications can affect AD-HIES patients. Analysis of a cumulative follow-up of 278.7 patient-years has shown that early diagnosis, adequate management at expertise centres for primary immunodeficiency, prophylactic antibiotic and antifungal therapy improve outcome and can positively influence patients’ life expectancy.

The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis (preprint)

Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.