Italian ancestral HLA haplotype predisposing to severe COVID-19 by low spike and high IFNalpha binding affinity

Background/Objectives: Validated association between COVID-19 and the most obvious candidate genes, e.g. HLA, is still missing. A weak association with class I HLA-C*04:01 was found for infection in Sardinians and for severity in another mixed population. Auto-antibodies to interferon type I have been implicated in the severity of COVID-19 in two studies. Method(s): The binding affinity between HLA molecules and SARS-CoV-2 spike protein and IFNalpha subunits was evaluated in silico. The presence of antibodies against one or more of the 12 IFNalpha subunits was evaluated in 160 hospitalized COVID-19 patients. The 10 most frequent haplotypes in the Italian population were tested in 1.997 SARS-CoV-2 infected patients (hospitalized versus not hospitalized). Result(s): The presence of auto-antibodies against at least one IFNalpha subunit was detected in 26% of patients. The haplotype A*24:02-B*35:02-C*04:01-DRB1*11:04-DQB1*03:01 was found to predispose to severity (p = 0.0018;p = 0.07 after Bonferroni correction) in patients <50 years. The haplotype includes alleles able to bind spike with low affinity (i.e. C*04:01 and DRB1*11:04) and IFNalpha with high affinity (i.e. DRB1*11:04). Conclusion(s): One of the 10 most frequent ancestral haplotype of the Italian population predisposes to severity likely reducing both innate immunity through IFNalpha auto-antibodies induction and adaptive immunity through weaker spike protein presentation.

Polymorphism of HLA and KIR affects severity of COVID-19 by shaping innate and adaptive immunity to SARS-CoV-2

Extreme polymorphism of HLA and Killer-cell Immunoglobulin-like Receptors (KIR) differentiates immune responses across individuals. Additional to Tcell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1,575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that the activating KIR2DS4*001 allotype is associated with severe disease (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). KIR2DS4*001 in presence of its specific HLA ligands and inhibitory KIR3DL2*002 in absence its HLA ligand are also enriched in severe COVID-19 patients (OR = 1.64, 95% CI 1.09-2.50, p = 0.019), suggesting this combination acts in tandem to increase risk of developing severe COVID-19. We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from hospitalization (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-alpha associated with COVID-19 severity were detected in 26% of hospitalized patients. HLA-C*08:02 was more frequent in patients with IFN-alpha autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN- alpha antibodies. We intend to expand this analysis in Greek and Spanish COVID-19 cohorts. These findings show that KIR and HLA polymorphism may play important roles in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

A magnetic approach for understanding the impact of Covid-19 lockdown on PM10 in Rome, Italy

The magnetic properties of PM10 daily filters collected in Rome and Latium region during and after the Covid-19 lockdown (9 March-18 May 2020) were compared for outlining the impact of the mobility restrictions on airborne particulate matter. In urban traffic sites, the average PM10 concentration levels did not significantly change after the end of the lockdown, when vehicular traffic returned to its usual levels. Conversely, the average magnetic susceptibility of PM10 daily filters approximately doubled after the lockdown, pinpointing the increase of metallic emissions related to vehicular traffic. The magnetic fraction of PM10 nearurban traffic sites was dominated by magnetite-like minerals mainly arising from brakes emissions.

POS-509 ANALYSIS AND MONITORING OF THE SPREAD OF SARS-COV-2 INFECTION AMONG HEALTH CARE WORKERS OF NEPHROLOGY-DIALYSIS UNITS IN PIEDMONT AND VALLE D'AOSTA

Introduction: The ongoing SARS-COV-2 pandemic hit world’s population since the first trimester of 2020. Since the beginning health care workers have been at higher risk of morbidity because of in-hospital infections. Moreover, health care workers can contribute to the spread of infection. The aim of the study was to monitor the spread and outcomes among health care workers in Nephrology-Dialysis units in Piedmont and Valle d’Aosta Regions, North-West Italy. Methods: A web platform accessible by Dialysis coordinators across the first and second wave of pandemic is still being used to collect and regularly update demographic and clinical data of health care workers. We present preliminary results on risk estimates and measures of association. Results: An overall of 163 cases has been monitored since March 2020. The cumulative incidence is 13,5% compared to 3,3% of the general population. A slightly higher cumulative incidence has been observed among Nurses 14%, while among Doctors it is 12%. A higher incidence rate among operators is observed in the second wave of infection compared to the first (9,5% and 4%, respectively). During Autumn 2020 Italian Government did not opt for a strict lockdown in high risk Regions such as Piedmont and Valle d’Aosta. Nonetheless, strict protocols for in-hospital treatments ensured that cumulative incidence grew at a slower rate than the rest of the population (incidence rate ratio of 3,3 for health care workers compared to 5,9 for the rest of the population). Conclusions: The study of an overall population of 163 showed a higher susceptibility to SARS-COV-2 infection for health care workers compared to the general population. We observed increased risks of infection in the second wave of pandemic compared to the first wave, suggesting that despite strict protocols to manage dialysis patients infection risks for health care workers could increase without strict general lockdowns. No conflict of interest

Children with Kawasaki disease or Kawasaki-like syndrome (MIS-C/PIMS) at the time of COVID-19: are they all the same? Case series and literature review.

Since the coronavirus disease 2019 (COVID-19) outbreak started, children have been considered marginally involved compared to adults, with a quite significant percentage of asymptomatic carriers. Very recently, an overwhelming inflammatory activation, which shares clinical similarities with Kawasaki disease (KD), has been described in children exposed to COVID-19. We report three KD-like cases that occurred during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a highly affected area of Northern Italy. The clinical presentation was characterized by the presence of unremitting fever, diarrhea and elevated inflammatory markers. Case #1 and Case #2 occurred one week apart and shared other clinical features: laboratory tests confirmed COVID-19 exposure and high inflammatory activation with myocardial involvement. Case #3 followed a more typical pattern for KD. Interestingly, this patient showed lower levels of procalcitonin, C-reactive protein, D-dimers, and ferritin compared to the other two cases, whereas platelet count was higher. We hypothesize that SARS-CoV-2 might act in children as a trigger, either inducing a classical KD phenotype or causing a systemic inflammatory response leading to a severe KD-like phenotype, eventually characterized by myocardial impairment. We think that bringing these cases and their differences to the attention of the rheumatology community during the COVID-19 pandemic will be beneficial in order to highlight the importance of early diagnosis and to increase awareness of this new phenomenon.