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European Journal of Human Genetics ; 31(Supplement 1):706-707, 2023.
Article in English | EMBASE | ID: covidwho-20232856


Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.

Pediatric Rheumatology ; 20(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1677521


Introduction: During COVID-19 pandemic, acute acral chilblain-like lesions (ACBLL), reminiscent of lupus pernio, were observed during both first and second COVID-19 peak among patients with highly suspected (but mostly unconfirmed) infection with SARS-CoV-2.The aetiology of this phenomenon has not been elucidated yet and pathogenetic mechanism remains unknown. Several studies have investigated cytokine and chemokine profile in patients with COVID-19 but an accurate characterization of ACBLL patients is lacking. Objectives: We aimed to describe the clinical, laboratory and immunological features of children presenting with ACBLL referred to our Institute during the COVID-19 pandemic spread. Methods: We prospectively collected data of children referred to our Institute from April 1st 2020 to February 28th 2021. We investigate the presence of SARS-CoV2 infection through RT-PCR from nasopharingeal swabs and three different serologic kit. All patients underwent a laboratory work-up including coagulation, viral serology and autoantibodies panel. Finally, we analysed peripheral blood IFN signature, a panel of inflammatory biomarkers in serum/plasma by a flow cytometry bead array (CXCL10, CXCL9, IL-6, IL-1β,TNFα) and the presence of SARS-CoV2 T specific lymphocytes. Results: We examined 36 children during the first peak, and 11 children during the second COVID-19 peak (F: 28 median age 12 y), at a median delay of 26 days after symptoms onset (2-73 days). Fifteen patients (31%) presented non-specific systemic symptoms preceding ACBLL onset. Nine patients (19%) reported a possible contagion from a close contact. All patients presented stereotypical features resembling classical chilblains with acral erythematousedematous violaceous plaques and nodules localized on the toes (n= 35, 74%), the fingers (n=5, 10%) or on both sites (n=7, 15%). SARSCoV- 2 RNA detection resulted negative except for 2 patients. Furthermore, ten patients observed during the first wave showed a recurrence during the second (F:6), which developed 1-4 weeks after the second COVID-19 peak the clinical features were comparable to those of the previous episode. Five of them (50%) reported nonspecific systemic symptoms before onset and/or close contact with SARS-CoV2 positive subject. Repeated SARS-CoV-2 specific IgG/IgA tests were negative for all patients except for three cases (two of them with positive swabs). Neither common virus serology nor coagulation studies revealed significative results. Two patients presented positive ANA and anti β2 glycoprotein, respectively. A positive IFN signature was detected in 12/ 33 patients (36%).Among the 35 patients tested, the cytokine array showed high levels of IP10 (n= 35, range 12.4-739 pg/ml, n.v. 0.0-0.2 pg/ml) and a mild increase of IL-6 (n=21, range 2.4-401 pg/ml, n.v. 0.5-2.2pg/ml), without alterations of CXCL9, IL-1β and TNFa. The detection of SARS-CoV2 specific lymphocytes showed the presence of SARS-CoV2 specific lymphocytes in 9/17 (52%) patients tested (validated with positive and negative controls), only one of them with a positive serological test. Conclusion: Albeit the pathogenetic mechanism of ACBLL remains to be elucidated, our preliminary results showed a significant increase in serum IP10 levels, not frankly associated with a peripheral blood IFN signature, which is instead a characteristic of pernio-related chilblains. We also proved the presence of a T-specific memory against in 50% of the tested patients, despite the negativity of coltures and serological tests, strengthening the link between SARS-CoV2 infection and this peculiar clinical manifestation.