Haploidentical CD3+ TCR αß/CD19+ depleted HSCT for MHC Class II deficiency and persistent SARS-CoV-2 pneumonitis.

Background & Objectives: SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterised by acute respiratory distress, needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against Covid-19 and have persistent disease. The authors describe a child with combined immunodeficiency, with favorable post-HSCT course following a haploidentical haematopoietic stem cell transplant in the presence of persistent SARS-CoV-2 infection. Methods & results: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution post-HSCT, she underwent a maternal (with a recent history of Covid-19 infection) haploidentical haematopoietic stem cell transplant. The patient received Regdanvimab® (post stem cell infusion) and Remdesivir (pre and post stem cell infusion). We noted a gradual increase in the Ct (cycle threshold) values, implying reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical/radiological improvement. Conclusions: Combination of adoptive transfer of maternal CD45RO+ memory add-back T-lymphocytes after haploidentical HSCT, use of Regdanvimab® (SARS-CoV-2 neutralising monoclonal antibody) and Remdesivir may have led to the successful outcome in our patient with severe immunodeficiency, undergoing HSCT. Our case highlights the role of novel antiviral strategies (monoclonal antibodies and CD45RO+ memory T-lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

Persistent SARS-CoV-2 infection in patients with secondary antibody deficiency: successful clearance following combination casirivimab and imdevimab (REGN-COV2) monoclonal antibody therapy.

BACKGROUND: There is growing evidence that antibody responses play a role in the resolution of SARS-CoV-2 infection. Patients with primary or secondary antibody deficiency are at increased risk of persistent infection. This challenging clinical scenario is associated with adverse patient outcome and potentially creates an ecological niche for the evolution of novel SARS-CoV-2 variants with immune evasion capacity. Case reports and/or series have implied a therapeutic role for convalescent plasma (CP) to secure virological clearance, although concerns have been raised about the effectiveness of CP and its potential to drive viral evolution, and it has largely been withdrawn from clinical use in the UK. CASE PRESENTATION: We report two cases in which persistent SARS-CoV-2 infection was cleared following administration of the monoclonal antibody combination casirivimab and imdevimab (REGN-COV2, Ronapreve). A 55-year-old male with follicular lymphoma, treated with B cell depleting therapy, developed SARS-CoV-2 infection in September 2020 which then persisted for over 200 days. He was hospitalised on four occasions with COVID-19 and suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days. CONCLUSIONS: These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation.

SARS-CoV-2 Testing of 11,884 Healthcare Workers at an Acute NHS Hospital Trust in England: A Retrospective Analysis.

Healthcare workers (HCWs) are known to be at increased risk of infection with SARS-CoV-2, although whether these risks are equal across all roles is uncertain. Here we report a retrospective analysis of a large real-world dataset obtained from 10 March to 6 July 2020 in an NHS Foundation Trust in England with 17,126 employees. 3,338 HCWs underwent symptomatic PCR testing (14.4% positive, 2.8% of all staff) and 11,103 HCWs underwent serological testing for SARS-CoV-2 IgG (8.4% positive, 5.5% of all staff). Seropositivity was lower than other hospital settings in England but higher than community estimates. Increased test positivity rates were observed in HCWs from BAME backgrounds and residents in areas of higher social deprivation. A multiple logistic regression model adjusting for ethnicity and social deprivation confirmed statistically significant increases in the odds of testing positive in certain occupational groups, most notably domestic services staff, nurses, and health-care assistants. PCR testing of symptomatic HCWs appeared to underestimate overall infection levels, probably due to asymptomatic seroconversion. Clinical outcomes were reassuring, with only a small minority of HCWs with COVID-19 requiring hospitalization (2.3%) or ICU management (0.7%) and with no deaths. Despite a relatively low level of HCW infection compared to other UK cohorts, there were nevertheless important differences in test positivity rates between occupational groups, robust to adjustment for demographic factors such as ethnic background and social deprivation. Quantitative and qualitative studies are needed to better understand the factors contributing to this risk. Robust informatics solutions for HCW exposure data are essential to inform occupational monitoring.