ABSTRACT
Purpose: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint pathway may related to hemophagocytic lymphohistiocytosis (HLH);the association between COVID-19 and HLH is still debated. Our aim is to describe a CTLA-4 deficient patient presenting with leishmania and EBV triggered-HLH, and the clinical and immune responses to SARS-CoV-2 generated during her follow-up Methods: NK-cytotoxic function assessed by 51Cr-K562 lytic assay;lymphocyte subsets, perforin expression, NK-cell degranulation and coexpression of CD25 and CD134 on memory T-cells by flow cytometry Whole exome sequencing with Sanger confirmation Results: A 16-year-old female was first admitted in March 2020 with severe thrombopenia and readmitted 3 months later to study polyadenopathy. In October 2020, she suffered a mild COVID-19 mild (ageusia, anosmia) showing positive IgG anti-SARS-CoV-2-Spike (694.0 UA/mL) 6 months after the infection. In March 2021 -during her third hospital admission- she fullfilled HLH criteria along with leishmaniasis infection and EBV reactivation. Later on we have found granulomatous-lymphocytic interstitial lung disease (GLILD). Normal serum immunoglobulins, weakly positive ASMA and anti-thyroglobulin autoantibodies were detected. Circulating lymphocytes and HLHoriented studies were all normal. A new, 'de novo' heterozygous missense mutation c.425G>A (p.Gly142Asp) in CTLA-4 was identified affecting a conserved domain of the protein and probably pathogenic according to our in silico results (PolyPhen). Following both the second (June 2021) and third SARS-CoV-2 BNT162b2 vaccine immunization specific IgG>40.000 UA/mL and positive anti-SARS-CoV-2-Spike memory CD4+ T-cell responses were detected Conclusion(s): We report a young patient with a new heterozygous germline mutation in CTLA-4 associating HLH induced by common triggers (leishmania, EBV) but no by SARS-CoV-2 infection. This case does not support a relevant role of SARS-Cov-2 as potential etiological trigger of HLH. Our patient has been able to generate robust specific responses against SARS-CoV-2, while other reported insufficient CTLA-4 patients show suboptimal antibody responses to SARS-CoV-2 probably due to their stronger immunosuppressor therapies.