Abstract
Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4 + T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.
Keywords: convalescent plasma (CP); coronavirus disease 2019 (COVID-19); innate immunity; primary antibody deficiency (PAD); primary immunodeficiencies (PID); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); type I interferons.
【저자키워드】 Innate immunity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronavirus disease 2019 (COVID-19), Convalescent plasma (CP), primary antibody deficiency (PAD), primary immunodeficiencies (PID), type I interferons., 【초록키워드】 COVID-19, Treatment, coronavirus disease, convalescent plasma, Monocytes, SARS-CoV-2, IgG, Coronavirus disease 2019, coronavirus, Risk factors, Mortality, innate immune response, Immunity, antibody, Innate immunity, T cells, monoclonal antibody, Comorbidities, interferons, immunodeficiency, interferon, viral shedding, peptide, Comorbidity, cytokine, outcome, Prophylactic, severe acute respiratory syndrome Coronavirus, CD4, viral clearance, flow cytometry, type I interferon, SARS-CoV-2 immunity, Peripheral blood, T cell, Viral, nucleocapsid, persistence, autoantibodies, morbidity, Patient, severe cases, phenotype, type I interferons, SARS-CoV-2 RNA, humoral immune response, respiratory, convalescent, expression, patients, T cell response, seronegative, Blood, SARS-CoV-2 spike, CD169, marker, cellular, mucosal, administration, Analysis, immunological mechanism, Primary immunodeficiencies, humoral, autoantibody, SIGLEC1, deficiency, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, healthy individuals, Inborn errors, naïve, Severe case, SARS-CoV-2 viral shedding, heterogeneous, fatal COVID-19, clinical disease, clearance, type I interferon response, immunological, primary antibody, robust, analyzed, lack, examined, detectable, elevated, median, characterized, activated, indicate, producing, excluded, peptide pool, severe COVID-19 patient, undetectable, with COVID-19, 【제목키워드】 COVID-19, SARS-CoV-2, response, Specific,