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.
Highlights
Severity of COVID-19 is associated with increased age, male sex, and comorbidities, such as diabetes, arterial hypertension or pulmonary disease [1]
We report clinical and immunological findings of 5 PAD patients with severe COVID-19 that failed to generate a specific humoral immune response to SARS-CoV-2
Similar to convalescent immunocompetent patients, where polyfunctional SARS-CoV-2-specific T cells have been described [36], triple cytokine-producing, activated T cells were observed in our PAD patients, indicating the generation of a memory-like phenotype [36, 37]
Summary
Severity of COVID-19 is associated with increased age, male sex, and comorbidities, such as diabetes, arterial hypertension or pulmonary disease [1]. In patients with inborn errors of immunity (IEI), morbidity and mortality of COVID-19 is increased [2–9]. Identified immunological host factors include type I interferon (IFN) autoantibodies or disruption of type I IFN signaling, affecting innate immune response to SARS-CoV-2 [12, 13]. These autoantibodies are found frequently in APS-1 (autoimmune polyendocrine syndrome) patients [14], general frequency of type I IFN autoantibodies in PAD patients are currently unknown and other immunological mechanisms underlying the predisposition to severe disease courses remain to be determined
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