COVID-19 and X-linked agammaglobulinemia (XLA) – insights from a monogenic antibody deficiency

Abstract

Purpose of reviewThe clinical outcomes from COVID-19 in monogenic causes of predominant antibody deficiency have pivotal implications for our understanding of the antiviral contribution of humoral immunity. This review summarizes the lessons learned from COVID-19 infection in X-linked agammaglobulinemia (XLA) due to genetic defects in Bruton's tyrosine kinase (BTK). Recent findingsKey molecular pathways underlying the development of severe COVID-19 are emerging, highlighting the possible contribution of BTK to hyperinflammation. SARS-CoV-2 specific T-cell responses and complement activation appear insufficient to achieve viral clearance in some B-cell deficient individuals. Whilst appearing efficacious in this group, use of convalescent plasma has been recently associated with the evolution of viral escape variants. Early data suggests individuals with XLA can mount a viral-specific T-cell vaccine response, however, the clinical significance of this is still emerging.

Do reduced numbers of plasmacytoid dendritic cells contribute to the aggressive clinical course of COVID‐19 in chronic lymphocytic leukaemia?

“…29,34 The outcome of COVID-19 in patients with XLA has varied from uneventful to more severe. 35,36 Based on all these findings, the increased numbers of pDC during BTKi treatment 12,13 would improve the prognosis and BTKi could potentially also act as general suppressant of the COVID-19 hyperinflammation itself. To this end, BTKi have been investigated in several clinical trials outside of CLL to elucidate their potential ameliorating effect on severe COVID-19 pneumonia, but without consensus on the outcome.…”

“…Similar to the effect of anti‐CD20 therapy, patients with another IEI, X‐linked agammaglobulinemia, XLA, an inherited defect in the BTK gene, 34 have essentially no B lymphocytes and cannot mount humoral immune responses 29,34 . The outcome of COVID‐19 in patients with XLA has varied from uneventful to more severe 35,36 …”

Common Variable Immunodeficiency Disorders as a Model for Assessing COVID-19 Vaccine Responses in Immunocompromised Patients

“…In contrast, most studies indicate patients with X-linked agammaglobulinemia (XLA) without comorbidities appear to be at lower risk, inferring antibodies can in some circumstances be detrimental (17)(18)(19)(20). Some authors are however less certain about the protective effect of XLA in COVID-19 outcomes (21,22).…”

Patient with agammaglobulinemia produces anti-SARS-CoV-2 reactive T-cells after CoronaVac vaccine

“…Authors related clinical symptoms with important inflammatory marker increase, associated with long viral persistence, suggesting a role for antibodies in reduction of viral load. [ 6 , 7 ] Ponsford et al (2021) observed that XLA patients remain susceptible to severe disease. Persistent infection was common and is likely to carry a significant risk of novel variant evolution.…”

“…Persistent infection was common and is likely to carry a significant risk of novel variant evolution. [ 6 , 7 ]…”