Immune paralysis in paediatric patients with multisystem inflammatory syndrome associated with COVID-19

ABSTRACT

Background: Paediatric SARS-CoV-2 infection is usually mild and often asymptomatic. Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 is a complication that occurs 4 to 6 weeks after primary infection. Typical symptoms are high fever, organ dysfunction and strongly elevated markers of inflammation. The immunopathology includes T-lymphocyte paralysis that is characterised by severely reduced circulating T-cells that have dysregulated activation and differentiation mechanisms, mainly CD4+ T-lymphocytes. Immune paralysis is defined as increased expression of PD-1 and TIM-3. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. Method: We present 3 paediatric patients (2 males, 1 female) with MIS-C aged 11 to 13 years admitted to paediatric intensive care unit in our University teaching hospital in Martin. Immunological parameters were measured after the admission to the hospital and continuously evaluated during the treatment. Results: In all patients we detected in immunological profile significant signs of immune paralysis of T-lymphocytes, both CD4+ and CD8+ T-lymphocytes. One patient had increased expression of PD-1 and TIM-3, other two patients had increased expression of PD-1. In two patients we detected depletion of NK cells. All patients had lymphopenia (moderate to severe) and highly elevated inflammatory markers (CRP, IL-6, ferritin) and procoagulant factors (fibrinogen, D-dimers). They were treated according to the protocol with combined immunomodulatory and anti-inflammatory therapies (intravenous immunoglobulins, corticosteroids, one patient with anakinra) with positive effect on immune profile and also on clinical condition. Conclusion: Children with MIS-C show various immunological abnormalities including T-cell reduction and cytokine release syndrome, which can be fatal. It is poorly understood how T-cell dysregulation can contribute to the pathogenesis, but hyperactivation of CD4+ T-lymphocytes and immune paralysis that promote further viral infection can drive pulmonary damage, cardiorenal syndrome and organ failure. Understanding of the immunopathology in MIS-C can help in development of better immune intervention therapies to prevent serious long-term effect of COVID-19 infection also in paediatric patients.