Discussion
COVID-19 has been associated with a significant dysregulation of the immune system, the ramifications of which are still being investigated. A number of maladaptive immune responses involving innate and adaptive immunity with abnormal cytokine/chemokine profiles have been described across the various clinical spectrum of COVID-19. Acute COVID-19 is often accompanied by a cytokine storm akin to macrophage activation syndrome, with the accompanying hallmark of elevated IL-6.4 Diorio et alhas found evidence of TMA in MIS-C3 and an autopsy of a child who died from MIS-C revealed significant viral particles in several tissues, that could be an emerging suggestion of a “second-hit” virus-mediated pathology.5
COVID-19 has been associated with several hematological manifestations, AIHA has been reported in children.6 New onset SLE associated with TTP in the setting of COVID19/MIS-C has not been previously reported in pediatrics. Patients with COVID-19 infection may develop a severe inflammatory response leading to cytokine release which can present similar to autoimmune diseases.7 Furthermore, it is well known that environmental triggers, such as viral infections, can trigger the activation of immune response with increased synthesis of cytokines, mainly TNF-α, IL-6 and IL-1β, IL-17, IL-18, in genetically predisposed patients.7,8Therefore, genetically predisposed patients, such as in the case presented (given the family history), who develop cytokine storm syndrome in COVID19/ MIS-C can theoretically be at risk of developing other autoimmune syndromes.9 The chain of events is not fully clear in this case, but most likely the patient encountered COVID-19 infection around the time his father had which followed by immune dysregulation and led to SLE onset.
It’s unclear whether or not COVID-19 triggered TTP directly or triggered the onset of SLE which led to his TTP. The role of his positive DAT in his cytopenias not yet explained. In TTP, loss of ADAMTS-13 leads to microangiopathic hemolytic anemia, thrombocytopenia, and organ injury.10 This hemolytic process is mechanical intravascular with increased schistocytes seen on a peripheral blood film; as opposed to Evan’s syndrome which is extravascular and usually DAT testing is negative.10 Thrombocytopenia and immune-mediated hemolysis based on DAT positivity in the setting of COVID19 led to the initial diagnosis of Evans Syndrome in our case.6,11However, the diagnosis of TTP was clinched by the worsening of schistocytes and the lack of clinical and other laboratory improvement despite received IVIG and methylprednisolone, coupled with new onset neurological symptoms. Furthermore, the results of a reduced ADAMTS-13 confirmed TTP diagnosis.
Overall, TTP is very rare in children with an estimated incidence of 0.09 children per million.12 However, Burnneret al 13reviewed all the cases of childhood onset TTP from 1975 to 1998 and 5 patients was diagnosed with idiopathic TTP; concluded that childhood TTP is commonly associated with SLE few years after initial diagnosis. But, none reported any pediatric case presented with TTP and SLE simultaneously at diagnosis as it has been reported in adults so far.5
To our knowledge this is the only reported case with COVID-19 associated with a positive DAT TTP in the setting of new onset SLE. Zenno et al 9 reported an adolescent case with DAT positive TTP initially diagnosed with Evans but failed outpatient steroid management. His SLE screening markers were negative and no concomitant infection.
In children, the MIS-C syndrome has been associated with cardiogenic findings similar to Kawasaki disease.14 Our patient presented with coronary. Coronary artery disease is rare but a known manifestation in SLE and TTP patients. However, usually it is a thrombotic event rather than ectasia.15
In conclusion, we believe that COVID-19/MIS-C can be a possible trigger in developing new onset SLE in genetically predisposed patients. Furthermore, TTP should strongly be considered in pediatric patients who presents with thrombocytopenia and immune mediated anemia with worsening schistocytosis who are refractory to steroids; this will allow early intervention with lifesaving plasma exchange and avoiding contraindicated platelets transfusion.