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.