COVID-19 is known to impose thrombotic risk and a risk of hyperinflammatory (systemic) syndromes on all age groups, but until recently, few studies assessing the actual characteristics of thrombotic events and risks in juvenile SARS-CoV-2 infected patients have been published.
What has been acknowledged, is that COVID-19 can cause hyperinflammatory syndrome in children during the period of infection or after recovery, characterized by symptoms similar to Kawasaki (SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children, Pediatrics Vol. 146, Issue 2, August 1, 2020; An outbreak of severe Kawasaki-like disease at the Italian epicenter of the SARS-CoV-2 epidemic: an observational cohort study, Lancet Vol. 395, Issue 10239 , P1171-1178, June 6, 2020).
MIS-C and Kawasaki-like or Toxic Shock Syndrome, leukemia and brain death in paediatric COVID-19
International studies report that previously healthy children and adolescents show Multisystemic Inflammatory Syndromes with features of Kawasaki or Toxic Shock Syndrome associated with COVID-19 (Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City, JAMA 2020 ; 324 (3): 294-296; see also "Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology 2020, 4 June 2020: 1-2"). There has been a shocking report of a three-year-old child who has contracted lymphocytic leukemia from coronavirus infection (Acute lymphoblastic leukemia onset in a 3-year-old-child with COVID-19, Pediatric Blood & Cancer Vol. 67, Issue 11 , November 2020). This child has no underlying medical condition, which underlines the toxicity of the coronavirus.
MIS-C and Kawasaki-like or Toxic Shock Syndrome, leukemia and brain death in paediatric COVID-19
International studies report that previously healthy children and adolescents show Multisystemic Inflammatory Syndromes with features of Kawasaki or Toxic Shock Syndrome associated with COVID-19 (Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City, JAMA 2020 ; 324 (3): 294-296; see also "Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology 2020, 4 June 2020: 1-2"). There has been a shocking report of a three-year-old child who has contracted lymphocytic leukemia from coronavirus infection (Acute lymphoblastic leukemia onset in a 3-year-old-child with COVID-19, Pediatric Blood & Cancer Vol. 67, Issue 11 , November 2020). This child has no underlying medical condition, which underlines the toxicity of the coronavirus.
A French study reports the records of a 16-year-old boy and 6-year-old child with no medical condition, diagnosed with COVID-related brain death (Severe and fatal forms of COVID-19 in children, Archives de Pédiatrie Vol. 27, Issue 5, July 2020 , P235-238). In systemic conditions, such as PIMS and MIS-C, the damage caused by SARS-CoV-2 can only be fully determined in the longer term.
Complement MAC (C5b-9) associated Thrombotic Microangiopathy
The December 2020 study provides evidence of thrombotic microangiopathy (TMA) in SARS-CoV-2 infected children, with COVID-19 ranging from minimal to severe. In children with minimal COVID as well as severe COVID and post-COVID MIS-C, markers for TMA were found to be elevated significantly. It is confirmed that complement activation is a major marker for thrombotic microangiopathy. Specifically, the complement C5b-9 Membrane Attack Complex (MAC) that is released by the body in order to lyse pathogens, is associated with TMA in juvenile COVID-19 patients (Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations, Blood Advances Vol. 4, Issue 23, December 08 2020).
Complement MAC (C5b-9) associated Thrombotic Microangiopathy
The December 2020 study provides evidence of thrombotic microangiopathy (TMA) in SARS-CoV-2 infected children, with COVID-19 ranging from minimal to severe. In children with minimal COVID as well as severe COVID and post-COVID MIS-C, markers for TMA were found to be elevated significantly. It is confirmed that complement activation is a major marker for thrombotic microangiopathy. Specifically, the complement C5b-9 Membrane Attack Complex (MAC) that is released by the body in order to lyse pathogens, is associated with TMA in juvenile COVID-19 patients (Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations, Blood Advances Vol. 4, Issue 23, December 08 2020).
The immune complex can most likely be ruled out as a driving force for complement activation in patients with COVID-TMA. In autopsy specimens and pathologic reports, published between 2010 and July 2020, evidence was found for activation of the Lectin Pathway through Mannose Binding Lectin (MBL). MAC C5b9 deposits were found in body tissue of SARS-CoV-1 (2003) and SARS-CoV-2 infected patients. Direct viral activation of this Lectin Pathway is a repeatedly and probable hypothesized cause of the MAC deposition.
Relevance
The recent findings are of great relevance, as once again it shows that the complement MAC (C5b-9) is a key feature in COVID-19 thrombotic risk that warrants further exploration. Complement activation is not the sole cause, as many factors are involved in the thrombotic risks that are characteristic for SARS-coronaviruses. Complement inhibitors should be considered as therapeutic options for COVID-infected children as well as adults. While there are specific therapeutics targeting the MAC, a side note is that complement inhibition should not become detrimental to the body's ability to perform pathogen clearance. The graphic shows some examples of complement inhibitors to target C5b9 (the MAC) and complement C5.
Relevance
The recent findings are of great relevance, as once again it shows that the complement MAC (C5b-9) is a key feature in COVID-19 thrombotic risk that warrants further exploration. Complement activation is not the sole cause, as many factors are involved in the thrombotic risks that are characteristic for SARS-coronaviruses. Complement inhibitors should be considered as therapeutic options for COVID-infected children as well as adults. While there are specific therapeutics targeting the MAC, a side note is that complement inhibition should not become detrimental to the body's ability to perform pathogen clearance. The graphic shows some examples of complement inhibitors to target C5b9 (the MAC) and complement C5.
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| Overview: therapeutic options for targeting the Complement cascade in COVID-19 |
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| The Complement system and its relation with coagulation: how complement cascades enhance thrombotic risk |
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| Reports: evidence of MAC depositions in SARS-coronavirus infections have been provided since 2003 |
