The successful use of eculizumab for treatment of thrombotic microangiopathy in pediatric acute SARSCoV2 infection and multisystem inflammatory syndrome in children

Aurora, Tarun; Joseph, Noel; Bhoopalan, Senthil Velan; Caniza, Miguela; Flerlage, Tim; Ghafoor, Saad; Hankins, Jane S.; Hijano, Diego R.; Jesudas, Rohith; Kirkham, Justin K.; Martinez, Hugo R.; Maron, Gabriela; Sharma, Akshay; Hines, Melissa

doi:10.3324/haematol.2022.280603

Cited by 7 publications

(11 citation statements)

References 12 publications

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“…Studies describing the plasma and serum proteomic analysis revealed that many complement components and their regulators were significantly upregulated in adult patients with COVID-19. 18,[39][40][41][42] Diorio et al 24 observed that soluble C5b-9, 13,22 MBL pathway, C3, and C4 levels were elevated in children with SARS-CoV-2 infection, 43 and complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection. 23 A 2022 study 44 determined that the MIS-C group exhibited increased frequencies of the complement factor H coding single nucleotide variants potentially predisposing to complement deregulation.…”

Section: Discussionmentioning

confidence: 99%

“…53 It has been previously found that the levels C3 and C5 levels were elevated in severe COVID-19 adult patients. 54 Diorio et al 24 observed that soluble C5b-9, 13,22 complement activation and complement-mediated thrombotic microangiopathy (TMA) have been associated with SARS-CoV-2 infection. 23 In our cohort of children, we found that the levels of C3 and C5a levels were elevated in children with MIS-C and acute COVID-19, which suggests that prolonged and excessive activation in the host may be what leads to pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Previous adult studies have demonstrated elevation of C5a and soluble C5b-9 in patients with COVID-19, as well as deposition of activated complement proteins in injured tissues and organs . Previous reports determined that MIS-C and acute COVID-19 children were associated with highly elevated levels of activation markers of the classical, alternative, and terminal pathways . Children with SARS-CoV-2 infection exhibited elevated levels of soluble C5b9, which correlated with disease severity .…”

Section: Introductionmentioning

confidence: 94%

“…21,22 Children with SARS-CoV-2 infection exhibited elevated levels of soluble C5b9, which correlated with disease severity. 13,[22][23][24][25] However, there remains a paucity of information on the degree and the possible involvement of complement in the pathogenesis of MIS-C and acute COVID-19 in children, especially from low middle-income countries. Therefore, we have performed an in-depth evaluation of the complement system in children with MIS-C, acute COVID-19, and convalescent COVID-19.…”

Section: Introductionmentioning

confidence: 99%

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Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

Rajamanickam¹,

Nathella

Venkataraman

et al. 2023

JAMA Netw Open

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ImportanceMultisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involvement, which occurs within a few weeks following the resolution of acute SARS-CoV-2 infection. The complement system is a vital part of the innate immune system and plays a role in COVID-19 pathogenesis.ObjectiveTo examine and compare the levels of complement components and regulators along with complement activation products in the different clinical spectrum of children with SARS-CoV-2 and a control group.Design, Setting, and ParticipantsThis cross-sectional study analyzed children with MIS-C admitted to a single hospital in India from June through September 2020. Eligible participants were children who were hospitalized of either sex, aged 1 to 18 years. Data were analyzed August 2022.MeasuresLevels of complement components and regulators along with complement activation products in all the groups of children. Mann-Whitney U test and Kruskal-Wallis analysis were used to compare the complement component levels, and Spearman rank correlation analysis was used to describe the association between complement components and laboratory and biochemical parameters.ResultsA total 145 children were included (median age, 5 years [range, 1 month-17 years); 84 [58%] male): 44 children with MIS-C, 33 with acute COVID-19 (reverse transcriptase–polymerase chain reaction [RT-PCR] positive), 47 with convalescent COVID-19 (immunoglobulin G–positive non-MIS-C) and 21 children for a control group (both serology and RT-PCR negative). Children with MIS-C and COVID-19 had higher levels of C1q (geometric mean [SD]: MIS-C, 61.5 [18.5] ng/mL; acute COVID-19, 56.9 [18.6] ng/mL; controls, 24.1 [3.3] ng/mL), C2 (MIS-C, 605.8 [219.7] ng/mL; acute COVID-19, 606.4 [167.7] ng/mL; controls, 255.9 [73.3] ng/mL), C3 (MIS-C, 318.2 [70.7] ng/mL; acute COVID-19, 237.7 [61.8] ng/mL; controls, 123.4 [15.7] ng/mL), C4b (MIS-C, 712.4 ng/mL; acute COVID-19, 640.7 ng/mL; controls, 351.5 ng/mL), C5 (MIS-C, 1487 ng/mL; acute COVID-19, 1364 ng/mL; controls, 561.9 ng/mL), C5a, (MIS-C, 2614.0 [336.2] ng/mL; acute COVID-19, 1826.0 [541.0] ng/mL; controls, 462.5 [132.4] ng/mL), C3b/iC3b (MIS-C, 3971.0 [635.1] ng/mL; acute COVID-19, 3702.0 [653.9] ng/mL; controls, 2039.0 [344.5] ng/mL), and factor B (MIS-C, 47.6 [7.8] ng/mL; acute COVID-19, 44.6 [6.3] ng/mL; controls, 27.5 [5.0] ng/mL), factor D (MIS-C, 44.0 [17.2] ng/mL; acute COVID-19, 33.8 [18.4] ng/mL; controls, 21.3 [6.1] ng/mL), and factor H (MIS-C, 53.1 [4.0] ng/mL; acute COVID-19, 50.8 [5.7] ng/mL; controls, 43.6 [3.8] ng/mL) in comparison with convalescent and control children. In addition, children with MIS-C had significantly elevated levels of C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) support as compared with those who did not require PICU support, and in children with COVID-19 who developed moderate to severe disease compared with those who developed mild disease. Overall, MIS-C and acute COVID-19 were associated with the hyperactivation of complement components and complement regulators.Conclusions and RelevanceIn this cross-sectional study, the complement system was associated with the pathogenesis of MIS-C and COVID-19 in children; complement inhibition could be further explored as a potential treatment option.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

Rajamanickam¹,

Nathella

Venkataraman

et al. 2023

JAMA Netw Open

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“…For example, patients with severe COVID-19 caused by SARS-CoV-2 have severe tissue damage attributed to increased complement activity ( 65 ). One small case series described the successful use of eculizumab in pediatric acute SARS-CoV2 infection, multisystem inflammatory syndrome and thrombotic microangiopathy ( 66 ). The same principle of complement inhibition has been tested in a small phase-II clinical trial of adult patients with severe COVID-19 caused by SARS-CoV-2.…”

Section: Complement Deficiencymentioning

confidence: 99%

Neonatal sepsis and transient immunodeficiency: Potential for novel immunoglobulin therapies?

et al. 2022

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Neonates, especially preterm neonates, have the highest risk of sepsis of all age groups. Transient immaturity of the neonatal immune system is an important risk factor. Neonates suffer from hypogammaglobulinemia as nor IgA nor IgM is transferred over the placenta and IgG is only transferred over the placenta late in gestation. In addition, neutrophil numbers and complement function are also decreased. This mini-review focuses on strategies to improve neonatal host-defense. Both clinical and preclinical studies have attempted to boost neonatal immunity to lower the incidence of sepsis and improve outcome. Recent advances in the development of (monoclonal) antibodies show promising results in preclinical studies but have yet to be tested in clinical trials. Strategies to increase complement activity seem efficient in vitro but potential disadvantages such as hyperinflammation have held back further clinical development. Increase of neutrophil numbers has been tested extensively in clinical trials but failed to show improvement in mortality. Future research should focus on clinical applicability of promising new prevention strategies for neonatal sepsis.

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Description of a national, multi‐center registry of patients with sickle cell disease and SARS‐CoV‐2 infection: Data from the Pediatric COVID‐19 United States Registry

Dain,

Diorio,

Fisher

et al. 2024

Pediatric Blood & Cancer

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Children with sickle cell disease (SCD) are at risk of complications from viral infections, including SARS‐CoV‐2. We present the clinical characteristics and outcomes of pediatric patients with SCD from the Pediatric COVID‐19 United States Registry who developed acute COVID‐19 due to SARS‐CoV‐2 infection (n = 259) or multisystem inflammatory syndrome in children (MIS‐C; n = 4). Nearly half of hospitalized children with SCD and SARS‐CoV‐2 infection required supplemental oxygen, though children with SCD had fewer intensive care (ICU) admissions compared to the general pediatric and immunocompromised populations. All registry patients with both SCD and MIS‐C required ICU admission. Children with SCD are at risk of severe disease with SARS‐CoV‐2 infection, highlighting the importance of vaccination in this vulnerable population.

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The successful use of eculizumab for treatment of thrombotic microangiopathy in pediatric acute SARSCoV2 infection and multisystem inflammatory syndrome in children

Abstract: Not available.

Cited by 7 publications

References 12 publications

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

Neonatal sepsis and transient immunodeficiency: Potential for novel immunoglobulin therapies?

Description of a national, multi‐center registry of patients with sickle cell disease and SARS‐CoV‐2 infection: Data from the Pediatric COVID‐19 United States Registry

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