Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations

Abstract

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

Graphical abstract

Figure 1.

Elevations in sC5b9 correlate with renal dysfunction. (A) Elevated sC5b9 levels in patients with minimal COVID-19 (n = 21), severe COVID-19 (n = 11), and MIS-C (n = 18) are significantly different relative to those of healthy control subjects (n = 26). (B) sC5b9 levels are significantly higher in those with AKI (n = 9) than without AKI (n = 38). Increases in sC5b9 levels in patients with all 3 manifestations of disease (N = 48) correlate in a statistically significant manner with elevations in creatinine (C) and in elevations of blood urea nitrogen (BUN; D) and GFR (E). Dotted line indicates upper limit of normal cutoff for sC5b9 of 247 ng/mL.

Figure 2.

Heatmaps of Pearson r correlations demonstrate clusertings of laboratory findings. Heatmaps of Pearson r correlations (A) and associated P values (B) for ancillary findings of thrombotic microangiopathy in patients with severe COVID-19 (n = 11) and patients with MIS-C (n = 18).

Figure 3.

Absence of correlation between sC5b9 elevatons and antibodies against SARS-CoV-2. Correlation between sC5b9 vs the logarithmically transformed value of IgG (A), IgM (B), and IgA (C) against the SARS-CoV-2 RBD protein for a subset of included patients with MIS-C (n = 10), severe disease (n = 11), and minimal disease (n = 12).