Defibrotide for the Treatment of Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 2 Pediatric Patients

Abstract

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.

Keywords: children; complement; coronavirus disease 2019; defibrotide; endotheliitis.

Figure 1.

Immunological and histological findings and course of laboratory parameters. A, Detection of T-cell response for patient 1. Overlapping peptide pools covering the sequence of major severe acute respiratory syndrome coronavirus 2 proteins (proteins M, N, and S) and irrelevant control peptides (MOG) were used to stimulate T cells independent of human leukocyte antigen types ex vivo for 16 hours followed by intracellular cytokine staining. Cumulative stimulation indexes of CD4+ and CD8+ T-cell responses are shown. Simultaneous expression of cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL] 2) and activation markers (CD154) in response to stimuli was calculated using Boolean gating. Stimulation indexes indicate quotients of stimulus and negative control (dimethyl sulfoxide [DMSO]) values for all 16 possible combinations of marker expression. B, Course of laboratory parameters for patient 1. Temporal course of D-dimers, thrombocytes, lymphocytes, bilirubin, troponin, ferritin, C-reactive protein, and procalcitonin during administration of defibrotide is shown. Defibrotide (DF) was started due to clinical deterioration and strongly increasing D-dimers, bilirubin, troponin, and thrombocytopenia. Parameters normalized rapidly after start of DF. No other antiinflammatory agents were used. C, Pathological specimen of the resected appendix from patient 1. A retrospective analysis revealed the presence of subserosal and intramural capillary endotheliitis without signs of bacterial infection 2 weeks prior to clinical deterioration. D, T-cell response for patient 2. Cumulative stimulation indexes of CD4+ and CD8+ T-cell responses are shown. Simultaneous expression of cytokines (IFN-γ, TNF-α, IL2) and activation markers (CD154) in response to stimuli was calculated using Boolean gating. Stimulation indexes indicate quotients of stimulus and negative control (DMSO) values for all 16 possible combinations of marker expression. E, Complement activation for patient 2. The membrane attack complex C5b-9 was measured at admission using enzyme-linked immunosorbent assay. A 2-fold elevated level was found compared with 4 healthy donors (gray bar depicts mean ±1 standard deviation). During DF administration, levels normalized. F and G, Thromboelastographic analysis for patient 2. Blood samples from patient 2 showed increased clot firmness and remarkable resistance to clot lysis after subsequent induction of fibrinolysis by tissue plasmin activator (F). This finding was significantly improved after the initiation of DF treatment (G). Abbreviations: CRP, C-reactive protein; MOG, myelin oligodendrocyte glycoprotein; protein M, membrane glycoprotein; protein N, nucleocapsid phosphoprotein; protein S, spike glycoprotein; SEB, staphylococcus enterotoxin B.