Multisystemic inflammatory syndrome in children is a condition characterized by fever, inflammation, and multiorgan dysfunction that manifest late in the course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Reference Henderson, Canna and Friedman1 Given the similarities between multisystemic inflammatory syndrome in children and Kawasaki disease, initially most patients with multisystemic inflammatory syndrome in children were treated with intravenous immunoglobulins and glucocorticoids with good response. Reference Mahmoud, El-Kalliny and Kotby2 Because multisystemic inflammatory syndrome in children appeared to be a rare syndrome, randomized trials of treatment strategies have been impeded. Several clinical guidances have been published, recommending biologics for refractory diseases. The ACR clinical guidance recommends infliximab or anakinra for refractory disease Reference Henderson, Canna and Friedman1 . In refractory Kawasaki disease patients or complicated with Kawasaki disease Shock Syndrome or Macrophage Activation Syndrome, cyclosporin-A has been used effectively. Reference García-Pavón, Yamazaki-Nakashimada, Báez, Borjas-Aguilar and Murata3–Reference Gamez-Gonzalez, Moribe-Quintero and Cisneros-Castolo6 Also, recently some reports have been published using cyclosporin-A in refractory multisystemic inflammatory syndrome in children. Reference Suzuki, Suenaga and Sakai7–Reference Kinoshita, Nishimura and Umemoto9 Using a similar therapeutic approach for multisystemic inflammatory syndrome in children and Kawasaki disease, we report one patient with refractory multisystemic inflammatory syndrome in children who responded to cyclosporin-A treatment.
Case report
A 12-year-old Mennonite boy presented to the Emergency Department with a five-day history of fever, vomiting, diarrhoea, and abdominal pain. He denied upper or lower respiratory tract symptoms, urinary symptoms, or skin rash. Physical examination revealed abdominal tenderness on palpation in the right lower fossa with positive Mc Burney sign. Appendicitis was suspected and abdominal CT showed mesenteric adenitis and periappendiceal inflammation. The blood test showed severe lymphopenia (lymphocyte 500/mm Reference García-Pavón, Yamazaki-Nakashimada, Báez, Borjas-Aguilar and Murata3 ), thrombocytopenia (platelet count 51,000/mm Reference García-Pavón, Yamazaki-Nakashimada, Báez, Borjas-Aguilar and Murata3 ), elevated C-reactive protein (255 mg/L), and liver enzymes (aspartate transaminase 63 U/L, alanine transaminase 32 U/L). Coagulation tests showed fibrinogen 317 mg/dL, elevation of prothrombin time test ratio (INR 1.3) and increase of D-dimer (4 mg/L), ferritin 731 ng/mL, NT-pro b-type natriuretic peptide 7210 ng/L, Creatine phosphokinase MB isoenzyme 17.6 ng/L, and high levels of Interleukin-6 (11.3 pg/mL). The patient was admitted to the Paediatric ICU due to haemodynamic instability. He required fluid resuscitation and vasopressors. Antibiotics and anticoagulation (enoxaparin 0.5 mg/kg/dose every 12 hours) were initiated. Multisystemic inflammatory syndrome in children associated to SARS-CoV2 infection was suspected, due to a positive reverse transcriptase polymerase obtained two days before admission and a negative IgM with a positive IgG test to SARS-CoV2.
He received treatment with IV methylprednisolone 30 mg/kg/day and intravenous immunoglobulin 2 g/kg. After the first dose of immunoglobulin, the patient remained febrile, with dyspnoea, and haemodynamic shock and received noradrenaline infusion. A CT of the chest revealed multiple lung opacities, initial echocardiography was normal except for a mild mitral valve insufficiency, and serial echocardiography showed left diastolic ventricular disfunction (ejection fraction 53%) and small pericardiac effusion. He received Dobutamine, his cardiac enzymes continued to be elevated, NT-proBNP increased to 17,700 ng/L and CK-Mb to 20.7, and troponin level was within normal limits. He received two additional doses of immunoglobulins and three methylprednisolone pulses without significant improvement. Monoclonal antibody treatment with Tocilizumab 8 mg/kg/day was initiated. Two days after starting biological therapy, his clinical status and inflammatory markers stabilised. However, he still required vasopressor support with dobutamine and had persistent elevation of CK MB, troponin, and proBNP levels. The patient received oral cyclosporine (3 mgkgday) and two days later dobutamine infusion was discontinued (Supplementary Figure 1). The patient was discharged on oral cyclosporine and oral corticosteroids which were suspended two weeks later, and the patient showed clinical improvement, with normalisation of cardiac enzymes and normalisation of the echocardiographic abnormalities two weeks after hospital discharge.
Discussion
Various therapies including additional immunoglobulins, corticosteroids, infliximab, tocilizumab, anakinra, and plasmapheresis have been used in patients with resistant multisystemic inflammatory syndrome in children with variable results. Reference Henderson, Canna and Friedman1,Reference Mahmoud, El-Kalliny and Kotby2,Reference Emeksiz, Özcan and Perk10
Children with multisystemic inflammatory syndrome in children share clinical features with other inflammatory syndromes such as primary haemophagocytic lymphohistiocytosis. Regardless of the mechanism, these clinical syndromes share features of elevated pro-inflammatory cytokines (IL-1, IL-6, and interferon-γ) produced by a dysregulated immune response in the host that converges in multi-organ involvement. Histopathological studies of the myocardium of patients with multisystemic inflammatory syndrome in children reveal inflammatory infiltrates consisting of lymphocytes, eosinophils, and neutrophils.
Cyclosporin-A an immunosuppressant targeting the Ca2++/NFAT signaling has proved to be effective in refractory Kawasaki disease. In a large study (KAIKA), the combination of immunoglobulins with cyclosporine compared to conventional immunoglobulins treatment alone was more effective to prevent coronary artery abnormalities in Kawasaki disease Reference García-Domínguez, Torres and Carreón-Guerrero11 Cyclosporin-A has also been used in Macrophage Activation Syndrome complicating Kawasaki disease and in Macrophage Activation Syndrome complicating multisystemic inflammatory syndrome in children successfully. Reference García-Pavón, Yamazaki-Nakashimada, Báez, Borjas-Aguilar and Murata3,Reference García-Domínguez, Torres and Carreón-Guerrero11,Reference Hiraoka, Tsuge and Kondo8 Three other multisystemic inflammatory syndrome in children patients receiving cyclosporin-A have been reported, all from Japan (Table 1). Interestingly, two of the patients presented venous stasis in the limbs, a feature not common in multisystemic inflammatory syndrome in children. Kinoshita et al. reported a 12-year-old male who presented multisystemic inflammatory syndrome in children refractory to a single dose of immunoglobulins and improved with the combination of cyclosporin-A and steroid pulse therapy. Reference Kinoshita, Nishimura and Umemoto9 Hiraoka et al. reported a 9-year-old female who was refractory to two immunoglobulins doses and eventually cyclosporin-A controlled the disease. They suggest that because of immunoglobulins retreatment in multisystemic inflammatory syndrome in children pose risk for overload and decompensation, cyclosporin-A can be an option as a second-line therapy. Reference Hiraoka, Tsuge and Kondo8 Suzuki et al. presented a 12-year-old boy who was refractory to immunoglobulins and three methylprednisolone pulses who responded to cyclosporin-A. Reference Suzuki, Suenaga and Sakai7 They attribute the effectiveness of cyclosporin-A to the suppression of cytokines such as IL-12, IL-18, and growth factors. Of note that it has been shown that cyclosporin-A possess antiviral properties against SARS-CoV2 in vitro. Reference Dittmar, Lee and Whig12 Intravenous and oral cyclosporin-A seems to be a safe and effective alternative treatment for refractory multisystemic inflammatory syndrome in children patients.
Cases of MIS-C treated with cyclosporine
IVIG = intravenous immunoglobulins; GI = gastrointetsinal; MPD = methylprednisolone; CAA = coronary artery abnormalities.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/S1047951122002748
Acknowledgements
We thank Dr Moises Ramirez-Lopez, Dr Claudia Peña-Varela, and Dr Marcela Colmenero-Rascon for the excellent care of the patient, invaluable input, and helpful discussions.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflict of interest
None.
