CASE REPORT published: 01 June 2021 doi: 10.3389/fimmu.2021.665824 Hemadsorption as a Treatment Option for Multisystem Inflammatory Syndrome in Children Associated With COVID-19. A Case Report Juan Carlos Ruiz-Rodrı́guez 1,2, Luis Chiscano-Camón 1,2*, Clara Palmada 1,2, Adolf Ruiz-Sanmartin 1,2, Marina Garcı́a-de-Acilu 1,2, Erika Plata-Menchaca 1,2, Janire Perurena-Prieto 3,4, Manuel Hernandez-Gonzalez 3,4, Marcos Pérez-Carrasco 1,2, Edited by: Pere Soler-Palacin 5 and Ricard Ferrer 1,2 Rudolf Lucas, 1 Intensive Care Department, Vall d’Hebron University Hospital, Barcelona, Spain, 2 Shock, Organ Dysfunction and Augusta University, United States Resuscitation Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain, 3 Immunology Division, Vall Reviewed by: d’Hebron University Hospital, Barcelona, Spain, 4 Diagnostic Immunology Research Group, Vall d’Hebron Research Institute, Danilo Buonsenso, Barcelona, Spain, 5 Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, Vall Catholic University of the Sacred d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain Heart, Italy Matej Podbregar, University of Ljubljana, Slovenia Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is Payaningal Somanath, University of Georgia, United States characterized by hypercytokinemia leading to overwhelming inflammation. We describe *Correspondence: the use of a hemadsorption device as part of the supportive treatment for cytokine storm. Luis Chiscano-Camón Keywords: hemoadsorption, inflammatory multisystemic syndrome, myocardial injury, cytokine - immunological lchiscano@vhebron.net terms, SARS-CoV-2 Specialty section: This article was submitted to Inflammation, INTRODUCTION a section of the journal Frontiers in Immunology There are significant clinical and immunological data describing the clinical consequences of MIS-C Received: 09 February 2021 as an immunopathogenic illness. Therefore, a key intervention would be the control of the cytokine Accepted: 04 May 2021 storm (1–3). Published: 01 June 2021 Citation: Ruiz-Rodrı´guez JC, Chiscano-Camón L, Palmada C, CASE REPORT/CASE PRESENTATION Ruiz-Sanmartin A, Garcı´a-de-Acilu M, Plata-Menchaca E, Perurena-Prieto J, We present a 17-year-old male with a history of fever, dyspnea, diffuse chest and abdominal pain, and Hernandez-Gonzalez M, generalized rash on day 13 of COVID-19 molecular diagnosis and within the first two weeks of clinical Pérez-Carrasco M, presentation. The polymerase chain reaction (PCR) test for COVID-19 was negative, while the serum Soler-Palacin P and Ferrer R (2021) IgG levels were present. The patient presented a rapid deterioration, which evolved into cardiogenic Hemadsorption as a Treatment shock with biventricular dysfunction (30% left ventricular ejection fraction on transthoracic Option for Multisystem Inflammatory echocardiography) and acute hypoxemic respiratory failure. The primary differential diagnoses Syndrome in Children Associated With COVID-19. A Case Report. were sepsis of bacterial origin (including staphylococcal and streptococcal toxic shock syndromes), Front. Immunol. 12:665824. other systemic viral infections (adenovirus, enterovirus), acute abdomen, Kawasaki disease, drug doi: 10.3389/fimmu.2021.665824 hypersensitivity, autoimmune or autoinflammatory diseases, and hemophagocytosis. Frontiers in Immunology | www.frontiersin.org 1 June 2021 | Volume 12 | Article 665824 Ruiz-Rodrı´guez et al. Case Report: Hemadsorption in Multisystem Inflammatory Syndrome The blood cultures were negative for bacteria and fungi. The Several official organizations, such as the Centers for Disease initial evaluations for hemophagocytosis and immunological or Control of the United States (CDC), the World Health pharmacological-related causes were negative. Chest and Organization (WHO), or RCPCH-UK, have tried to define the abdominal CT imaging were performed. The patient general characteristics of MIS-C. However, there is no consensus had CT findings of ileitis. Blood analyses showed a regarding case definition and clinical management (10, 11). hyperinflammatory profile (Table 1). He required orotracheal Treatment includes IV immunoglobulin (12), high-dose IV intubation and rescue maneuvers for severe hypoxemia. The final corticosteroids, and control of hypercytokinemia. For the control diagnosis was narrowed into acute myocarditis secondary to of hypercytokinemia, the use of interleukin-1 (IL-1) (13) antagonist MIS-C (diagnosis of exclusion). The patient fulfilled the Royal (anakinra) and interleukin 6 (IL-6) receptor antagonist College of Pediatrics and Child Health of the United Kingdom (tocilizumab) (14) has been suggested. Recent studies in SARS- (RCPCH-UK) criteria for MIS-C associated with COVID-19 (4). CoV-2 patients have shown that these antagonists do not improve He received empirical treatment with intravenous (IV) mortality (15–19), and tocilizumab has been associated with an amoxicillin-clavulanic, IV methylprednisolone (2mg/kg/day), increased risk of nosocomial infections (20). However, these studies IV immunoglobulin (1g/kg/d) for three days, and cytokine have been performed in adults, and their results should not be hemadsorption by a 24-hour treatment with Cytosorb®. The extrapolated to younger patients, such as ours. patient received the adjunctive therapy with hemoadsorption Regarding infection risk, hemoadsorption treatment sessions during the first 24 hours of ICU admission. Informed consent for are of short duration. Thus, the risk of infection of intravascular the initiation of the hemoadsorptive technique was requested devices used for extracorporeal support seems low, particularly from the patient’s family. He required vasopressor and inotropic in critical care units where preventive measures are widely support that was retired after 4 days of treatment (Table 1). implemented. Short- or mid-term hemoadsorption-associated Focused bedside transthoracic ultrasound showed progressive infections have not been described. improvement of biventricular global function after The extracorporeal cytokine hemoadsorption device (Cytosorb ®) hemoadsorptive treatment. The patient was discharged from (21) was approved for its use in critically ill COVID19 patients (22, the ICU on day 5 and discharged from the hospital on day 20. 23). The cartridge has been previously used for cytokine storm- In the subsequent outpatient follow-up, the patient has fully related hyperinflammatory conditions (24) and has been subject to recovered to his baseline level of activity, and no chronic sequelae many recent studies (25). Cytokine storm encompasses a have been detected. heterogeneous group of disorders characterized by life-threatening hyperinflammation, and may be present in non-infectious pathologies (26). We hypothesized that cytokine removal may DISCUSSION/CONCLUSION ameliorate cytokine storm and provide clinical benefits in our patient´s clinical scenario. Previous experience published in sepsis In critically ill adult patients, hyperinflammation plays a shows that cytokine hemoadsorption is a safe procedure with no significant role in the pathophysiology of multiple organ failure associated adverse effects (27). (5, 6). The clinical and laboratory features of hyperinflammation, In our patient, hemoadsorption achieved a safe and rapid timing from SARS-CoV-2 infection onset, and similarities in the reduction of cytokine levels. From a clinical point of view, fast disease pattern among adults with COVID-19, support the improvements in shock and multiorgan dysfunction parameters hypothesis that MIS-C results from immune-mediated injury were observed. He had no adverse effects associated with the triggered by SARS-CoV-2 infection (7). Currently, there are technique, vasopressor support was reduced by more than 80%, clinical, microbiological, and immunological data describing and organic dysfunction, measured by the SOFA score, improved MIS-C as a novel immunopathogenic illness (8, 9). from 14 to 6 points in 24 hours. Cytokine levels decreased TABLE 1 | Evolution of the vasopressor support, clinical anf laboratory values. PreHA PostHA 48h ICU admission 60h ICU admission Reference values CRP/ (mg/dL) 30.68 36.25 20.2 19.98 0.03-0.50 Ferritin (ng/mL) 399 619 400 394 25.00-400.0 IL-6 (pg/mL) 3457 47.8 41.92 28.13 0.00-4.30 IL-10 (pg/mL) 90.3 9.24 6.9 7.88 0.00-7.80 CD25s (pg/mL) 16969 16596 12038 14914 400.00-2000.00 DD (ng/mL) 902 1368 603 725 0.00-243.00 SOFA 14 6 2 2 – P/F 60 400 432 – – S/F – – – 326 – NAD (mg/kg/min) 0.8 0.08 0 0 – DBT (mg/kg/min) 2 2 0.2 0 – The hemoadsorption (HA) technique was performed within the first 24h of ICU admission. CRP, C-reactive protein; IL-6, interleukin-6; IL-10, interleukin-10; CD25s, interleukin-2 soluble- receptor; DD, D-dimer; SOFA, Sequential Organ Failure Assessment (points); P/F, PaO2/FIO2 ratio; S/F, SpO2/FiO2 ratio; NAD, noradrenaline; DBT, dobutamine; HA, hemoadsorption (duration 24h). Frontiers in Immunology | www.frontiersin.org 2 June 2021 | Volume 12 | Article 665824 Ruiz-Rodrı´guez et al. Case Report: Hemadsorption in Multisystem Inflammatory Syndrome considerably, and the rest of the acute phase parameters were despite having received conventional treatment. Impressively, he progressively reduced in the following hours once the was discharged from the ICU on day 5 of admission. The hyperinflammatory stimulus was attenuated. The downstream cytokine measurements are those included in our institution´s effects (C-reactive protein, soluble CD25 [sCD25], and ferritin clinical analyses panel. levels) are minimal since it mainly reduces acute phase mediators Beyond being the first to describe the potential usefulness of that can be eliminated by hemoadsorption. However, such hemoadsoption for MIS-C associated with COVID-19, the main mediators are reduced after the attenuation of the cytokine storm. strength of this case report relies on the rapid control of Ferritin as an example, is not removed by hemoadsorption, thus we hyperinflammation observed by cytokine hemadsorption. In understand the rise of ferritin as corresponding to the evolution of combination with conventional treatment, cytokine the base process; the ascent occurs in the first 24 hours and hemoadsorption can achieve early clinical improvements. This decreased rapidly from this moment on due to the case report supports the effectiveness of hemoadsorption in treatment implemented. hypercytokinemia control, though larger and controlled studies As this is a case report, causality cannot be confirmed, particularly are essential to draw any meaningful conclusion. when considering the other treatment interventions required (e.g., corticosteroids, immunoglobulins, and multiorgan support). However, there was a close temporal relationship between the initiation of hemoadsorption and the reductions in cytokine levels DATA AVAILABILITY STATEMENT and clinical improvement. IL-6 and IL-10 levels were significantly The raw data supporting the conclusions of this article will be reduced in 24 hours. Rapid improvements in respiratory function made available by the authors, without undue reservation. (PaO2/FiO2 ratio improved from 60 to 400), shock and organ dysfunction parameters (SOFA score improved from 14 to 6 points) were documented 24 hours from initiation of therapy. The patient´s favorable clinical evolution should be attributed to all ETHICS STATEMENT therapeutic interventions, though the rapid clinical improvement We complied with the guidelines for human studies and our may be attributed to cytokine elimination by hemoadsorption, as it research was conducted ethically in accordance with the World has not been described as a pharmacological effect of corticosteroids Medical Association Declaration of Helsinki. Subject gave their or immunoglobulins. MIS-C requires multifactorial treatment. written informed consent to publish their case. Information Although corticosteroids and immunoglobulins could have revealing the subject’s identity is to be avoided. progressively and ultimately modulated inflammation, we consider hemoadsorption responsible for the rapid improvement in respiratory, hemodynamic, and organ dysfunction. Consequently, we consider hemoadsorption a potential adjunctive therapy in AUTHOR CONTRIBUTIONS patients with MISC-C severe multiorgan dysfunction. Our results must be confirmed in larger studies. Substantial contributions to the conception or design of the Our case report has several limitations. We report an isolated work. Drafting the work or revising it critically for important clinical case, and a cause-effect relationship cannot be confirmed. intellectual content. Revising the manuscript critically for However, we are aware of the critical role cytokine storm-control important intellectual content. All authors contributed to the had in the rapid reduction of multiorgan support in our patient, article and approved the submitted version. 6. Ye Q, Wang B, Mao J. The Pathogenesis and Treatment of the “Cytokine REFERENCES Storm” in COVID-19. J Infect (2020) 80:607–13. doi: 10.1016/ 1. Buonsenso D, Riitano F, Valentini P. Pediatric Inflammatory Multisystem j.jinf.2020.03.037 Syndrome Temporally Related With SARS-CoV-2: Immunological 7. Feldstein LR, Rose EB, Horwitz SM, Collin JP, Newhams MM, Son MBF, Similarities With Acute Rheumatic Fever and Toxic Shock Syndrome. et al. Multisystem Inflammatory Syndrome in US Children and Front Pediatr (2020) 8:574. doi: 10.3389/fped.2020.00574 Adolescents. N Engl J Med (2020) 383(4):334–46. doi: 10.1056/NEJMoa 2. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. 2021680 Hyperinflammatory Shock in Children During COVID-19 Pandemic. Lancet 8. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones C, Shah P, et al. Clinical (2020) 395(10237):1607–8. doi: 10.1016/S0140-6736(20)31094-1 Characteristics of 58 Children With a Pediatric Inflammatory Multisystem 3. Carter MJ, Fish M, Jennings A, Doores K, Wellman P, Seow LJ, et al. Syndrome Temporallyassociated With SARS-Cov-2. JAMA (2020) 324:259– Peripheral Immunophenotypes in Children With Multisystem 69. doi: 10.1001/jama.2020.10369 Inflammatory Syndrome Associated With SARS-CoV-2 Infection. Nat Med 9. Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, et al. (2020) 26(11):1701–7. doi: 10.1038/s41591-020-1054-6 The Immunology of Multisystem Inflammatory Syndrome in Children 4. Nijman R, Guchtenaere A, Koletzko, Russell R, Copley S, Titomanlio L, et al. With COVID-19. Cell (2020) 183(4):968–81.e7. doi: 10.1016/ Peadiatric Infammatory Multisystem Syndrome: Statement by the Peadiatric j.cell.2020.09.016 Section of the European Society for Emergency Medicine and European 10. Guidance: Paediatric Multisystem Inflammatory Syndrome Temporally Academy of Pediatrics. Front Pediatr (2020) 8:490. doi: 10.3389/fped.2020.00490 Associated With COVID-19 (2020). Available at: https://www.rcpch.ac.uk/ 5. Moore BJB, June CH. Cytokine Release Syndrome in Severe COVID-19. resources/guidancepaediatric-multisystem-inflammatory-syndrome- Science (2020) 368:473–74. doi: 10.1126/science.abb8925 temporally-associated-covid-19. Frontiers in Immunology | www.frontiersin.org 3 June 2021 | Volume 12 | Article 665824 Ruiz-Rodrı´guez et al. Case Report: Hemadsorption in Multisystem Inflammatory Syndrome 11. Rapid Risk Assessment: Paediatric Inflammatory Multisystem Syndrome and 21. Cytosorbents Corporation and CytoSorbents Medical Inc. CytoSorb_ – A First- SARS -CoV-2 Infection in Children (2020). Available at: https://www.ecdc. in-Class Cytokine Filter Approved in the European Union. Available at: www. europa.eu/en/publications-data/paediatric-inflammatory-multisystem- cytosorbents.com/tech.htm. syndromeand-sars-cov-2-rapid-risk-assessment. 22. U.S. Food and Drug Administration. CytoSorb ® 300 Ml Device Approved by 12. Sperotto F, Friedman KG, Son MBF, VanderPluym CJ, Newburger JW, FDA for Emergency Treatment of COVID-19. (2020). Dionne A. Cardiac Manifestations in SARS-CoV-2-associated Multisystem 23. Yang X-H, Sun R-H, Chen E-Z, Liu J, Wang H-L, Yang R-L, et al. Expert Inflammatory Syndrome in Children: A Comprehensive Review and Recommendations on Blood Purification Treatment Protocol for Patients Proposed Clinical Approach. Eur J Pediatr (2020) 15:1–16. doi: 10.1007/ With Severe COVID-19. Chronic Dis Transl Med (2020). doi: 10.1016/ s00431-020-03766-6 j.cdtm.2020.04.002 13. Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. 24. Napp L, Bauersachs. Extracorporeal Hemoadsorption: An Option for Anakinra for Severe Forms of COVID19: A Cohort Study. Lancet Rheumatol COVID-19 Associated Cytokine Storm Syndrome. Shock (2020) 18:10. (2020) 2:e393–400. doi: 10.1016/S2665-9913(20)30164-8 doi: 10.1097/SHK.0000000000001568 14. Carter M, Shankar-Hari M, Tibby S. Pediatric Inflammatory Multisystem Syndrome 25. Al Shareef K, Bakouri M. Cytokine Blood Filtration Responses in COVID-19. Temporally Associated With SARS-CoV-2 Infection: An Overview. Intensive Care Blood Purif (2020) 28:1–9. doi: 10.1159/000508278 Med (2020) 14:1–4. doi: 10.1007/s00134-020-06273-2 26. Weaver LK, Behrens EM. Weathering the Storm: Improving Therapeutic 15. Holt GE, Batra M, Murthi M, Kambali S, Santos K, Perez Bastidas M, et al. Lack Interventions for Cytokine Storm Syndromes by Targeting Disease of Tocilizumab Effect on Mortality in COVID19 Patients. Sci Rep (2020) Pathogenesis. Curr Treatm Opt Rheumatol (2017) 3:33–48. doi: 10.1007/s40674- 10:17100. doi: 10.1038/s41598-020-74328-x 017-0059-x 16. Kewan T, Covut F, Al-Jaghbeer M, Rose L, Gopalakrishan K, Akbik B. 27. Honore P, Hoste E, Molná r Z, Jacobs R, Joannes-Boyau O, Malbrain M, Tocilizumab for Treatment of Patients With Severe COVID–19: A et al. Cytokine Removal in Human Septic Shock: Where are We and Retrospective Cohort Study. EClinicalMedicine (2020) 24:100418. doi: Where are We Going. Ann Intensive Care (2019) 9:56. doi: 10.1186/s13613- 10.1016/j.eclinm.2020.100418 019-0530-y 17. Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I. Anakinra for Severe Forms of COVID-19: A Cohort Study. Lancet Rheumatol Conflict of Interest: The authors declare that the research was conducted in the (2020) 2(7):e393–400. doi: 10.1016/S2665-9913(20)30164-8 absence of any commercial or financial relationships that could be construed as a 18. Salama C, Han J, Yau L, Reiss W, Kramer B, Neidhart J, et al. Tocilizumab in potential conflict of interest. Patients Hospitalized With COVID-19 Pneumonia. N Engl J Med (2020) 384 (1):20–30. doi: 10.1056/NEJMoa2030340 Copyright © 2021 Ruiz-Rodrı ́guez, Chiscano-Camón, Palmada, Ruiz-Sanmartin, 19. Stone J, Frigault M, Serling-Boyd N, Fernandes A, Harvey L, Foulkes A. Garcı ́a-de-Acilu, Plata-Menchaca, Perurena-Prieto, Hernandez-Gonzalez, Efficacy of Tocilizumab in Patients Hospitalized With COVID-19. N Engl J Pérez-Carrasco, Soler-Palacin and Ferrer. This is an open-access article distributed Med (2020) 383:2333–44. doi: 10.1056/NEJMoa2028836 under the terms of the Creative Commons Attribution License (CC BY). The use, 20. Pawar A, Desai RJ, Solomon DH, Santiago Ortiz AJ, Gale S, Bao M, et al. Risk distribution or reproduction in other forums is permitted, provided the original author of Serious Infections in Tocilizumab Versus Other Biologic Drugs in Patients (s) and the copyright owner(s) are credited and that the original publication in this With Rheumatoid Arthritis: A Multidatabase Cohort Study. Ann Rheum Dis journal is cited, in accordance with accepted academic practice. No use, distribution or (2019) 78(4):456–64. doi: 10.1136/annrheumdis-2018-214367 reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 4 June 2021 | Volume 12 | Article 665824