An Algorithmic Approach to Multisystem Inflammatory Syndrome in Children with COVID-19: Tehran Children’s Medical Center Protocol

AUTHORS

Vahid Ziaee ORCID 1 , 2 , 3 , * , Raheleh Assari ORCID 1 , 2 , Setarh Mamishi ORCID 2 , 4 , 5 , Aliakbar Zeinaloo ORCID 2 , 6 , Masoud Mohammadpour ORCID 2 , 7 , Iran Malekzadeh 2 , 8 , MIS-C COVID-19 Collaborators Groups 1 , 3 , 4 , 6 , 7 , 8

1 Rheumatology Subgroup, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran

2 Children’s Medical Center, Pediatrics Center of Excellence, Tehran, Iran

3 Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran

4 Infectious Diseases Subgroup, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran

5 Pediatrics Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran

6 Cardiology Subgroup, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran

7 Intensive Care Subgroup, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran

8 Emergency Subgroup, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran

9 Bahrami Children's Hospital, Tehran, Iran

10 Imam Khomeini Complex Hospital, Tehran, Iran

How to Cite: Ziaee V, Assari R , Mamishi S, Zeinaloo A, Mohammadpour M, et al. An Algorithmic Approach to Multisystem Inflammatory Syndrome in Children with COVID-19: Tehran Children’s Medical Center Protocol, Iran J Pediatr. 2020 ; 30(5):e108617. doi: 10.5812/ijp.108617.

ARTICLE INFORMATION

Iranian Journal of Pediatrics: 30 (5); e108617
Published Online: September 25, 2020
Article Type: Methods Article
Received: August 22, 2020
Accepted: August 22, 2020
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Abstract

COVID-19 as a viral infection is usually asymptomatic in children, but complication of this disease in children is not rare and may be fatal. Hyper inflammation of COVID-19 is a potential fatal in undiagnosed children. It is very similar to Kawasaki disease but with higher mortality and morbidity. Multisystem inflammatory syndrome in children (MIS-C) and multi-organ involvement was reported in hyper inflammation syndrome following COVID19. Herein we report our algorithmic approach to Kawasaki-like syndromes due to COVID-19 in our center. Based-on this approach we had no mortality during the last 5 months.

1. Background

The World Health Organization (WHO) declared coronavirus outbreak a global pandemic on 11th March 2020 (1). The first children's coronavirus cases were reported in Wuhan, the epicenter of COVID-19, showing mild respiratory symptoms and fever with positive SARS-CoV-2 RNA in nasopharyngeal/throat swabs (2, 3). However, the first report from United Kingdom (UK) introduced shared clinical manifestations of the new syndrome with other critical syndromes, such as toxic shock syndrome (TSS), atypical Kawasaki disease (KD), Kawasaki disease shock syndrome (KDSS), and secondary hemophagocytic lymphohistiocytosis (HLH) with antibody SARS-CoV-2 positive (4). This was followed by reports from Italy (5) and Switzerland (6). Thus, on 14th May, the United States Centers for Disease Control and Prevention (CDC) named multisystem inflammatory syndrome in children (MIS-C) on these manifestations of SARS-CoV-2 in children (7).

Children have been associated with the early phase of the virus replication with positive SARS-CoV-2 RNA of nasopharyngeal involvement with mild symptoms and delayed phase of inflammation and immune dysregulation with seropositive SARS-CoV-2 due to MIS-C (4, 5, 8-10).

In Iran, especially at the second peak, several patients and consultations with KD and/or MIS-C, according to CDC criteria, were referred to our hospital. Hence, this kind of approach to patients with MIS-C in the Tehran Children’s Medical Center, (affiliated to Tehran University of Medical Sciences) is confirmed and advised by pediatric rheumatologists, pediatric infectious disease specialists, and pediatric cardiologists. According to this experience, we have some research and report on a different aspect of MIS-C recently (11, 12).

2. Kawasaki Disease and Kawasaki-Like Diseases

Kawasaki disease (KD) is an inflammatory disease that damages mucous membranes (eyes, lips and oral mucosa), skin (rashes), lymph nodes, and medium-sized vessels (vasculitis, specially coronary arteries) (13). Nowadays, similar clinical manifestations of KD and MIS-C have attracted the attention of clinicians to a higher prevalence of Asian vasculitis.

The seasonal incidence of viral infection and Kawasaki disease suggests the viral trigger factor of the immune system to be involved in KD.

The seasonal incidence of viral infection and KD led to the speculation that viral infection may be a trigger factor of the immune system in KD (14). The association of SARS-COV1 and KD was described (15). However, this theory has not been accepted by subsequent studies. A 30-fold increased incidence of KD after the COVID-19 pandemic compared to the same period in the last five years in the Italian literature may confirm the triggering role of SARS-CoV-2 in KD patients with higher affinity than SARS-CoV1 (5). Thus, the first complete KD with positive SARS-CoV-2 RNA-PCR was reported with a significant response to intravenous immunoglobulin (IVIg) treatment without MIS-C presentations (16).

Kawasaki disease shock syndrome (KDSS) is one of the severe manifestations of KD (1% - 5%) with decreased ejection fraction (EF), thrombocytopenia, anemia, and increased inflammatory laboratory data (ESR, CRP). KDSS patients were older, with more coronary involvement and IVIg resistance (17).

In the acute phase of KD as a hyper-inflammatory condition, the levels of cytokines, such as TNF, IL6, IL1β, IL17, and GCS-F are increased. In IVIg- resistant KD patients, IL6 and IL10 levels are higher with more coronary involvement than IVIg-responsive KD patients (18) Thus, increased levels of IL6, IL10, and interferon-gamma (IFN‐γ) were reported in IVIG-resistant KDSS patients (17). Hence, MIS-C patients may be resistant to IVIg treatment.

IVIg is prepared from the serum of 1000 - 15000 blood donors. IVIg targets both innate and adaptive immune systems. The endocytosis of macrophages and dendritic cells is inhibited by blocking the activation of the immune complex. Thus, it would be helpful in the early phase of the inflammatory cascade. In contrast, due to high concentrations and increased plasma viscosity should be dealt with the volume overload and thrombotic events, especially in cardiogenic shock (CS) and hyper-coagulative states, such as KDSS and MIS-C (19).

To the best of our knowledge, there are two aspects of COVID-19 KD in childhood nowadays:

First, at a younger age (less than five years old), the results of the SARS-CoV-2 PCR-RNA become more positive than antibody test in patients with complete or incomplete KD (according to AHA criteria) and this group is responder to IVIg treatment (IVIg-responsive patients).

Second, at an older age (older than five years), patients with incomplete KD criteria or Kawasaki-like disease resembling KDSS exhibit higher coronary and valvular involvement. In this group, antibodies become more positive than SARS-CoV-2 PCR-RNA and do not respond to IVIg treatment (non-IVIg-responsive patients) (8, 9).

3. Cytokine Storm and MISC

Macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm phenomenon arising from malignancies, rheumatic disorders, or viral infections. The dysregulation of NK cells and cytolytic CD8 T cells (CTL) lead to inherited or acquired antigen-presenting activation and INF-y. TNFα secretion, on the other hand, causes the recruitment of other inflammatory cells, such as neutrophils and lymphocytes, leading to increased secretion of cytokines and activation of macrophages, along with the production of pro-inflammatory cytokines, TNF-α, IL-6, IL-1, IL-18, and hemostatic tissue factor (TF). The activated macrophages exhibit HLH and hyperferritinemia. This cycle continues until a cytokine storm occurs ultimately (20).

The same pathway may be taken in a cytokine storm, or MIS-C phenomenon of SARS-CoV-2 as a secondary HLH triggered by a viral infection with antibody-mediated stimulation (21, 22). Secondary HLH, like the primary HLH, may occur with a fundamental role of a genetic disorder (23). Therefore, it may be a response to the question why the first MIS-C reports were from European children of specific races as opposed to Asian children with higher susceptibility to KD and the source of SARS-CoV-2 from this population.

MAS is a life-threatening condition, which requires prompt evaluation and treatment. Due to the highly increased cytokines, the antagonists of key cytokines, such as anti-IL1, anti-IL6, and INF, were administered and evaluated in the treatment of the cytokine storm phenomena (24). Although there is no consensus and evidence on efficacy of pulsed intravenous methylprednisolone (IVMP), rapid resolution of hypercoagulable state and critical response to MAS with suppression of activated macrophages lead to administration of IV pulses of methylprednisolone in one to three doses (25-27). Indeed, the economic state and availability of medicine in the immediate therapeutic intervention should be noticed.

In the recent pandemic state, corticosteroids in patients with MIS-C are prescribed and yield good results (8, 9, 11, 12, 28), Therefore, the majority of MIS-C patients are SARS-CoV-2 PCR-RNA negative accompanied by SARS-CoV-2 antibody positive with delayed presentation, leading to conducting clinical trials to suppress the inflammatory response process rather than virus suppression.

Tehran Children’s Medical Center, Pediatrics Center of Excellence in Iran as a tertiary pediatric referral center has been encountered with more than 50 MIS-C cases during 3 months. So, all relative departments including rheumatology, infectious disease, intensive care, cardiology and emergency departments were involved in designing an algorithmic approach for diagnosis and treatment of children suspicious to MIS-C and Kawasaki like disease following COVID-19. This approach is presented in this report. Based on this approach we diagnosed all patients as soon as possible and treated all suspected children without any mortality or morbidity (Figures 1-5).

Figure 1. Approach to Kawasaki-like syndromes in pandemic COVID-19: The Tehran Children’s Medical Center Protocol (algorithm 1); designed by Pediatric Rheumatology Department confirmed by Pediatric Infectious Diseases, Pediatric Intensive Care, Pediatric Cardiology, and Pediatric Emergency Departments.
Figure 2. Approach to Kawasaki-like syndromes in pandemic COVID-19: The Tehran Children’s Medical Center Protocol (algorithm 2); designed by Pediatric Rheumatology Department confirmed by Pediatric Infectious Diseases, Pediatric Intensive Care, Pediatric Cardiology, and Pediatric Emergency Departments.
Figure 3. Approach to Kawasaki-like syndromes in pandemic COVID-19: The Tehran Children’s Medical Center Protocol (algorithm 3); designed by Pediatric Rheumatology Department confirmed by Pediatric Infectious Diseases, Pediatric Intensive Care, Pediatric Cardiology, and Pediatric Emergency Departments.
Figure 4. Approach to Kawasaki-like syndromes in pandemic COVID-19: The Tehran Children’s Medical Center Protocol (algorithm 4); designed by Pediatric Rheumatology Department confirmed by Pediatric Infectious Diseases, Pediatric Intensive Care, Pediatric Cardiology, and Pediatric Emergency Departments.
Figure 5. Approach to Kawasaki-like syndromes in pandemic COVID-19: The Tehran Children’s Medical Center Protocol (algorithm 5); designed by Pediatric Rheumatology Department confirmed by Pediatric Infectious Diseases, Pediatric Intensive Care, Pediatric Cardiology, and Pediatric Emergency Departments.

Contributor Information

MIS-C COVID-19 Collaborators Groups:

Fatemeh Tahghighi ORCID 1,2, Payman Sadeghi ORCID 1,9, Mahdieh Sadat Mousavi ORCID 1,2, Seyed Reza Raeeskarami ORCID 1,10, Hamid Eshaghi ORCID 2,4, Mahmoud Khodabandeh ORCID 2,4, Mohamedreza Abdosalehi ORCID 2,4, Ehsan Aghaei Moghadam ORCID 2,6, Keyhan Sayadpour Zanjani ORCID 2,6, Mojtaba Gorji2,6, Reza Shabanian ORCID 2,6, Elaheh Malakan Rad ORCID 2,6, Bahare Yaghmaei2,7, Meisam Sharifzadeh ORCID 2,7, Mohammad-Taghi Majnoon ORCID 2,6, Abbas Hassani2,7, Zeinab Najafi2,7, Layla Tahernia2,7, Mahsa Asadabadi ORCID 2,8, Sara Memarian ORCID 2,8, Elmira Hajiesmaeil Memar2,8, Parisa Sadeghirad2,8, Mahsa Soti2,8, Mahya Mohamadi2,8, Parastoo Sharifi2,8

Footnotes

References

  • 1.

    WHO Director. General's opening remarks at the media briefing on COVID-19 - 11 March 2020. 2020. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020.

  • 2.

    Liu W, Zhang Q, Chen J, Xiang R, Song H, Shu S, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020;382(14):1370-1. doi: 10.1056/NEJMc2003717. [PubMed: 32163697]. [PubMed Central: PMC7121643].

  • 3.

    Jiehao C, Jin X, Daojiong L, Zhi Y, Lei X, Zhenghai Q, et al. A Case Series of Children With 2019 Novel Coronavirus Infection: Clinical and Epidemiological Features. Clin Infect Dis. 2020;71(6):1547-51. doi: 10.1093/cid/ciaa198. [PubMed: 32112072]. [PubMed Central: PMC7108143].

  • 4.

    Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-8. doi: 10.1016/S0140-6736(20)31094-1. [PubMed: 32386565]. [PubMed Central: PMC7204765].

  • 5.

    Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. The Lancet. 2020;395(10239):1771-8. doi: 10.1016/s0140-6736(20)31103-x.

  • 6.

    Belhadjer Z, Meot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020. doi: 10.1161/CIRCULATIONAHA.120.048360. [PubMed: 32418446].

  • 7.

    CDC Health Alert Network. Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). 2020, [cited 2020 May 22]. Available from: https://emency.cdc.gov/han/2020/han00432.asprge.

  • 8.

    Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. 2020;383(4):334-46. doi: 10.1056/NEJMoa2021680. [PubMed: 32598831]. [PubMed Central: PMC7346765].

  • 9.

    Kaushik S, Aydin SI, Derespina KR, Bansal PB, Kowalsky S, Trachtman R, et al. Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City. J Pediatr. 2020;224:24-9. doi: 10.1016/j.jpeds.2020.06.045. [PubMed: 32553861]. [PubMed Central: PMC7293760].

  • 10.

    Pan Y, Zhang D, Yang P, Poon LLM, Wang Q. Viral load of SARS-CoV-2 in clinical samples. Lancet Infect Dis. 2020;20(4):411-2. doi: 10.1016/S1473-3099(20)30113-4. [PubMed: 32105638]. [PubMed Central: PMC7128099].

  • 11.

    Memar EH, Tahghighi F, Yousefzadegan S, Sadeghirad P, Mousavi A, Mahmoudabadi RZ, et al. Acute Abdomen as a Clinical Presentation of COVOD19 in Children. Surgery J. 2020.

  • 12.

    Mahmoudi S, Mehdizadeh M, Shervin Badv R, Navaeian A, Pourakbari B, Rostamyan M, et al. The Coronavirus Disease 2019 (COVID-19) in Children: A Study in an Iranian Children's Referral Hospital. Infect Drug Resist. 2020;13:2649-55. doi: 10.2147/IDR.S259064. [PubMed: 32801803]. [PubMed Central: PMC7406067].

  • 13.

    McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-99. doi: 10.1161/CIR.0000000000000484. [PubMed: 28356445].

  • 14.

    Rypdal M, Rypdal V, Burney JA, Cayan D, Bainto E, Skochko S, et al. Author Correction: Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers. Sci Rep. 2019;9(1):7401. doi: 10.1038/s41598-019-42137-6. [PubMed: 31068599]. [PubMed Central: PMC6506480].

  • 15.

    Dominguez SR, Anderson MS, Glode MP, Robinson CC, Holmes KV. Blinded case-control study of the relationship between human coronavirus NL63 and Kawasaki syndrome. J Infect Dis. 2006;194(12):1697-701. doi: 10.1086/509509. [PubMed: 17109341]. [PubMed Central: PMC7199878].

  • 16.

    Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Segal JB, et al. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case. Hosp Pediatr. 2020;10(6):537-40. doi: 10.1542/hpeds.2020-0123. [PubMed: 32265235].

  • 17.

    Li Y, Zheng Q, Zou L, Wu J, Guo L, Teng L, et al. Kawasaki disease shock syndrome: clinical characteristics and possible use of IL-6, IL-10 and IFN-gamma as biomarkers for early recognition. Pediatr Rheumatol Online J. 2019;17(1):1. doi: 10.1186/s12969-018-0303-4. [PubMed: 30611297]. [PubMed Central: PMC6321686].

  • 18.

    Wang Y, Wang W, Gong F, Fu S, Zhang Q, Hu J, et al. Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. Arthritis Rheum. 2013;65(3):805-14. doi: 10.1002/art.37815. [PubMed: 23440694].

  • 19.

    Ballow M. Safety of IGIV therapy and infusion-related adverse events. Immunol Res. 2007;38(1-3):122-32. doi: 10.1007/s12026-007-0003-5. [PubMed: 17917017].

  • 20.

    Shimabukuro-Vornhagen A, Godel P, Subklewe M, Stemmler HJ, Schlosser HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. doi: 10.1186/s40425-018-0343-9. [PubMed: 29907163]. [PubMed Central: PMC6003181].

  • 21.

    Soy M, Keser G, Atagunduz P, Tabak F, Atagunduz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085-94. doi: 10.1007/s10067-020-05190-5. [PubMed: 32474885]. [PubMed Central: PMC7260446].

  • 22.

    Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children (Basel). 2020;7(7). doi: 10.3390/children7070069. [PubMed: 32630212]. [PubMed Central: PMC7401880].

  • 23.

    Vastert SJ, van Wijk R, D'Urbano LE, de Vooght KM, de Jager W, Ravelli A, et al. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford). 2010;49(3):441-9. doi: 10.1093/rheumatology/kep418. [PubMed: 20019066].

  • 24.

    Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12(5):259-68. doi: 10.1038/nrrheum.2015.179. [PubMed: 27009539]. [PubMed Central: PMC5851441].

  • 25.

    Mastropietro CW, Valentine KM. Secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and hyperferritinemic sepsis-induced multiple-organ dysfunction syndrome in the pediatric ICU. Pediatr Crit Care. 2018:245–255.

  • 26.

    Boom V, Anton J, Lahdenne P, Quartier P, Ravelli A, Wulffraat NM, et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13:55. doi: 10.1186/s12969-015-0055-3. [PubMed: 26634252]. [PubMed Central: PMC4669611].

  • 27.

    Assari R, Sadeghi P, Mirmohammadsadeghi A, Ebadi F, Ziaee V. Macrophage activation syndrome as a complication of rheumatologic disorders, a report from Iran. Reumatismo. 2020;71(4):189-98. doi: 10.4081/reumatismo.2019.1204. [PubMed: 31995957].

  • 28.

    Mousavi MS, Assari R, Tahghighi F, Eshaghi H, Ziaee V. Prolonged fever and intravenous immunoglobulin resistance in kawasaki disease: Should macrophage activation syndrome be considered? Iran J Pediatr. 2019;In Press(In Press). doi: 10.5812/ijp.69170.

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