Clinical and Laboratory Characteristics of the Multisystem Inflammatory Syndrome in Children: A Case Series of 75 Patients

authors:

avatar Shabnam Hajiani Ghotbabadi 1 , avatar Maryam Mollaie 2 , * , avatar Seyedeh Sedigheh Hamzavi ORCID 3 , avatar Anahita Sanaei Dashti ORCID 3 , **

Shiraz University of Medical Sciences, Shiraz, Iran
Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
Professor Alborzi Clinical Microbiology Center, Nemazee Teaching Hospital, Shiraz, Iran
Corresponding Authors:

how to cite: Hajiani Ghotbabadi S, Mollaie M, Hamzavi S S, Sanaei Dashti A. Clinical and Laboratory Characteristics of the Multisystem Inflammatory Syndrome in Children: A Case Series of 75 Patients. Arch Pediatr Infect Dis.In Press(In Press):e120863. doi: 10.5812/pedinfect-120863.

Abstract

Background:

SARS-CoV-2 has been characterized since December 2019 as the etiology of severe pneumonia throughout the world. However, the majority of children and adolescents with the respective infection have mild COVID-19. In April 2020, a warning was issued by the National Health Service (NHS), based on which a multisystem inflammatory syndrome in children (MIS-C) could be associated with COVID-19, presenting with cardiovascular shock, fever, and hyperinflammation. The syndrome presents with fever and organ involvement but with no pathognomonic findings or diagnostic tests, while some of the manifestations are almost the same as those of Kawasaki disease.

Objectives:

Knowledge of clinical course, demographic data, treatment, and prognosis can contribute to the more efficient management of the patients and, consequently, a decrease in morbidity and mortality.

Methods:

Seventy-five patients < 18 years from September 22, 2020, to March 10, 2021, in Namazi hospital, Shiraz, Iran, with a diagnosis as per MIS-C defined criteria, were recruited.

Results:

Median age of the patients was 6.2 years, and 58.6% were male. Of the patients, 46% had positive SARS-CoV-2 RT-PCR, antibody, or both. Thirty percent of the total patients reported contact with proven COVID-19 cases. The abdominal free fluid in 17 patients, hepatitis in one patient, and stasis in both kidneys of one patient were detected. Upon echocardiography on the first day, 77%, 48%, 21%, and one patient were with tricuspid regurgitation, mitral regurgitation, abnormal LV function, and myocarditis, respectively; however, after 5 - 7 days, the repeated echocardiography revealed 44% of patients with tricuspid regurgitation, 30% with mitral regurgitation, and 6% with abnormal LV function. For the treatment, 18% of the patients received inotropes, 60% ASA, 32% IVIG, 84% glucocorticoids, and 25.3% received furosemide. All of the patients received antibiotics as well. Finally, 97% of the patients were discharged alive, while two cases died.

Conclusions:

The results of this study suggest the importance of cardiac consultation along with early hospital care during the course of MIS-C in order to prevent the associated short-term and long-term complications.

1. Background

The pandemic of severe pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged since December 2019 (1). The first corresponding cases originated in Wuhan, China, and rapidly spread to other countries (2). Symptoms in adults with severe COVID-19 typically present during the second week of illness, when viral loads have decreased, and laboratory evidence of inflammation has increased (3). These observations show that dysregulated innate and adaptive immune responses have a crucial role in the severity of the condition (4). However, most children and adolescents with SARS-CoV-2 infection have mild COVID-19 (5).

The National Health Service (NHS) issued a warning in April 2020 that a multisystem inflammatory syndrome in children (MIS-C) could be linked to COVID-19, presenting with cardiovascular shock, fever, and hyper inflammation (6). MIS-C case definitions vary but generally include the age younger than 21 years, persistent fever, multi-organ dysfunction, laboratory evidence of inflammation, lack of an alternative diagnosis, and prior SARS-CoV-2 infection (7). Many factors, including being overweight, asthma, and ethnic origin, black or Asian, may be risk factors for MIS-C (8).

In the published case series, many patients with MIS-C have had some clinical and paraclinical presentations similar to those of Kawasaki disease (6, 9). Some patients also presented with the characteristics of toxic shock syndrome or macrophage activation syndrome (10). MIS-C is a syndrome presenting with fever and organ involvement but without pathognomonic findings or diagnostic tests (11). Unlike Kawasaki disease, MIS-C reportedly mainly occurs in adolescents and children older than five years of age (6, 12).

2. Objectives

Knowledge of demography, clinical course, para clinical data, treatment, and prognosis of MIS-C can contribute to the better management of the patients and, as a result, reduced mortality and morbidity rates. This study summarized the demographical and clinical characteristics of 75 children with MIS-C in Shiraz, southern Iran.

3. Methods

In the present observational and retrospective study, we included people under 18 years of age, from September 22, 2020, to March 10, 2021, in Namazi hospital, Shiraz, Iran, with a diagnosis that met the MIS-C definition criteria. The case definition included seven criteria: age < 21 years, severe diseases leading to hospitalization, fever lasting for at least 24 hours, laboratory markers of significant inflammation, one or more organ involvement, proof of infection with SARS-CoV-2 based on RT-PCR, antibody testing, exposure to a person with COVID-19 in the past month, and lack of an alternative diagnosis. Inclusion criteria in our study were the same as diagnostic criteria for MIS-C, and the exclusion criteria were age >18 and no consent to participate.

4. Results

We included 75 children who met the criteria for confirmed MIS-C in the study. The median age was 6.2 years (interquartile range, 1 to 16), with 44 (58.6%) males. Thirty-five patients (46%) had positive tests for SARS-CoV-2 RT-PCR, antibody testing, or both, and 30% had a history of contact with COVID-19 cases. Three patients had a personal account of COVID-19, with an average time of four weeks between COVID-19 infection and the onset of MIS-C symptoms (Table 1).

Table 1. Demographic Characteristics of 75 Pediatric Patients with the Multisystem Inflammatory Syndrome in Children (MIS-C) a
CharacteristicsValues
Age (y), median6.2 (1 - 16)
Male sex44 (58.6)
Positive SARS-Cov-2 PCR test 1 (1.3)
Positive SARS-Cov-2 antibody test 32 (42.6)
Positive SARS-Cov-2 PCR or antibody test 33 (44)
Positive SARS-Cov-2 PCR and antibody test 2 (2.6)
Contact a person with COVID-1923 (30.6)
A history of COVID-193 (4)

Imaging and echocardiographic results (Table 2)

Table 2. Ultrasonographic and Echocardiographic Findings of 75 Pediatric Patients with the Multisystem Inflammatory Syndrome in Children (MIS-C)
VariablesNo. (%)
Abdominal free fluid17 (22)
Hepatitis1 (1.3)
Stasis in kidneys1 (1.3)
First-day echocardiography
Tricuspid regurgitation58 (77.3)
Mitral regurgitation36 (48)
Abnormal LV function15 (21)
Myocarditis1 (1.3)
Second echocardiography
Tricuspid regurgitation33 (44)
Mitral regurgitation23 (30)
Abnormal LV function5 (6)

None of the patients had organomegaly in abdominopelvic sonography. Abdominal free fluid was present in 17 patients (22%). One patient had hepatitis, and one had stasis in both kidneys. On the first day of echocardiography, 77% of patients had tricuspid regurgitation, of which 44% was trivial, 21% were mild, and 12% were moderate. In addition, 48% had mitral regurgitation, of which 10.7% was trivial, 26.7% was mild, and 10.7% was moderate. Also, 21% had abnormal LV function, of which 4% was poor, and one patient had myocarditis. After 5 - 7 days, repeated echocardiography revealed 44% of patients with tricuspid regurgitation, of which 30.7% were trivial, 12% were mild, and 1.3% were moderate. Moreover, 30% had mitral regurgitation, of which 24% was trivial, and 6% was mild. Finally, 6% had abnormal LV function, of which 2.6% were poor.

Moreover, 18% of the patients received inotropes (digoxin, dopamine, and dobutamine), 60% ASA, 32% IVIG, 84% glucocorticoid (methylprednisolone 2 mg/kg/day IV), and 25.3% received furosemide. Antibiotics were used for all the patients, whereas remdesivir and tocilizumab were not used. Eighteen patients (24%) cared for in an intensive care unit, and five cases (7.4%) required invasive mechanical ventilation. Seventy-three patients (97.4%) recovered, and two patients (2.6%) died (Table 3).

Table 3. Outcome and Main Treatment Strategies Applied for the Management of 75 Pediatric Patients with the Multisystem Inflammatory Syndrome (MIS-C) (N = 75)
ParametersNo. (%)
Antibiotics75 (100)
Glucocorticoid63 (84)
Aspirin45 (60)
Intravenous immunoglobulin (IVIG)24 (32)
Furosemide19 (25.3)
Inotropes14 (18)
ICU admission18 (24)
Mechanical ventilation5 (7.4)
Mortality2 (2.6)
Discharged from hospital73 (97.4)

5. Discussion

This survey reported one of the first series of patients from Iran with MIS-C, of whom 3% died and 24% required admission to PICU. The median age of 6.2 years in our population is similar to other reports (13-15). Unlike a previous report (16), none of the patients in our study was under one year old. Clinical guidelines recommend assessing antibodies and PCR to diagnose MIS-C due to the high quantity of patients with MIS-C and negative COVID-19 PCR results (12). Also, 41% of the patients had negative PCR results and positive SARS-CoV-2 antibody tests, emphasizing the role of measuring SARS-CoV-2 antibody in MIS-C diagnosis. Furthermore, in patients with atypical manifestations of MIS-C, positive antibody results should be considered to enhance clinical recognition of this condition (17). It should be noted that the percentage of the patients with positive SARS-CoV-2 antibody tests in our study was lower than that in other studies, which may be due to the reasons, such as poor quality of kits or very early checking of SARS-CoV-2 antibodies. Also, the use of a set of inflammatory markers, hypercoagulability tests, and organ damage indicators (e.g., CRP, ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) would be helpful in the early identification of this COVID-19-associated condition (17).

In the present study, the mean level of inflammatory markers (CRP, ESR, procalcitonin, and ferritin) was significantly higher than usual (Table 4). It should be noted that in the studied population, unlike other provocative tests, WBC counts were variable from 2700 to 31200.

Among the enrolled patients, many came to the hospital late; the median time from the onset of MIS-C symptoms was 7.7 days, which shows delayed referral of patients compared to previous studies (18-20). These findings also reinforce the need to educate parents and physicians regarding the early diagnosis of the disease.

Table 4. Laboratory Test Results of 75 Pediatric Patients with the Multisystem Inflammatory Syndrome in Children (MIS-C)
TestsValues
Mean white blood cell count (cell/mL)9600
Mean hemoglobin level (g/dL)12.8
Platelet under 100000 µL13 (17%)
Abnormal troponin (> 0.005 ng/mL)31 (41%)
Abnormal aspartate aminotransferase (AST) level (>33 U/L)7 (9.3%)
Abnormal alanine aminotransferase (ALT) level (> 40 U/L)9 (12%)
Hypoalbuminemia (< 3.4 g/dL)10 (13.3%)
Mean C-reactive protein serum level (mg/L)45.55 (IQR, 1-202)
Erythrocyte sedimentation rate, mm/h48 (IQR, 1-131)
Procalcitonin10.1 (IQR, 0.05-80)
Ferritin792.1 (IQR, 1-2543)

Unlike other studies (19-21), in which gastrointestinal symptoms were the predominant presenting symptoms of MIS-C patients (on average 80% compared to 26% in our study), fever and Kawasaki-like features, like conjunctivitis (53%) and strawberry tongue (26.7%) appeared predominantly as the presenting features of patients in our study. In addition to fever and features of Kawasaki, like conjunctivitis (53%) and strawberry tongue (26.7%), the patients in our study exhibited cough (20%) and neurological problems (34%) (Table 5).

Table 5. Clinical Signs and Symptoms of 75 Pediatric Patients with the Multisystem Inflammatory Syndrome in Children (MIS-C)
CharacteristicsNo. (%)
Duration of symptoms before hospitalization, day7.7
Fever41 (54)
Conjunctivitis40 (53)
Neurological problems26 (34)
Strawberry tongue20 (26.7)
Periorbital edema19 (25.3)
Truncal rash18 (24)
Cough15 (20)
Facial rash13 (17)
Generalized rash8 (10.7)
LAP8 (10.7)
Rhinorrhea2 (2.7)
Generalized edema1 (1.3)
Cough0 (0)
Sneeze0 (0)

MIS-C is significantly associated with cardiac manifestations, including ventricular dysfunction and valvular regurgitation (22). In the present study, the echocardiography performed on the first day of admission of patients demonstrated that 21% had LV dysfunction upon arrival at the hospital, though only 6% of them had LV dysfunction at the time of discharge. These findings may indicate the importance of early hospital care and cardiac consultations during MIS-C to prevent short-term and long-term complications.

Currently, there are some controversies regarding the treatment of MIS-C. In our center, most patients (84%) received glucocorticoids, with IVIG administered to 32% of them. The use of corticosteroids and IVIG could improve the clinical status and reduce the inflammatory process in patients. Antibiotics were used in all cases. Also, 18% of the patients received inotropes, similar to 20% in the Italian cohort (23), and 24% of the patients transferred to the ICU. In contrast with European studies (Riphagen et al. 2020 (6) and Belhadjer et al. 2021 (12)) and an American study conducted by Kaushik et al. 2020 (17), fewer patients in our study required mechanical ventilation (7.4%). Clinical improvement was seen in 97% of cases, and similar to another study (17), 3% died. A noteworthy point in the clinical findings of the two patients who died is that one of them had LV dysfunction and moderate mitral regurgitation at the time of admission, and his heart condition did not improve despite medical treatment, but the other one had normal LV function and trivial mitral regurgitation at the time of admission, and during hospitalization, he developed LV dysfunction. It should be noted that our patient’s mortality rate was relatively higher than that in some other studies, which may be due to our center as a referral center and accepting critically ill patients.

The present study has some limitations: First, misdiagnosis of MIS-C due to the similarity of respective clinical manifestations to those of other viral diseases, and second, the small sample size.

Acknowledgements

References

  • 1.

    Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33. doi: 10.1056/NEJMoa2001017. [PubMed: 31978945]. [PubMed Central: PMC7092803].

  • 2.

    Paules CI, Marston HD, Fauci AS. Coronavirus Infections-More Than Just the Common Cold. JAMA. 2020;323(8):707-8. doi: 10.1001/jama.2020.0757. [PubMed: 31971553].

  • 3.

    Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20(5):269-70. doi: 10.1038/s41577-020-0308-3. [PubMed: 32273594]. [PubMed Central: PMC7143200].

  • 4.

    Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663-5. doi: 10.1056/NEJMc2005073. [PubMed: 32187458]. [PubMed Central: PMC7121177].

  • 5.

    Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6). doi: 10.1542/peds.2020-0702. [PubMed: 32179660].

  • 6.

    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].

  • 7.

    Rafferty MS, Burrows H, Joseph JP, Leveille J, Nihtianova S, Amirian ES. Multisystem inflammatory syndrome in children (MIS-C) and the coronavirus pandemic: Current knowledge and implications for public health. J Infect Public Health. 2021;14(4):484-94. doi: 10.1016/j.jiph.2021.01.008. [PubMed: 33743370]. [PubMed Central: PMC7813487].

  • 8.

    Tsabouri S, Makis A, Kosmeri C, Siomou E. Risk Factors for Severity in Children with Coronavirus Disease 2019: A Comprehensive Literature Review. Pediatr Clin North Am. 2021;68(1):321-38. doi: 10.1016/j.pcl.2020.07.014. [PubMed: 33228941]. [PubMed Central: PMC7392074].

  • 9.

    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].

  • 10.

    Wang W, Gong F, Zhu W, Fu S, Zhang Q. Macrophage activation syndrome in Kawasaki disease: more common than we thought? Semin Arthritis Rheum. 2015;44(4):405-10. doi: 10.1016/j.semarthrit.2014.07.007. [PubMed: 25200945].

  • 11.

    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].

  • 12.

    Belhadjer Z, Meot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic. Circulation. 2020;142(5):429-36. doi: 10.1161/CIRCULATIONAHA.120.048360. [PubMed: 32418446].

  • 13.

    Belot A, Antona D, Renolleau S, Javouhey E, Hentgen V, Angoulvant F, et al. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020. Euro Surveill. 2020;25(22). doi: 10.2807/1560-7917.ES.2020.25.22.2001010. [PubMed: 32524957]. [PubMed Central: PMC7336112].

  • 14.

    Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020;324(3):259-69. doi: 10.1001/jama.2020.10369. [PubMed: 32511692]. [PubMed Central: PMC7281356].

  • 15.

    Torres JP, Izquierdo G, Acuna M, Pavez D, Reyes F, Fritis A, et al. Multisystem inflammatory syndrome in children (MIS-C): Report of the clinical and epidemiological characteristics of cases in Santiago de Chile during the SARS-CoV-2 pandemic. Int J Infect Dis. 2020;100:75-81. doi: 10.1016/j.ijid.2020.08.062. [PubMed: 32861823]. [PubMed Central: PMC7452906].

  • 16.

    Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. 2020;370:m3249. doi: 10.1136/bmj.m3249. [PubMed: 32960186]. [PubMed Central: PMC7488201].

  • 17.

    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].

  • 18.

    Mamishi S, Movahedi Z, Mohammadi M, Ziaee V, Khodabandeh M, Abdolsalehi MR, et al. Multisystem inflammatory syndrome associated with SARS-CoV-2 infection in 45 children: a first report from Iran. Epidemiol Infect. 2020;148. e196. doi: 10.1017/S095026882000196X. [PubMed: 32854812]. [PubMed Central: PMC7484297].

  • 19.

    Mastrolia MV, Agostiniani R, Azzari C, Bernardini R, Bottone U, Calabri GB, et al. Correspondence to 'Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort'. Ann Rheum Dis. 2020. doi: 10.1136/annrheumdis-2020-218797. [PubMed: 32958508].

  • 20.

    Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, et al. Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City. JAMA. 2020;324(3):294-6. doi: 10.1001/jama.2020.10374. [PubMed: 32511676]. [PubMed Central: PMC7281352].

  • 21.

    Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis KG. Gastrointestinal Symptoms as a Major Presentation Component of a Novel Multisystem Inflammatory Syndrome in Children That Is Related to Coronavirus Disease 2019: A Single Center Experience of 44 Cases. Gastroenterology. 2020;159(4):1571-1574 e2. doi: 10.1053/j.gastro.2020.05.079. [PubMed: 32505742]. [PubMed Central: PMC7270806].

  • 22.

    Di Filippo P, Raso M, Cacciatore M, Patacchiola R, Renda G, Rossi N, et al. Case Report: Mitral Valve Involvement and First-Degree Atrial-Ventricular Block in Two Patients With Multisystem Inflammatory Syndrome in Children. Front Pediatr. 2021;9:676934. doi: 10.3389/fped.2021.676934. [PubMed: 34422717]. [PubMed Central: PMC8377535].

  • 23.

    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. Lancet. 2020;395(10239):1771-8. doi: 10.1016/s0140-6736(20)31103-x.

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