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International Journal of Research and Review
DOI: https://doi.org/10.52403/ijrr.20210768
Vol.8; Issue: 7; July 2021
Website: www.ijrrjournal.com
Review Article E-ISSN: 2349-9788; P-ISSN: 2454-2237
Multisystem Inflammatory Syndrome in Children;
an Emerging Global Threat - A Review
AR Shabaraya1, Archana KU2
1
Professor & Head, 2Student Pharm D,
Department of Pharmacy Practice, Srinivas College of Pharmacy, Valachil, Mangalore, Karnataka-574143
Corresponding Author: Archana K U
ABSTRACT rashes, Gastrointestinal symptoms such as
(abdominal pain, vomiting, diarrhea),
MIS C (Multisystem Inflammatory Syndrome in hypotension and shock [1]. On April 25,
Children) is a disease related to post COVID- 2020, the United Kingdom's National Health
19 sequelae. Differential diagnosis includes
Service alerted physicians of a newly
Kawasaki disease, Bacterial sepsis, toxic shock
recognized syndrome with severe
syndrome, Appendicitis, Macrophage activation
syndrome. Clinical Presentations include high multisystem inflammation in children with
grade fever, rashes, Gastrointestinal symptoms clinical features similar to those found in
like (abdominal pain, vomiting, diarrhea), Kawasaki disease and toxic shock syndrome
[2]
hypotension and shock. The pathogenesis of . The new illness was temporally linked to
MIS-C is unknown, and a postinfective etiology COVID-19, with symptoms appearing 3-4
has been hypothetical but unproven. Antibodies weeks after an increase in COVID-19
to SARS-CoV-2 appear in the second week occurrence in a specific geographic area.
following infection, although their existence Additional cases of children with a hyper
does not suggest infection resolution. inflammatory syndrome involving several
Laboratory markers of inflammation, such as
systems were reported in subsequent
CRP, are elevated. IVIG, Glucocorticoids such
publications from different European
as methyl prednisolone, Antibiotics,
thromboprophylaxis with Light Molecular nations and the United States [5].
Weight Heparin are the management options. DEFINITION
Since the available information doesn't allow to According to CDC, the case
formulate well-established guidelines or definition for MIS C is a person younger
recommendations for MIS-C treatment, and
than 21 years of age with fever (>38.0°C for
therefore the long-term sequelae of the illness
aren't yet known. ≥24 hours), signs of inflammation in the
laboratory(increased C-reactive protein
Keywords: MIS C, IVIG, Kawasaki disease (CRP), erythrocyte sedimentation rate
(ESR), fibrinogen, procalcitonin, d-dimer,
INTRODUCTION ferritin, lactic acid dehydrogenase (LDH),
According to current data there are interleukin 6 (IL-6), elevated neutrophils,
3,07,95, 716 SARS Covid 19 active cases in reduced lymphocytes and low albumin)and
india and 4,07,145 deaths were reported [3]. signs of clinically serious illness requiring
MIS C is a disease associated with post hospitalization with multisystem organ
COVID 19 sequelae. Differential diagnosis involved [4].
includes Kawasaki disease, Bacterial sepsis, Kawasaki Disease
Toxic shock syndrome, Appendicitis, Kawasaki disease (KD), also known
Macrophage activation syndrome. Clinical as Kawasaki syndrome, is a febrile sickness
Presentations include high grade fever, with unknown etiology that mostly affects
International Journal of Research and Review (ijrrjournal.com) 481
Vol.8; Issue: 7; July 2021A R Shabaraya et.al. Multisystem inflammatory syndrome in children; an emerging global threat-a review
children under the age of five. Clinical signs proBNP and Troponin, coronary
include fever, rash, swelling of the hands aneurysm, hypoperfusion, hypotension
and feet, irritation and redness of the whites Tachycardia
of the eyes, swollen lymph glands in the Respiratory symptoms such as cough,
neck, and irritation and inflammation of the tachypnea, chest congestion, chest
mouth, lips, and throat[9]. Laboratory infiltrates [7],[8].
markers of inflammation, such as CRP, are
elevated, similar to MIS-C. Patients with PATHOPHYSIOLOGY
KD exhibit leukocytosis with neutrophil The pathogenesis of MIS-C is
predominance and thrombocytosis, which unknown, and a post infective etiology has
are slightly different hematologic disorders. been hypothetical but unproven. Antibodies
Thrombocytopenia has been reported in KD to SARS-CoV-2 appear in the second week
patients, however it is uncommon. The following infection, although their existence
cardiac findings in MIS-C differ from those does not suggest infection resolution. In
in KD because MIS-C patients are comparison to adults with severe COVID-
substantially more likely to have cardiac 19 causing acute respiratory distress
dysfunction and hypotension than coronary syndrome (ARDS) and adults who
artery anomalies. recovered from mild disease, a recent study
found inefficient and reduced neutralising
Toxic shock syndrome antibody activity against SARS–CoV-2 in
Toxic shock syndrome (TSS) is a patients with MIS-C, implying a reduced
life-threatening condition marked by fever, protective serological response[11]. The virus
hypotension, a sunburn-like rash, and end- is rarely found in the respiratory system of
organ destruction. TSS was once linked to MIS-C patients, but other organs, such as
the use of high-absorbency tampons by the gastrointestinal tract, have yet to be
menstruation women; however these were studied [12].
finally phased out of the market. Since then, Although the presence of SARS-
it's been increasingly crucial to consider CoV-2-specific T cells in the peripheral
non-menstrual instances. TSS is thought to blood of recovered and COVID-ARDS
affect 0.8 to 3.4 per 100,000 in the United adult patients has recently been reported, no
States [10]. such reports have yet been reported in
children, and the biological significance of
CLINICAL FEATURES SARS-CoV-2-reactive T cells, whether
MIS C patients present with protective or even detrimental, is still
symptoms similar to Kawasaki disease like unknown[13].
symptoms such as Fever, Conjunctivitis, It's also been suggested that the
rash, myalgia, stomatitis, lymphadenopathy, SARS-CoV-2 Spike protein shape has a
extensively swelling with erythema. direct effect on immunological activation.
Gastrointestinal symptoms similar to Indeed, new evidence suggests that the
viral gastroenteritis which include SARS-CoV-2 Spike protein has a
nausea, vomiting, abdominal pain, superantigen-like domain with sequence and
diarrhea elevated AST/ALT [6]. structural similarities to Staphylococcal
Kawasaki disease like features were enterotoxin B, which could be responsible
seen in many patients such as skin rash, for the hyperinflammation seen in MIS-C
oral mucosal changes such red lips, and adults with severe COVID-19 and
strawberry like tongue. cytokine storm[14].
Cardiovascular abnormalities such
myocardial dysfunction, elevated
International Journal of Research and Review (ijrrjournal.com) 482
Vol.8; Issue: 7; July 2021A R Shabaraya et.al. Multisystem inflammatory syndrome in children; an emerging global threat-a review
DIAGNOSIS
Laboratory Investigations Complete blood count: leukocytosis and lymphopenia can be seen.
CRP: CRP elevation
Coagulation: Hyperfibrinogenemia is typical, PT and PTT should be monitored to investigate a
prothrombotic state. In case D-dimer is measured, high levels should be interpreted as
potentially related to the hyperinflammatory state.
Electrolytes: Hyponatremia may be seen.
Liver function tests: MIS-C cases with gallbladder hydrops (that may cause
hyperbilirubinemia) have been described.
Kidney function tests: MIS-C cases with acute kidney injury have been observed.
Blood gas analysis: To assess gas exchange and the presence of metabolic acidosis. High
lactates have been described in MIS-C patients without evidence of sepsis.
Cultures of blood, urine, and faeces
EBV, Mycoplasma Pneumoniae, Coxackievirus, Echovirus, Adenovirus, Influenza, and VRS
serologies When serologies are positive, PCR testing should be obtained as soon as possible.
Performed in case of Peripheral smear
Hyperinflammatory state in Triglycerides, Total protein, Total Albumin levels
laboratory investigations CPK, LDH
Troponins and NTpro-BNP
Imaging EKG + Echocardiogram: to look for evidence of myocarditis, valvular insufficiency,
pericarditis, cardiac tamponade, and coronary abnormalities (if cardiac enzymes are elevated or
if clinical suspicion exists). In the event of a cardiac arrest, an echocardiogram may be used to
rule out dehydration.
Chest X-RAY
Abdomen US: in case of gastrointestinal symptoms[15].
TREATMENT 3. Consider Dexamethasone 10 mg/m2 q1d
The goal of the treatment may vary just in case of sHLH or CNS
consistent with the patient. The treatment involvement
may depend on the clinical presentations of i or ii should be chosen counting on
the patient. Medications given below are disease severity, supported clinical/
that the common treatment approach laboratory features. Methylprednisolone
observed in several studies. pulses are recommended just in case of
sHLH diagnosis/suspicion.
IVIG
2g/kg IV (up to 70-80 g) to be ALTENATIVETREATMENTOPTIONS
administered over a minimum of 12 h in Large-spectrum antibiotics: while
patients with heart failure immunoglobulins expecting microbiology tests
should be administered over a minimum of Acetylsalicylic acid: 5 mg/kg for a
16 h or, alternatively, the whole dose minimum of 6-8 wks. Just in case coronary
should be splitted in two infusions 12 h abnormalities are found, ask AHA
apart. A second dose of immunoglobulins recommendations for Kawasaki Disease [16].
should be considered just in case of Thromboprophylaxis with LMWH:
inadequate response [19]. Since adults with COVID-19 are at high risk
of thromboembolism, and given the high
GLUCOCORTICOIDS inflammatory state of youngsters with MIS-
To be administered with IVIG C, it appears reasonable to start out
upfront just in case of heart involvement, prophylaxis with LMWH. As per ISTH
severe disease, impendings HLH or toxic recommendations [17], risk stratification
shock syndrome. should be done supported D-Dimer and
1. Methylprednisolone1 mg/kg BID IV other known pro-thrombotic factors. Just in
2. Methylprednisolone 30 mg/kg (max 1 g) case of D-Dimer>5X normal values and/or
IV pulse q1d for 1-3 days, followed by presence of other known pro-thrombotic
Methylprednisolone i.v./Prednisone factors, Enoxaparin100UI/kg BID should be
orally, supported the severity of administered. Eculizumab: just in case of
clinical/laboratory features acute renal failure and evidence of
International Journal of Research and Review (ijrrjournal.com) 483
Vol.8; Issue: 7; July 2021A R Shabaraya et.al. Multisystem inflammatory syndrome in children; an emerging global threat-a review
microangiopathy, consider treatment with 4. Centers for Disease Control and Prevention.
eculizumab [18]. 2021. Multisystem Inflammatory Syndrome
(MIS). [online] Available at:
CONCLUSION
The clinical features of multisystem [Accessed 6 June 2021].
5. Abrams JY, Godfred-Cato SE, Oster ME,
inflammatory syndrome are similar to that Chow EJ, Koumans EH, Bryant B, Leung
of Kawasaki disease. Elucidating the JW, Belay ED. Multisystem inflammatory
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children with SARS-CoV-2 infection D, Legendre A, Abakka S, Auriau J,
ultimately develop MIS-C. Given the Grimaud M, Oualha M, Beghetti M, Wacker
frequent overlap of clinical manifestations J. Acute heart failure in multisystem
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known. 8. Dufort EM, Koumans EH, Chow EJ,
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Acknowledgement: None Barranco MA, Maxted AM, Rosenberg ES,
Easton D, Udo T. Multisystem
inflammatory syndrome in children in New
Conflict of Interest: None York State. New England Journal of
Medicine. 2020 Jul 23;383(4):347-58.
Source of Funding: None 9. Case Definition | Kawasaki Disease | CDC .
Cdc.gov. 2021 [cited 10 July 2021].
Ethical Approval: Not required Available from:
https://www.cdc.gov/kawasaki/case-
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AL, Jackson MA, Takahashi M, Shah PB, How to cite this article: A R Shabaraya,
Kobayashi T. Diagnosis, treatment, and Archana K U. Multisystem inflammatory
long-term management of Kawasaki syndrome in children; an emerging global
disease: a scientific statement for health threat-a review. International Journal of
professionals from the American Heart Research and Review. 2021; 8(7): 481-485.
Association. Circulation. 2017 Apr 25;135 DOI: https://doi.org/10.52403/ijrr.20210768
(17):e927-99.
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