Multisystem Inflammatory Syndrome in Children (MIS-C)

Original Editor - Rishika Babburu
Top Contributors - Rishika Babburu

Introduction[edit | edit source]

A multisystem inflammatory syndrome in children (MIS-C) is associated with coronavirus disease 2019.[1]A novel coronavirus named ‘2019-nCoV’ or ‘2019 novel coronavirus’ or ‘COVID-19’ by the World Health Organization (WHO) is the cause of the existing outbreak of pneumonia.It began at the beginning of December 2019 near in Wuhan City, Hubei Province, China.[2][3] Multisystem inflammatory disorder in children (MIS-C) most commonly affects young, school-aged children and is characterized by persistent fever, systemic hyperinflammation, and multisystem organ dysfunction.[4] In early May, the United Kingdom and several European countries reported the occurrence of a hyperinflammatory process in children that had features similar to atypical Kawasaki’s disease, Kawasaki’s disease shock syndrome, and toxic shock syndrome, possibly related to SARS-CoV-2 infection.[1][5][6]Patients with this condition have some overlapping signs and symptoms with those of Kawasaki disease (KD), but also display clinical features that are uncommon or less frequent in this illness, such as diarrhea, abdominal pain and myocardial involvement. The sickest patients may develop multiorgan failure and shock, usually due to myocarditis.[7]

Preliminary case definition[edit | edit source]

  • Children and adolescents 0–19 years of age with fever > 3 days
  • Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin
  • No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes.
  • Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.
  • Any two of the following:                                                  
  1. Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet).
  2. Hypotension or shock.
  3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP),
  4. Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).
  5. Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain).[1]
Multisystem Inflammatory Syndrome in Children


Pathological Process[edit | edit source]

The pathophysiology of MIS-C is yet to be understood full fledged.

Immune dysregulation[edit | edit source]

It has been suggested that the syndrome results from an abnormal immune response to the virus, with some clinical similarities to Kawasaki disease (KD), macrophage activation syndrome (MAS), and cytokine release syndrome. However, based on the available studies, MIS-C appears to have an immunophenotype that is distinct from KD and MAS. The exact mechanisms by which SARS-CoV-2 triggers the abnormal immune response are unknown. Preliminary studies suggest that patients with severe MIS-C have persistent immunoglobulin G (IgG) antibodies with enhanced ability to activate monocytes, persistent cytopenias (particularly T cell lymphopenia), and greater activation of CD8+ T cells that differ from findings in acute COVID-19 infection.[9]

SARS-CoV-2 virus[edit | edit source]

Many affected children have negative polymerase chain reaction (PCR) testing for SARS-CoV-2 but have positive serology, a finding that further supports the hypothesis that MIS-C is related to immune dysregulation occurring after acute infection has passed. However, some children do have positive PCR testing.[9]

Mechanisms of myocardial injury[edit | edit source]

The mechanisms of myocardial injury in MIS-C are not well characterized. Possible causes include injury from systemic inflammation, acute viral myocarditis, hypoxia, stress cardiomyopathy, and, rarely, ischemia caused by coronary artery (CA) involvement. Cardiac dysfunction may result from a combination of these mechanisms in some patients.[9]

Clinical Presentation[edit | edit source]

Present in all patients:

  • Persistent fever >38.5°C

Present in most :

Present in some patients:

  • Abdominal pain
  • Confusion
  • Conjunctivitis
  • Cough
  • Diarrhoea
  • Headache
  • Lymphadenopathy
  • Mucus membrane changes
  • Neck swelling
  • Rash
  • Respiratory symptoms
  • Sore throat
  • Swollen hands and feet
  • Syncope
  • Vomiting

Investigations[edit | edit source]

  • Full Blood Count
  • Urea and electrolytes
  • Liver function test
  • Glucose
  • Blood gas with lactate
  • Coagulation + fibrinogen
  • D-Dimer
  • Lactate Dehydrogenase(LDH)
  • Triglycerides
  • Ferritin
  • Troponin
  • Pro-BNP
  • Creatine Kinase(CK)
  • Vitamin D
  • Amylase
  • Urinalysis
  • Save EDTA and serum for PCR and serological studies (ideally pre IVIG)
  • Blood culture
  • Urine and Stool culture
  • Throat swab culture
  • NPA or throat swab for respiratory panel plus SARS-CoV-2 PCR
  • Stool and blood for SARS-CoV-2 PCR
  • Pneumococcal, Meningococcal, Group A strep, Staph aureus Blood PCR
  • Antistreptolysin O titer (ASOT)
  • SARS-CoV-2 serology
  • EBV, CMV, Adenovirus, Enterovirus PCR on blood
  • Stool for virology

Laboratory Findings[edit | edit source]

  • Abnormal Fibrinogen
  • Absence of potential causative organisms (other than SARS-CoV-2)
  • High CRP
  • High D-Dimers
  • High ferritin
  • Hypoalbuminaemia
  • Lymphopenia
  • Neutrophilia in most – normal neutrophils in some
  • Acute kidney injury
  • Anaemia
  • Coagulopathy
  • Neutrophilia
  • Proteinuria
  • Raised CK
  • Raised LDH
  • Raised triglycerides
  • Raised troponin
  • Thrombocytopenia
  • Transaminitis

Imaging and ECG[edit | edit source]

  1. Echo and ECG – myocarditis, valvulitis, pericardial effusion, coronary artery dilatation
  2. Chest X Ray – patchy symmetrical infiltrates, pleural effusion
  3. Abdominal ultrasound – colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly
  4. CT chest – as for chest x ray – may demonstrate coronary artery abnormalities if with contrast[10]

Management / Interventions[edit | edit source]

  • The optimal treatment for MIS-C is unknown.
  • Several retrospective reviews support the clinical impression that myocardial function normalizes more quickly in children who receive corticosteroid with intravenous gammaglobulin-IVIG[11][12] [13].
  • The optimal dose of corticosteroid for MIS-C remains unknown, but in two studies, doses in the 1–2-mg/kg/day range were used; many centers use a tapering dose regimen over a 2–3-week period.[11][12]
  • The role of IVIG in treatment remains unclear.
  • Some centers have had success with corticosteroid treatment without IVIG in some patients[14] [15].
  • Anakinra or Infliximab are the line of treatment in patients who do not appear to respond to IVIG and corticosteroid but the efficacy and role of these agents are also presently unknown.
  • It also should be recognized that milder cases of MIS-C may be self-limited and could improve with supportive care alone[16]


Physiotherapy[edit | edit source]

  • Children admitted to intensive care units are prone to acquired muscle weakness.
  • Physiotherapy can be initiated to treat critical illness myopathy.[18]
  • Play therapy, as a form of therapy in children,has a crucial role to increase the range of motions in the joints, strength, breathing capacity, cardiovascular tolerance during work out result in favorable pulmonary function.[19]
  • Signs of intolerance such as respiratory distress, arrythmias, reduced level of consciousness and many other such factors should be keenly observed while treating.
  • All invasive lines, ventilator tubings must be taken care of during positioning.
  • Patient should not be disconnected from the circuit at any point of time.
  • Specialization of physiotherapy intervention plans based upon assessment and reassessment is crucial in children.
  • Tools for patient education such as charts in language understood, audio-visual aids, and mike systems should be used to encourage contactless therapy[20].
  • Close contact with the child during positioning, play therapy, and ambulation can spread the infection ; could prove fatal[19]
  • Hence, Covid 19 protocols must be strictly followed by the Physiotherapist.

Differential Diagnosis
[edit | edit source]

Multisystem Inflammatory syndrome in children shares common features with other paediatric inflammatory conditions including: Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndromes. It can also present with unusual abdominal symptoms with excessive inflammatory markers.[10]

References[edit | edit source]

  1. 1.0 1.1 1.2
  2. Hui DS, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health—the latest 2019 novel coronavirus outbreak in Wuhan, China. Inte J Infectious Dis. 2020;91:264–266.
  3. Fong SJ, Li G, Dey N, Crespo RG, Herrera-Viedma E (2020) composite monte carlo decision making under high uncertainty of novel coronavirus epidemic using hybridized deep learning and fuzzy rule induction. arXiv preprint
  5. European Centre for Disease Prevention and Control. Rapid risk assessment: paediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children. May 15, 2020. [1]
  6. Verdoni L, Mazza A, Gervasoni A, 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;395:1771-1778.
  7. Frontiers | Multisystem Inflammatory Syndrome in Children: Unique Disease or Part of the Kawasaki Disease Spectrum? | Pediatrics (
  9. 9.0 9.1 9.2
  10. 10.0 10.1
  11. 11.0 11.1 Belhadjer Z, Auriau J, Méot M, Oualha M, Renolleau S, Houyel L, Bonnet D. Addition of corticosteroids to immunoglobulins is associated with recovery of cardiac function in multi-inflammatory syndrome in children. Circulation. 2020;142:2282–4.
  12. 12.0 12.1 Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA. 2021;325:855–64.
  13. Son MBF, Murray N, Friedman K, et al (2021) Multisystem inflammatory syndrome in children - initial therapy and outcomes. N Engl J Med 385:23–34.
  14. Bar-Meir M, Guri A, Godfrey ME, Shack AR, Hashkes PJ, Goldzweig O, Megged O. Characterizing the differences between multisystem inflammatory syndrome in children and Kawasaki disease. Sci Rep. 2021;11:13840.
  15. V Vukomanovic S Krasic S Prijic S Ninic S Popovic G Petrovic S Ristic R Simic I CerovicD Nesic 2021 Recent experience: corticosteroids as a first-line therapy in children with multisystem inflammatory syndrome and COVID-19-related myocardial damage Pediatr Infect Dis J
  16. Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and immunological features of SARS–CoV-2–induced multisystem inflammatory syndrome in children. J Clin Invest. 2020;130:5942–50.
  19. 19.0 19.1 Mohammad, Seyed & Hashemipour, Amin & Id, Nasrin & Ghiasi, & Id, Parisa & Arzani, Parisa & Id, & Valizadeh, Rohollah. (2021). ):e24 Epidemiology and Prevention Immunopathol Persa. 24.