Multisystem Inflammatory Syndrome in Children (MIS-C)

Original Editor - User Name
Top Contributors - Rishika Babburu

Introduction

A multisystem inflammatory syndrome in children (MIS-C) is associated with coronavirus disease 2019.Since December 2019, the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has resulted in high morbidity and mortality worldwide. One of the most intriguing and mysterious phenomena observed during the COVID-19 pandemic has been represented by the occurrence of the multisystem inflammatory syndrome in children and adolescents (MIS-C). 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. 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.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.

Preliminary case definition

Children and adolescents 0–19 years of age with fever > 3 days

AND 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).

And

Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin.

And

No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes.

And

Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.

Multisystem Inflammatory Syndrome in Children

Pathological Process

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

Immune dysregulation

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.

SARS-CoV-2 virus

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.

Mechanisms of myocardial injury

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.

Clinical Presentation

Observed in All patients:

• Persistent fever >38.5°C

Observed in Most:

• Oxygen requirement
• Hypotension

Presented in Some:

• 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

• 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

• 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

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
   

Management / Interventions

• 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 IVIG .
• 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.
• The role of IVIG in treatment remains unclear.
• Some centers have had success with corticosteroid treatment without IVIG in some patients .
• 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
  

Physiotherapy

• Children admitted to intensive care units are prone to acquired muscle weakness.
• Physiotherapy can be initiated to treat critical illness myopathy.
• 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.
• 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.
• Close contact with the child during positioning, play therapy, and ambulation can spread the infection ; could prove fatal
• Hence, Covid 19 protocols must be strictly followed by the Physiotherapist.

Differential Diagnosis

This rare syndrome 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.

Resources

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