slcp

1. MANAGEMENT OF COVID-19 INFECTION IN CHILDREN
Multisystem inflammatory syndrome in children (MIS-C)
1. INTRODUCTION
COVID-19 is usually mild in children. However, in some rare cases, children can be severely
affected. In April of 2020, United Kingdom reports a case series of eight children presenting
similar to incomplete Kawasaki disease (KD) or toxic shock syndrome. Since then, there have
been reports of similarly affected children in other parts of the world. In Sri Lanka, we are also
experiencing an increasing number of cases, some of them needing ICU care, although there were
no fatalities. The condition has been termed multisystem inflammatory syndrome in children
(MIS-C; also referred to as pediatric multisystem inflammatory syndrome [PMIS]
2. EPIDEMIOLOGY
While the incidence of MIS-C is uncertain, it appears to be a relatively rare complication of
COVID-19 in children, occurring in <1 percent of children with confirmed SARS-CoV-2
infection. Most MIS-C cases have occurred in older children and adolescents who were previously
healthy. The most common comorbidities had been obesity and asthma and the median age 8 to
11 years (range 1 to 20 years).
3. PATHOPHYSIOLOGY
The pathophysiology of MIS-C is not well understood. Many affected children have negative
polymerase chain reaction (PCR) testing for SARS-CoV-2 but have positive serology.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.
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 involvement.

2. 4. CLINICAL MANIFESTATIONS
Onset of symptoms: The usual duration between acute infection and onset of MIS-C symptoms is
two to six weeks. However, rare cases may occur >6 weeks after the acute SARS-CoV-2 infection.
 Fever
 Mucocutaneous symptoms – Rash, Conjunctivitis, red or swollen lips, strawberry tongue
 Myalgia
 Swollen hands/feet
 Cervical Lymphadenopathy
 Gastrointestinal symptoms - Abdominal pain, vomiting and diarrhea are particularly common
and prominent, with the presentation in some children mimicking appendicitis.
Some present with clinical evidence of Hepatitis or hepatomegaly.
 Cardiovascular symptoms – Cardiac involvement is common. Hypotension, Myocardial
dysfunction, Shock and Arrhythmia
 Respiratory symptoms - Tachypnea, labored breathing may be due to shock or cardiogenic
pulmonary edema. Cough is uncommon. Severe pulmonary involvement is not a prominent
feature.
 Serositis - Small pleural, pericardial, and ascitic effusions.
 Acute kidney injury - most cases are mild
 Neurocognitive symptoms - Headache, lethargy, confusion, or irritability. More severe
neurologic manifestations, including encephalopathy, seizures, coma, stroke,
meningoencephalitis, muscle weakness, and brainstem and/or cerebellar signs are rare.
5. LABORATORY FINDINGS
 FBC: Lymphocytopenia, neutrophilia, mild anemia, and thrombocytopenia
 Elevated inflammatory markers: C-reactive protein (CRP), erythrocyte sedimentation (ESR),
D-dimer, Fibrinogen, ferritin, procalcitonin, interleukin-6 (IL-6)
 Elevated cardiac markers: Troponin I (Peak at 24 hour and last for 2 weeks), BNP or N-terminal
pro-BNP (NT-pro-BNP)
 Hypoalbuminemia
 Mildly elevated liver enzymes
 Elevated lactate dehydrogenase
 Hypertriglyceridemia
**Laboratory markers of inflammation appear to correlate with severity of illness
 Echocardiographic findings: Depressed LV function, coronary artery (CA) abnormalities,
including dilation or aneurysm, mitral regurgitation, pericardial effusion
 ECGs - Nonspecific (eg, Abnormal ST- or T-wave segments), Arrhythmia and Heart block
 Chest radiograph: Many patients had normal chest radiographs. Abnormal findings included
pleural effusions, patchy consolidations, focal consolidation, and atelectasis

3.  Testing for SARS-CoV-2
All patients with suspected MIS-C should be tested for SARS-CoV-2, including both serology and
reverse transcription PCR (RT-PCR) on a nasopharyngeal swab. RT-PCR could be either positive
or negative. A minority of patients have negative results on both tests. In these cases, the diagnosis
of MIS-C requires an epidemiologic link to SARS-CoV-2 (eg, exposure to an individual with
known COVID-19 within the four weeks prior to the onset of symptoms)
 Exclude other infections:
Blood culture, urine culture, throat culture, stool culture, nasopharyngeal aspirate or throat swab
for respiratory viral panel, epstein-Barr virus serology and PCR, cytomegalovirus serology and
PCR, enterovirus PCR, adenovirus PCR
6. WHO CASE DEFINITION
Children and adolescents 0–19 years of age with fever > 3 days
AND two of the following:
a) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral,
hands or feet).
b) Hypotension or shock.
c) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities
(including ECHO findings or elevated Troponin/NT-proBNP),
d) Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).
e) 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.
Consider this syndrome in children with features of typical or atypical Kawasaki disease or toxic
shock syndrome.
7. DIFFERENTIAL DIAGNOSIS
 Kawasaki disease (KD)
 Severe acute COVID-19
 Bacterial sepsis
 Toxic shock syndrome
 Appendicitis

4.  Other viral/bacterial infections
 Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)
 Systemic lupus erythematosus (SLE)
 Vasculitis
Clinical Spectrum of COVID 19 associated MIS-C
Febrile Inflammatory
state
Kawasaki Disease like
illness
Severe MIS-C
 Persistent Fever and
mild symptoms
(Headache, Fatigue)
 Inflammatory markers
may be elevated
 Severe multisystem
involvement is lacking
 Meet criteria for
Complete or incomplete
KD
 No shock or severe
multisystem
involvement
 Markedly elevated inflammatory markers
 Severe multisystem involvement.
 Cardiac involvement
 Shock
 Neurologic manifestations
 Other manifestations requiring pediatric
intensive care unit [PICU] care
8. MANAGEMENT
Setting of care
Setting of care to be decided by treating clinician depending on severity of the illness. Whether or
not to isolate depends on cycle threshold (CT value) of RT-PCR. Usually, the CT value is inversely
proportional to the infectivity.
 Aspirin is recommended for all patients
Low-dose aspirin 3 to 5 mg/kg daily (Max 81mg/day) for minimum duration is 4 weeks.
To be continued until platelet count becomes normal or coronary arteries become normal
 IVIG is recommended for all patients
2 g/kg administered in a single infusion over 8 to 12 hours.
In obese patients, the dose should be based upon ideal body weight. In significant LV dysfunction,
it can be given in divided doses over two days
Consider 2nd
dose in refractory disease
Patients should have blood drawn for serologic testing for SARS-CoV-2 and other pathogens prior
to administration of IVIG. In addition, immunoglobulins elevate the erythrocyte sedimentation
rate (ESR). So that ESR is less useful after delivering a 2 g/kg dose of IVIG. Other inflammatory
markers (eg, C-reactive protein, ferritin) are more reliable for serial monitoring after IVIG.

5.  Antibiotics are recommended for all patients
Patients with COVID-19 are at risk for bacteremia or other secondary bacterial or viral co-
infections (e.g., pneumonia)
Patients presenting with severe multisystem involvement and shock should receive prompt empiric
broad-spectrum antibiotic therapy within 1 hour of initial recognition of shock, pending culture
results.
Suggested antibiotics:
Ceftriaxone plus Vancomycin OR
Flucloxacillin / Teicoplanin plus Piperacillin-tazobactam is an alternative regimen, particularly for
children with acute kidney injury.
Clindamycin is added if there are features consistent with toxin-mediated illness (eg,
erythroderma)
 Glucocorticoids
In patients who initially have less severe manifestations, glucocorticoids may be given as a second-
line treatment if there is an inadequate response to IVIG (eg, persistent fevers, rising inflammatory
markers)
For patients with moderate or severe manifestations, glucocorticoid therapy is typically given
concomitantly with IVIG.
Dose - IV methylprednisolone 2 mg/kg/day in two divided doses for 3-5 days
In life-threatening circumstances or refractory cases, methylprednisolone pulse therapy can be
used. Dose Intravenous methylprednisolone 30 mg/kg/dose, (maximum of 1 g) for 3-5 days
Once the patient has improved clinically, this can be transitioned to oral prednisolone dose of
2mg/kg/day .
This oral prednisolone dose is reduced by 25% per week and tapered over four weeks.
 Enoxheparin
Rationale:
Patients with MIS-C are at risk of experiencing thrombotic complications. For example, patients
with severe LV dysfunction are at risk for apical LV thrombus and those with CA aneurysms are
at risk for myocardial infarction. The diagnosis of COVID-19-related MIS-C itself should be
considered a major risk factor for venous thromboembolism (VTE), including deep vein
thrombosis and pulmonary embolus, due to hypercoagulability associated with COVID-19
Indications:
Severe MIS-C, Current or prior VTE, Severe LV dysfunction, Large or giant CA aneurysms,
Patients with other severe MIS-C manifestations requiring PICU care, Patients with less severe
MIS-C – Decision to administer an anticoagulant in addition to low-dose aspirin for VTE
prophylaxis is individualized, weighing the risk of thrombosis and risk of bleeding.

6. Dose:
Therapeutic dose in current or prior VTE, Severe LV dysfunction, Large or giant CA aneurysms,
Patients with other severe MIS-C manifestations requiring PICU care. Patients with less severe
MIS-C if the D-dimer level is markedly elevated ( >10 times the upper limit of normal)
Prophylactic doses in patients with less severe MIS-C if the D-dimer level is <10 times the upper
limit of normal
Duration: Continue until D-dimer levels become normal
Age dependent dose of Enoxaparin
<2 months ≥2 months
Treatment Dose 1.5mg/kg/dose b.d 1mg/kg/dose b.d
Prophylaxis Dose 0.75mg/kg/dose b.d 0.5mg/kg/dose b.d
 Inotropes
Some children with MIS-C may present with vasodilatory shock that is refractory to volume
expansion. These children need inotropic support.
Epinephrine is preferred over Norepinephrine when there is evidence of left ventricular
dysfunction. Milrinone or Dobutamine for severe left ventricular dysfunction
 Refractory MIS-C
 2nd
dose of IVIG
 Pulse doses of intravenous methylprednisolone daily for 3-5 days
(30 mg/kg/dose, maximum of 1 g)
 Antiviral therapy
The role of SARS-CoV-2 antiviral therapies (eg, Remdesivir) in the management of MIS-C is
uncertain.
 Adjunctive therapies
Use of adjunctive therapies are uncertain.
o Interleukin-1 [IL-1] inhibitors [eg, Anakinra 2-10 mg/kg/dose, (Maximum 100 mg/dose)
SC/IV q6-12h)]
o IL-6 inhibitors [eg, Tocilizumab 4-8mg/kg per dose]
o Convalescent plasma from recovered COVID-19 patients)

7.  Treatment considerations based on presentation findings
Shock:
Should be resuscitated according to standard protocols
Inotropes Epinephrine is preferred over Norepinephrine when there is evidence of left ventricular
dysfunction. Milrinone or Dobutamine for severe left ventricular dysfunction
Features of Kawasaki disease:
Treat as per Kawasaki disease treatment protocol
Cardiac dysfunction:
Give IVIG and corticosteroids for all patients with cardiac involvement. Guided by Serial
echocardiographic assessment, BNP or troponin I levels.
In cases of fulminant disease, extracorporeal membrane oxygenation (ECMO) or a ventricular
assist device may be needed.
9. FOLLOW-UP
 Monitor inflammatory markers: C-reactive protein, Serum Ferritin
 Monitoring ESR is less useful after delivering a 2 g/kg dose of IVIG as immunoglobulins
elevate the erythrocyte sedimentation rate (ESR)
 Troponin I – Will take about 14 days to normalize. Repeat only if clinically indicated.
 Echocardiography
o 1-2 weeks: In patients who initially have normal function and normal coronary artery (CA)
dimensions, to recheck CA size.
o 2-3 days: In patients who have CA dilation/aneurysm on initial echocardiogram,
echocardiography is repeated every two to three days until CA size is stable and then every one
to two weeks for the next four to six weeks.
o For patients with systolic dysfunction and normal CAs on initial echocardiogram, the
echocardiogram is repeated as clinically indicated, including repeat imaging of the CAs with
each study.
o For patients who had evidence of CA involvement or systolic dysfunction in the acute phase,
cardiac magnetic resonance imaging can be considered at approximately two to six months after
the acute illness to assess ventricular function and evaluate for edema, diffuse fibrosis, and scar
by myocardial delayed enhancement.

8.  Aspirin:
Continue Aspirin for 4 weeks or more until platelet count becomes normal or coronary arteries
become normal. Minimum duration is 4 weeks
 Enoxheparin:
Start therapeutic or prophylactic dose depend on indication, continue until D-dimer levels
become normal

9. Appendix 1
Approach to immune-modifying therapy in children with MIS-C
Presence of moderate to severe manifestations
of MIS-C including ≥ 1 of the following
1. Shock requiring vasopressor therapy
2. LV systolic dysfunction
3. Coronary artery aneurysms (Z Score ≥ 2.5)
4. Elevated Troponin I or BNP
5. Arrythmia
6. Other severe manifestations requiring ICU care
Yes NO
IVIG alone
IVIG + Glucocorticoids
Inadequate Response
Adequate Response
Inadequate Response
Monitor for
Complications
2nd
Dose of IVIG
Glucocorticoids
Consider Adjunctive
Therapy

10. Appendix 2
Approach to Antithrombotic therapy in children with MIS-C
Contra indications to Antithrombotic Therapy
1. Platelet count < 50 × 103/µmol
2. Active Bleeding
3. Bleeding Diathesis
No
Yes
Monitor for resolution of contraindications
Once resolved start antithrombotic therapy
according to the algorithm to the right
Start low dose Aspirin
3-5mg/kg/d daily (Max 81mg)
Presence of
1. Current or prior VTE
2. Severe LV dysfunction
3. Large or Giant CA aneurysm
4. Markedly elevated D-dimer (ie, >10
times the upper limit of normal)
Treatment dose of Anticoagulation
LMW Heparin
If the child is Critically Ill or
Elevated D-dimer (ie, <10 times
the upper limit of normal)
Yes No
Prophylaxis dose of Anticoagulation
LMW Heparin