MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN WITH COVID-19
How common is covid-19 in children?
What is multisystem inflammatory syndrome
in children (MIS-C)?
Also called
Pediatric multisystem inflammatory syndrome (PMIS)
Pediatric inflammatory multisystem syndrome (PIMS)
Pediatric hyperinflammatory syndrome or shock.
This KD like illness was
first reported from United Kingdom in mid-April. There was a case series published
from Italy as well. However, after that many cases have been reported from
other European countries, USA (particularly New York) and Canada.
Although it is a rare
presentation, pediatricians and parents should be aware of such condition which
has a significant risk factor for mortality and morbidity.
How is MIS-C similar to Kawasaki
disease?
How does it differ from Kawasaki disease?
KD is more common in infant and younger age groups whereas
MIS-C is common in older and adolescent.
KD rarely present with KD shock syndrome whereas MIS-C
usually present with shock.
The risk of coronary artery aneurysm is found to be higher
in MIS-C compared to KD.
KD is common in East Asian children whereas MIS-C common
black children.
What is the pathophysiology of MIS-C?
The exaggerated and inappropriate immune response leads to
multisystem inflammatory response.
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What are the most common symptoms at
presentation?
Fever in 100%
Most of the children present with GI symptoms like abdominal
pain, vomiting mimicking appendicitis.
Some with documented ileitis in imaging.
Respiratory symptoms, rash, conjunctivitis, neurocognitive
symptoms like -headache, confusion, sore throat, swollen hands and feet can be
present.
Most of the cases presented with fever for 4-5 days followed
by warm shock.
Shock are often fluid refractory, requiring vasopressors and
mechanical ventilation.
Respiratory involvement is not a prominent feature although
many patients presented with tachypnea, labored breathing due to shock and
required mechanical ventilation.
What are the common clinical findings?
KD diagnostic
criteria in 50 to 64%
Myocardial dysfunction
Acute respiratory failure in 52-68%
AKI
Serositis
Acute hepatic failure
What are the laboratory findings?
CBC-
Lymphocytopenia is characteristics
Neutrophilia, mild anemia and thrombocytopenia may occur.
Elevated Inflammatory markers
CRP
ESR
Procalcitonin
Ferritin
Elevated D-dimers, fibrinogen
Elevated cytokines like- IL-6
Elevated cardiac markers: Troponin
and BNP or NT-pro-BNP
Hypoalbuminemia
Elevated liver enzymes
Elevated LDH
Hypertriglyceridemia.
IL-6 plays an important role in cytokine storm and if IL-6 measurement facility is available in labs it can act as early indicator of MIS-C. It starts rising within 3 hours of MIS-C as compared to 48-72 hours of serum ferritin.
What are the imaging findings?
Echocardiography- LV systolic dysfunction, Pericardial effusion, mitral and other valvular regurgitation and coronary artery abnormalities including dilatation.
CXR, CT chest – atelectasis, pleural effusion, consolidation
In CT nodular ground glass opacification may be present.
Abdominal USG/CT- free fluid, ascites and bowel and
mesenteric inflammation
How does CDC (Center for disease
control and Prevention) define MIS-C?
The CDC case definition
MIS-C
is defined by meeting all of the following criteria:
·
An individual
aged <21 years
presenting with fever*
evidence of inflammation#,
and
evidence of clinically
severe illness requiring hospitalization, with
multisystem (>2)
organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal,
dermatologic or neurological); AND
- No
alternative plausible diagnoses; AND
- Positive
for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen
test; or COVID-19 exposure within the 4 weeks prior to the onset of
symptoms
*Fever >38.0°C
for ≥24 hours, or report of subjective fever lasting ≥24 hours
#Including, but not limited to, one or more of the following: an
elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR),
fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH),
or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low
albumin
Additional comments
- Some
individuals may fulfill full or partial criteria for Kawasaki disease but
should be reported if they meet the case definition for MIS-C
- Consider
MIS-C in any pediatric death with evidence of SARS-CoV-2 infection.
What is the WHO case definition for
MIS-C?
The case definition is children and adolescents aged 0–19 with fever for more than three days who have two of the following:
- Rash or bilateral non-purulent
conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet)
- Hypotension or shock
- Features of myocardial
dysfunction, pericarditis, valvulitis, or coronary abnormalities
(including ECHO findings or elevated Troponin/NT-proBNP)
- Evidence of coagulopathy (by
PT, PTT, elevated d-Dimers)
- Acute gastrointestinal problems
(diarrhea, vomiting, or abdominal pain)
AND
- Elevated markers of
inflammation such as erythrocyte sedimentation rate (ESR), C-reactive
protein (CRP), 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
What are the spectrums of covid-19 disease
in children?
Covid -19
with mild symptoms- persistent fever and mild symptoms with elevated ferritin
Covid-19
associated KD – Covid-19 patients fulfilling complete or incomplete criteria
for KD but do not develop shock and multisystem disorder.
Covid-19 with
MIS-C – multisystem involvement. Cardiac involvement and shock are common.
How do we proceed in a suspected
case of covid-19 MIS-C?
In mild cases with persistent fever but only mild symptoms do CBC and CRP to follow up and to do additional tests as per requirement.
In moderate to severe cases
CBC, RFT, LFT, Serum electrolytes, CRP, ESR, Procalcitonin,
Triglyceride, Ferritin, urinalysis, troponin, BNP, INR, APTT, D-dimer,
Fibrinogen
If available cytokine panel.
Test for SARS-COV-2
by RT-PCR or Serology or Antigen panel
What do we expect in SARS-COV-2?
Since, it is
a post infectious immune reaction serological test is likely to be positive
rather than the PCR and in most of the cases this is what is observed.
Most of the
cases are PCR negative and serology positive
Few cases are
positive in PCR as well as serology
Few are only
PCR positive
In very few
cases both are negative.
Is it necessary to rule out other infections?
It is also important to rule out other causes so following
investigations are to be done in moderate to severe cases:
Blood c/s, urine c/s, throat c/s, stool c/s, EBV PCR, CMV
PCR, Adenovirus PCR.
Echocardiography is to be done and if abnormalities the most important being coronary artery aneurysm if present should be followed up.
What are the differential diagnosis?
Cardiac involvement like CA aneurysm is less common in bacterial
sepsis
Microbiological testing can differentiate between MIS-C and
bacterial sepsis
KD
Already discussed
Toxic
shock syndrome
Microbiological testing is needed to differentiate
Appendicitis
Abdominal imaging is required
Other
viral infections
Other viral infections like EBV, influenza, adeno, entero
can also present with MIS-C.
HLH/MAS
Similar presentation with less cardiac and GIT manifestations
with more neurological manifestations.
They are present in person with rheumatological illness
SLE
with multisystem illness
Neurological and renal features are more common.
Most of the cases are known cases of SLE and they have been
ill for extended duration of time unlike MIS-C children.
Vasculitis
Children with MIS-c also present with rash but the rash is
not vasculitic rash.
Management
Multi-disciplinary approach
Moderate to severe cases should be admitted in PICU with
proper monitoring
All cases treat as septic shock before microbiological
diagnosis with proper antibiotics
PCR positive cases may be treated with Remdesivir or
other anti-viral as per the treating physician.
Warm shock – fluid and in cases of fluid refractory start
with EPINEPHRINE
In cases of significant myocardial dysfunction – milrinone
may be helpful. Significant ventricular dysfunction must be treated with judicious
use of diuretics, milrinone, dopamine and dobutamine. Although evidence is
lacking some physician use IVIG for severe myocarditis with ventricular dysfunction
Fulminant myocardial dysfunction might require ECMO or
Ventricular assist Device(VAD)
If
child is meeting the criteria for KD --- IVIG, aspirin and in refractory cases
treat as refractory KD
Kobayashi
score can be applied and treat accordingly if suspicion of refractory KD in the
first place.
What is the role of anti-thrombotic therapy?
All cases of significant myocardial dysfunction may be started
on aspirin. However, this can be decided on case to case basis.
For children with MIS-C not fulfilling KD criteria but have
moderate to severe disease the starting of antithrombotic should be individualized
outweighing the risk of bleeding and other concomitant illness.
This can be an area of debate. We can start steroids, IVIG, Anakinra or Tocilizumab with consultation of pediatric infectious disease expert. All these therapies are under investigation regarding their role in MIS-C. The starting of the therapy is clinician’s choice and may be started with the intent of conducting clinical trials.
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