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PEDIATRIC MULTISYSTEM
INFLAMMATORY SYNDROME AND
KAWASAKI LIKE DISEASE STATE IN
COVID 19 ERA
SPEAKER:DR SHAHRIAR RAHMAN
Royal college of pediatrics and child
health definition-PIMS-TS april,20
Persistent
fever
>38.5*c
Clinical and
lab marker of
inflammation
Evidence of
single or
multiorgan
dysfunction
Exclusion
criteria
Sars-cov-2
PCR +/-
CASE DEFINITION PIMS
• WHO DEFINITION:(15/5/2020)
Children and adolescent of 0-19 yrs. with fever>=3 days
AND any 2 of the following;
• rash or bilateral non purulent conjunctivitis or mucocutaneous inflammatory sign( of
hand or feet or oral)
• Hypotension or shock
• Features of myocardial dysfunction.
• Evidence of coagulopathy
• Acute gastrointestinal problem
AND
Elevated marker of inflammation like ESR,CRP, Procalcitonin
AND
No other obvious microbiological cause of inflammation
AND evidence of covid19 or likely contact with covid19
(consider this syndrome in child with features of typical or atypical Kawasaki
disease or tss)
CDC case Definition
CCMC case definition MAY,20
EPIDEMIOLOGY-EVOLUTION OF THE
RATE OF KD/100 ADMISSION• +497% with p value 0.0011 in covid pandemic compared
to+365% in h1n1 outbreak with p value .0053.
• Ouldali et all, lancet child and adolescent health
EVOLUTION OF RESPIRATORY
PATHOGEN IN COVID ERA
TEMPORAL ASSOCIATION WITH
COVID19 WITH 4-5 WEEKS DELAYED
PEAK(Belot et al., Euro survailance,2020)
EPIDEMIOLOGY
• Alert confirmation: temporo-spatial association of KD/SARS-CoV2
occurring 2-4 weeks after the peak/post infectious complication
• No data from china .Only from Europe and some Asian continents.
• 60% patients are male
• Black predominance-high number in ethnic minorities, African,afro-
carribean, Hispanic group
• MAY 13 outbreak of KD like disease Italian epicenter.
• End of April 100 case Europe reported 100 cases
• May 6,2020 –higher incidendence of KD/IKD from WB
• May 22,2020 novel corona virus mimicking KD from Kolkata in an
infant.
• 2nd July emergence of KD related to SARS-CoV-2 infection in French
epicenter.
• 1000 cases reported till mid July worldwide.
ACE-2 RECEPTORS
• TYPE 1 membrane protein expressed in
• Lungs
• Heart
• Kidney
• Intestine
• Thymus/Lymph Node
PATHOPHYSIOLOGY
Continued…
Proposed mechanism of PIMS-TS
.
1. Antibodies may enhance
severity of sars-cov-2 by
triggering inflammation
,mediated by organ damage
2. Aberrant t-cell/B-cell
response due to underlying
genetic architecture
supports similarity b/w
SIMS-TS with KD
3.SARS-CoV-2 spikes has a
sequence and structure
motif similar to bacterial
super antigen
PATHOLOGY
.Sidiqqi H et All..
SIGNS AND SYMPTOMS
DISEASE SPECTRUM OF MIS-C
HOST
PIMS-TS
Acutely ill
children
Hemodynami
c
presentation
like shock
Favourable
evolution
Follow up
sequel?
Coronary?
Kidney?
Heart failure?
Major
inflammatory
response
Inflammatory
vacuities with
major endothelial
dysfunction
CLINICAL AND LAB FEATURES
SARS-CoV-2 PCR often Negative
SARS-CoV-2 IgG mostly Positive
Fever
Rash
Conjunctivitis
Abdominal pain
Diarrhoea
Vomiting
headache
Shock
Myocardial
dysfunction
ecg abnormalities
Coronary artery
dilatation
Bowel inflammation
Low lymphocytes
High neutrophils
Very high CRP
LOW ALBUMIN
High ferritin
High fibrinogen
High d dimer
High troponin
High NT-BNP
Clinical picture of KD-TS
Comparing indicators: pre-pandemic
classic KD vs. PIMS/MIS-C
CLASSIC PREPANDEMIC KD PIMS
Age <5 yrs. mean 2 yrs. 7-11 yrs. mean 10
ethnicity Asians African heritage
Gastrointestinal symptoms + +++
Cardiac dysfunction + +++
coagulopathy + ++
shock + ++
MAS + ++
Marked elevated CRP ++ ++++
Elevated ferritin + ++
Elevated NT pro
BNP,troponin
+ ++
thrombocytopenia Rare, thrombocytosis by
D10-14
++
Coronary abnormalities ++ +
Kidney involvement Very rare ++
Comparing PIMS-TS with paediatric
TSS
SEVERE COVID VS PIMS-TS
(Behrens et al,journal of clinical investigations,30 July)
SEVERE
COVID
INFECTION
CYTOKINE PROFILE
TNF Alfa
IL-10
Viral cycle
threshold
Blood smear-
BURR cell
Soluble C5b-9
PIMS-
TS/MIS-C
Factors in favour of PIMS
• Persistent fever
• High inflammatory marker(high CRP)
• Persistent shock- VIS-70, Moderate LV dysfunction(
high cpk, troponin, pro BNP, coronaries dilated z score
>2SD
• MODS( AKI, Liver injury)
• Cytokine storm( high ferritin >6000, extremely high IL-6
>800 pg.)
• Culture negative/ tropical infection negative
• Covid negative but no obvious contact history
• Age.>5 years
Subtype –phenotypes
(Clinical characteristic of 58 children with PIMS-TS
,Elizabeth Whittaker , MD JAMA2020)
• Three phenotype – coronary artery aneurysm
in all
.
FEVER AND
INFLAMMATORY
n=23
BAME 56%
Abdominal pain 57%
Rash 39%
IVIG 61%
Steroids 52%
CAA 4%
Evidence of SARS-CoV- 2
74%
CRP median 17
Troponin 8
. SHOCK COHORT
n= 28
BAME 69%
Abdominal pain 62%
Rash 50%
IVIG 61%
Steroids 66%
CAA 17%
Evidence of SARS-CoV-2 86%
CRP median 321
Troponin 124
.
KAWASAKI LIKE COHORT(4/5
clinical criteria)
n= 7
BAME 29%
Abdominal pain 14%
Rash 100%
IVIG 100%
Steroids 100%
CAA 14%
Evidence of SARS-CoV-2 57%
Crp median238
Troponin 10
INVESTIGATIONS..
CBC
Full biochemical profile
CRP, PCT, ESR
Ferritin,TG, trop-t , D-Dimer, CK,
NT-proBNP, LDH
Blood gas with lactate
Coagulation profile(including
Fibrinogen)
Blood/Urine culture
Chest x-ray
Abdominal imaging
echocardiography
Core
investigation
In children <2 yrs. rule out SCID,
CD4:CD8 ratio and quantitative
immunoglobins
CD25 , D-Dimer, IL 6
Vitamin d , amylase ASOT, Cortisol
Liposaccaride binding protein
Blood grouping crosshatch (considering
ECMO)
Virology for SARS-CoV-2 PCR on stool
,NPA, BAL and blood, serology for
SARS-CoV-2
M cns: BAL , urine throat swab
Standard respiratory viral panel-NPA
or throat swab
Viral serology blood pcr:EBV, CMV,
adeno
Additional
investigation
for PICU
admission
Diagnosis pathway(ACR Clinical guidance)
Treatment Pathway PIMS-TS
(European CDC June 2020 rec..)
PIMS-TSFulfils case
definition
1. IVIG 2g/kg+ pulsed MP therapy
2. Fluid bolus + inotropes
3. Broad spectrum antibiotics.
Vancomycin,clindamycin,
ceftriaxone
4. Respiratory support ECMO ,
NIV.
SHOCK
As per Kawasaki ds
treatment protocol
KAWASAKI DS.
Consider MDT
STEROID+IVIG+Biologics+
low dose aspirin
Other undefined
inflammatory
presentation
1)Regular cardiac asscessment:new murmur, troponin, CK-MB,
pro-BNP,ECG,ECHO
2)Broad spectrum antibiotics for all
3)LMWH –thromboprophylaxis for all children
4) MDT approach with speciality consultation.
.
TREATMENT(IJAM July edition)
IMMUNOMODULATORS-BIOLOGICS
TOCILIZUMAB
• IL-6 inhibitor
• 80 mg vial
• Dissolve in 100 ml
and give over 1 h
• Repeat dose >12 h
<24 hr.
• Dose <30 kg 12
mg/kg ; >=30 kg 8
mg/kg max 800 mg
IV
ANAKINRA
• IL-1 receptor
antagonist.
• 100 mg in .67 ml
prefilled syringe
• Dose: iv 2mg/kg BD
up to max 6 mg/kg
BD max 400mg/day
• Dilute in ns give
over 3-5 min
• Indicated in
treatment
refractory to
IVIG+steroid
INFLIXIMAB
• TNF-alfa receptor
blocker
• IV powder for
reconstitution 100
mg
• Dose:6 mg/kg
infuse over 2 hour
A Multicenter observational Study in UK over 90
children: Lancet child and adolescent health
LOW DOSE ASPIRIN AND EARLY
STEROID
WHY CHILDREN NOT SUFFERING
FROM SEVERE DISEASE?
Children
vs. adult
Appropriate infection
handling ,live
vaccination , repeated
viral infection
Less ACE2
EXPRESSION IN
RESPIRATORY
TRACT
Less risk factors
, less obesity ,
smoking
Early isolation,
closure of school ,
movement restriction
SUMMARY
• Increased number of children presented with shock/toxic shock
syndrome.
• Phenomenon changing from respiratory to toxic shock.
• Systemic hyper inflammation.
• Not all this group RT-PCR positive.
• Because PIMS has only recently been recognized, it is not possible
to make evidence based recommendation about when to undertake
laboratory testing in young patients who present with unexplained
fever.
• However certain principles must be kept in mind, when suspecting
MIS-C.As MIS-C appears to be rare, children with this syndrome
deteriorates quickly , a high degree of suspicion must be
maintained
• It is believed that early recognition and management are important
for optimal outcomes in children affected with MIS-C
Take home message
• Early suspicion early diagnosis better outcome
• Basic investigations
• Begins few weeks after peak
• Male>female older age group(>5 yrs)
• Three types febrile inflammatory state(FIS), KD
, Shock
THANK YOU

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Pediatric multisystem inflammatory syndrome and kawasaki like disease

  • 1. PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME AND KAWASAKI LIKE DISEASE STATE IN COVID 19 ERA SPEAKER:DR SHAHRIAR RAHMAN
  • 2. Royal college of pediatrics and child health definition-PIMS-TS april,20 Persistent fever >38.5*c Clinical and lab marker of inflammation Evidence of single or multiorgan dysfunction Exclusion criteria Sars-cov-2 PCR +/-
  • 3. CASE DEFINITION PIMS • WHO DEFINITION:(15/5/2020) Children and adolescent of 0-19 yrs. with fever>=3 days AND any 2 of the following; • rash or bilateral non purulent conjunctivitis or mucocutaneous inflammatory sign( of hand or feet or oral) • Hypotension or shock • Features of myocardial dysfunction. • Evidence of coagulopathy • Acute gastrointestinal problem AND Elevated marker of inflammation like ESR,CRP, Procalcitonin AND No other obvious microbiological cause of inflammation AND evidence of covid19 or likely contact with covid19 (consider this syndrome in child with features of typical or atypical Kawasaki disease or tss)
  • 6. EPIDEMIOLOGY-EVOLUTION OF THE RATE OF KD/100 ADMISSION• +497% with p value 0.0011 in covid pandemic compared to+365% in h1n1 outbreak with p value .0053. • Ouldali et all, lancet child and adolescent health
  • 8. TEMPORAL ASSOCIATION WITH COVID19 WITH 4-5 WEEKS DELAYED PEAK(Belot et al., Euro survailance,2020)
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  • 10. EPIDEMIOLOGY • Alert confirmation: temporo-spatial association of KD/SARS-CoV2 occurring 2-4 weeks after the peak/post infectious complication • No data from china .Only from Europe and some Asian continents. • 60% patients are male • Black predominance-high number in ethnic minorities, African,afro- carribean, Hispanic group • MAY 13 outbreak of KD like disease Italian epicenter. • End of April 100 case Europe reported 100 cases • May 6,2020 –higher incidendence of KD/IKD from WB • May 22,2020 novel corona virus mimicking KD from Kolkata in an infant. • 2nd July emergence of KD related to SARS-CoV-2 infection in French epicenter. • 1000 cases reported till mid July worldwide.
  • 11. ACE-2 RECEPTORS • TYPE 1 membrane protein expressed in • Lungs • Heart • Kidney • Intestine • Thymus/Lymph Node
  • 14. Proposed mechanism of PIMS-TS . 1. Antibodies may enhance severity of sars-cov-2 by triggering inflammation ,mediated by organ damage 2. Aberrant t-cell/B-cell response due to underlying genetic architecture supports similarity b/w SIMS-TS with KD 3.SARS-CoV-2 spikes has a sequence and structure motif similar to bacterial super antigen
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  • 18. DISEASE SPECTRUM OF MIS-C HOST PIMS-TS Acutely ill children Hemodynami c presentation like shock Favourable evolution Follow up sequel? Coronary? Kidney? Heart failure? Major inflammatory response Inflammatory vacuities with major endothelial dysfunction
  • 19. CLINICAL AND LAB FEATURES SARS-CoV-2 PCR often Negative SARS-CoV-2 IgG mostly Positive Fever Rash Conjunctivitis Abdominal pain Diarrhoea Vomiting headache Shock Myocardial dysfunction ecg abnormalities Coronary artery dilatation Bowel inflammation Low lymphocytes High neutrophils Very high CRP LOW ALBUMIN High ferritin High fibrinogen High d dimer High troponin High NT-BNP
  • 21. Comparing indicators: pre-pandemic classic KD vs. PIMS/MIS-C CLASSIC PREPANDEMIC KD PIMS Age <5 yrs. mean 2 yrs. 7-11 yrs. mean 10 ethnicity Asians African heritage Gastrointestinal symptoms + +++ Cardiac dysfunction + +++ coagulopathy + ++ shock + ++ MAS + ++ Marked elevated CRP ++ ++++ Elevated ferritin + ++ Elevated NT pro BNP,troponin + ++ thrombocytopenia Rare, thrombocytosis by D10-14 ++ Coronary abnormalities ++ + Kidney involvement Very rare ++
  • 22. Comparing PIMS-TS with paediatric TSS
  • 23. SEVERE COVID VS PIMS-TS (Behrens et al,journal of clinical investigations,30 July) SEVERE COVID INFECTION CYTOKINE PROFILE TNF Alfa IL-10 Viral cycle threshold Blood smear- BURR cell Soluble C5b-9 PIMS- TS/MIS-C
  • 24. Factors in favour of PIMS • Persistent fever • High inflammatory marker(high CRP) • Persistent shock- VIS-70, Moderate LV dysfunction( high cpk, troponin, pro BNP, coronaries dilated z score >2SD • MODS( AKI, Liver injury) • Cytokine storm( high ferritin >6000, extremely high IL-6 >800 pg.) • Culture negative/ tropical infection negative • Covid negative but no obvious contact history • Age.>5 years
  • 25. Subtype –phenotypes (Clinical characteristic of 58 children with PIMS-TS ,Elizabeth Whittaker , MD JAMA2020) • Three phenotype – coronary artery aneurysm in all . FEVER AND INFLAMMATORY n=23 BAME 56% Abdominal pain 57% Rash 39% IVIG 61% Steroids 52% CAA 4% Evidence of SARS-CoV- 2 74% CRP median 17 Troponin 8 . SHOCK COHORT n= 28 BAME 69% Abdominal pain 62% Rash 50% IVIG 61% Steroids 66% CAA 17% Evidence of SARS-CoV-2 86% CRP median 321 Troponin 124 . KAWASAKI LIKE COHORT(4/5 clinical criteria) n= 7 BAME 29% Abdominal pain 14% Rash 100% IVIG 100% Steroids 100% CAA 14% Evidence of SARS-CoV-2 57% Crp median238 Troponin 10
  • 26. INVESTIGATIONS.. CBC Full biochemical profile CRP, PCT, ESR Ferritin,TG, trop-t , D-Dimer, CK, NT-proBNP, LDH Blood gas with lactate Coagulation profile(including Fibrinogen) Blood/Urine culture Chest x-ray Abdominal imaging echocardiography Core investigation In children <2 yrs. rule out SCID, CD4:CD8 ratio and quantitative immunoglobins CD25 , D-Dimer, IL 6 Vitamin d , amylase ASOT, Cortisol Liposaccaride binding protein Blood grouping crosshatch (considering ECMO) Virology for SARS-CoV-2 PCR on stool ,NPA, BAL and blood, serology for SARS-CoV-2 M cns: BAL , urine throat swab Standard respiratory viral panel-NPA or throat swab Viral serology blood pcr:EBV, CMV, adeno Additional investigation for PICU admission
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  • 30. Treatment Pathway PIMS-TS (European CDC June 2020 rec..) PIMS-TSFulfils case definition 1. IVIG 2g/kg+ pulsed MP therapy 2. Fluid bolus + inotropes 3. Broad spectrum antibiotics. Vancomycin,clindamycin, ceftriaxone 4. Respiratory support ECMO , NIV. SHOCK As per Kawasaki ds treatment protocol KAWASAKI DS. Consider MDT STEROID+IVIG+Biologics+ low dose aspirin Other undefined inflammatory presentation 1)Regular cardiac asscessment:new murmur, troponin, CK-MB, pro-BNP,ECG,ECHO 2)Broad spectrum antibiotics for all 3)LMWH –thromboprophylaxis for all children 4) MDT approach with speciality consultation. .
  • 32. IMMUNOMODULATORS-BIOLOGICS TOCILIZUMAB • IL-6 inhibitor • 80 mg vial • Dissolve in 100 ml and give over 1 h • Repeat dose >12 h <24 hr. • Dose <30 kg 12 mg/kg ; >=30 kg 8 mg/kg max 800 mg IV ANAKINRA • IL-1 receptor antagonist. • 100 mg in .67 ml prefilled syringe • Dose: iv 2mg/kg BD up to max 6 mg/kg BD max 400mg/day • Dilute in ns give over 3-5 min • Indicated in treatment refractory to IVIG+steroid INFLIXIMAB • TNF-alfa receptor blocker • IV powder for reconstitution 100 mg • Dose:6 mg/kg infuse over 2 hour
  • 33. A Multicenter observational Study in UK over 90 children: Lancet child and adolescent health
  • 34. LOW DOSE ASPIRIN AND EARLY STEROID
  • 35. WHY CHILDREN NOT SUFFERING FROM SEVERE DISEASE? Children vs. adult Appropriate infection handling ,live vaccination , repeated viral infection Less ACE2 EXPRESSION IN RESPIRATORY TRACT Less risk factors , less obesity , smoking Early isolation, closure of school , movement restriction
  • 36. SUMMARY • Increased number of children presented with shock/toxic shock syndrome. • Phenomenon changing from respiratory to toxic shock. • Systemic hyper inflammation. • Not all this group RT-PCR positive. • Because PIMS has only recently been recognized, it is not possible to make evidence based recommendation about when to undertake laboratory testing in young patients who present with unexplained fever. • However certain principles must be kept in mind, when suspecting MIS-C.As MIS-C appears to be rare, children with this syndrome deteriorates quickly , a high degree of suspicion must be maintained • It is believed that early recognition and management are important for optimal outcomes in children affected with MIS-C
  • 37. Take home message • Early suspicion early diagnosis better outcome • Basic investigations • Begins few weeks after peak • Male>female older age group(>5 yrs) • Three types febrile inflammatory state(FIS), KD , Shock