Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19 - - PowerPoint PPT Presentation

Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19

ALLISON AGWU, MD, ScM

Associate Professor of Pediatric and Adult Infectious Diseases

NICOLE SALAZAR-AUSTIN, MD

Assistant Professor of Pediatrics

JODY HOOPER, MD

Associate Professor of Pathology

Session Overview

• Epidemiology of COVID-19 in children
• Clinical case presentation
• Review of MIS-C clinical characteristics
• Discussion of therapeutic options for MIS-C
• Pathology presentation
• Discussion

Epidemiology of COVID-19 in Children

Data in Children: China

• Nationwide case series of 2135 pediatric cases of SARS-CoV-2

infection reported to Chinese CDC from 1/16/20 through 2/8/20

• Children = <18 years old
• 728 (34.1%) laboratory-confirmed
• 1407 (65.9%) suspected
• Exposed to COVID-19 patient or living in an epidemic area + two of the following:
• Fever, respiratory or GI symptoms, or fatigue
• WBC normal or decreased or CRP elevated
• Abnormal chest radiograph

Dong Y et al. Pediatrics. 2020 Jun;145(6):e20200702. doi: 10.1542/peds.2020-0702. Epub 2020 Mar 16.

Data in Children: China

• Illness severity definitions
• Asymptomatic: + SARS-CoV-2 PCR, no signs/symptoms, normal CXR
• Mild: Upper respiratory tract symptoms OR only digestive symptoms without

fever, normal lung exam

• Moderate: Pneumonia, not hypoxic, no SOB, abnormal lung exam OR no signs
• r symptoms but CT findings of lung lesions
• Severe: Symptoms + oxygen saturation is <92% with other hypoxia

manifestations.

• Critical: ARDS or respiratory failure, or shock, encephalopathy, myocardial

injury or heart failure, coagulation dysfunction, acute kidney injury, other end-

• rgan damage

Dong Y et al. Pediatrics. 2020 Jun;145(6):e20200702. doi: 10.1542/peds.2020-0702. Epub 2020 Mar 16.

Data in Children: China

• Median age 7y [IQR 2-13 years]
• 1208 (56.6%) male
• >90% asymptomatic, mild, or moderate disease
• 94 (4.4%) asymptomatic, 1088 (51.0%) mild, 826 (38.7%) moderate
• 5.9% severe or critical (18.5% of adult cases in China severe or critical as
• f Feb)
• 1 death
• Severe and critical cases by age group
• 10.6% <1 year of age
• 7.3% ages 1 to 5
• 4.2% ages 6 to 10
• 4.1% ages 11 to 15
• 3.0% aged ≥16

Dong Y et al. Pediatrics. 2020 Jun;145(6):e20200702. doi: 10.1542/peds.2020-0702. Epub 2020 Mar 16.

Data in Children: China

Dong Y et al. Pediatrics. 2020 Jun;145(6):e20200702. doi: 10.1542/peds.2020-0702. Epub 2020 Mar 16.

Data in Children: China

• Median number of days from illness onset to diagnosis = 2 days

(range: 0–42 days)

• Most cases diagnosed in the first week after illness onset occurred

Dong Y et al. Pediatrics. 2020 Jun;145(6):e20200702. doi: 10.1542/peds.2020-0702. Epub 2020 Mar 16.

Data in Children: United States

• Baseline US demographics
• 22% of population comprised of infants, children and adolescents <18y
• COVID-19 data through 4/2/20
• >890,000 cases and >45,000 deaths worldwide
• 239,279 cases and 5443 deaths in the US
• Analysis of 149,760 laboratory-confirmed cases 2/12 through 4/2
• 2572 (1.7%) among children aged <18y
• Voluntary reporting via standardized case report form
• Data available for only small proportion of patients on many variables

MMWR Morb Mortal Wkly Rep 2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4

Data in Children: United States

• 2572 pediatric cases
• 850 (33%) from New

York City

• 584 (23%) from the rest of New

York state

• 393 (15%) from New Jersey
• 745 (29%) from other jurisdictions
• Similar to adult cases save lower

proportion (14%) from NY state

• Median age 11 years
• 813 (32%) reported cases in

children 15-17y

• 682 (27%) in children 10-14y
• 398 (15%) in children aged <1 year
• 388 (15%) in children aged 5-9y
• 291 (11%) in children aged 1-4y

MMWR Morb Mortal Wkly Rep 2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4

Data in Children: US Demographics

• 1408 (57%) in males (vs 53% in adults aged ≥18y)
• Predominance of males in all pediatric age groups
• Among the 184 (7.2%) with known exposure information:
• 168 (91%) had exposure to a COVID-19 patient
• 16 (9%) associated with travel
• Underlying conditions (data available on 13%)
• 23% had at least one, including all six admitted to ICU
• Most common: chronic lung disease, cardiovascular disease,

immunosuppression

MMWR Morb Mortal Wkly Rep 2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4

Pediatric Clinical Data

• Signs and symptoms (data available
• n 11% of patients)
• 73% had fever, cough, or dyspnea (vs.

93% adults 18-64y)

• 56% fever; 54% cough; 13% dyspnea
• Versus 71%, 80%, and 43% among adults

18-64y

MMWR Morb Mortal Wkly Rep 2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4

Pediatric Clinical Data: U.S.

• Hospitalization status (data available on 29%)
• 5.7% hospitalized (vs 10% adults 18-64y)
• 0.58% to ICU (vs 1.4%)
• 20% of those for whom status known (vs. 33% adults)
• 2% to ICU (vs. 4.5%)
• Children <1 year accounted for highest proportion of

hospitalized children

• Three deaths

MMWR Morb Mortal Wkly Rep 2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4

Take-Home Points

• COVID-19 is typically less severe in children than adults
• Serious illness resulting in hospitalization still occurs
• Slight preponderance of cases in boys
• Physical distancing and other measures remain important given

concern that less symptomatic persons may still contribute to disease transmission

Multisystem Inflammatory Syndrome in Children (MIS-C)

Clinical Case

Case Presentation

• 15 year old previously healthy African American female presented to

another hospital with one week of epigastric pain, initially waxing and waning, then progressively worsening with loss of appetite.

• 2 days prior to admission developed nasal congestion and rhinorrhea

without sore throat, dyspnea, or cough. She also endorsed loss of smell and taste, which she attributed to nasal congestion.

• One day prior to presentation developed myalgia
• ROS: negative for fever, headache, nausea, vomiting, diarrhea, vaginal

discharge (LMP 1 week prior to symptoms), urinary symptoms

History

• PMH: none
• SH: lives with mother and 2 sisters (both had sore throat and cold-

like symptoms the week prior); +social distancing

• FH: MGM hypothyroid

At the First Hospital

• PE: T 36.5°C HR 88 RR 18 O2 Sat 100% on RA
• mild epigastric tenderness without rebound/guarding
• WBC 18.9 S15.7%
• Urinalysis negative, urine pregnancy test negative
• SARS-CoV-2 PCR NEGATIVE
• Abdominal CT: Fat stranding and prominent lymph nodes (<1 cm) in

the epigastric region surrounding a loop of proximal jejunum. Mildly prominent lymph nodes (<1 cm) in the left retroperitoneum.

• Transferred to JHU for further surgical evaluation

JHU ED course

• Tm 38.1°C HR 90s-110s BP 110s/50s Weight 95.7 kg (BMI 31)
• PE: RUQ tenderness without rebound or guarding.
• Labs: WBC 16.2 (S-91% L-5% M-1.5%), ALC 790
• Chemistries, urinalysis: unremarkable
• ESR 74 CRP 24.3
• SARS-CoV-2 PCR NEGATIVE
• GC/CT NEGATIVE
• GI cocktail à unclear improvement, admitted for observation

Hospital Course

• HD #1-2 (illness day 8-9): abdominal pain and fluid intake improved,

but continued to have fever and tachycardia

• Tm 38.9°C CRP 24.3 ESR 74
• HD #3 (illness day 10): worsening abdominal pain, diffuse myalgia

(diffuse paraspinal), throat discomfort (L>R), pleuritic chest discomfort without shortness of breath. Faint erythematous maculopapular rash noted on chest, back, palms, and soles.

• Tm 37.7°C, d-dimer 1.09, CRP 30.4, LFTs nl, troponin <.04, ferritin 137
• WBC 18.8, B-24%, Plt 272K

Hospital Course

• HD#4 (illness day 11): developed worsened fever (39.9°C), continued

abdominal discomfort, tachycardia, hypotension requiring fluid boluses, and increased work of breathing. Transferred to PICU

• CRP 33.7 ESR 107 d-dimer 1.55
• WBC 27.7 B-43%
• Troponin >.04, proBNP 652, Fibrinogen 965 mg/dL (170-422)
• Repeat imaging à

B A D C Figure 1. Imaging at hospital admission (Panels A and B) and at admission to the PICU (Panels C and D). Axial CT of the chest showed normal lungs (Panel A) with coronal IV contrast enhanced CT (Panel B) showing enlarged mesenteric and retroperitoneal nodes (arrows) and normal

• bowel. On HD 4, repeat chest CT (Panel C) showed bilateral

lower lobe consolidation without pulmonary embolism and coronal IV contrast enhanced CT (Panel D) demonstrated new wall thickening of the distal transverse colon, gallbladder wall edema, and mesenteric stranding (arrows). Both chest and abdominal CT at that time showed prominent diffuse supraclavicular, hilar, mediastinal, abdominal, and retroperitoneal lymphadenopathy (Panels C and D).

HD #1 HD #4

MIS-C: Clinical Characteristics

Initial Report: Hyperinflammatory Shock Similar to Kawasaki Disease and Toxic Shock Syndrome During the COVID-19 Pandemic

• Cluster of 8 children in London, mid April 2020
• Unrelenting fever, rash, conjunctivitis, peripheral edema, generalized extremity pain, GI

symptoms

• Warm, vasoplegic shock
• Refractory shock requiring ECMO (n=1)
• Children age 4 - 14 years without significant comorbidities
• Hyperinflammation: elevated CRP, procalcitonin, ferritin, TAG, D-dimer
• Dilated coronary vessels, giant coronary aneurysm; biventricular dysfunction
• All SARS-CoV-2 PCR negative; several with household exposures
• Riphagen. Lancet 6 May 2020

Second Case Report Describing New Syndrome Similar to Kawasaki Disease During the COVID-19 Pandemic

Incidence of Kawasaki Disease Bergamo, Italy 2015-2020 Timing of KD Cases Among ED Visits during COVID Epidemic Bergamo, Italy Feb-Apr 2020

Verdoni, Lancet May 13, 2020 4-6 weeks after height

• f epidemic

Cases appeared 4-6 weeks after peak COVID-19 cases Suggests post-infectious inflammatory syndrome 30-fold increased incidence of Kawasaki Disease

Kawasaki Disease (KD)

• Acute, self-limiting vasculitis of medium-size vessels involving multiple organs
• 10x more common in Japan than US
• Winter/spring predominance, often clustered
• Associated with HCoV-NH and HCoV-229E
• Young children
• >90% of cases <5 years
• Peak incidence 6-11 months, rare < 6 mo

Kawasaki Disease (KD)

• Presentation: Fever, bilateral nonexudative conjunctivitis, mucositis, polymorphous

rash, extremity changes, cervical lymphadenopathy

• Inflammatory state:
• ↑WBC, Plt, CRP, ESR, ↑AST/ALT, ↓albumin, normocytic anemia, sterile pyuria
• Cardiac Involvement
• Reversible coronary artery dilation or aneurysm
• Mild to moderate ventricular dysfunction common
• Rarely severe (KD Shock Syndrome) with

associated myocarditis

Multisystem Inflammatory Syndrome (MIS-C) in Children

also known as Pediatric Inflammatory Multisystem Syndrome (PIMS-TS)

CDC Criteria

• < 21 years
• Fever for ≧24 hours
• Multisystem (≧ 2) involvement
• cardiac, kidney, respiratory, hematologic,

gastrointestinal, dermatologic or neurologic

• Laboratory evidence of inflammation:
• Increased CRP

, ESR, Fibrinogen, D-dimer, Ferritin, LDH, IL-6

• Low albumin
• Elevated neutrophils, reduced lymphocytes
• No alternative diagnosis
• Positive SARS-CoV-2 (PCR, serology, antigen) or

known exposure within the prior 4 weeks

WHO Criteria

• 0-19 years of age
• Fever >3 days
• Two of the following:
• Rash or bilateral nonpurulent conjunctivitis or mucocutaneous

signs

• Hypotension or shock
• Myocardial dysfunction, pericarditis, valvulitis, coronary

abnormalities

• Coagulopathy (RT, APTT, D-dimer)
• Acute gastrointestinal problems (v/d/pain)
• Elevated markers of inflammation (ESR, CRP

, procalcitonin)

• No other obvious cause
• Positive COVID-19 testing or likely contact with

COVID-19 Royal College of Physicians (UK): Fever, Inflammation, Single or multiorgan dysfunction with special characteristics, No alternative diagnosis, +/- evidence of SARS-CoV-2

MIS-C Presentation Similar to but Different from Kawasaki Disease

Verdoni, et al. Lancet 13 May, 2020

• Belhadjer. Circulation 17 May 2020

Toubiana BMJ 26 May 2020

• Older children (median 7-10 years)
• Prominent GI symptoms (50-95%)
• Exploratory laparotomy in several patients
• Prior to onset of KD-like symptoms and shock
• Neurologic (20-30%)
• Irritability, headache, confusion and meningeal

signs

• Polymorphous Rash (50-60%)
• Maculopapular, targetoid, etc.
• High proportion of patients with cardiac

dysfunction and shock (45-80%)

• LVEF <30% (up to 33%)
• Pressors (up to 80%)
• ECMO (0-28%)

Whittaker, JAMA 8 June 2020 Capone J Pediatrics 10 June 2020

COVID-19 T esting

• SARS-CoV-2 PCR Positive 26-38%
• SARS-CoV-2 IgM/IgG Positive 87-100%

Wider Spectrum of Illness than Initially Described

• Retrospective case series at 8 hospitals in the UK
• Collected all clinical and laboratory data on children meeting UK, WHO

and/or CDC criteria

• 3 Distinct Syndromes

1. Persistent fever and elevated inflammatory markers (n=23) 2. Kawasaki Disease-like (n=13) 3. Shock with clinical, echo and lab evidence of myocardial injury (n=29)

Whittaker, et al. JAMA 8 June 2020

Inflammatory Markers Distinguish MIS-C from other Pediatric Inflammatory Disorders

Older Age Lower Lymphocyte Count Lower Platelet Count

Whittaker, et al. JAMA 8 June 2020

Higher Ferritin Higher Troponin Higher D-dimer Higher Neutrophil Count Higher CRP Higher WBC

Inflammatory Markers Distinguish Children with MIS-C at Risk of Shock but not Coronary Artery Abnormalities

• Children with MIS-C and shock showed signs of higher inflammation and cardiac damage
• Higher CRP and neutrophil counts, lower lymphocyte counts and albumin
• Elevated troponin and proBNP
• No clinical or laboratory markers distinguished children with MIS-C who developed

coronary artery dilatation or aneurysms (n=8)

• Found in all 3 subsets
• Not associated with degree of inflammation
• Important implications for evaluation and treatment
• No distinguishing laboratory characteristics for children who did and did not have

evidence of SARS-CoV-2

Whittaker, et al. JAMA 8 June 2020

Clinical Case

Hospital Course (cont’d)

• HD#4 (illness day 11):
• ECHO: normal LV systolic function, normal coronary arteries
• Received cefepime, metronidazole, doxycycline
• Initially improved and weaned vasoactive support

Hospital Course (cont’d)

• 12 hours after transfer to PICU
• SARS-CoV-2 IgG and IgA positive
• IVIG administered due to concern for MIS-C
• Developed progressive hypoxemic respiratory failure à intubation
• Hypotension developed post-intubation, requiring norepinephrine and

vasopressin support

• Ultrasound: severely diminished LV EF and adequate right ventricle filling with

normal septal position. Pro-BNP 8328 pg/mL

• IL-6 239 CRP 30.9 ESR 118
• WBC 37.5, B-28%, ALC 750, PLT 280K

MIS-C: Treatment

Treatment of Kawasaki Disease

• IVIG
• Reduced coronary artery aneurysms by 75% and mortality by 95% when given in the

first 10 days of illness

• ASA
• Reduce risk of coronary thrombosis, given for 4-6 weeks
• Enoxaparin for large/giant aneurysms
• Steroids
• IVIG non-responders or at high risk of IVIG resistance
• Immunomodulators for IVIG and steroid-resistant KD (10-15%):
• Infliximab
• Anakinra (Phase 1/II ongoing)

Newburger Circulation 2004 Burns PIDJ 1998 Kobayashi Lancet 2012 Tremoulet Lancet 2014 Burns J Pediatr 2008 Dusser Front Pharmacol 2017

Minimal Data to Guide Treatment of MIS-C

• General Approach
• Apply KD therapeutic

principles

• Individualized Plans
• Collaborative approach

between many subspecialties

• Treatment
• IVIG: Universal
• ASA: coronary artery abnormalities and KD
• Steroids: Shock, ventricular dysfunction
• Immunomodulators: Unresponsive to IVIG and

steroids

• Anakinra, Infliximab, Tocilizumab
• Outcomes
• Limited data
• Rapid recovery with IVIG ± steroids
• Cardiac function restored in 70% by ICU

discharge

• Some deaths reported
• Riphagen. Lancet 6 May 2020

Verdoni, et al. Lancet 13 May, 2020

• Belhadjer. Circulation 17 May 2020

Toubiana BMJ 26 May 2020 Whittaker, JAMA 8 June 2020 Capone J Pediatrics 10 June 2020

Clinical Case

Hospital Course (cont’d)

• PICU course
• Hypotension persisted despite bolus epinephrine à pulseless electrical

activity arrest à CPR à quick return to perfusing rhythm à 2 additional PEA arrests

• Attempt to initiate ECMO (refractory hypotension and cardiac dysfunction),

unsuccessful due to engorged femoral vein and retrograde flow into the femoral artery.

• 90 minutes of CPR following 3rd arrest, resuscitative efforts were ceased
• 3rd SARS-CoV-2 PCR positive

Autopsy Findings

Jody E. Hooper, MD Director of Autopsy Director, Legacy Gift Rapid Autopsy Program Associate Professor of Pathology and Oncology

Autopsy Results

• Diffuse cardiac inflammatory infiltrate, most marked in septum.
• Inflammation in small arterioles, veins, & lymphatics.
• Only very focal myocardial damage seen.
• No significant inflammation in other organs.
• No significant abdominal/GI findings.
• Limited procedure did not verify clot in aorta.
• Inflammatory syndrome likely caused more myocardial damage than

visible, triggering sequence of events ending in death.

MIS-C: Key Points

• There appear to be three distinct syndromes:
• Prolonged fever with elevated inflammatory makers with variable symptoms
• Syndrome similar to Kawasaki disease
• Shock with myocardial injury
• There is no single diagnostic test, though patterns of inflammatory

markers distinguish it from other pediatric inflammatory disorders

• Most children have a rapid recovery with IVIG and Steroids
• There are limited data on long-term outcomes

“Please say her name and share her story. T each others. I don’t want my baby to have died in vain.”

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