⼤ 綱

TCVGH Children’s Medical Center

• 1.案例分享
兒童多系統發炎症候群 • 2.MIS-C的診治
Multisystem Inflammatory Syndrome in Children
• 3.中榮的初步經驗
(MIS-C)
台中榮總兒童心臟科主任
詹聖霖醫師
• 4.MIS-C vs KD
陽明交大/高醫大兼任副教授
Sheng-Ling Jan, MD, PhD
Director of Pediatric Cardiology, VGHTC Children’s Medical Center
• 5.結論和討論
Associate Professor, National Yang-Ming Chiao-Tung University
and Kaohsiung
1 Medical University, TAIWAN
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Case Scenario Present illness

● 18 y/o, Male, 165cm, 73.4kg (BMI: 26.9) 2021 ● 18 y/o, Male, 165cm, 73.4kg (BMI: 26.9)
03/16 ● dizziness, headache, sore throat, myalgia,
● Birth Hx：GA 30+ wks , via NSD
and fever
● Past Hx：ADHD (attention deficit hyperactivity disorder) ● fever x 3 days, SOB, dyspnea and chest pain, N/V
03/18
● Developmental Hx：appropriate for his age LMD ER with poor activity and poor appetite
ER → hypotension, tachycardia, tachypnea
● Family Hx：nil
○ BT : 38.5’C
● TOCC Hx：nil ○ HR :150 bpm
○ RR : 25 /min
● CC：SOB for 1 day
1803051I ○ BP : 82/55 mmHg
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 Acute Myocarditis Acute Myocarditis

CDC working case definitions for acute myocarditis CDC working case definitions for acute myocarditis

1.臨床症狀
胸痛/胸悶
呼吸困難/喘
• Clinically suspected myocarditis if
⼼悸
暈倒 ≥1 clinical + ≥1 Lab/Imaging
2.實驗室檢查
Troponin上升
⼼電圖異常 • Clinically confirmed myocarditis if
⼼超異常
MRI異常 ≥1 clinical + EMB or ≥1 clinical + Tn + cMR (EKG+echo)
3.排除其他
原因
5 愛心. 當責 .品質. 創新 Circulation. 2021 Jul; 144:471–484 6 愛心. 當責 .品質. 創新 Circulation. 2021 Jul; 144:471–484

Acute Myocarditis KD ?
CBC/DC
X X age WBC 19360
Hb 15.3
Platelet 222
NEUT 94.4
V LYM 2.6

Biochemistry
BUN 10
Cr 1.01
V hsCRP 20.2
Viral infection is the most common etiology, but several other ALT 31
etiologies of myocarditis have also been implicated. V
Albumin 3.2
Nature Reviews Cardiology. 2015; 12, 670–680

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 Discharge diagnosis OPD f/u

04/01 ● Periungual desquamation (bil. hands & feet)
Acute myocarditis with multiorgan involvement (16 day
(shock, heart, lung, liver, hema, brain, skin, mucosa, muscle, GU) after onset)
s/p ETT+MV (2021/03/19-03/21)
s/p IVIG (2021/03/19)

● CXR : mild increased infiltrations over BLL

● ECG : NSR, HR 83 bpm
● Echo : normal LV function, LVEF 75%, normal CA
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Multisystem Inflammatory Syndrome

in Children (MIS-C) ?
兒童多系統發炎症候群?

Davies P, Evans C, Kanthimathinathan HK, et al. Intensive care admissions of children with
paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-
TS) in the UK: a multicentre observational study. Lancet Child Adolesc Health. 2020
Sep;4(9):669-677. doi: 10.1016/S2352-4642(20)30215-7. Epub 2020 Jul 9. PMID: 32653054

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 MIS-C Lag coincidence of MIS-C

2021/1
• MIS-C: multisystem inflammatory syndrome in children
• PIMS: pediatric inflammatory multisystem syndrome 2021/9

• PIMS-TS: pediatric inflammatory multisystem syndrome 2020/5

temporally associated with SARS-CoV-2
• Kawasaki-Like hyperinflammatory syndrome
• Pediatric hyperinflammatory syndrome
This 3-4 week lag coincides with the timing of acquired immunity and suggests that MIS-C
• Hyperinflammatory shock in children 2020/5 in UK may represent a post-viral infectious complication rather than acute infection.
https://www.nbcnews.com/

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Epidemiology of MIS-C Epidemiology of MIS-C

MIS-C/100,000 <18y children in Israel 10萬
75 • 322 per 100,000 SARS-CoV-2 infection
54.5
49.2
in individuals <21 y/o
50
• 2 per 100,000 population
10萬
25
14.3 x incidence of KD in children under 5 y/o
12.9 x
188-308 per 100,000 in Japan;
3.8 1x 28-60 per 100,000 in Taiwan;
0 9-20 per 100,000 in US/EU.
Alpha Delta Omicron N Engl J Med. 2020;383(4):347
JAMA. 2022 Jun 28;327(24):2452-2454

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 兒童多系統發炎症候群(MIS-C)
Epidemiology of MIS-C
<5歲
>5歲

Black
Hispanic
White
MIS-C發⽣率 預期⼈數
Asia
38⼈/百萬⼈/⽉       12⼈/⽉
4x5.1x0.1/3⽉

322⼈/百萬感染數 8⼈/⽉
322x0.8x0.1/3⽉

死亡率 1.8%-9%     0-1⼈/⽉

 
N Engl J Med. 2020;383(4):334
N Engl J Med. 2020;383(4):347
Lancet Child Adolesc Health. 2020;4(9):669
JAMA Network Open. 2021;4:e2116420
17 愛心. 當責 .品質. 創新 US-CDC ; BMC Pediatrics 2021;21:516 18 愛心. 當責 .品質. 創新

Pathophysiology of MIS-C Pathophysiology of MIS-C

• not well understood 60%

60%
• 1.Immune dysregulation
Kawasaki disease 45%
34%
Macrophage activation syndrome 30%
Cytokine release syndrome
15%
• 2.SARS-CoV-2 virus 5%
0%
Ab(+) Ab&PCR(+) Ab&PCR(-)

Nat Rev Immunol. 2020 Aug;20(8):453-454

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 MIS-C related myocarditis?

(dysfunction)
兒童多系統發炎症候群(MIS-C) 台灣疾病管制署
11 y/o Brazil child with MIS-C with cardiac failure and died after 1 day of
admission. •年齡0-19歲
Diffuse myocardial interstitial
inflammation. Part of a •發燒≧3天
cardiomyocyte, with viral particles •下列至少兩項
(arrows) within a cytoplasmic area (1)出疹/結膜炎/
close to the nucleus. 黏膜症狀
(2)急性腸胃症狀
This pathological results support (3)心肌功能受損
the direct effect of SARS-CoV-2 (4)低血壓或休克
infection on cardiac tissue was a (5)凝血功能異常
major contributor to myocarditis •發炎指數上升(CRP/ESR/PCT)
and heart failure in this patient.  •排除其他原因
•(2-6周)感染/接觸過
Lancet Child Adolesc Health. 2020;4(10):790
Children. 2020;7(7):69 
21 愛心. 當責 .品質. 創新 22 愛心. 當責 .品質. 創新 新型冠狀病毒感染臨床處置指引v18

MIS-C S/S
兒童多系統發炎症候群

(MID-C) (MIS-C) (PIMS-TS)

(MID-C)
1
2 (≥ 3 days) (≥ 1 day)
(≥ 38.5C)
• 1.Fever: Most patients 3-5 days.
3
≥ 2 s/s

≥ 2 s/s ≥ 1+1 s/s

3天
4天
4 ≥5天
5

6 N Engl J Med. 2020;383(4):334

CRP>3, ESR>40, PCT>0.5, Ferritin>160, WBC>110k, N>7.5k,
愛心. L<1.1k or 10%, Plt<150k,
當責 .品質. 創新 D-dimer>2, Alb<3 Rheumatol Int. 2020 Nov 21; 1-14 24 愛心. 當責 .品質. 創新

 MIS-C S/S MIS-C S/S

• 2. KD-like s/s: • 3. GI symptoms: 60-100%
Conjunctivitis : 30-81%
abdominal pain, vomiting, diarrhea,
Red lips/strawberry tongue: 27-76%
some like appendicitis or ileitis
Cervical LAP: 6-16%
Rash: 45-76% • 4. Shock/Hypotension: 32-76%
Ext. change: 9-16% • 5. CV: myocardial dysfunction: 51-90% (echo/Lab)
arrhythmia: 12%
•Criteria met for complete KD: 22-64%
N Engl J Med. 2020;383(4):334 N Engl J Med. 2020;383(4):334

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MIS-C S/S MIS-C S/S

• 6. Resp. symptoms: 21-65% • 9. Neuro Symptoms: 29-58%
tachypnea, dyspnea, uncommon cough, rare ARDS mild: headache, lethargy, confusion, irritable
severe (6-8%): encephalopathy, seizures, coma,
• acute respiratory failure needed resp. support: 28-52%
• secondary to shock or cariogenic pulmonary edema stroke, meningoencephalitis, muscle weakness,
and brainstem and/or cerebellar signs
• 7. Kidney: 8-52% (usually mild AKI) life-threatening (3%): severe encephalopathy, CNS
• 8. Liver: 5-21% (hepatitis/hepatomegaly) demyelination, stroke, acute fulminant cerebral
edema, and GB syndrome.
N Engl J Med. 2020;383(4):334 JAMA Neurol. 2021 May 1;78(5):536-547

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 Classic Viral Myocarditis, MIS-C Myocarditis,

MIS-C Lab and COVID-19 Vaccine Myocarditis in Children
Abnormal CBC Elevated cardiac markers
•Neutrophilia 68 to 90 •Troponin 50 to 90 Troponin BNP Lymphopenia
•Lymphocytopenia 80 to 95 •BNP or NT-pro-BNP 73 to 90
•Anemia 70 Other systems involvement
•Thrombocytopenia 31 to 80 •Hypoalbuminemia 48 to 95
Elevated inflammatory markers •Elevated liver enzymes 62 to 70
•CRP 90 to 100 •Elevated LDH 10 to 60
•ESR 75 to 80 •Hypertriglyceridemia 70
Leukocytosis CRP Thrombocytopenia
•D-dimer 67 to 100 •Electrolytes
•Fibrinogen 80 to 100 •Renal function
•Ferritin 55 to 76 •Urinalysis
•Coagulation studies 0 0
•Procalcitonin 80 to 95 0
(PT/aPTT)
•IL-6 80 to 100 2022 UpToDate

29 愛心. 當責 .品質. 創新 30 愛心. 當責 .品質. 創新 Patel T, et al. medRxiv 2021.10.05.21264581

Kawasaki disease
IVIG and/or Steroid for MIS-C?
2020/06-2021/2

23 countries

N Engl J Med. 2021 Jul 1;385(1):11-22

ALC
愛心. 當責 .品質. 創新
Modified 2022 UpToDate, BCH, CHOP clinical pathway and Arthritis Rheumatol. 2022 Apr;74(4):e1-e20 32 愛心. 當責 .品質. 創新

 IVIG IVIG

IVIG or Steroid for MIS-C?

23 Nov 2021 23 Nov 2021
+ +
IVIG Steroid Steroid Steroid IVIG Steroid

Death
Steroid > IVIG+Steroid > IVIG
MV
support

Hemo
support

CA
dilation

LV
dysfunction

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Mx of MIS-C MIS-C in VGHTC

Moderate-to-severe manifestations ? ANY following
1. Met KD criteria
2. Shock needed vasopressor Tx
• 2022/6/5-2022/7/21 共8位MIS-C
• 5.6 ± 3.0 歲
3. LV systolic dysfunction or CA dilation (Z-score ≥2.5)
4. Elevated Tn or BNP <5歲 Male
5. Arrhythmia
Female
Low dose aspirin
6. Requiring ICU care
• 6M/2F >5歲
yes Antibiotics ? if shock no
all pt with plt >100k
IVIG + Steroid + ASA* IVIG or Steroid alone + ASA*
Anticoagulation
Responsive ? Fever and rising CRP, D-dimer, and/or ferritin
Venous TE
Severe LV dysfunction yes no yes no
≥ Large CAA
Needed ICU Mornitor Adjunctive Mornitor Add
D-dimer >10x complications therapies  complications steroid
35 愛心. 當責 .品質. 創新 Modified 2022 UpToDate and WHO guideline 36 愛心. 當責 .品質. 創新

 MIS-C in VGHTC MIS-C in VGHTC

• 2022/6/5-2022/7/21 共8位MIS-C • COVID Dx: 6位確診過、2位抗體陽性
• COVID to MIS-C: 30 ± 15天 (8-52天)
COVID Dx+ COVID Dx- 37.5% 37.5%
38%
輕症x1
29% 25%
中症x6
19%
重症x1
10%

0%
COVID&PCR+ COVID&PCR- Anti-N+
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Common (>66%) Frequent (33%-66%) Occasional (<33%)

MIS-C in VGHTC Rey eyes MIS-C
87.5% in VGHTC
Skin rash/cLAP 50% Full KD 12.5%
Red lips 87.5% Cough 50% Ext. changes 25%
CRP>3 87.5% Abd. pain 37.5% Headache 12.5%
• Fever: 5 ± 1 天 Ferritin>160 75% Vomiting 50% Sore-throat 12.5%
PCT>0.5 75% ESR>40 37.5% Diarrhea 25%
• DOH: 6 ± 3 天 3天
Anemia 75% Leukocytosis>11k 62.5% Arthragia 25%
BNP↑ 75% Neutrophilia>7.5k 62.5% Shock 12.5%
4天 Lymphopenia<1.1k 50% PT↑ 25%
≥5天 Thrombocytopenia 62.5% Troponin↑ 12.5%
D-dimer>2 62.5%
GOT/GPT↑ 50%
Albumin<3 37.5%
aPTT↑ 37.5%
39 愛心. 當責 .品質. 創新 40 Abnormal
愛心.echo
當責 .品質. 37.5%
創新

 MIS-C in VGHTC Prophylaxis of MIS-C

Multisystem Inflammatory Syndrome in Children
• Mx: IVIG ± steroid by COVID-19 Vaccination Status of Adolescents in France
Michael Levy, et al. PICU, Hopital Universitaire Robert-Debre, Paris, France
• IVIG resistance: 37.5% JAMA. 2022 Jan 18;327(3):281-283

IVIG (-)
IVIG alone More than 95% of vaccinated adolescents received BNT162b2 (Pfizer-BioNTech), less than 5%received mRNA-1273 (Moderna),

IVIG+steroid and less than 1% received other COVID-19 vaccines

從2021/9/1到2021/10/31，共107個法國住院的MIS-C兒童，其中其中33⼈(31%)
是有資格接種疫苗(>12y)的青少年。 其中0⼈已完全接種，7⼈已接種1劑疫苗。
與未接種疫苗相比，接種疫苗得MIS-C 的危險機率(HR)為0.09 (P < 0.001)。
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Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Incidence and clinical phenotype of multisystem inflammatory syndrome in
Inflammatory Syndrome in Children Among Persons Aged 12-18 Years- USA, July-Dec 2021 children after infection with the SARS-CoV-2 delta variant by vaccination
status: a Danish nationwide prospective cohort study

Lancet Child Adolesc Health. 2022 Jul;6(7):459-465

Delta流⾏期間發現51例MIS-C病例未接種疫苗及1例完全接種疫苗的青少
2021/7-2021/9共102名MIS-C病患和181名住院對照中，2劑輝瑞BNT疫苗對MIS-C 年。青少年MIS-C的發⽣率是4300分之1未接種疫苗和9900分之1名有接種
的估計有效性為91% 。所有38名重症需要⽣命⽀持的MIS-C患者均未接種疫苗。 疫苗。估計的疫苗在5-17歲對MIS-C的有效性為94%。

 比較項目 兒童多系統發炎症候群 川崎病

Prophylaxis of MIS-C 發生率
好發種族
約2-50/10萬<18歲孩童 約29-60/10萬<5歲兒童
非裔/拉丁裔 亞裔
好發年齡 6-12歲 <6歲
台灣兒童新罐疫苗開打時程 <5歲 >5歲 好發性別
發燒天數
男 (1.2-1.6)
≥ 3天
男 (1.5-1.7)
≥ 5天
新冠疾病史 有 無
5-11歲 2022/6 發生原因 不明 不明
台灣 典型川崎病症狀 22-64% 80-85%
<5歲 影響多重器官 較 常 見 較 少 見
低血壓或休克 較 常 見 較 少 見
>5歲
2021/9 2022/5 MIS-C 2022/7 心肌炎/心臟功能異常 較 常 見 較 少 見
冠狀動脈病變 較 高 較 低
治療方式 免疫球蛋白/類固醇 免疫球蛋白/類固醇
美國 免疫球蛋白效果不佳 較常發生 偶爾發生
重症照護 經常需要 很少需要
12-18歲 6⽉-4歲 強心劑 可能需要 很少需要
死亡率 很低(1-2%) 罕見(<0.1%)
台中榮總兒童心臟科詹聖霖醫師 製表
45 愛心. 當責 .品質. 創新 愛心. 當責 .品質. 創新 參考資料fped.2021640118/2022uptodate

多系統炎症徵候群MIS-C警訊症狀

MIS-C vs KD 兒童新冠病毒感染後注意事項
●兒童及青少年感染後⼆⾄六周，若出現持續發燒超過三天，
• 12字訣: 東 ⻄ 合併⼀個以上下列症狀時，請就醫尋求協助。

⼤ ⼩ ●⽪疹 ●腹痛 ●嘔吐

長 短 ●眼睛紅 ●腹瀉 ●頭暈/頭痛
內 外 ●若合併出現下列其中症狀，請儘速就醫！
⾼ 低 昏睡或意識不佳、⾏為異常、呼吸困難、
胸痛或胸悶、嘴唇或膚⾊發紫、嚴重腹痛
輕 重
www.cdc/gov/mis/mis-c html
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新型冠狀病毒感染臨床處置指引v18