NEW PARADIGM OF

COVID-19 CLINICAL COURSE

IN CHILDREN: MULTI-SYSTEM
INFLAMMATORY SYNDROME

Dominicus Husada
 OUTLINE
• Introduction
• Pediatric Multi-System Inflammatory
Syndrome
• Take Home Message
INTRODUCTION
 INTRODUCTION
• Covid-19 (SARS-CoV 2) telah menjangkiti lebih
dari 4,6 juta orang di seluruh dunia, sejak
akhir 2019; kematian >300 ribu
• Anak yang terkena relatif sangat sedikit ; anak
yang dirawat hanya sekitar 1%-2%
• USA 1,7%; Belanda 1%; UK 2%; China 1%
• TESSy (The European Surveillance System):
2,1% usia <14 tahun
Y. Dong et al. Pediatrics 2020. https://doi.org/10.101542/peds.2020-0702
EJ Molloy, CF Bearer. Ped Res 2020; https://doi.org/10.1038/s41390-020-0881-y
RM Vinner, E Whittaker. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)31129-6
MMWR 6 April 2020
ECDC 15 Mei 2020.
 INTRODUCTION
• Data IDAI (04052020): 280 anak
• Kematian di China:
– <9 tahun: 0
• Kematian di Inggris:
– Termuda: 6 minggu (confirmed) dan bayi 3
hari (ibu pneumonia Covid-19)
• Belum cukup bukti penularan vertikal
 INTRODUCTION
• Anak menunjukkan spektrum klinik dan
laboratorik yang agak berbeda
dibandingkan dengan dewasa
• Mayoritas anak yang terkena adalah
asimtomatik atau bergejala dan tanda
ringan

Y. Dong et al. Pediatrics 2020. https://doi.org/10.101542/peds.2020-0702

EJ Molloy, CF Bearer. Ped Res 2020; https://doi.org/10.1038/s41390-020-0881-y
 INTRODUCTION
Kemungkinan penyebab perbedaan anak vs
dewasa:
• Reseptor pada renin angiotensin system
(RAS)
• Perbedaan respon inflamasi terhadap
patogen (kuantitatif dan kualitatif)
• Antibodi ibu?
• Kompetisi dengan virus lain?
• Trained immunity?
Y. Dong et al. Pediatrics 2020. https://doi.org/10.101542/peds.2020-0702
EJ Molloy, CF Bearer. Ped Res 2020; https://doi.org/10.1038/s41390-020-0881-y
P Broddin. Acta Pediatr 2020. doi:10.1111/apa.15271
S Felsenstein, et al. Clin Immunol.2020; 215:108448.
 INTRODUCTION
• Peningkatan sitokin proinflamasi berhubungan
dengan fungsi netrofil dan usia, dan berperan
menentukan keparahan
• Mieloperoksidase, IL-10, IL-6, dan p-selectin
bertambah banyak sesuai usia
• ICAM-1 lebih banyak pada neonatus
• Pada anak dengan syok septik (bukan Covid-19)
ada 2360 gen netrofil, 965 gen monosit, dan 109
gen limfosit yang diaktifkan
• Transkriptomik pada anak dengan syok septik
juga berbeda
L Zhu, X. Lu, L. Chen, et al.Pediatr Res.2020. https://doi.org/10/1038/s41390.020-0892-8
P. Mehta, et al. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)30628-0
HR Wong ,et al. Pediatr.Crit.Care Med.2010;11:349-55.
JL Wynn, etal. Mol. Med 2011;17:1146-56.
 INTRODUCTION
• Ontogeni produksi sitokin sebagai
respons fitohemaglutinin, dari neonatus
ke dewasa à kenaikan IL-10 pada
neonatus menjadi komposisi lebih
seimbang antara IL-10/Th1/Th2/Th17
• Terjadi proteksi terhadap patogen namun
meringankan badai sitokin
M Jeljeli, et al. Pediatr Res.2019;86:63-70.
 PEDIATRIC MULTI-SYSTEM
INFLAMMATORY SYNDROME
 PEDIATRIC MULTY-SYSTEM
INFLAMMATORY SYNDROME
• Ada sekelompok kecil anak dengan
manifestasi klinik yang berbeda dari
kebanyakan penderita usia anak
• Significant systemic inflammatory
response
• Laporan dari Itali, Spanyol, Inggris, & AS
• Awalnya tidak ada di Pantai Barat AS,
Jepang, & Korea à strain ?
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
L Verdoni, et al. Lancet 2020.https://doi.org/10.1016/S0140-6736(20)31103-X
 PEDIATRIC MULTY-SYSTEM
INFLAMMATORY SYNDROME
• Inflammatory complications were
delayed à temporally related
• Tidak ada gejala dan tanda nyata ketika
terinfeksi Covid-19
• Aspek genetik ?
• Spektrum lengkap belum diketahui
• Penelitian sedang dilanjuutkan
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
 KRONOLOGI
• Pernyataan pertama di UK 27 April 2020 à
peningkatan kasus Kawasaki; respiratory
symptoms were not present in all cases
• Guideline RCPCH 1 Mei 2020 à case
definitions
• Publikasi Italia/Bergamo (10 kasus)
• UK 6 Mei 2020 – publikasi di Lancet: 8 kasus
• Perancis 12 Mei 2020 à laporan 125 kasus
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19
ECDC 15 May 2020.
S Riphagen et al. Lancet 2020..
L Verdoni et al. Lancet 2020. https”//doi.org/10.1016/S0140-6736(20)31103-X
 KRONOLOGI
• CDC 14 Mei 2020 à multisystem inflammatory
syndrome in children (MIS-C); terdeteksi sejak 7 April
2020 (Kawasaki+Covid-19); px I bayi perempuan usia
6 bulan; 3 kematian
• ECDC (Stockholm) 15 Mei 2020 à 230 kasus di
EU/EEA/UK dengan 2 kematian (1 di UK, 1 Perancis) ;
Jerman 10 kasus, Swis 10 kasus; Tidak meningkat di
Austria, Yunani, Swedia, Jepang, dan Korea Selatan
• WHO 15 Mei 2020 à Preliminary case definition
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19
ECDC 15 May 2020.
S Riphagen et al. Lancet 2020..
L Verdoni et al. Lancet 2020. https”//doi.org/10.1016/S0140-6736(20)31103-X
 PMIS – NEW YORK
• 15 kasus antara 17 April – 4 Mei 2020
• 4/15 PCR (+), 10 (-), 1 indeterminate
• 6/10 yang PCR (-) mempunyai antibodi

• 10 Mei 2020 : 85 kasus, 3 kematian

• 12 Mei 2020 : 102 kasus , 3 di California;
New York: 5-9 tahun 29%, 10-14 tahun
28% CDC 2000
ECDC 15 May 2020
 PEDIATRIC MULTY-SYSTEM
INFLAMMATORY SYNDROME
• Mempunyai gejala dan tanda klinik yang
mirip dengan :
– Penyakit Kawasaki
– Staphylococcal and streptococcal toxic
shock syndrome dan bacterial sepsis
– Macrophage activation syndrome
– Simptom abdomen yang tidak lazim
disertai excessive inflammatory markers
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
B Jonat, E Cheung. New York Prebyterian Kids Hospital
 PEDIATRIC MULTY-SYSTEM
INFLAMMATORY SYNDROME
• Definisi kasus (RCPCH):
– A child presenting with fever, inflammation
(neutrophilia, elevated CRP, and
lymphopenia), and evidence of single or
multi-organ dysfunction (shock, cardiac,
respiratory, renal, GI, or neurological
disorder) with additional features (clinical,
laboratory, imaging, ECG). Including full or
partial Kawasaki.
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
B Jonat, E Cheung. New York Prebyterian Kids Hospital
 PEDIATRIC MULTY-SYSTEM
INFLAMMATORY SYNDROME
• Definisi kasus (RCPCH)
– Harus mengeksklusi penyebab mikroba
yang lain, termasuk sepsis bakterial,
staphylococcal or streptococcal shock
syndromes, infeksi yang berhubungan
dengan miokarditis seperti enterovirus
– PCR SARS-CoV-2 bisa positif maupun
negatif
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
B Jonat, E Cheung. New York Prebyterian Kids Hospital
 WHO 15 MEI 2020
• Urgent need for collection of
standardized data describing clinical
presentations, severity, outcomes, and
epidemiology.
• WHO has developed a preliminary case
definition and case report form for
multisystem inflammatory disorder in
children and adolescents.
 WHO 15 MEI 2020 –
PRELIMINARY CASE DEFINITIONS
• 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).
 WHO 15 MEI 2020 –
PRELIMINARY CASE DEFINITIONS
• 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.
 PEDIATRIC MULTI-SYSTEM
INFLAMMATORY SYNDROME
• Systemic inflammation • Mucocutaneous
– Fever • Rash
– Myalgia • Lip swelling/cracking
– Tachycardia • Straberry tongue
– Hypo or hyperperfusion • Extremity swelling
– Lymphadenopathi • Conjunctivitis
• Cardiopulmonary • Blisters or erosions
– Respiratory distress • Gastrointestinal
– Chest pain • Nausea/vomiting
• Neurologic • Diarrhea
– Headache • Abdominal pain
– Altered mental status
– Meningismus
– Focal deficit B Jonat, E Cheung. New York Prebyterian Kids Hospital
– Seizure
 PENYAKIT KAWASAKI
Gejala klinis:
• Demam tinggi terus menerus
• Ruam – makulopapular
• Pembesaran kelenjar leher
• Konjungtivitis
• Edema dan eritema telapak tangan dan kaki
• Lidah stroberi
• Pengelupasan di ujung jari bawah kuku dan
sekitar anus
 PMIS – EARLY MEDICAL
MANAGEMENT - RCPCH
• Early medical management:
– PPE yang sesuai
– Resusitasi APLS standar dan terapi suportif
– Antibiotika empiris sesuai protokol sepsis
setempat, dengan pengambilan kultur darah
– Perburukan keadaan bisa cepat
– Pengawasan ketat untuk kardiorespirasi termasuk
continuous saturation and ECG with BP
monitoring
– 12-lead ECG diindikasikan di saat awal
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
 PMIS – EARLY MEDICAL
MANAGEMENT - RCPCH
• Cari keterlibatan multi-organ
• Pertimbangkan IVIG dan aspirin (Kawasaki)
• Pertimbangkan IVIG (TSS)
• Kasus dengan keterlibatan kardio (troponin
meningkat, perubahan ECG, abnormalitas
Echo) à pindah ke pusat jantung, dengan
konsultasi infeksi secara berkesinambungan
• (Sesuaikan mild/moderate/severe)
• Semua harus diduga Covid-19
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
B Jonat, E Cheung. New York Prebyterian Kids Hospital
 PMIS – CLINICAL FEATURE (UK)
• All : persistent fever > 38,5oC • Beberapa:
• Mayoritas: – Pembesaran kelenjar
– Butuh oksigen – Perubahan membran
– Hipotensi mukosa
• Beberapa: – Pembengkakan leher
– Nyeri perut – Ruam
– Konjungtivitias – Gejala saluran nafas
– Confusion – Sore throat
– Batuk – Bengkak tangan dan kaki
– Diare – Sinkop
– Nyeri kepala – Muntah
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
 PMIS – LABORATORY FEATURES
All: Beberapa:
• Abnormal fibrinogen • AKI
• Penyebab potensial tidak • Anemia
terdeteksi • Koagulopati
• CRP tinggi • IL 10 dan IL 6 tinggi
• D-dimer tinggi • Netrofilia
• Ferritin tinggi • Proteinuria
• Hipoalbumin • CK dan LDH meningkat
• Limfopenia • Trigliserida dan troponin
• Netrofil kebanyakan rendah, meningkat
sebagian normal • Trombositopenia
• Transaminitis
RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
 PMIS – IMAGING AND ECG
• Echo dan EKG: miokarditis, valvulitis,
efusi perikardial, dilatasi arteri koroner
• CXR: infiltrat patchy simetris, efusi pleura
• Abdominal USG: colitis, ileitis,
limfadenopati, asites,
hepatosplenomegali
• CT scan thorax seperti CXR

RCPCH. 2020. Guidance: Paediatric multisystem inflammatory syndrome temporarily associated with Covid-19.
YANG TERJADI PADA SISTEM IMUN
• Covid-19 dapat mengaktifkan sistem imun
alamiah dan adaptif
• Inflammatory innate responses yang tidak
terkendali dan respon imun adaptif yang tidak
sempurna dapat menyebabkan kerusakan
jaringan
• Severe diseases = higher Ig G response = higher
total antibody titre à Antibody dependent
enhancement (ADE) ?
• “Trained immunity” mengurangi suseptibilitas
dan severitas?
X Cao. Nat Rev Immunol.2020.https://doi.org/10.1058/s41577-020-0308-3
Netea MG, et al. Cell 2020.https://doi.org/10.1016/j.cell.2020.04.042
K Kadkhoda. mSphere 2020. https://doi.org/10.1128/mSphere.00344-20
Y Wan, et al. J Virol.2020.;94:e02015-9
YANG TERJADI PADA SISTEM IMUN
• Massive inflammatory cells infiltration of the
lungs
• Higly elevated inflammatory markers in the
serum
• Monocyte/macrophage activation
• Activated coagulation, pro-inflammatory
cytokines, and chemokine profiles
• Inflammation intensifies after viral clearance
S Felsenstein, et al. Clin Immunol.2020; 215:108448.
 PATOFISIOLOGI PEDIATRIC MODS
• Persistent macrophage activation à
pathophysiology basis for MODS
• Full recovery à epithelial, endothelial,
mitochondrial, and immune cell
regeneration and reprogramming is
completed

JA Carcillo, et al. Pediatr Crit Care Med 2017;18 (3 Suppl.1):S32-45

 WUHAN (171 ANAK) – LU et al - NEJM
GEJALA DAN TANDA PROSENTASE
Batuk 48,5
Eritema faring 46,2
Demam 41,5
Diare 8,8
Kelelahan 7,6
Pilek 7,6
Muntah 6,4
Hidung buntu 5,3
Takipnea saat masuk 28,7
Takikardia saat masuk 42,1
Saturasi oksigen rendah 2,3
 DATA LAIN
• Chongqing (12 anak): gejala dan tanda klinik
serupa dengan Wuhan
• Madrid (41/365 anak):
– URI 31%
– FWS 27%
– Viral-like pneumonia 15%
– Bronchiolitis 12%
– GE or vomiting 5%
– Asthma 2%
J Chen, et al. Genes & Diseases 2020. https://doi.org/10.1016/jgendis.2020.03.008
A Tagarro et al. JAMA Pediatr.2020; e201346
 PERBANDINGAN CHINA-ITALI-AS
CHARACTERISTICS ITALY (n=100) CHINA (n=171) US CDC (n=2572);
CONFIDENCE LU et al; NEJM MMWR
Fever, cough, or shortness of 51.8 NA 73.2
breath
Fever 54 41.5 56
Cough 44 48.5 54.3
Shortness of breath 11 NA 13.4
Feeding difficulty 23 NA NA
Rhinorrhea 22 7.6 7.2
Drowsiness 11 NA NA
Nausea/vomiting 10 NA 10.6
Fatigue 9 7.6 NA
Diarrhea 9 8.8 12.7
Abdominal pain 4 NA 5.8
Headache 4 NA 27.8
Sore throat 4 NA 24.4
Rash 3 NA NA
Cyanosis 1 NA NA
Apnea 1 NA NA
Tachypnea NA 28.7 NA
P Zimmerman, N Curtis. Ped Infect Dis J.2020;396:469-77
 CHINESE EXPERT’ CONSENSUS
STATEMENT
• Mostly with fever, dry cough, and fatigue
• Few children with upper respiratory symptoms
• Some may have atypical symptoms, such as
vomiting, diarrhea, poor spirit, and shortness of
breath
• Some shows obvious dyspnea, and may rapidly
progress to acute respiratory distress syndrome,
septic shock, refractory metabolic acidosis,
coagulation dysfunction, and multiple organ
failure
• Ada warning indicators

KL Shen, et al. World J Pediatr.2020.https://doi.org/10.1007/s12519-020-00362-4

 OTHER CORONAVIRUS COMPARISON
• Commonly circulating coronavirus (4-8% among
outpatients) à fever and cough
• SARS-CoV:
– 2% asymptomatic
– 91-100% with fever
• MERS-CoV:
– 42% asymptomatic
– 91-100% have fever
• SARS-CoV-2:
– 50% had fever P Zimmerman, N Curtis. Ped Infect Dis J.2020;39:355-68
 KONSEKUENSI TERAPI
• Antiinflamasi
• Antisitokin
• Steroid
• HCQ
• Convalescent plasma
• IVIG
• Mesenchymal stem cell therapy
A Golchin, et al. Stem Cell Rev Reports.2020. https://doi.org/10.1007/s12015-020-09973-w
TAKE HOME MESSAGE
 TAKE HOME MESSAGE
• Jumlah pasien anak relatif sedikit
• Derajat keparahan lebih ringan daripada
dewasa
• Ada sekelompok kecil yang tidak seperti
pasien Covid-19 lain dan menunjukkan
gambaran klinis dan laboratoris sindroma
inflamasi multi sistem, termasuk Penyakit
Kawasaki dan atau TSS
 TAKE HOME MESSAGE
• Ingat Kawasaki, ingat Covid-19 !!!
 TAKE HOME MESSAGE
• Many questions, limited evidence
• Penelitian terus berlangsung
• Keterlibatan multi disiplin
THANK YOU