Emergence of Fatal Hand Foot & Mouth Disease, Thailand, 2006 Rome Buathong, MD., FETP. Surveillance & Outbreak Investigation Bureau of Epidemiology, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand

Hand Foot and Mouth Disease (HFMD) Viral illness Caused by non-poliolo enterovirus: Coxsackies A & B, Echovirus, Enterovirus 68-71 Manifestation: Fever and vesicular lesions (Hands, Feet, Oral mucosa) Mode of transmission: oral-fecal and respiratory droplet Case fatality rates were usually low (< 1 %) but total deaths may be high in outbreak setting Hand foot and mouth is an enteroviral illness which is characterized by fever and vesicular skin lesions on hand foot and also mouth.

Large Outbreaks of HFMD in Asia Japan 1978 36,301/ ? Thailand2005 4,646/ 0 Taiwan 1998 129,106/ 78 Malaysia1997 5,999/ 31 Malaysia2005 14,253/ ? Chronological large outbreak of HFMD in Asia occurred in Japan in 1978 with 36,301 cases and Malaysia 1997 with 5,999 cases and 31 deaths then the largest outbreak was raised in Taiwan 1998 with 129,106 cases and 78 deaths. Outbreak continued to be noted in Singapore with more than 4000 cases and 7 deaths. In 2005 , there are outbreak in two country Thailand total number showed more than 4 thousands case and no death found , and in late 2005 to early 2006 there was outbreak in Malaysia with more than 14 thousands cases and unknown deaths Singapore 2000 > 4,000/ 7

HFMD Reported Cases, Thailand, 2003-2007 Source : Notifiable Disease, Reported 506, Bureau of Epidemiology

รายละเอียดผู้ป่วยที่จังหวัดนครราชสีมา   1 2 3 4 5 อายุ 1 ปี 5 เดือน 2 ปี 3 ปี 3 เดือน 4 เดือน 5 ปี 7 เดือน เพศ ชาย หญิง ที่อยู่ ต.หัวทะเล อ.เมือง ต.ลาดบัวขาว อ.สีคิ้ว ต.หนองไผ่น้ำ อ.เมือง อ.เมือง Contact no yes ไข้ 2 วัน 3 วัน 7 วัน RS no URI หอบ d2-> shock O2sat 68%, PR180bpm no URI, หอบ d3-> HR เร็ว,เบา ไอ น้ำมูก หอบ d3 no URI หอบ d3  GI ถ่ายเหลว d3 อาเจียน CVS Sinus tach 180-200 atrial tach 200 Sinus tach 200 bpm ST 200 bpm CNS ซึม d2 ซึม CBC Hct42%, Wbc33,000, Plt410,000 N82, L6, M4, band 8 Hct35%, Wbc15,000, Plt373,000 N60, L33, M5 Hct40%,Wbc22,500, Plt346,000 N72 c toxic granule, L21 Hct39%,Wbc16,000, N68 c toxic granule, L21,M10 Hct40%, Wbc1,400, Plt205,000 N42, L53,aL3 CRP 12.5 neg 12.9 Cardiac enz increase ไม่ได้ส่ง WNL CXR ground glass, bilat.alv.inf pul.edema no cardiomegaly

รายละเอียดผู้ป่วยที่จังหวัดนครราชสีมา   1 2 3 4 5 อายุ 1 ปี 5 เดือน 2 ปี 3 ปี 3 เดือน 4 เดือน 5 ปี 7 เดือน เพศ ชาย หญิง ที่อยู่ ต.หัวทะเล อ.เมือง ต.ลาดบัวขาว อ.สีคิ้ว ต.หนองไผ่น้ำ อ.เมือง อ.เมือง Echo EF 68%, WNL ไม่ได้ทำ EF 10% EF 20% WNL Culture H/C, Heart blood C/S -NG H/C, TSC-NG H/C-NG Viral studies no blood Course tachycardia+shock+pul.edema IVIG ไม่มีไข้ adenosine+cardioversionไม่ดีขึ้น 3hr death 21hr death ATB=Cefipime->Meropenem amiodaroneไม่ดีขึ้น 6hr death 16hr death

CXR เวลา 9.05 น. เวลา 11.11 น. เวลา 20.37 น. ให้ Intropic drug

ตรวจสอบการระบาดจำนวนผู้ป่วยที่มีไข้ ที่สถานีอนามัย

ผลตรวจ active case finding Province Index Case Active Case Finding Laboratory Outcome of Active Case จังหวัดนครราชสีมา 4 cases 30 cases Enterovirus71 = 4 cases Coxsackies B = 3 cases Other Enterovirus = 3 cases Negative Isolation = 15 cases Not Available = 5 cases อำเภอเมือง 2 cases 15 cases Enterovirus71 = 2 cases Other Enterovirus = 2 cases Negative Isolation = 10 cases Not Available = 1 cases อำเภอสีคิ้ว Other Enterovirus = 1 cases Negative Isolation = 5 cases Not Available = 4 cases

การสอบสวนเฉพาะราย ผู้ป่วยเด็ก กรุงเทพมหานคร อายุ 1 ปี 7 เดือน ที่อยู่ 22/465 หมู่ 7 ถ.แผ่นดิน ตำบลแสมดำ บางขุนเทียน กทม. เริ่มป่วย 27 มิถุนายน 2549 ด้วยอาการปวดศีรษะ อาเจียนหลังกินนม มาพบแพทย์ ที่รพ. วันที่ 28 มิถุนายน 2549 วันที่ 1 ก.ค. 2549 มาพบแพทย์อีกครั้งที่โรงพยาบาล แพทย์ตรวจพบผื่นที่ขา ให้การวินิจฉัยว่าเป็น Hand foot and mouth disease ให้นอนโรงพยาบาลเนื่องจากเด็กกินไม่ได้วันที่ 2 ก.ค. 2549 เวลา 5.00 น. มีอาการหอบเหนื่อย จนต้องใส่ท่อช่วยหายใจ พบ pulmonary edema มีอาการชัก 1 ครั้ง

Lab 1 กค 49 CBC : Hct 35% WC 15000, Plt 391,000, Hb 11.8 1 กค 49 Electrolyte: Na 134,K 10.1, Ca 4.2, Cl 20 2 กค 49 Electrolyte: Na 132,K 10.5, Ca 5.0, Cl 18 2 กค 49: BUN 17, Cr 0.7

ภาพถ่ายเอ็กซเรย์ปอด

HFMD cases reported to Bureau of Epidemiology, Thailand, 2001-2006 Year Cases Fatal 2001 1,547 0 2002 3,533 2 2003 1,218 2 2004 769 2 2005 4,646 0 2006 3,532 7* 2007 16,846 3* CFR = 0.05 %

14

Location of Fatal HFMD Cases by Chronological Date BKK/June BKK/July Phrae/August Khonkhan/August Kumphang/September Petchabun/October Nakhorn Sawan/November 15

Results

HFMD Fatal Cases by Date of Onset, Thailand, 2006 17

Characteristics of Fatal HFMD Cases ( N=7 ) Median age (months) 11 ( 7-19 ) Age < 12 months 71% Male Hospitalized case 100% Median length of illness* (days) 6 (4–20) Attending school/day care 14 % * During from date of onset to dead

Clinical Manifestations of Fatal HFMD Cases, Thailand, 2006 Symptom Percent

Laboratory Results WBC: Median (range) 35,450 (25,500- 44,200) WBC: Neutrophils 67% (42 – 92) WBC: Lymphocyte 26% (2 – 48) Blood sugar: Hyperglycemia 71% (75 - 425) CXR: Pulmonary edema 100 % (7/7) CSF: Aseptic meningitis 100 % (3/3) Hemoculture: No growth 100 % (5/5)

Laboratory Results Enterovirus isolation: Fatal Case ( 6 cases ) Specimen Number Test Result Stool 2 Viral isolation 1* / EV71 Nasopharyngeal swab 1 Viral isolation 1* / EV71 Tracheal suction 6 Viral isolation Negative * Same case

Laboratory Results Enterovirus Isolation: Contact tracing* Specimen Number Test Result Stool 2 Viral isolation EV71 * Demonstrate evidence of epidemiological linkage

Result: Environmental Survey All 7 fatal cases had different backgrounds but most (5) were middle socioeconomic status (SES) and the remaining 2 cases were low SES. No significant data regarding travel history, history of HFMD outbreak in the area or even school attendance

อภิปราย A cause of fatal HFMD reported during the Taiwanese outbreaks was brainstem infection resulting in cardiopulmonary failure And 7 cases of fatal HFMD in Thailand showed evidence of brainstem infection including Pulmonary edema/hemorrhage Hyperglycemia Tachycardia Leukocytosis

Coxsackie's Virus Predominated EV71 Predominated Coxsackie's Virus Predominated EV71 Predominated 25

1 – 11 months 5 yr 26

จำนวนรายงานผู้ป่วย HFM จำแนกตามสัปดาห์เริ่มป่วย

Acknowledgement Special thank for Provincial SRRT’s staffs NIH, Department of Medical Science, MOPH Our staffs at Outbreak Investigation and Surveillance Section, Bureau of Epidemiology And Dr. Wanna Hanshoaworakul, chief of OI&SS, BoE

Thanks 29 29

Pathogenesis : 2 1 3 Sympathetic over-stimulation Reticular formation involvement autonomic dysfunction Damage of some area of brain stem esp. medullary vasomotor center Sympathetic over-stimulation Pulmonary veins constriction Excessive release of cathecolamine & cortisol 2 Inc. pulmonary capillary hydrostatic pressure 1 HT,Tachycardia,Sweating Hyperglycemia 3 Pulmonary edema

Discussion The most frequent age of fatal HFMD cases was below 12 months Many serosurveys indicated that children age < 12 months had no immunity while maternal antibodies rapidly decline after the first month of life

Discussions If lab investigation result among fatal HFMD cases was not available, the lab investigation for contact tracing or survived cases would be useful for identifying an etiologic pathogen In 2006, EV71 was the main etiology to explain the cause of HFMD outbreak which included many fatal case occurrences

Conclusions Sporadic fatal HFMDs were detected among children below 2 years of age in Thailand No evidence of fatal outcome occurred in the outbreak setting EV71 played a major role of a fatal outcome and a cause of outbreak countrywide Cause of death corresponded to brainstem infection.

Public Health Actions Taken Established a working group between epidemiologists and pediatricians that aimed at advocating clinical and epidemiological characteristics of fatal HFMD Set criteria for full laboratory investigation Public education through various medias, including TV, newspaper and internet Strengthen surveillance and lab capacity countrywide

Limitations Specimen was not available for diagnosis confirmation in some fatal HFMD cases Lack of skills to collect and transport specimens that required for Enterovirus isolation Only laboratory for viral isolation was NIH Delay in detection and report of severe HFMD was common

Question?

Background In early July, 2006, FETP-Thailand received notification from the Department of Health of Bangkok Metropolitan Administration about a severe HFMD case admitted in ICU of a private hospital and he subsequently developed brain death The attending clinician initially suspected viral meningoencephalitis and viral myocarditis as the cause of death

Background Up to 31st December 2006, a total of 7 fatal HFMD cases were reported and the disease caused panic among parents of young children countrywide FETP conducted case investigation for those seven fatal HFMD cases

Objectives 1.To identify an etiology of fatal HFMD cases 2.To describe clinical and epidemiological characteristics of fatal HFMD 3.To strengthen surveillance for HFMD 4.To implement appropriate disease control and prevention measures

Methods 1.Descriptive Epidemiology: 2.Laboratory Investigation Reviewed medical records including disease notification forms Interviewed clinicians and parents of all fatal cases: demographics, symptoms, epidemiological linkage, personal hygiene, household sanitation and environment factors 2.Laboratory Investigation Fatal cases Active cases finding Tracing of close contact 3.Environmental Survey

Case Definition A Fatal HFMD Case is defined as A child who developed fever with hand, foot and mouth (all 3) lesions* and had a fatal outcome during January 1st - December 31st, 2006 in Thailand

Age distribution of reported HFMD cases, Thailand, 2006 Male:Female = 1.5:1 Median age = 24 month (12,36) 42