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Rome Buathong , MD., MIH., FETP. Wanna Hanshoaworakul , MD. MSc . Michael O’Reilly, MD., MPH.

Outbreak of Fatal Cardiopulmonary Failure among Children Caused by an Emerging Strain of Enterovirus 71 - Nakhorn Ratchasima Province, Thailand, 2006. Rome Buathong , MD., MIH., FETP. Wanna Hanshoaworakul , MD. MSc . Michael O’Reilly, MD., MPH. Kumnuan Ungchusak , MD., MPH.

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Rome Buathong , MD., MIH., FETP. Wanna Hanshoaworakul , MD. MSc . Michael O’Reilly, MD., MPH.

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  1. Outbreak of Fatal Cardiopulmonary Failure among ChildrenCaused by an Emerging Strain of Enterovirus 71 - NakhornRatchasima Province, Thailand, 2006 Rome Buathong, MD., MIH., FETP. WannaHanshoaworakul, MD. MSc. Michael O’Reilly, MD., MPH. KumnuanUngchusak, MD., MPH. Bureau of Epidemiology Ministry of Public Health

  2. Enteroviruses • Family Picornaviridae • Small particle size (20-30 nm) & stable • Resistant to pH & temperature change, lipid Solvents & detergents • Single-stranded RNA Genome • Transmission: mainly fecal-oral route and respiratory droplets

  3. Classification of Human Enteroviruses • Poliovirus Types 1, 2, 3 • Coxsackievirus A Types 1- 24 • Coxsackievirus B Types 1- 6 • Echovirus Types 1-3 4 • Enterovirus Types 68 - 71

  4. Febrile illness URI Asymptomatic HFMD, Herpangina Pneumonia Enterovirus 71 Meningitis/ Encephalitis/AFP Diarrhea/ Gastroenteritis Myocarditis/ Pericarditis Pulmonary edema/ hemorrhage Myopathy Clinical Manifestations of EV71

  5. Etiological Agent of HFMD CoX A (24 spp) Echo (34 spp) HFMD EV68-71 (4 spp) CoX B (6 spp) Total 68 spp.

  6. Background • July 4th, 2006: Nakhorn Rachasima health officer reported 4 unexplained sudden deaths among young children in 3 days. • An attending clinician primarily suspected myocarditis as the cause of death • The BoE promptly started an investigation

  7. Objectives • To identify the cause of death for these 4 children • To define the scope of the epidemic by active case finding • To describe clinical characteristics of the fatal cases • To rapidly implement control and prevention measure

  8. Descriptive Study Fatal cases: • Reviewed medical records • Interviewed parents of fatal cases • Interviewed medical staff Non fatal cases: • Active case finding (screening) in affected communities: Districts A and B

  9. Laboratory Investigation • Viral isolation • Paired sera for micro-nuetralization antibody of EV71 • Nucleotide sequencing • Electron Microscopy

  10. Case Definitions Suspect Case: Any child < 15 years old, living in the same village where a fatal case occurred, who had one or both of the following: • Fever (history or T > 37.8 C) or • Any lesion on buccal mucosa, hands or feet Period: June – August 2006 Probable Case: Met suspect case criteria and died without confirmatory testing Confirmed Case: Met the inclusion criteria with laboratory confirmation for any Enterovirus species

  11. Results

  12. Demographic Characteristics of Four Fatal Cases, Thailand , 2006

  13. Clinical Manifestations among Four fatal Cases, Thailand 2006

  14. Laboratory and Imaging Results among Four Fatal Cases, Thailand 2006

  15. Bilateral Pulmonary Edema No Cardiomegaly Chest X-Ray, Case 2 Non - Cardiogenic Pulmonary Edema

  16. Autopsy Findings: Case 1 • Brain: diffuse brain edema; small numbers of lymphocytes and histiocytes in the subarachnoid space; scattered foci of necrosis in the thalamus, pons and medulla • Heart: diffuse congestion; no pericarditis, myocarditis or endocarditis; no infarct • Lungs: diffuse pulmonary edema & hemorrhage; small numbers of neutrophiles and lymphocytess present in the interstitium of alveolar septa

  17. Formalin-fixed Brain Tissue Viral-like particles, 20 nm in average diameter, non-enveloped, cytoplasm

  18. Nucleotide Sequencing • EV71 in Case 2 identified into Genogroup C4 • Nearest strain to the isolate was Shzh01-8 (nucleotide homology: 95.8%) • This strain had not previously been identified in Thailand

  19. Previously Case 2 Previously 0.01 B2 B3 3799/SIN/98 B4 MY104/9/SAR/97 7673-CT-87 2222-IA-88 2258-CA-79 B1 100 N5101-TW-98 N7008-TW-99 2609-AUS-74 18/Sin/97 5511/SIN/00 91.8 73.3 TH_SI 06/01 TH_SI 08/01 78.6 CN04104/SAR/00 A 2027/SIN/01 SB2864/SAR/00 TW-00 TW-00 AB204852 AB204853 100 100 U22521 C4 100 shzh03-58 SHH02-6 73.6 shzh04-J41 C3 100 KOR-00 99.9 KOR-00 shzh01-8 KOR-00 TH_SI 01/06 100 100 N5202-TW-98 shzh03-105 98.5 2286-TX-97 1M/AUS/12/00 2641-AUS-95 03784-MAA-97 C2 5026-SIN-02 6F/AUS/6/99 1117-MAA-98 S11051/SAR/98 S18191/SAR/02 0948-MAA-00 S40221/SAR/00 SB9564-SAR-03 C1 Courtesy of Puthawathana P.

  20. shzh02-40 C4 Subgenogroup shzh03-106 AFP9811134 shzh01-8 shzh04-J39 H26-CHN-00 SHH02-17 Seksan-THAI VP1 97-56-CHN- F2-CHN-00 shzh04-3 shzh03-58 shzh04-12 E20051733- E2004104-T ZJ-CHN-3-0 shzh04-38 EV71-CQ03- SHH02-6 638-Yamaga 2779-Yamag Courtesy ofPuthawathana P. 1530-Yamag 0.01

  21. HFMD: 12 Herpangina:1 Febrile: 25 Active Case Finding • 38 non-fatal cases detected. • Age: all cases < 10 years; median age 24 months (3 – 120 months). • Male : Female Ratio = 1:1 (19:19) • Clinical manifestations

  22. Viral Isolation Results

  23. Number of Cases by Onset of Cases in District A and B, Jun – Aug, 2007

  24. Conclusion • Etiology: Enterovirus 71 (Genogroup C4) • Cause of Death: Brain stem encephalitis, +/- Myocarditis, pulmonay edema and hemorrhage, respiratory failure • Strain: Emerging strain • High Case Fatality Proportion: 9.5%

  25. Discussion • Previous reports of fatalities associated with EV 71 outbreaks in East Asia have occurred in the context of large (thousands, tens of thousands) HFMD outbreaks and low CFRs. • In this outbreak, CFR was high (9.5%) and fatal cases did not manifest classic HFM signs. • This is a new epidemiologic pattern for EV 71 in Thailand. Careful monitoring of HFMD and pediatric cardiopulmonary failure cases is needed.

  26. Chronological Change of EV71 Subgenogroups in West Pacific Region(K.H. Lin et. al. J. Med. Virol. 78)

  27. Pathogenesis of Enterovirus Infection

  28. Clinical Stage of Enterovirus 71 Stage I : Symptom onset stage (24-72 hrs) • Fever , loss of appetite, oro-pharyngeal symptoms, skin manifestation and cough Stage II : Symptom generalized Stage (12-24 hrs ) • Irritable, restlessness, unable to get into sleep, abdominal distension, paralytic ileus, vomiting, headache, photophobia, startle response

  29. Clinical Stage of Enterovirus 71 Stage III : Brainstem dysfunction Stage ( 12-24 hrs ) • Generalized brainstem symptoms • Apathic, dullness, myoclonic jerks, sleepy, drowsy, visual or auditory or vestibular hallucinations • Localized brainstem symptoms • Mono-/Hemi-/or General weakness, ataxia, tension tremor, panic of unknown reason, conjugated ocular disturbance, CN palsy ( VI,VII,IX,X,XII) • Autonomic dysfunction symptoms • Tachycardia, cold sweating, poor peripheral circulation, HR > 160 bpm

  30. Clinical Stage of Enterovirus 71 Stage IV : Deteriorating Stage ( 6 – 12 hrs ) • Hypothermia, hemorrhagic cystitis • Tachycardia > 200 bpm • Apnea, respiratory disturbance, opsoclonia • Neurogenic shock, conscious disturbance

  31. Clinical Stage of Enterovirus 71 Stage V : Terminal Stage ( 6-12 hrs ) • Cardiopulmonary failure • ARDS • Comatose • Expired

  32. Timeline of Clinical Stage (Involved Brain Stem) 1 1.5 2 2.25 2.75 Onset Infect 3 4 5 5.5 6 3-5 days 1-3 days ½ - 1day ½ - 1 day ¼ - ½ day ½ day Incubation period Stage I Stage II Stage III Stage IV Stage V The longest length of clinical course – 6 days The shortest length of clinical course – < 3 days

  33. Public Health Actions • Established a working group of epidemiologists and pediatricians aimed at studying clinical and epidemiological aspects of fatal EV71 infections • Strengthened lab capacity for identifying enteroviral infections (12 new labs w/ PCR) • Created new national surveillance system for pediatric cardiopulmonary failure and fatal HFMD cases in Thailand • Media campaign for educating public about HFMD and non-HFMD EV71 infection by TV, newspaper and internet

  34. Limitations • No specimens available to confirm etiology in most cases, including most fatal cases • Etiology determined in only 14/42 cases (2/4 fatalities) • Investigation delayed for almost 2 weeks after fatalities occurred; may have missed non-fatal cases and overestimated CFR

  35. Acknowledgements Nakhorn Ratchasima Health Office Maharaj Nakhorn Ratchasima Regional Hospital Srikue Community Hospital National Institute of Health, Department of Medical Science, MOPH Department of Microbiology, Siriraj Hospital and Faculty of Medicine, Mahidol University Thailand MoPH – US CDC Collaboration (TUC) ** Travel Budget supported by IEIP, TUC

  36. Thank You for Your Kind Attention

  37. Notice for Dengue Lovers! The Second International Conference on Dengue and Dengue Hemorrhagic Fever 2008 • Will be held at the Hilton Phuket Arcadia Resort & Spa, Karon Beach, Phuket, Thailand • On October 15th – 17th , 2008 Further information please visit www.dengue2008phuket.com

  38. Viral Study Result among Fatal Cases

  39. Seroprevalence of Anti-EV71 among Singaporean Child, 2005 Highly Susceptible Age: 1 mo – 5 yr

  40. Pathogenesis: “unclear” Reticular formation involvement autonomic dysfunction Damage of some area of brain stem esp. medullary vasomotor center Sympathetic over-stimulation Pulmonary veins constriction Excessive release hormonal of Cathecolamine & Cortisol Inc. pulmonary capillary hydrostatic pressure HT, Tachycardia, Sweating, Hyperglycemia Pulmonary edema

  41. EV71 • In Taiwanese outbreak, cause of death was brainstem EV71 infection resulting in cardiopulmonary failure • All 6 cases of fatal confirmed EV71 infection occurring in Thailand since 2006 have shown evidence of multiple indicators of brainstem infection including • Pulmonary edema/hemorrhage • Hyperglycemia • Tachycardia • Leukocytosis

  42. Case 3 and Case 4 They had the indicators of brainstem infection or damage resulting to cardiopulmonary malfunction which including 1. Non-cardiogenic pulmonary edema 2. Increased sympathetic activity • Hyperglycemia • Extreme tachycardia with irregular pattern 3. Leukocytosis

  43. Situation of Fatal EV71 Infection in Thailand 2006 In 2006, we found 15 cases of EV71 infection with death • 8 cases presented with fever and acute pulmonary edema (non-cardiogenic) without HFMD • Of these 8 cases the laboratory confirmed for EV71 in 3 cases ( all other 2 cases specimen unavailable, 3 cases negative for any EV ) • 7 cases presented with fever and acute pulmonary edema with HFMD • Of these 7 cases the laboratory confirmed for EV71 in 3 cases ( all other were no specimen available)

  44. Viral Pathogen’s Structures causing Brain Stem Infection

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