2. Chikungunya Infection Khachornsakdi Silpapojakul MD Prince of Songkla University Hat yai, Thailand

3. What ???

4. Chikungunya ( Swahili = “that which bends up”) One of “viral arthritides” which include O’ nyong nyong fever in Africa ( Acholi = joint breaker), Ross River fever in Australia, Sindbis fever in the Western Pacific and Mayaro fever in South America. Tesh RB. Arthritides caused by mosquito-borne viruses. Ann Rev Med 1982;32:31-40

5. Chikungunya Virus

6. Arbovirus = Arthropod-borne viruses (~ 500) Family Genus Viruses Togaviridae Alphavirus Chikungunya O’nyong nyong Ross River Flaviviridae Flavivirus Dengue, JE West Nile Bunyaviridae Rift Valley fever

7. Am J Trop Med Hyg 1958;7;561-573

10. Chikungunya & Thailand

12. Chikungunya Outbreak: Bangkok 1962 In 1962, an estimated 40,000 patients sought medical attention in the urban complex of 2 million inhabitants. This intensive transmission in mosquitoes was accomplished by large population of Ae. aegypti breeding in water storage jars ubiquitous in Thai homes as a consequenceof the lack of piped water distribution system. Halstead SB, Nimmannitya S, Margiotta MR. Dengue andchikungunya virus infection in man in Thailand, 1962-1964,II: Observations on disease in outpatients. Am J Trop Med Hyg 1969;18:972-83.

13. Chikungunya: Disappeared?? - Burke DS et al : Disappearance of Chikungunya virus from Bangkok. (Trans R Soc Trop Med Hyg 1985;79:419)

14. Aug 19,1984 - A 50 yr old, Dean of a medical school - Fever with rash, 1 wk - 2 days later, some petechiae appeared - Cough, myalgia esp. at the back - PE febrile, generalized rash with some petechiae - Hct 43 % ; WBC 14,067 P 65 % L 23 %, M10 % - Platelet count = 210,000

15. Aug 19,1984Aug 27,1984 Dengue 21:1601:160 Dengue 41:3201:320 Chikungunya1:51201:5120

16. ACUTE PUO, SONGKLA Hospital : Hat-Yai & Rattapum Hospitals Year : Oct. 1991 - Jan. 1993 No. of patients =335 Adults =182 Children =153

17. ACUTE PUO, SONGKLA Adults Children Total 1. Scrub typhus 21 20 41(12.2%) 2. Leptospirosis 19 6 25(7.5%) 3. Dengue infection 8 17 25(7.5%) 4. Murine typhus 12 7 19(5.7%) 5. Chikungunya 2 7 9(2.7%) 6. J.E.V. 1 4 5(1.5%) Total known 124(37.0%)

18. July 1991 KhonKaen (96 cases) July1995 NakomSiThammaraj(576 cases) August 1995 Nong Khai (331 cases) Southeast Asian J Trop Med Publ Health 1997;28:359-364

19. Why is it important now ??

20. Lancet Infect Dis 2007;7:319–27

21. Where ???

22. 266000 1,400,000

23. Chikungunya outbreaks, India

24. Chikungunya suspects, India

25. Chikungunya: High attack rate, Highly symptomatic, Low mortality Kenya (Lamu) outbreak (July 2004) = 75% of the population. Comoros Island (2005)= 63% Mayotte (2005) = 26% Reunion Island (2005) = 266,000/77500 (46,000 new cases in week 6) with 254 deaths(~1 in 1000 clinical cases). Lancet Infect Dis 2007;7:319–27

26. Rezza et al. Infection with chikungunya virus in Italy: an outbreak in a temperate region. Lancet 2007; 370: 1840–46.

27. www.thelancet.com Vol 370 December 1, 2007

28. N Engl J Med 2007;356;768-771

29. EID 2007;13:147-149

30. A ProMED-mail post http://www.promedmail.org Date: 5 Sep 2008 Source: Singapore Ministry of Health [edited] ---Since January 2008, Singapore has been experiencing outbreaks of both imported and local cases of Chikungunya fever. There have been an additional 28 cases (including 16 imported) since the last update. As of 4 Sep 2008, a total of 178 cases have been notified this year. Of these, 86 were imported cases with history of travel to Johor (69 cases) and other states of Malaysia (8 cases), Indonesia (4 cases), Sri Lanka (2 cases), India (2 cases) and the Maldives (one case). The rest were locally acquired infections

31. 82 คน,, Median age = 54 ปี (range=8-81), < 15 yr old= 2

33. 2008-2009 Chikungunya Outbreak, Southern Thailand

34. สงขลา 7921 ราย นราธิวาส 7837 ราย ปัตตานี 3350 ราย ยะลา 1684 ราย ตรัง 96 ราย พัทลุง 12 ราย สตูล 0 ราย รวมทั้งหมด20900 ราย

36. 189 6 216 21 55 30 44 207 18 52 2 10 15

37. 216 18

38. Why?

39. 230 0 3610 536 1373 1649 0 1 325 90 0 0 30 24 30

40. Why ???

41. Emerging Diseases: Factors Man Microbes Environment

42. Transmission: How ???

43. Transmission African Chikungunya = rural, sylvatic cycle Wild primates Forest mosquitoes Man ( Ae. africanus Ae. fureifer ) Asian Chikungunya = urban, domestic cycle Man Mosquitoes Man ( Ae. aegypti Ae. albopictus )

44. การสอบสวนโรคไข้ออกผื่นปวดข้อ อำเภอเซกา จังหวัดหนองคาย พ.ศ. 2538 สุนทร เหรียญภูมิการกิจ และคณะ

45. ตารางที่ 1 ผลการศึกษาลูกน้ำยุงลายแยกตามพื้นที่ในเขตสุขาภิบาล (หมู่ที่ 7, 16) และนอกเขตสุขาภิบาล (หมู่ที่ 2) ตำบลเซกา อำเภอเซกา จังหวัดหนองคาย ผลการศึกษาลูกน้ำ ยุงลาย นอกเขตสุขาภิบาล (หมู่ ที่ 2) เขตสุขาภิบาล (หมู่ที่ 7, 16) Breteau Index240.00320.00 Containner Index29.6343.05 House Index86.6093.30 หมายเหตุ 1.Breteau Index คือ จำนวนภาชนะที่พบลูกน้ำยุงลายใน 100 บ้านที่ สำรวจ 2.Containner Indexคือ ร้อยละของภาชนะที่พบลูกน้ำยุงลายในภาชนะที่ สำรวจ 3.House Index คือร้อยละของบ้านที่พบลูกน้ำยุงลายจากบ้านที่สำรวจ

46. July 1991 KhonKaen (96 cases) July1995 NakomSiThammaraj(576 cases) August 1995 Nong Khai (331 cases) Southeast Asian J Trop Med Publ Health 1997;28:359-364

47. Thailand had 3 chikungunya outbreaks during the 1990s: Why not so widespread like the present outbreak ?

48. Chikungunya, India Since May 2007, a renewed outbreak of fever has occurred in Kerala. About 3.6 million fever cases were recorded during 2007 (11.3% of the total population of the state), compared with about 1.8 million in 2006 and 1.2 million in 2005. The hilly and forested districts Kottayam and Pathanamthitta were the worst affected.They have abundant rubber plantations, which supported prolific breeding of Ae. albopictus mosquitoes. Kumar NP et al. A226V mutation in virus during the 2007 chikungunya outbreak in Kerala, India. J Gen Virol. 2008 ;89:1945-8

51. Dengue Bulletin 2003;27:197-198

53. “In both districts the plantations with active rubber tapping, no sap-collecting containers using rain guards were found to be having rainwater.”

55. “NEW DELHI (Reuters) - Rubber prices in India, the world's fourth-biggest producer, could flare and its limited exports grind to a halt as a disease outbreak among tappers threatens to slash annual output. Collecting rubber from trees is still done manually and has been severely hit in the key state of Kerala by the highly contagious Chikungunya disease, said K.T. Thomas, president of the All India Rubber Industries Association.”

56. Emerging Diseases: Factors Man Microbes Environment

57. ??? Pandemics & Why??? Pandemics are severe outbreaks that rapidly progress to involve all parts of the world. They are usually associated with the emergence of a virus to which the overall population possess no immunity.

58. Other factors??? Parola et al. detected a viral load of 10 ⁹ copies per mL in one case.Such high levels of viraemia are uncommon in arthropod borne diseases such as dengue fever and West Nile disease. Parola P et al. Novel chikungunya virus variant in travelers returning from Indian Ocean Islands. Emerg Infect Dis 2006; 12: 1493–98.

59. Other factors??? Mutation (A226V) of the virus coat protein (E1), which potentially allows it to more- easily infected the mosquitoes. (reduced gut- barrier effect) Schuffenecker I et al. Genome microevolution of Chikungunyaviruses causing the Indian Ocean outbreak. PLoS Med. 2006 Jul;3(7):e263

60. The most important disease vector

61. Other factors that might have contributed to epidemics of chikungunya fever (2004–07) 1.East Africa drought. Household water-stores. 2. International and domestic travel. 3. Previous introduction of exotic A albopictus to Indian Ocean islands and Italy (used tyres). 4. Genetic adaptation in virus to A albopictus during epidemic. 5. Warm European summer with high abundance of vector. Chretien JP, Linthicum KJ. Lancet 2007; 307:1805-6

62. In Kenya,the Comoros and India, the vector of the chikungunya virus was Aedes aegypti, In contrast, in Reunion Mauritius and Italy, A. albopictus, the Asian tiger mosquito, was the primary vector. N Engl J Med 2007;356;769

63. Aedes albopictus (Asian tiger mosquito)

64. A albopictus Aggressive (35-48 bites/hr.) Diurnal ( bednets are ineffective ) Flight radius = 400–600 m.. Lancet Infect Dis 2007;7:319–27

65. A albopictus Relatively long-lived (4–8 weeks) Eggs can survive through the dry season, giving rise to larvae the following rainy season. ? Trans- ovarial infection ?.

66. A. albopictus Originating from Asia. Initially sylvatic, but well-adapted to urbanization. Spread by vegetative eggs contained in timber and used tyres exported from Asia. Superseded A aegypti in China, the Seychelles, and Hawaii..

67. World Distribution of the Aedes albopictus Mosquito. N Engl J Med 2007;356;769

68. Aedes albopictus this native Asian mosquito now inhabits Pacific islands, parts of Africa and Latin America, 14 European countries, and 28 US States. www.thelancet.com Vol 370 December 1, 2007

69. Chikungunya: When?? Incubation period = 2-3 d(range = 1-12 d)

70. Chikungunya – duration of fever 6.3% > 7 days Nimmannittaya S et al.

71. Duration of Arthralgia/arthritis 4 months: ~33% 20 months,15% 3–5 years, 10% Brighton SW,et al. S Afr Med J 1983; 63:313–15. Fourie ED, Morrison JG. S Afr Med J 1979; 56: 130–02. Kennedy AC, et al.. J Rheumatol 1980; 7: 231–36.

72. Clinical presentations: How ??

73. 82 คน,, Median age = 54 ปี (range=8-81), < 15 yr old= 2

75. Lancet Infect Dis 2007;7:319–27

76. Bone scan of the wrists and hands showing an intense focus of technetium- 99m–labeled methylene diphosphonate tracer uptake. Parola P et al. Novel Chikungunya virus variant in travelers returning from Indian Ocean islands. Emerg Infect Dis 2006;12:1493-9.

78. Chikungunya Epidemics in History Carey DE ; Chikungunya and Dengue: A Case of Mistaken Identity? J His Med Allied Sci 1971;26: 243-262

85. Lancet Infect Dis 2007; 7:319–27

87. ACUTE PUO : Skin rash Dengue fever - 10% had rash (Krisanapan S ) - 2 types of rashes - early (24-48 hr): transient generalized erythema - Second rash : coincides with or 1-2 days after defervescence, may be petechial on legs (day 4-9); may desquamated (convalescent rash)

88. ACUTE PUO : Skin rash - Chikungunya disease - 60% occurrence - may consisted of petechial spots but not confluenced petechial rash or ecchymosis (Nimmannitaya S et al : Am J Trop Med Hyg 1969;18:954 ) (Sarey DE et al : Trans R Soc Trop Med Hyg 1969;63:434)

90. Chikungunya in India: Skin rash “Lymphadenopathy and rash was not a significant presentation.” M Chhabra et al. Chikungunya Fever: A Re-emerging Viral Infection. Indian Journal of Medical Microbiology, (2008) 26(1): 5-12

91. KhonKaen: 50% Nong Khai: 72% NakomSiThammaraj: 21% Prevalece of Rash in Thai Chikungunya Southeast Asian J Trop Med Publ Health 1997;28:359-364

93. Conjunctivitis in a 31-year-old woman with a severe viremic chikungunya infection. Parola P et al. Novel Chikungunya virus variant in travelers returning from Indian Ocean islands. Emerg Infect Dis 2006;12:1493-9.

94. Chikungunya vs Dengue in History Carey DE ; Chikungunya and Dengue: A Case of Mistaken Identity? J His Med Allied Sci 1971;26: 243-262

95. Chikungunya vs Dengue

98. Bull WHO 1966; 35:42-43 98 of dengue vs. 29 of chikungunya

99. 1.In chikungunya, no shock or severe haemorrhage manifested as melaena or haematemesis occurred. 2.70% of chikungunya patients came to hospital as early as the first day of illness because of high fever. 3.Convulsion associated with high fever was observed three times as frequently in chikungunya as in dengue.

100. 4. The duration of fever in chikungunya was much shorter than in dengue; 50% of chikungunya patients had fever for only two days. 5. In chikungunya, the petechiae were usually tiny and scanty. Complete subcutaneous or intracutaneous haemorrhage (purpuric spots) was not observed in chikungunya.

101. Chikungunya – ??? No Shock

102. Eight (24%) of 33 patients who were admitted into ICU, had an associated acute infectious disease, all with severe sepsis or septic shock

103. Chikungunya infection is not always a benign disease.

104. Who are going to die???

106. A study of 33 ICU cases. Median age = 62 yr.(range:23–86) DM =12/33, Alcoholism= 3/33, COPD =6/33 IHD =8/33 14 had encephalopathy. one case each of myocarditis, hepatitis and Guillain Barre´ syndrome.

107. Chikungunya and Pregnancy Among the 35 women who were ill at delivery,30 delivered an infected newborn baby.Most these neonatal infections were severe. Cordel H. Euro Surveill2006; 11: E060302.3.

108. PLoS Med 5(3): e60. doi:10.1371/journal.pmed.0050060

109. Year 2005-2006 7504 pregnant women 739 (9.8%) had symptomatic chikungunya 678 (9%)= antepartum ( >7 days before labor) 61 (0.8%)= between Day -7 and Day 2 post partum

110. 678 women had Chikungunya antepartum (onset >7 days before labor) 16 fetal deaths and 687 viable neonates 3 of 7 fetal deaths before Week 22 were due to chikungunya None of 9 fetal deaths after Week 22 were due to chikungunya None of 687 viable neonates were infected

111. 22 women had symptomatic chikungunya between Day -7 and Day -3 pre labor None transmitted chikungunya to offsprings

112. 39 women had symptomatic chikungunya intrapartum (onset between Day -2 and Day 2 post partum) 19(48.7%) transmitted the chikungunya to their offspring. Therefore, overall, only 2.5% (19/749) of viable neonates became infected. Cesarean section had no protective effect on transmission

113. 19 infected neonates were asymptomatic at birth. 4 d later (range 3–7 d). Developed symptoms (fever, poor feeding, and pain) distal joint edema (78.9%), petechiae (47.3%), or skin rash (89.4%) and thrombocytopenia (89.4%) 10 (52.6%) = severe (9=encephalopathy,6=shock)

115. Lancet Infect Dis 2007; 7:319–27

116. 4 neonates with encephalopathy had permanent disabilities ( cerebral palsy, blind, or seizure) 15 others were normal upon 16-24 month follow up.

117. Dx: How ???

118. Chikungunya blood culture yield Do D1 D2 D3 D4 D7 7/8 14/15 3/3 2/2 0/1 0/1 Nimmannittaya S et al.

119. ผลการตรวจ ผู้ป่วยเก่า 1 (ร้อยละ) ผู้ป่วย ใหม่ (ร้อยละ) ผู้ที่ไม่มี อาการ 2 (ร้อยละ) ผลบวกเฉพาะ HI2 (4.9%)0 (0.0%)5 (29.4%) ผลบวก IgM (ELISA) 3 36 (87.8%) 5 (45.5%) 3 (17.7%) ให้ผลลบต่อการ ตรวจ 3 (7.3%)6 (54.5%) 9 (52.9%) จำนวนตัวอย่าง41 (100%) 11 (100%) 17 (100%) สุนทร เหรียญภูมิการกิจ และคณะ

120. Am J Trop Med Hyg 1969; 18:954-971

121. “Recent group A virus infection was assumed only when a fourfold or greater HI antihody response to chikungunya antigen was observed in paired specimens.”

123. Chikungunya HI Haemagglutination inhibition (HI) and neutralizing antibodies can usually be detected after day 5 with fading viraemia. Carey DE, et al. The 1964. Chikungunya epidemic at Vellore, South India, including observations on concurrent dengue. Trans R Soc Trop Med Hyg 1969;63:434-45.

124. Lancet Infect Dis 2007; 7:319–27

125. Prevention??? ??? Blood transfusion transmission potential. One case report of direct human-to-human transmission in France. Parola P et al. Novel Chikungunya virus variant in travelers returning from Indian Ocean islands. Emerg Infect Dis 2006;12:1493-9. Bednets should be used in hospitals and day- care facilities. - Reiter P, Sprenger D.J Am Mosq Control Assoc 1987; 3: 494–501.

126. Vaccine trial Edelman R et al. Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218. Am J Trop Med Hyg 2000;62: 681–85.

127. To kill the mosquitoes ??? Large-scale prevention campaigns using DDT have been eff ective against A aegypti but not A albopictus. Control of A aegypti has rarely been achieved and never sustained. Reiter P, et al. Aedes albopictus as an epidemic vector of chikungunya virus: another emerging problem? Lancet Infect Dis2006; 6: 463–64.

128. “For knockdown, well-planned fogging operations are strongly recommended with 2% pyrethrum space sprayin high- risk villages/wards where clustering of cases has been reported.” M Chhabra et al. Chikungunya Fever: A Re-emerging Viral Infection. Indian Journal of Medical Microbiology, (2008) 26(1): 5-12