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CONTINUING MEDICAL EDUCATION
Chikungunya Virus Infection
I-C Sam, MRCPath, S AbuBakar, PhD
Department of Medical Microbiology, Faculty of Medicine,
University of Malaya, 50603 Kuala Lumpur
Introduction
Between March and April 2006, a Chikungunya(CHIKV) outbreak
affected over 200 people in BaganPanchor, Perak l , This is the
second outbreak reportedin Malaysia, after 51 infections were
reported in Klangbetween December 1998 and February 19992, TheBagan
Panchor outbreak coincides with ongoingCHIKV outbreaks in the
Indian Ocean (includingMauritius, La Reunion, and Seychelles) and
India,which have reportedly affected several hundredthousand
people, including imported cases intoEurope3,
VirologyCHIKV is a re-emerging, mosquito-borne viral
infectioncausing epidemic fever, rash and arthralgia.
Historicaldescriptions of outbreaks characteristic of CHIKV
datefrom the 18th Century', but the virus was only firstisolated in
Tanzania in 19525 CHIKV is a single-stranded RNA alphavirus, from
the family Togaviridae.
Other alphaviruses also cause fever, rash and
arthralgia,including O'nyong-nyong, Mayaro, Barmah Forest,Ross
River and Sindbis virusesG CHIKV is most closelyrelated to
O'nyong-nyong, but remains geneticallydistinct".
Transmission and EpidemiologyCHIKV disease occurs in Africa and
Asia, includingIndia38, Sri Lanka9, Myanmar!O, Thailand4,l\
Indonesial2,13,the Philippinesl " and Malaysial ,2. There is
historicalevidence that CHIKV originated in Africa, andsubsequently
spread to Asia'. Phylogenetic studiessupport this theory, with
CHIKV strains falling intothree distinct genotypes based on origin
from WestAfrica, Central/East Africa or Asia, the latter
groupincluding Malaysian isolates from the Klang outbreak7,15.
A distinctive feature of CHIKV is that it causesexplosive
outbreaks, before apparently disappearingfor a period of several
years to decades!3,!6, This is in
This article was accepted: 8 May 2006Corresponding Author: Jamal
I-Ching Sam, Department of Medical Microbiology, Faculty of
Medicine, University of Malaya,50603 Kuala Lumpur
264 Med J Malaysia Vol 61 No 2 June 2006
-
contrast to the endemic nature of dengue, which shareswith CHIKV
the same mosquito vectors of Aedesaegypti and Ae. albopictus. CHIKV
is also known to betransmitted by several other mosquito species.
InAfrica, it is transmitted mainly by the Ae.furcifer-taylorigroup,
which feed on humans and other primates17The isolation of virus
from non-human primates, othervertebrates such as squirrels and
bats, and zoophilicmosquito species (that feed on animals) supports
theexistence of sylvatic transmission cycles in Africa,which may
maintain the virus in the wild during inter-epidemic years17 .
In Asia, transmission appears to be mainly from Ae.aegypti and
Ae. albopictus to man in urban settings. Itis not known if and how
virus is maintained in the wildin Asia. No animal reservoirs have
been definitivelyidentified yet, although the presence of
neutralisingantibodies to CHIKV in Malaysian monkeys suggeststhat
these primates may be hosts18. Unlike dengue,transovarial
transmission of CHIKV in mosquitoes hasnot been demonstrated19.
Different geographical strainsof Aedes mosquitoes vary in their
susceptibility toinfection and ability to transmit the virus, which
may becritical in determining CHIKV endemicity in a givenarea'o.
The episodic nature of CHIKV outbreaks stillcannot be explained,
but likely depends on aninterplay of factors, including human21 and
vectorsusceptibility to infection, high density of
mosquitovectors,,8,!1 and the introduction of virus from
otherendemic areas. The latter has become increasinglylikely in
this age of increased travel by, for example,immigrants and
tourists.
As with other arboviruses, factors such as urbanisation,global
warming, travel and transportation may lead toincreasing numbers of
mosquito vectors, or theintroduction of vectors into new
geographical areas".In the future, therefore, the epidemiology of
CHIKVmay change, just as it apparently spread from Africainto
Asia.
Chikungunya in MalaysiaThe Klang outbreak was the first time
that CHIKV wasisolated and reported to cause clinical disease
inMalaysia. Earlier studies in Malaysia showed only thepresence of
CHIKV antibodies in the human populationin northern and eastern
states bordering Thailand,where CHIKV is known to be present21
Seropositivityhas also been found in people in East
Malaysia",especially among immigrants from neighbouringcountries".
This suggests that CHIKV has been inexistence in certain parts of
Malaysia, and that
Med J Malaysia Vol 61 No 2 June 2006
Chikungunya Virus Infedion
transmission was probably low-level, sporadic, andundiagnosed.
Interestingly, Marchette et al. predictedin 1980 that if an
outbreak were to happen in Malaysia,it would most likely occur in
urban centers of west-central states (including Selangor and
Perak), whichhave almost no population immunity and widespreadAe.
aegyptPl. In both recent CHIKV outbreaks, it isspeculated that a
viraemic migrant worker introducedthe virus into the antibody-naive
populationl.2.
Clinical FindingsIt has been reported that attack rates in
susceptiblepopulations maybe as high as 40-85%, and the ratio
ofsymptomatic to asymptomatic patients is about 1.2:p2.The
incubation period may be up to ten days, but isusually between two
to four days. The classicalsymptoms are fever, myalgia, arthralgia
and rash (Table0. Onset of fever and arthralgia is usually abrupt.
Thesmall joints of the hands and feet, wrists and ankles are
m~st commonly involved, but larger joints such asknees and
shoulders may be affected. Arthralgia ismore common than overt
'!rthritis. In the first few daysthere may be accompanying
headache, pharyngitis andconjunctivitis. After 3-5 days, a
maculopapular rash(which may be itchy) appears on the trunk and
limbs,along with cervical or generalised lymphadenopathy.Fever may
show a biphasic pattern, with a febrileperiod of 1 to 6 days
followed by an apyrexial interval,and then a shorter second bout of
fever. Children areless likely to experience joint pain, but may
have otherfeatures such as febrile fits, vomiting, abdominal
painand constipation4 Mild haemorrhagic symptoms suchas a positive
tourniquet test, epistaxis and a petechialrash, are sometimes seen
in Asia4,8-lo,12.13. Very rarely,severe haemorrhage and deaths have
occurred inCHIKV-infected patients during outbreaks in India andSri
Lanka, but it is unclear if CHIKV was directlyresponsible or
coincidentally presentB,9. In the ongoingIndian Ocean outbreaks,
some CKIKV-infected patientshave reportedly developed severe
neurological diseaseor fulminant hepatitis3. In uncomplicated
infections,acute symptoms generally last no more than ten days,but
arthralgia may persist for weeks to months. Themajority of patients
recover completely. However, oneretrospective study from South
Africa found that somepatients had continued joint pain, stiffness
andeffusions 3-5 years after infection25
Differential DiagnosisAs they share the same vectors, CHIKV and
dengue areoften found in the same areas, and dual infections in
asingle patient have been reported lO It is likely,however, that
CHIKV is undiagnosed or mistaken for
265
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CONTINUING MEDICAL EDUCATION
dengue as the clinical presentations overlap, especiallyin
children, who more frequently have haemorrhagicsymptoms with
CHIKV4,1O. Furthermore, awareness ofCHIKV and laboratory diagnostic
capabilities aregenerally lacking due to the relative rarity of
thedisease. The presence of a rash, conjunctivitis,arthralgia and
myalgia are more common in CHIKV,and should aid in differentiation
from dengue4
There are many other viruses that cause polyarthritis.The most
well-known are rubella (also a togavirus) andparvovirus B19, which
cause joint symptomsparticularly in women. Rarer causes include
hepatitisB, mumps, herpesviruses (VZV, EBV, CMV) andretroviruses
(HTLV-l, HIV). As outbreaks of febrilepolyarthralgia are
characteristic of alphaviruses (TableII)6 with similar clinical
features, diagnosis of thecausative agent depends on knowledge of
thegeographical distribution of each virus, and thepatient's
history of contact with the affected areas. Up-to-date outbreak
reports may be obtained fromwebsites run by the World Health
Organisation(http://www.who.int/csr/en/) or the
InternationalSociety for Infectious
Diseases(http://www.promedmail.org).
Laboratory DiagnosisCHIKV can be diagnosed by serology, virus
isolation ornucleic acid amplification, depending on the timing
ofthe patient's blood specimen in relation to onset ofsymptoms. The
gold standard and most specific test isviral culture in Vero
(monkey kidney) or C6/36 (Ae.albopictus) cells, or newborn mice.
Isolation is mostlikely to be successful if the sample is collected
in thefirst three days of illness. Cell culture also
allowspotential isolation of a wide range of viruses, and
istherefore useful for isolation of novel or unexpectedagents.
Reverse transcription-PCRl 5 is a powerful toolthat can detect
nucleic acid from non-viable viruses,and thus may be used for blood
samples obtainedbeyond three days. However, once the patient
startsproducing antibodies, the probability of a positive
266
culture or PCR decrease. IgM is detectable from 3-5days by
ELISNO,I' or indirect immunofluorescent assay',and declines within
three months l1 . Convalescent seramay be tested for IgG by ELISN',
haemagglutinationinhibition or neutralisation testIS. Serological
detectionof IgM and IgG is most useful in retrospectivediagnosis,
particularly if a significant rise in antibodytitre can be
demonstrated.
Treatnlent and PreventionTreatment for CHIKV is mainly
supportive, withanalgesics and rehydration as necessary. No
antiviralshave been used clinically. In an open trial,
chloroquinewas found to improve symptoms of patients withchronic
arthritis following CHIKV infection, butcontrolled studies are
needed26 A live CHIKV vaccine,developed by the United States Army,
was found to besafe and immunogenic in Phase II studies, but has
notbeen tested further'7. Like dengue, prevention andcontrol of
outbreaks has been focused on communityeducation and vector control
methods, such as sprayingof insecticides and elimination of
breeding sites'.Surveillance is also important for early
identification ofoutbreaks.
ConclusionGlobal changes in human activities and
ecologicalfactors have led to many emerging ~nd
re-emerginginfectious diseases in recent years22 CHIKV, a
relativelyrare disease in Malaysia, has now caused a secondoutbreak
seven years after it was described here for thefirst time'. The
re-emergence of CHIKV in Malaysiaraises many questions. It is not
known why theoutbreaks occurred; whether the virus is endemic
here(as it is in neighbouring countries), and if so, how it
ismaintained; and what the true burden of CHIKVdisease is. A
clearer understanding of the disease mayhelp with prevention of the
disease becoming endemic,and better preparation towards early
detection andlimitation of future outbreaks.
Med J Malaysia Vol 61 No 2 June 2006
-
s: CD 0.. s: c Q-;;; o' ~ 0- z o N ~ c :::> CD N o o 0- N 0-
'-J
Table
I:Sig
nsan
dsy
mpt
oms
ofCh
ikung
unya
infe
ctio
ndu
ring
outb
reak
sin
diffe
rent
coun
tries
Loca
tion
and
Mal
aysia
Thail
and
Indo
nesia
SriL
anka
Indi
aye
arof
outb
reak
Klan
g(19
98-9)
Khon
Kaen
(1991
),Ba
ngko
kYo
gyak
arta
Wes
tJav
aCo
lombo
Mah
aras
htra
Nakh
onSi
Tham
mar
at(19
62-4)
1998
-9)
(2001
-2)(19
65)
(1973
)(19
95),
NonQ
Khai
(1995
)Re
feren
ce5
111
1213
98
No.o
fpati
ents
with
clinic
alda
ta22
1001
4916
117
910
614
24(ch
ildren
)Fe
ver
100%
92-1
00%
100%
60%
76-7
8%10
0%99
%Ar
thra
lgia
82%
80-9
8%}
40%
76%
81-8
9%88
%99
%(ar
thritis
)(29
%)(20
-25%)
Mya
lgia
50%
-52
%69
-72%
15%
-
Rash
50%
21-7
2%59
%30
%38
-49%
28%
"up
to70
%"
Head
ache
50%
56%
42%
71%
70-7
1%}8
3%"ch
arac
teris
tic"
Back
ache
50%
--
--
-
Lym
phad
enop
athy
-15
-30%
31%
--
54%
"m
ost"
Coug
h-
-16
%34
%-
--
Sore
thro
at9%
-83
%-
--
-
Haem
orrh
agic
man
ifesta
tions
0%Po
sitive
tour
nique
tBl
eedin
gEp
istax
is,Pe
techia
eEp
istax
is,tes
t(56%
),pete
chiae
gums
(5%)
bleed
ing(3%
)gin
givitis
(31%)
,epis
taxis
(13%)
gums
(8%)
("occa
siona
lly")
Othe
rRe
tro-o
rbita
lVo
mitin
g(28
%),
Conju
nctivi
tis(56
%),
Chills
Prur
itus
Vom
iting,
pain
(14%)
abdo
mina
lpain
(13%)
vom
iting
(59%)
,(34
%),
(48%)
diarrh
oea
abdo
mina
lpain
(32%)
(0.4%
)-=No
tstat
ed
() :::r~ c: :::l to c: ~ ~ 2 V> S- [ o :::l
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CONTINUING MEDICAL EDUCATION
VirusTable II: Geographic distribution of alphaviruses causing
fever, rash and arthralgia
DistributionChikungunya0'nyong-nyongMayaroBarmah ForestRoss
RiverSindbis
1. Shahrul H. 'Infected foreigner' blamed for fever. NewStraits
Times 2006; Apr 4.
2. Lam SK, Chua KB, Hooi PS et al. Chikungunya infection- an
emerging disease in Malaysia. Southeast Asian] TropMed Pub Health
2001; 32: 447-51.
3. Schuffenecker I, !ternan I, Michault A et at.
Genomemicroevolution of Chikungunya viruses causing theIndian Ocean
Outbreak. PLOS Med 2006; 3: e263.
4. Halstead SB. Arboviruses of the Pacific and SoutheastAsia.
In: Feigin RD, Cherry ]D Ceds). Textbook ofPediatric Infectious
Diseases C3rd ed). Philadelphia: WESaunders, 1992; 1468-89.
5. Ross RW. The Newala epidemic. III. The virus:
isolation,pathogenic properties and relationship to the epidemic.
]Hyg 1956; 54: 177-91.
6. Laine M, Luukkainen R, Toivanen A. Sindbis viruses andother
alphaviruses as cause of human arthritic disease. ]Intern Med 2004;
256: 457-71.
7. Powers AM, Brault AC, Tesh RB, Weaver Sc. Re-emergence of
chikungunya and o'nyong-nyong viruses:evidence for distinct
geographical lineages and distantevolutionary relationships. ] Gen
Virol 2000; 81: 471-9.
8. Padbidri VS, Gnaneswar TT. Epidemiologicalinvestigations of
chikungunya epidemic at Barsi,Maharashtra State, India. ] Hyg
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Africa, India, Southeast Asia, PhilippinesAfricaSouth America,
TrinidadAustraliaAustralia, Melanesia, South PacificEurope, Africa,
Asia, Australia
9. Hermon YEo Virological investigations of arbovirusinfections
in Ceylon, with special reference to the recentChikungunya fever
epidemic. Ceylon Med] 1967; 12: 81-92.
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indirect enzyme-linked immunosorbent assay forthe detection of
immunoglobulin M antibody in serumfrom patients following an
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11. Thaikruea L, Charearnsook 0, Reanphumkarnkit S et
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ofChikungunya virus transmission in Yogyakarta,Indonesia: evidence
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Health 2004; 35: 408-15.
13. Laras K, Sukri NC, Larasati RP et at. Tracking the
re-emergence of epidemic chikungunya virus in Indonesia.Trans R Soc
Trop Med Hyg 2005; 99: 128-41.
14. Centers for Disease Control. Chikungunya fever amongU.S.
Peace Corps volunteers - Republic of the Philippines.MMWR Morb
Mortal Wkly Rep 1986; 35: 573-4.
15. Hasebe F, Parquet MC, Pandey BD et at. Combineddetection and
genotyping of Chikungunya virus by aspecific reverse
transcription-polymerase chain reaction.] Med Virol 2002; 67:
370-4.
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16. Pavri K. Disappearance of Chikungunya virus from Indiaand
South East Asia. Trans R Soc Trop Med Hyg 1986;80: 491.
17. Diallo M, Thonnon], Traore-Lamizana M, Fontenille D.Vectors
of Chikungunya virus in Senegal: current dataand transmission
cycles. Am] Trop Med Hyg 1999; 60:281-6.
18. Marchette N], Rudnick A, Garcia R, MacVean DW.Alphaviruses
in Peninsular Malaysia: I. Virus isolationsand animal serology.
Southeast Asian] Trop Med PubHealth 1978; 9: 317-29.
19. Mourya DT. Absence of transovarial transmission
ofChikungunya virus in Aedes aegypti & Ae.
albopictusmosquitoes. Indian] Med Res 1987; 85: 593-5.
20. Banerjee K, Mourya DT, Malunjkar AS. Susceptibility
andtransmissibility of different geographical strains of
Aedesaegypti mosquitoes to Chikungunya virus. Indian] MedRes 1988;
87: 134-38.
21. Marchette N], Rudnick A, Garcia R. Alphaviruses inPeninsular
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22. Hui EKW. Reasons for the increase in emerging and
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23. Bowen ET, Simpson DI, Platt GS et at. Arbovirusinfections in
Sarawak, October 1968-February 1970:human serological studies in a
land Dyak village. TransR Soc Trop Med Hyg 1975; 69: 182-6.
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310-6.
25. Brighton SW, Prozesky OW, De la Harpe AL.Chikungunya virus
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313-5.
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217-8.
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681-5.
269
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CONTINUING MEDICAL EDUCATION
Chikungunya Virus InfectionMultiple Choice Questions
(MCQs)T=True F=False
1. The following are common features of Chikungunya infection:A.
Arthralgia.B. Purpuric rash.e. Headache.D. Lymphadenopathy.E.
Melaena.
2. Which of the following are important in the management of a
patient with acute Chikungunya infection?A. Aciclovir.B.
Chloroquine.C. Notification to Public Health.D. Mosquito vector
control.E. Vaccination of household contacts.
3. Which of the following are true concerning Chikungunya:A. It
is a DNA virus.B. In Asia, the main vectors are Aedes albopictus
and Aedes aegypti.e. There is a well recognised sylvatic cycle in
Malaysia.D. Chikungunya is in the same virus family as rubella.E.
Non-human primates are thought to be important reservoirs in
Africa.
4. The following tests are appropriate for a patient suspected
of acute Chikungunya infection:A. Chikungunya PCR (serum sample).B.
Dengue IgM (serum sample).e. Viral culture (serum sample).D. Viral
culture (throat swab).E. Haemagglutination-inhibition assay (acute
and convalescent sera).
5. Which of the following is true about Chikungunya in Asia?A.
Haemorrhagic symptoms occur more frequently in children.B.
Chikungunya probably originated in Asia.e. Some patients suspected
of dengue infection may in fact have Chikungunya.D. Prior to 1998,
Chikungunya seropositivity was most frequently found in populations
on the Malaysian-Thai
border.E. Deaths have been directly attributable to
Chikungunya.
270 Med J Malaysia Vol 61 No 2 June 2006
