Chikungunya infection in Malaysia: Comparison with dengue infection in adults and predictors of persistent arthralgia

Journal of Clinical Virology 56 (2013) 141–145
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Journal of Clinical Virology
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Chikungunya infection in Malaysia: Comparison with dengue infection in adults
and predictors of persistent arthralgia
M.A. Mohd Zim a , I.-C. Sam b,∗, S.F. Syed Omar c , Y.F. Chan b , S. AbuBakar b , A. Kamarulzaman c
a Department of Medicine, Faculty of Medicine, Universiti Teknologi MARA, Shah Alam, Malaysia
b Tropical Infectious Diseases Research and Education Centre, Department of Medical Microbiology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
c Infectious Diseases Unit, Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
a r t i c l e i n f o
Article history:
Received 10 April 2012
Received in revised form 2 October 2012
Accepted 30 October 2012
Keywords:
Chikungunya virus
Dengue virus
Malaysia
Arthralgia
Rash
Differential diagnosis
a b s t r a c t
Background: Chikungunya virus (CHIKV) and dengue virus (DENV) co-circulate in areas endemic with
the Aedes mosquito vectors. Both viruses cause similar illnesses which may be difficult to distinguish
clinically. CHIKV is also associated with persistent arthralgia.
Objectives: To compare and describe factors which differentiate between DENV and CHIKV infections on
presentation; and to describe predictors of persistent arthralgia in CHIKV patients.
Study design: Patients aged >14 years diagnosed with acute CHIKV and DENV infections in Kuala Lumpur,
Malaysia were retrospectively identified. Clinical and laboratory data were obtained from medical
records, and compared. CHIKV patients were telephoned 15–24 months later and interviewed about
persistent symptoms. Logistic regression analysis was performed.
Results: A total of 53 CHIKV and 113 DENV patients were included. CHIKV patients were older and more
likely to be female. CHIKV was independently associated with arthralgia and rash, while DENV was asso-
ciated with myalgia, raised aspartate transaminase, and leucopaenia. Forty CHIKV patients were followed
up, with a median duration of self-reported arthralgia of 3 months (range, 0–24 months). Eighteen (45%)
had persistent arthralgia beyond 4 months, for which age >40 years was an independent predictor. At 1
year, 9 (22.5%) patients had arthralgia.
Conclusion: In Kuala Lumpur, selected clinical and laboratory predictors help to distinguish between
DENV and CHIKV infections. Persistent arthralgia was a frequent sequel of CHIKV infection in this cohort.
© 2012 Elsevier B.V. All rights reserved.
1. Background
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that
has caused large outbreaks affecting millions around the world in
recent years, particularly in the Indian Ocean,1 Asia,2 and Africa.3 In
Malaysia, there have been sporadic limited outbreaks in the past,4,5
prior to the largest reported outbreak affecting the whole country
in 2008–2010.6 Dengue virus (DENV) is endemic in Malaysia.
Both CHIKV and DENV are transmitted by the mosquito vec-
tors Aedes aegypti and Ae. albopictus. Both diseases cause similar
presentations, with fever, myalgia, headache, arthralgia, and rash.
Both viruses potentially co-circulate in the same Aedes-endemic
areas.7 As these are mainly developing countries where facilities
for virological diagnosis are often limited, the ability to clinically
Abbreviations: AST, aspartate transaminase; CHIKV, Chikungunya virus; CI, con-
fidence intervals; DENV, dengue virus; OR, odds ratio.
∗ Corresponding author. Tel.: [phone]; fax: [phone].
E-mail address: [e-mail] (I.-C. Sam).
differentiate between the two diseases assumes greater impor-
tance, in view of their different clinical courses and outcomes.
Comparative clinical studies between the two diseases in adults are
scarce, often limited by small numbers, and differences in clinical
presentations in one country may not be applicable to another.
Although the acute symptoms of CHIKV generally last about a
week and are self-limiting, an earlier study from South Africa sug-
gested that some patients do experience chronic arthralgia lasting
for months to years.8 The recent global outbreaks have brought this
potential burden of long-term morbidity into focus.9.10 As there are
conflicting reports on how common persistent arthralgia is, further
follow-up data from different cohorts would be useful.
2. Objectives
This study aimed to compare and describe factors which would
help differentiate between DENV and CHIKV infections on presen-
tation. A secondary objective was to ascertain the rate and describe
predictors of persistent arthralgia in CHIKV patients.
1386-6532/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jcv.2012.10.019

142 M.A. Mohd Zim et al. / Journal of Clinical Virology 56 (2013) 141–145
3. Study design
This study was conducted at the University Malaya Medical Cen-
tre, in Kuala Lumpur, Malaysia. Patients aged >14 years with acute
CHIKV and DENV infections confirmed by the diagnostic virology
laboratory from April 2008 to July 2009 were retrospectively iden-
tified. Two DENV cases were randomly selected for each CHIKV case
identified. Confirmed CHIKV infections had a positive culture, pos-
itive PCR detection of the E1 gene,11 or positive IgM by indirect
immunofluorescence.4 As serum samples were taken at different
time-points after onset of symptoms for each patient, not all CHIKV
patients were tested by all three methods. We used a positive viral
culture as specific confirmation of acute DENV infection, as a sin-
gle positive dengue IgM may also indicate infection up to several
months ago. Cultures were performed using Vero (African green
monkey kidney) and C6/36 (Ae. albopictus) cells, and identified
with polyclonal anti-CHIKV or monoclonal anti-DENV antibodies.
The medical records of the identified patients were reviewed for
demographic, clinical and laboratory data on initial presentation at
the hospital. Ethical approval for the study was obtained from the
hospital’s Medical Ethics Committee.
For follow-up, CHIKV patients were contacted by telephone in
2011. Informed consent was first obtained. The interview was con-
ducted using a predefined structured questionnaire. Data collected
included duration of symptoms, the intensity of self-reported pain
during the initial attack and chronic phases, and impact of symp-
toms on activities of daily living. Declarative numerical rating scales
(NRS) were used to evaluate the pain intensity during the acute
and chronic phases. The pain score ranges between 0 and 10, and
were categorized into pain-free (0), mild (1–3), moderate (4–6)
and severe (7–10).12 In two previous studies, including one from
Malaysia, >95% of patients were pain-free by 3 months.3,5 For this
study, persistent arthralgia was defined as the presence of self-
reported pain more than 4 months after the acute illness.
Data were analyzed using SPSS 15.0 (SPSS Inc., Chicago, IL). For
univariate analysis, Mann–Whitney U tests were used for contin-
uous variables, and Fisher’s exact or chi-squared tests were used
for categorical variables. Logistic regression analysis was carried
out for two separate outcomes: first, to predict either DENV or
CHIKV infection; and second, to predict CHIKV patients with persis-
tent arthralgia. Univariate logistic regression was initially carried
out for selected variables, based on previous studies and biological
plausibility. Odds ratio (OR) and 95% confidence intervals (CI) were
calculated. Those variables significant at p < 0.2 were entered into
the multivariate regression model, and retained based on the likeli-
hood ratio test. Final values of p < 0.05 were considered significant.
The final model was then tested for collinearity, and assessed with
the Hosmer and Lemeshow goodness-of-fit test and calculation of
the area under the receiver operating characteristic curve.
4. Results
A total of 60 patients with confirmed CHIKV and 120 patients
with confirmed DENV were identified from laboratory records, for
which medical records could not be located for 7 CHIKV and 7
DENV patients. A total of 53 CHIKV patients and 113 DENV patients
were therefore included in the study. For CHIKV, 35 patients were
diagnosed by IgM, 12 by PCR, and 17 by culture, or a combina-
tion of these. The predominant DENV serotypes were DENV1 (46,
40.7%) and DENV2 (46, 40.7%), followed by DENV3 (20, 17.7%) and
DENV4 (1, 0.9%). The patients’ demographic details are shown in
Table 1. Compared to DENV patients, CHIKV patients were signifi-
cantly older and more likely to be female. There was a significant
difference in ethnicity, due to a greater number of non-Malaysian
nationals (n = 28, 24.8%) diagnosed with DENV. These comprised
patients from Bangladesh (n = 12), Nepal (n = 11), Indonesia (n = 4),
and Vietnam (n = 1). There were 82 (72.6%) admissions in the DENV
group, and only 12 (22.6%) in the CHIKV group (2 = 36.6, p < 0.001).
Clinical and biochemical test comparisons between CHIKV and
DENV patients at presentation are shown in Table 2. The 5 most
frequently reported presenting symptoms in CHIKV patients were
fever (96.2%), arthralgia (96.2%), rash (58.5%), myalgia (32.1%), and
headache (22.6%). DENV patients commonly reported fever (96.4%),
myalgia (74.3%), nausea/vomiting (66.4%), headache (57.5%), and
diarrhoea (39.8%). On univariate analysis, DENV patients were more
likely to have headache, nausea/vomiting, diarrhoea, and myalgia;
while CHIKV patients were more likely to report rash and arthral-
gia. CHIKV patients had significantly lower aspartate transaminase
levels (AST; 114.0 vs. 144.9 U/L, p < 0.001), higher white cell counts
(5.9 vs. 2.9 × 109 /L, p < 0.001), and higher platelet counts (200.9 vs.
78.5 × 109 /L, p = 0.001).
On multivariate analysis, CHIKV was associated with arthralgia
(OR 159.0, 95% CI 17.7–1430.1) and rash (OR 4.4, 95% CI 1.1–17.8);
and absence of myalgia (OR 0.04, 95% CI 0.01–0.2), absence of raised
AST (OR 0.09, 95% CI 0.02–0.4), and absence of leucopaenia (OR 0.09,
95% CI 0.02–0.4). This model had satisfactory fit (2 = 5.3, p = 0.72)
and discrimination (area under the curve = 0.97, 95% CI 0.95–0.99,
p < 0.001). At a predicted probability cut-off value of 0.5, this model
had a sensitivity of 88.7%, specificity of 96.3%, positive predictive
value of 92.2%, negative predictive value of 94.5%, positive likeli-
hood ratio of 24.0, and negative likelihood ratio of 0.12.
Patients with CHIKV were then telephoned for follow-up inter-
views, a mean duration of 20 ± 2 months (range, 15–24 months)
after the initial illness. Out of 53 CHIKV patients, 40 patients
were interviewed. Of the 13 patients not interviewed, 10 had the
incorrect contact numbers in their medical records, 1 patient had
migrated, and 2 patients had died – one death was associated with
CHIKV, as previously described,13 while the other death was due to
unrelated causes. At the time of interview, 31 (77.5%) were pain-
free, while 9 (22.5%) still had arthralgia, of which 6 had mild pain
and 3 had moderate pain. In 17 (42.5%) patients, arthralgia affected
at least one daily activity for <30 days, 20 (50%) patients were
affected for 30–90 days, and 3 (7.5%) were affected for >90 days. The
median self-reported duration of arthralgia was 3 months (range,
0–24 months), with 18 (45.0%) of the patients reporting persistent
arthralgia beyond 4 months, and 9/40 (22.5%) beyond 1 year.
Analysis of selected predictors of persistent arthralgia is shown
in Table 3. Only age >40 years was shown to be an independent
Table 1
Demographic characteristics of patients with Chikungunya (n = 53) and dengue (n = 113).
Factor Dengue patients (n, %) Chikungunya patients (n, %) Total 2 p-Value
Age (years; mean ± standard deviation) 31.0 ± 13.2 49.2 ± 14.0 – <0.001
Gender
Male 79 (69.9) 22 (41.5) 101 (60.8) 12.2 0.001
Female 34 (30.1) 31 (58.5) 65 (39.2)
Ethnicity
Malay 47 (41.6) 30 (56.6) 77 (46.4) 13.4 0.004
Chinese 22 (19.5) 14 (26.4) 36 (21.7)
Indian 16 (14.2) 8 (15.1) 24 (14.5)
Others 28 (24.8) 1 (1.9) 29 (17.5)