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470 CID 2008:47 (15 August) Borgherini et al.

Table 1. Joint pain in 56 patients with persistent arthralgia.

Characteristic

Patients

(n p 56)

Continuous pain 31 (55.4)

Intermittent pain

Overall 25 (45.6)

At least once per week 12/25 (48)

At least once per month 10/25 (40)

Not specified 3/25 (12)

Experienced relapse 12 (21.4)

Mean no. of relapses per patient SD 1.5 1.2

Period between acute chikungunya and first relapse, mean months SD 8 5.4

Morning stiffness 40 (71.4)

Discomfort in everyday activities 26 (46.4)

Symmetrical joint pain 36 (64.3)

NOTE. Data are no. (%) or proportion (%) of patients, unless otherwise indicated.

Throughout the Indian Ocean epidemic, imported cases of

chikungunya virus infection in travelers returning from affected

areas were reported in several European and American coun-

tries [1417]. In August 2007, autochthonous cases of chikun-

gunya virus infection were detected in northeastern Italy [18],

the first time that this disease occurred in a temperate country.

The presence of 1 of the competent vectors, A. albopictus, in

a growing number of countries and the always-increasing num-

ber of international travelers raise major concerns about the

introduction of chikungunya virus into other previously unex-

posed areas.

Although the clinical features of acute chikungunya virus

infection have already been described in several reports [1, 10,

19], little is known about the long-term outcomes of the disease.Persistent arthralgia was already observed by Robinson [1] in

the first description of chikungunya virus infection, but the

only study that evaluated long-term persistent arthralgia in a

substantial number of patients was by Brighton et al. [20] in

1983; this study examined a group of South African patients 3

years after the acute phase of illness. In the report by Brighton

et al. [20], in which almost one-half of the patients were !17

years of age, most patients were fully recovered within 1 year.

In our experience, the persistence of arthralgia in adult patients

from Reunion Island appeared to be more significant than in

report by Brighton et al. [20] which incited us to perform our

study. Our studys objectives were to evaluate the prevalenceand nature of and risk factors associated with persistent ar-

thralgia in a population previously affected by acute chikun-

gunya virus infection.

PATIENTS AND METHODS

Reunion Island is a French overseas territory located in the

southwestern part of the Indian Ocean, east of Madagascar.

The medical system and accessibility to medical care are the

same as in France. The Groupe Hospitalier Sud Reunion is a

tertiary nonteaching institution with a referral population of

350,000 individuals.

Patients. We studied a cohort of patients with laboratory-

confirmed acute chikungunya virus infection who were referred

to our institution from March 2005 through April 2006. For

this cohort, the following inclusion criteria had to be met: age

16 years, clinical presentation consistent with chikungunya

virus infection (e.g., abrupt onset of fever and/or polyarthral-

gia), onset of symptoms within 10 days preceding the referral,

and laboratory confirmation of chikungunya virus infection by

positive RT-PCR results, paired serum sample seroconversion,

or positive IgM serologic test results. For all of the patients,

data on clinical features and laboratory findings during theacute phase of illness were available. All of the enrolled patients

were contacted by telephone (when the telephone number was

available in the medical file), several times if necessary, by a

member of the Centre dInvestigation Clinique and invited to

participate to the study. All the patients consented to their

involvement in the study.

Assessments. Patients were assessed in our department

(Service de Pneumologie et Maladies Infectieuses, Groupe Hos-

pitalier Sud Reunion; Saint Pierre, La Reunion, France) from

August 2007 through October 2007 and were assessed a mean

(SD) of months after acute illness. Three physi-18.7 2.1

cians interrogated the patients using a standard form and per-formed the physical examination. The standard form was used

for abstracting previous history of arthralgia and the nature of

current symptoms (i.e., their frequency, localization, and im-

pact on everyday life).

We defined persistent arthralgia as an intermittent or con-

tinuous joint pain that, in the judgment of the patient, was

related to chikungunya virus infection. If the patient was already

affected by joint pain before acute chikungunya virus infection,


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Arthralgia and Chikungunya Virus Infection CID 2008:47 (15 August) 471

Table 2. Localization of joint pain in 56 patients with persistent

arthralgia.

Characteristic

Self-reported

pain

Pain on physical

examination

Mean no. of involved joints SD 6.2 4.2 3 3.8

Localization

Metacarpophalangeal joints 32 (57.1) 15 (26.8)

Metatarsal joints 27 (48.2) 15 (26.8)

Wrists 28 (50) 9 (16.1)

Ankles 26 (46.4) 16 (28.6)

Elbows 13 (23.2) 8 (14.3)

Shoulders 25 (44.6) 17 (30.4)

Knees 32 (57.1) 12 (21.4)

Rachis 13 (23.2) 7 (12.5)

Sternoclavicular joints 1 (1.8) 1 (1.8)

Hips 10 (17.9) 3 (5.4)

NOTE. Data are no. (%) of patients, unless otherwise indicated.

arthralgia was considered to be secondary to chikungunya virus

infection if it differed in intensity or localization from the prior

symptoms. Arthralgia was considered to be continuous when

joint pain was present every day, even if it fluctuated in severity.

For the patients who presented with intermittent arthralgia, we

determined the localization of the joint pain during the most

recent episode of arthralgia. Relapse was defined as a bout of

joint pain that lasted 11 day with an intensity that was equiv-

alent to or greater than that associated with acute illness and

that occurred 11 month after acute chikungunya virus infection

after a symptom-free period of 11 month.

The physical examination was focused on articular signs;

all of the joints were inspected for the presence of swelling

and checked for pain elicited by passive movement. All thepatients were tested for the presence of IgM antibodies to

chikungunya virus in serum samples obtained on the day of

the assessment. Chikungunya virusspecific IgM antibody was

detected by IgM-capture ELISA using a chikungunya virus

antigen produced by the Centre National de Reference des

Arbovirus (Lyon, France) [21].

Statistical analysis. Results are expressed as mean value

(SD) and as number (percentage) of patients. The Mann-

WhitneyUtest was used to calculate differences in laboratory

findings and continuous variables between patients with per-

sistent arthralgia and patients who had experienced recovery.

Analysis was conducted using the x2

test, with use of Fishersexact test, as needed, for comparison of categorical variables

between patients with persistent arthralgia and patients who

had experienced recovery. was considered to be statis-P! .05

tically significant.

RESULTS

A total of 202 patients who fulfilled the inclusion criteria were

identified. The mean age (SD) of the patients was 57.7

years; the male-to-female ratio was 1.1 :1.0. For 60 patients19.9

(29.7%), the telephone number was unavailable or incorrect.

One hundred forty-two households were contacted by tele-

phone. Sixteen (7.9%) of 202 patients died in the months after

acute illness. The mean age (SD) of the patients who died

was years; the male-to-female ratio of the patients74.6 11.2

who died was 1.3:1.0. In 8 patients, it was possible to assess

the cause of death; in each case, death was secondary to anaggravation of an underlying disease. Of the 126 patients who

were contacted by telephone, 36 (28.6%) did not agree to par-

ticipate or were unable to participate in the study. Two patients

were secondarily excluded, because they were not tested for

IgM antibodies.

Eighty-eight patients were included in this study. The mean

age (SD) age was years; the male-female ratio was58.3 18

1.1:1.0. At least 1 underlying illness was present in 63 patients

(71.6%); the most frequent illnesses were hypertension and

diabetes mellitus. A history of chronic arthralgia preceding the

chikungunya virus infection was reported by 39 patients

(44.3%). The 2 most frequently reported causes of arthralgia

were osteoarthritis (26 patients; 66.6%) and gout (7 patients;

17.9%).

Fifty-eight patients (65.9%) had been hospitalized with acute

chikungunya virus infection. Among the patients included in

the study, the laboratory diagnosis of acute chikungunya virus

infection was made by positive RT-PCR results in 31 patients,

seroconversion in 7 patients, and positive IgM test results in

50 patients. The mean delay (SD) between onset of symptoms

and IgM positivity was days. At the time of assess-10.1 6.5

ment, test results were still positive for IgM antibodies specific

to chikungunya virus in 35 patients (39.7%).At the time of assessment, 32 patients (36.4%) considered

themselves to have recovered from arthralgia related to chi-

kungunya virus infection. For these patients, the mean duration

of chikungunya virusrelated arthralgia (SD) was2.9 2.4

months. In this group, 10 patients, all of whom had already

been affected by chronic arthralgia before chikungunya virus

infection, were still experiencing joint pain at the time of as-

sessment that they attributed to the preexisting illness. Relapse

of joint pain was reported by 1 patient.

At the time of assessment, 56 patients (63.8%) reported per-

sistent arthralgia related to chikungunya virus infection. The

nature and localizations of arthralgia are summarized in tables1 and 2. For 31 patients (55.4%), joint pain was continuous.

Arthralgia was polyarticular in all patients. Discomfort in per-

forming the activities of everyday life (e.g., walking, eating, and

getting dressed) was identified in 26 patients (46.4%). Relapses

were reported by 12 patients (21%). Joint swelling, which was

mainly observed in the ankles, was noted in 9 patients (16.1%).

Taking self-reported pain into consideration, metacarpophal-

angeal joints (in 57.1% of patients) and knees (57.1%) were


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Table

3.

Demographicdataandclinicalandlaboratoryfindings

forpatientswithpersistentarthralgiaan

dpatientswhoexperiencedrecovery.

Characteristic

Patientswith

persistentarthralgia

(np

56)

Patientswho

e

xperiencedrecovery

(np

32)

P

Age,meanyears

SD

59.8

17

56.2

21

.62

Sex

.26

Male

27/56(48.2

)

20/32(62.5

)

Female

29/56(51.8

)

12/32(37.5

)

Periodbetweenacutechikungunyavirusinfectionandassessment,meanmonths

SD

18.7

2.1

18.7

1.9

.70

Comorbidity

40/56(71.4

)

23/32(71.8

)

1.99

Bloodhypertension

23/52(44.2

)

11/30(36.7

)

.64

Ischemicheartdisease

21/56(37.5

)

5/32(15.6

)

.06

Diabetesmellitus

18/56(32)

9/32(28)

.81

Preexistingarthralgia

29/56(51.8

)

10/32(31.2

)

.07

Hospitalizationduringacutechikungunyavirusinfection

37/56(66)

21/32(65.6

)

1.99

Swollenjointsduringacut

echikungunyavirus

21/54(38.8

)

15/30(50)

.64

Rashduringacutechikungunyavirusinfection

28/56(50)

18/28(64.3

)

.82

Gastrointestinalsymptomsduringacutechikungunyavirusinfectiona

31/55(56.4

)

16/30(53.3

)

.82

Relapse

12/56(21)

1/32(3.1

)

.03

Plateletcount,meanplate

lets

103platelets/mm3

SD(reference

range,150500

103platelets/mm3)

Days01

174

61

146

68

.03

Days35

193

95

117

49

.006

Lymphocytecountonday

s01,meancells/mm3

SD(referencera

nge,10004000cells/mm3)

856

511

926

686

.76

C-reactiveproteinlevelon

days01,meanmg/dL

SD(referencerange,112mg/dL)

38.3

34.9

55

54.5

.18

Creatininelevelondays0

1,meanmmol/L

SD(referencerange,50120mmol/L)

105

74

113

61

.15

Serum

calcium

levelondays01,meanmmol/L

SD(referencera

nge,2.252.65mmol/L)

2.26

0.16

2.22

0.15

.37

Aspartateaminotransferas

elevel,meanU/L

SD(referencerange,

845U/L)

Days01

44.5

32.5

67.7

49.2

.01

Days35

35.8

12.5

70.6

36

.001

Alanineaminotransferase

level,meanU/L

SD(referencerange,865U/L)

Days01

35.8

35.5

46.4

39.3

.05

Days35

28.5

18

65.5

48

.001

Creatininekinaselevelon

days01,meanU/L

SD(referencerange,20210U/L)

191

173

379

716

.90

PositiveIgM

serologictes

tresult

21/56(37.5

)

14/32(43.7

)

.65

MeanIgM

antibodiestiter

SDb

30

37

23.7

24.2

.75

NOTE.

Dataareno.orproportionofpatients(%),unlessotherwiseindicated.Daysaredaysfrom

theonsetofsymptomsduringacutechikungunyavirusinfection.

a

Gastrointestinalsymptom

sincludeddiarrhea,vomiting,and/orabdominalp

ain.

b

Thresholdforapositives

erologictestresult,

20.


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the most affected joints; on physical examination, shoulders

(30.4%) and ankles (28.6%) were more frequently involved.

Patients with persistent arthralgia and patients who had ex-

perienced recovery were compared. Analysis of demographic

data and clinical and laboratory findings during acute chikun-

gunya virus infection was performed, and the results are re-

ported in table 3.

In the group of patients who experienced recovery, throm-bocytopenia and elevated liver enzyme levels were significantly

more common on days 01 and days 35. Comparison of other

laboratory findings on days 35 are not reported in table 3,

because they did not reveal any statistically significant difference.

DISCUSSION

The recent Indian Ocean epidemic and the Italian outbreak in

2007 [18] have drawn new attention to chikungunya virus in-

fection, a long-neglected disease. Still, many aspects of this

disease have been poorly studied. Although it is already well

established that severe arthralgia is one of the hallmark clinicalfeatures of acute chikungunya virus infection [1, 10, 19, 22,

23], little is known about the long-term persistence of this

symptom.

In our study, 56 (63.8%) of the enrolled patients were still

presenting with joint pain 18 months after acute chikungunya

virus infection that, in their judgment, was secondary to the

chikungunya virus infection. Persistent arthralgia (always po-

lyarticular) was continuous for 31 (55.4%) of these patients,

and almost one-half of them reported some difficulties in per-

forming activities of daily life.

To our knowledge, only 1 other report in the international

literature has studied long-term, persistent arthralgia in a largegroup of patients with laboratory-confirmed chikungunya virus

infection [20]. In this study, performed in South Africa in 1980

by Brighton et al. [20], in which several patients were ques-

tioned only by telephone, 94 (87.9%) of 107 patients were free

of symptoms 35 years after acute infection. The discordance

between this study [20], which reported a much higher pro-

portion of patients who experienced recovery, and our study

can be easily explained. In the study by Brighton et al. [20],

patients were assessed later than they were in our study, and

almost one-half of the patients were !17 years of age; it is

known that arthralgia has a milder course in children [24, 25].

In a more recent French report with a shorter-term follow-up,Simon et al. [23] studied a cohort of 47 travelers (46 adults

and 1 infant; mean age, 45.1 years) returning from the Indian

Ocean islands. In this series, in which 11 patients required

hospitalization, 48% of patients were still symptomatic 6

months after disease onset.

The other objective of our study was to identify the possible

predictors of persistent arthralgia; therefore, we compared sev-

eral risk factors in the group of patients who experienced re-

covery and the group of patients who still had arthralgia. A

lower platelet count and an elevation of liver enzyme levels

during acute chikungunya virus infection in patients who ex-

perienced recovery and a higher number of relapses among the

patients with persistent arthralgia were the only significant dif-

ferences between the 2 groups. The laboratory results could

suggest that a more severe acute illness can predict, paradox-

ically, a favorable outcome, but the clinical significance of thisfinding is uncertain.

Relapse of severe joint pain was reported by 12 (21.4%) of

the patients, confirming the fluctuating nature of arthralgia

associated with chikungunya virus infection. Relapses of ar-

thralgia have already been reported by other authors [23, 26]

as being a common feature in the months after acute chikun-

gunya virus infection; however, in these previous studies, no

definition of relapse was given. We have tried to eliminate this

bias in our study to obtain a more accurate estimation of the

finding.

Preexisting joint pain, which has been significantly associated

with a worse evolution of Ross River virus infection [27], was

more frequent among patients with persistent arthralgia, al-

though the difference was not statistically significant.

A previous seroprevalence study [21] found that 55.5% of

patients were IgM positive 1318 months after acute chikun-

gunya virus infection; this study shows an unusual persistence

of specific IgM antibodies, with 25 (39.7%) of 45 patients test-

ing IgM positive. It is noteworthy that, for infection due to

West Nile virus [28], which is another arborvirus associated

with long-term sequelae, the same phenomenon has been ob-

served. The pathogenesis of arthropathy in chikungunya virus

infection has not yet been clearly understood, but it is likelythat, as with Ross River virus infection [29], the immune re-

sponse plays an essential role. Therefore, it was particularly

interesting to check whether there was any statistically signif-

icant association between the presence of IgM antibodies and

persistent arthralgia. This association has been ruled out in our

study, in which the prevalence of positive IgM test results was

even higher among the patients who experienced recovery.

Our report has several limitations. We relied on the voluntary

participation of individuals from a retrospective cohort, and

one-quarter of the patients who were contacted did not par-

ticipate in the study. Therefore, the possibility of selection bias,

particularly in favor of patients with more-severe illness, hasto be considered. The enrolled individuals represent a group

of patients who presented with a more-severe form of chikun-

gunya virus infection, who often need hospitalization and can-

not be considered to be representative of the general popula-

tion. In addition, our cohort was largely composed of

middle-aged and elderly people, which partially reflects the

estimate of the surveillance system on Reunion Island, which

found a predominance of adults in the affected population [12].


6/7

474 CID 2008:47 (15 August) Borgherini et al.

The same age distribution was reported in the recent Italian

outbreak, in which the median age of the patients affected by

chikungunya virus infection was 61 years [18]. Another bias

of this study is related to the subjectivity of the symptoms.

Although we tried to reduce this bias by directly questioning

the patients and performing physical examinations, it was

clearly difficult to objectively assess the relationship between

persistent arthralgia and chikungunya virus infection. Apartfrom elicited pain, findings on physical examination were

scarce, and in the few patients who presented with swollen

joints (usually the ankles), this sign could be attributed to other

underlying illnesses. The discordance between the localization

of self-reported pain and the findings on physical examination

can be seen as a consequence of the doubtful reliability of self-

reported symptoms; however, we have to remember that many

patients reported intermittent pain and, therefore, were symp-

tom free the day of the assessment; in addition, another char-

acteristic of chikungunya virusrelated arthralgia is its migra-

tory nature.

A further issue was the fact that 29 of 56 patients with per-

sistent arthralgia reported a prior history of joint symptoms,

which made establishing the real cause of joint pain difficult.

For this reason, we used a definition of persistent arthralgia

that was designed to reduce this bias, stressing how the present

pain was not comparable to previous pain.

The fact that, among the patients who experienced recovery,

10 patients still had arthralgia but did not attribute their joint

pain to chikungunya virus infection (because the pain was sim-

ilar to that which they felt before the infection) seems to in-

dicate that patients can differentiate the nature of their pain.

Even if we had not considered patients with previous arthralgia,the proportion of patients still affected by persistent arthralgia

(30.7%) would have been noteworthy. This difficulty in relating

a persistent joint pain to a viral arthritis has already been re-

ported [27, 3032] for Ross River virus infection, for which

several surveys regarding the evolution of rheumatic manifes-

tations have produced conflicting data.

We could have obtained more-reliable data by comparing

our group of patients with a control group of uninfected pa-

tients. However, several issues made this kind of study difficult

to perform on Reunion Island. As previously shown by a se-

roprevalence study [33], 38% of the general population on

Reunion Island were infected by chikungunya virus during the20052006 outbreak. The proportion of infected patients was

even higher in the southern part of the island, where our in-

stitution is located, and a seroprevalence 150% was reported

among the elderly patients, which made recruitment of an un-

infected control group problematic.

The real burden of chikungunya virus infectiona disease

that, for a long time, was considered to be benignhas yet to

be precisely estimated. At the acute stage of the illness, lost

productivity is a frequent concern; a study conducted among

hospital staff on Reunion Island found that 76.8% of affected

patients took time off from work [26]. In another report [34],

in a population of military policemen, quality of life was still

severely impaired several weeks after acute infection. Even

though it has limitations, our study shows how persistent ar-

thralgia, often continuous and debilitating, is a frequent con-

cern among patients with chikungunya virus infection. This isespecially the case among middle-aged and elderly patients, one

of the populations most affected in the recent epidemics. Fur-

ther consultations and hospitalizations may be needed because

of the pain and disability associated with chikungunya virus

infection; this should be included in the assessment of the

overall economic impact of chikungunya virus infection, a dis-

ease which, considering the globalization of one of its com-

petent vectors, A. albopictus, is at risk of becoming a major

public health threat. To have a more accurate estimate of per-

sistent arthralgia related to chikungunya virus infection in the

general population, a prospective, case-control study that in-

volves a larger number of patients and includes patients withmilder forms of the disease at the acute stage is needed.

Acknowledgments

We thank Ms. Corinne Mussard, for tracing the patients and contacting

them by telephone, and the senior nurse, nurses, and secretaries of our

department, for their help.

Potential conflict of interests. All authors: no conflicts.

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