National Center for Emerging and Zoonotic Infectious Diseases

Chronic arthralgia after chikungunya

Nicole Lindsey, MS

CDC Deputy Lead, Chikungunya Vaccines Work Group

Arboviral Diseases Branch

Centers for Disease Control and Prevention
Clinical outcomes of chikungunya virus disease

 Acute symptoms typically resolve in 7-10 days

 Mortality is very rare

 Significant proportion of patients have continued or recurrent arthralgia in 

months and years following acute illness

 Additional long-term complications reported less frequently

– Fatigue

– Depression

– Alopecia

− Impaired memory

− Sleep disorders

− Lowered quality of life
Chronic joint symptoms after chikungunya

 Many published studies with high variability in results based on:

– Study methodology

– Definitions and ascertainment of symptoms

– Duration of follow up

– Characteristics of patient cohort (e.g., location, demographics)

 Previous meta-analyses with varying outcomes and inclusion criteria

– None used outcome and criteria most of interest to guide vaccine 

recommendation process
Systematic review and meta-analysis

 Objective to estimate percentage of patients with chronic arthralgia (≥3 

months) following chikungunya virus infection

 Literature search for articles published Jan 1, 2000 – Oct 24, 2022, 

describing primary data on arthralgia following chikungunya infection

 Excluded articles:

– Without laboratory confirmation of all infections 

– Specific subgroups (e.g., children, people with co-infections, large 

proportion of cases hospitalized for acute disease)

– Non-English language
Study selection process

1,167

• Articles identified through search. All abstracts reviewed

• 1,087 did not meet criteria and were excluded

80

• Articles with a full text review

• 53 did not meet criteria and were excluded

27

• Articles met inclusion criteria

• Standardized data extraction into spreadsheet tool
Characteristics of 27 included studies (N=4,079)

 Most clustered in 1 of 2 time periods (2005–2006 and 2014–2015)

 23 communities with outbreaks, 4 travelers to outbreak locations

 14 locations in Americas, 8 Indian Ocean, 4 Asia, 1 Europe

 4 studies included control group of non-infected persons

 Range of severity of illnesses (0–33% hospitalized) 

 Varied demographics of included participants
Chronic arthralgia following chikungunya virus disease*

0%

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0 3 6 9 12 15 18 21 24 27 30 33 36

Percentage with chronic arthralgia

Months after illness onset

*Some studies estimated proportion with chronic arthralgia at >1 time point
Chronic arthralgia following chikungunya virus disease*

0%

10%

20%

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0 3 6 9 12 15 18 21 24 27 30 33 36

Percentage with chronic arthralgia

Months after illness onset

*Some studies estimated proportion with chronic arthralgia at >1 time point
 7 studies included accounting for a total of 733 patients

 All included patients who sought healthcare 

 Two traveler cohorts and five cohorts from communities with outbreaks

– Travelers to countries in Indian Ocean and Americas

– Outbreaks: Brazil, French Guiana, Martinique, Sint Maarten, Thailand

 Predominance of females (range 52–74%)

 Range of study mean/median ages (35–51 years)

 Range of severity (hospitalization range 0–17%)

Arthralgia 3 months after chikungunya infection 
Arthralgia 3 months after chikungunya infection (N=7)

Study Location Sample Rate (95% CI )

Bocanegra 2016 Travelers to the Americas, 2014-2015 34 50% (33, 67)

Simon 2007 Travelers to the Indian Ocean, 2005-2006 47 86% (75, 95)

Bertolotti 2020 Martinique, 2014 167 55% (48, 62)

Benjamanukul 2021 Thailand, 2018 164 53% (46, 60)

Peters 2018 Sint Marteen, 2014 56 52% (39, 64)

Silva 2021 Brazil, 2014-2016 153 43% (36, 50)

Bonifay 2018 French Guiana, 2014 112 42% (33, 51)

Summary estimate* 51% (44, 58)

0 20 40 60 80 100

*Random effects model
Arthralgia 6 months after chikungunya infection

 9 studies included accounting for a total of 961 patients

 All included patients who sought healthcare 

 Three traveler cohorts and six cohorts from communities with outbreaks

– Travelers to countries in Indian Ocean

– Outbreaks: Bangladesh, French Guiana, Martinique, Mexico, 

Suriname, Thailand

 Predominance of females (range 52–68%)

 Range of study mean/median ages (32–60 years)

 Range of severity (hospitalization range 0–33%)
Arthralgia 6 months after chikungunya infection (N=9)

Study Location Sample Rate (95% CI )

Schilte 2013 Reunion Island, 2005-2006 180 70% (63, 77)

Simon 2007 Travelers to Indian Ocean, 2005-2006 47 48% (35, 63)

Feldstein 2017 USVI, 2014-2015 165 44% (37, 52)

Murillo-Zamora 2017 Mexico, 2015 136 42% (34, 50)

Bertolotti 2020 Martinique, 2014 167 36% (29, 43)

Bonifay 2018 French Guiana, 2014 112 31% (23, 40)

van Genderen 2016 Suriname, 2013 90 22% (14, 31)

Taubitz 2007 Travelers to Indian Ocean, 2006 16 13% (0, 29)

Anwar 2020 Bangladesh, 2017 48 13% (0, 22)

Summary estimate* 35% (24, 47)

*Random effects model 0 20 40 60 80 100
Arthralgia 12 months after chikungunya infection

 10 studies included accounting for a total of 1,539 patients

 9 included patients who sought healthcare; 1 population-based sample

 All cohorts from communities with outbreaks: Aruba, Bangladesh, Brazil, 

Grenada, Italy, Malaysia, Martinique, Reunion Island, US Virgin Islands (2)

 Predominance of females (range 52–73%)

 Range of study mean/median ages (33–60 years)

 Range of severity (hospitalization range 0–23%)
Arthralgia 12 months after chikungunya infection (N=10)

*Random effects model

Study Location Sample Rate (95% CI )

de Moraes 2020 Brazil, 2016-2018 107 61% (52, 70)

Moro 2012 Italy, 2007 250 61% (55, 67)

Schilte 2013 Reunion Island, 2005-2006 180 58% (51, 65)

Heath 2018 Grenada, 2014 240 35% (29, 41)

Feldstein 2017 USVI, 2014-2015 165 33% (26, 40)

Bertolotti 2020 Martinique, 2014 167 31% (24, 38)

Hennessey 2018 USVI, 2014-2015 171 31% (24, 38)

Huits 2018 Aruba, 2014 171 26% (19, 32)

Mohd Zim 2013 Malaysia, 2008 40 23% (10, 35)

Anwar 2020 Bangladesh, 2017 48 19% (8, 30)

Summary estimate* 38% (29, 46)

0 20 40 60 80 100
Chronic arthralgia following chikungunya virus disease*

*Among 9 studies that estimated proportion with chronic arthralgia at >1 time point

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Chronic arthralgia estimates among travelers (N=4)

Reference Location, Year N Population description 3m 6m 24m

Simon 2007 Indian Ocean, 2005-2006 47

French travelers treated at 

Lavaren Hospital in Marseilles 86% 48%

Larrieu 2010 Indian Ocean, 2005-2006 29

French travelers treated at 

University Hospital in Bordeaux 59%

Taubitz 2007 Indian Ocean, 2006 16

German travelers treated at 

Institute of Trop Med in Hamburg 13%

Bocanegra 2016 Americas, 2014-2015 34

Spanish travelers who presented 

to public health 50%
Limitations

 Variability in case definitions, populations included, findings

 Almost all persons who seek healthcare for symptoms; not representative 

of all cases

 Very few studies included control group to account for background rates of 

arthralgia in population

– Crude estimates from all studies used to calculate summary estimates
Chronic arthralgia in controlled studies

 Soumahoro 2009 (Reunion 2005-2006)

– 199 CHIKV+, 199 CHIKV-

– At 17m, CHIKV+ more joint pain than CHIKV- (53% vs 28%)

– Estimated 47% (95% CI 37%–55%) of pain in case-patients attributed to CHIK

 Gerardin 2011 (Reunion 2005-2006)

– 512 CHIKV+, 582 CHIKV-

– At 16m, CHIKV+ more likely to complain of musculoskeletal pain (43% vs 17%) 

– Estimated 60% (95% CI 52% - 68%) of pain in case-patients attributed to CHIK
Chronic arthralgia in controlled studies (cont.)

 Feldstein 2017 (USVI 2014-2015)

– 165 CHIKV+, 167 CHIKV-

– At 6m, difference in arthralgia between case-patients and controls 32% (95% 

CI 24%–40%) after adjusting for age, sex, history of arthritis

– At 12m, adjusted difference was 19% (95% CI 11%–28%)

 Hennessey 2018 (USVI 2014-2015)

– 171 CHIKV+, 338 CHIKV-

– At 12m, 31% case-patients, 26% of controls joint pain in last week

– Estimated 23% (95% CI 9% - 37%) of continued joint pain in case-patients 

attributed to CHIK infection
Review of key points

 A substantial proportion of patients who seek care for their acute illness have 

chronic arthralgia following chikungunya virus infection

– Estimated ~one-half have arthralgia at 3 months

– Rates decrease and ~one-third estimated with arthralgia at 12 months

 All proportions likely overestimates of chronic arthralgia in patients overall as 

studies:

– Almost exclusively included persons who sought health care (i.e., likely 

more severe disease)

– Do not account for background rate of arthralgia in population
Summary

 Difficult to provide precise estimate of incidence of long-term joint pain 

after chikungunya

 Percentages with long-term joint pain likely variable based on severity of 

acute illness, age, sex, comorbidities

 Long-term joint pain important complication of chikungunya that could be 

prevented by vaccination