Open Forum Infectious Diseases MAJOR ARTICLE e I Th dentification of Risk Factors for Chronic Chikungunya Arthralgia in Grenada, West Indies: A Cross-Sectional Cohort Study 1,2 2,3 2,3 2 1 4 2,3 Claire J. Heath, Jason Lowther, Trevor P. Noël, Idis Mark-George, Derek. B. Boothroyd, George Mitchell, Calum MacPherson, and A. Desiree LaBeaud 1 2 3 4 Stanford University, School of Medicine, California; WINDREF, St. George’s, Grenada; St. George’s University, School of Medicine, Grenada; Ministry of Health, St. George’s, Grenada Background. Chikungunya virus (CHIKV) is a re-emerging arboviral pathogen. In 2014, an explosive CHIKV outbreak occurred in Grenada, West Indies, infecting approximately 60% of the population. In approximately 50% of cases, CHIKV infection transitions to painful arthralgia that can persist for years. Elucidation of the risk factors for chronic disease is imperative to the de- velopment of effective risk management strategies and specific therapeutics. Methods. We conducted a cross-sectional study of 240 people who were tested for CHIKV during the outbreak. We adminis- tered questionnaires to examine demographic, behavioral, psychological, social, and environmental factors to identify associations with chronic disease. Physical examinations were performed and persistent symptoms were recorded. Results. Ethnicity and socioeconomic status were not associated with risk of chronic joint pain. Female sex increased risk, and age was demonstrated to be predictive of chronic CHIKV sequelae. Mosquito avoidance behaviors did not reduce risk. Patients suf- fering joint pains, generalized body ache, and weakness in the extremities during acute infection were more likely to develop chronic arthralgia, and an increased duration of acute disease also increased risk. Conclusions. es Th e data demonstrate that chronic CHIKV ae ff cts people across the ethnic and socioeconomic spectrum, and it is not reduced by vector avoidance activity. Increased duration of acute symptoms, in particular acute joint pain, was strongly correlated with the risk of persistent arthralgia, thus effective clinical management of acute CHIKV disease could reduce burden of chronic CHIKV. Keywords. arthralgia; arthritis; Caribbean; Chikungunya; Grenada. Chikungunya virus (CHIKV) is an arthropod-borne virus the region from neighboring mainland countries and also travel (arbovirus), transmitted by Aedes albopictus and Aedes aegyp- between islands in the region. tiae species mosquitoes . Arthropod-borne viruses (arbo- Chikungunya virus causes both acute and chronic disabling viruses) comprise many of the most important “emerging” illness. Initial week-long prostrating fevers are oen f ft ollowed by pathogens due to their geographic expansion and their increas- severe skeletal and joint pain, frank arthritis, and, more rarely, ing global health impact on naive populations. Chikungunya eye inflammation, vision loss, Guillain-Barre Syndrome, paral- virus is a rapidly re-emerging pathogen that, over the last dec- ysis, vasculitis, encephalitis, hepatitis, and/or myopericarditis ade, has expanded its range across Africa and Asia and then [7–9]. The term “chikungunya” means “that which bends up” emerged in Europe, the Pacific Region, and the Americas [2–5]. in reference to the severe arthralgia associated with the acute In 2013, CHIKV re-emerged in the America’s on the phase of infection and the resulting posture of those afflicted. Caribbean Island of St. Martin, and it was first identified in To date, the precise mechanisms for CHIKV’s disabling Southeast Asia by the Asian genotype . The rapid spread of sequelae remain to be fully elucidated unknown. Underlying the virus throughout the Caribbean was facilitated by an immu- comorbidities such as cardiovascular disease, hypertension, nologically naive population and large numbers of travelers to concomitant osteoarthritis, obesity, and diabetes have been identified as potentially increasing the severity of CHIKV dis- ease [7, 8, 10–17]. In addition, age at the time of acute infection Received 18 August 2017; editorial decision 16 October 2017; accepted 8 November 2017. has been reported by several investigators to be predictive of Correspondence: C. J. Heath, PhD, Stanford University School of Medicine, 300 Pasteur persistent arthralgia aer CHIKV inf ft ection [15, 17–23]. Drive, Palo Alto, CA (firstname.lastname@example.org). ® As the threat of CHIKV expansion looms, there is a specific Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases need to study the determinants of severe human disease. The Society of America. This is an Open Access article distributed under the terms of the Creative lessons learned will be valuable to assess risk and suitable ther- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any apies for severe disease. medium, provided the original work is not altered or transformed in any way, and that the work Currently, there are no specific therapies or approved CHIKV is properly cited. For commercial re-use, please contact email@example.com. vaccines. Ninety percent of those infected with CHIKV suffer DOI: 10.1093/ofid/ofx234 Chronic Chikungunya Disease in Grenada • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 joint pain, which can persist for years in up to 50% of patients were conducted by 1 of 2 members of our field research team, to . Characterization of the risk factors and mechanisms ensure consistency in technique and reporting. underlying chronic disease is imperative to identify the deter- Physical Exam minants of severe human disease, assess risk, and ultimately Study subjects then undertook a comprehensive physical exam- develop risk control measures and specific therapies for this ination administered by a single Grenadian registered nurse, debilitating disease. In addition, syndromic surveillance may again to ensure consistency and standardization of assessment. prove diagnostically valuable, in regions where CHIKV is Height, weight, blood pressure, visual acuity, and reflex meas- endemic and laboratory confirmation of the disease is limited. urements were recorded. Current arthritis/arthralgia symptoms Our study site, Grenada, is the main island of a tri-island state were documented, and extensive joint examinations were con- of Grenada, Carriacou, and Petit Martinique in the southern ducted to measure swelling, stiffness or restricted motion, and Antilles. Between July and November of 2014, an explosive to verify reported symptoms. outbreak of CHIKV occurred in Grenada with even the most Arthritis Severity Scoring conservative estimates of attack rate at approximately 60% of The severity of disease sequelae in “chronic” participants was the population ae ff cted [24–26]. In this study, we investigate the quantified using the internationally validated AIMS score [27, epidemiological, demographical, physical, and behavioral risk 28]. The scale assesses the impact of arthritis/arthralgia on the factors associated with development of CHIKV-related chronic participant’s functionality in various domains of life. The phys- arthralgia in Grenada. ical and symptom domains measure the impact of disease on METHODS the patient’s ability to move joints normally and their reported degree of pain, respectively. The affect and social domains of Participant Recruitment the scale assess the impact of arthralgia on the subject’s mood, Between November 2015 and January 2016, study participants sense of well being, social interactions, the pursuit of hobbies/ were recruited from a health service database of patients who leisure, and care of others. had had their blood tested for CHIKV during the outbreak be- tween July and November of 2014 [24, 25]. Chikungunya virus Statistical Analysis infection had been confirmed by polymerase chain reaction Demographic, ethnicity, physical, environmental, behavioral, and/or immunoglobulin M enzyme-linked immunosorbent and social factors were analyzed as they pertained to risk of suf- assay as we have previously described . The database fering from persistent, chronic CHIKV-associated arthralgia. included people who had presented at primary care facilities, Subjects suffering from “chronic” arthralgia were defined as hospitals, and also to St. George’s University Health Centre. those that answered positively to the question “Have you suf- All persons on this database were eligible for recruitment to fered from joint pain since your initial CHIKV illness?” AND our study. Healthcare in Grenada is provided free of charge also answered “yes” to one of the questions; “Have you suffered to its citizens, and facilities include a General Hospital, larger joint pain in the last day/week/month?” Because our study local health centers in each Parish, and smaller health stations was conducted 1 year after the end of the Grenadian outbreak, throughout the island, which are organized so that no house- people answering positively to these questions have suffered hold is more than 3 miles from a healthcare provider. symptoms within the chronic phase of the disease as classified Participants were contacted via telephone and invited to by international consensus [29–31]. attend a one-time appointment at one of the various healthcare Initially, unadjusted univariate analyses were performed facilities throughout the island. Home visit appointments were using Fisher’s exact test, to give crude associations of each also oer ff ed to ensure maximum accessibility to the study. variable or prognostic factor with the risk of chronic CHIKV Interview arthralgia. The category boundaries for age group were as fol- In an in-person interview, informed consent (or parental con- lows: <25 years, 25–44 years, 45–64 years, and ≥65 years. These sent for those aged <18 years) was obtained, and participants were chosen to allow for comparison of data with other similar were administered questionnaires (Supplementary Figure 1) on studies [15, 17, 23]. Subsequently, multivariate logistic regres- the demographical, physical, environmental, behavioral, and sion models adjusting for both sex and age group were fitted social factors of their daily lives, and medical history, includ- to each of the other variables in turn for estimating adjusted ing any comorbidities, was also recorded. In particular, the odds ratios and associated 95% confidence intervals (CIs) for symptoms suffered during their acute CHIKV illness, and any developing chronic CHIKV arthralgia status. For evaluating symptoms suffered since, were recorded. Subjects who reported sex and age group, only those 2 variables were included in 1 persistent arthralgia, defined as suffering joint pains within logistic regression model. Wald χ tests were used to calculate the last month, were asked to complete the Arthritis Impact P values for binary variables, and likelihood ratio χ tests were Measurement Scale (AIMS) questionnaire [27, 28], in order that used for nominal variables, to give χ likelihood ratios and pre- the severity of their disease could be assessed. All interviews cision estimates. 2 • OFID • Heath et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 For the variables of length of initial symptoms and length of the reference group, the highest relative risk was in the 45- to initial joint pain, a Cochran-Armitage trend test was performed 64-year-olds category (OR, 2.20; 95% CI, 0.93–5.18), followed initially to test for associations of these with the risk of chronic by the 25–44 years group (OR, 1.17; 95% CI, 0.53–2.58), then joint pain. Subsequently, a multicategory logistic regression the ≥65 years group (OR, 0.42; 95%, CI 0.04–11.19) (P = .043). model was used to determine the odds ratio per category in- e et Th hnic distribution of participants in this study was crease in duration. representative of the demography of Grenada with 193 of 240 participants (80.8%) being of African descent. Of the other par- RESULTS ticipants, 12 were white (5%), 5 were East Indian (2.1%), 2 were Asian (0.8%), and 27 subjects (11.3%) identified as “Other”. A total of 240 participants were recruited to the study. Of these, When adjusted for age and sex, no association was observed 85 of the participants (35.4%) satisfied our criteria for suffering between ethnicity and chronic disease risk (P = .5130), and, in from chronic arthralgia and were administered the AIMS ques- particular, African descent was not indicative of increased risk tionnaire to determine severity. The average time to follow up when compared with all other ethnic groups (P = .5761; OR, from initial presentation was 448 days (range, 391–556 days). 0.81; 95% CI, 0.39–1.70) (Table 1). Of 240 participants, 64 (26.6%) were male and 176 (73.4%) St. George’s parish is the most urbanized, auen ffl t, and were female. The age range of participants was 4–89 years, with densely populated parish in Grenada, and residents of this par- both the mean and the median age being 40 years. ish represented 138 of 240 (57%) of our study subjects (Table 1). In our cohort, unadjusted estimates found that female sex No differences in the risk of developing chronic CHIKV arth- did increase the risk of chronic CHIKV joint pain, although ralgia were detected in participants from St. George’s compared narrowly missing the threshold for significance (P = .058). with any of the other less auen ffl t, more rural, parishes (OR, However, when adjusted for age, this aeff ct was reduced 1.15; 95% CI, 0.65–2.05; P = .6273). (P = .123; odds ratio [OR], 1.68; 95% CI, 0.87–3.26), suggest- We have previously reported the characteristics of the ing that age was a more important predictor of chronic CHIKV patients seeking care at the time of the outbreak . Among arthralgia (Table 1). the participants in the current study, during acute illness, the Indeed, unadjusted analysis of participant age demonstrated most commonly recorded symptom was joint pain (Table 2), an association with the risk of chronic arthralgia. This associ- which was experienced by 91% of study participants and is a ation varied by age group (43% chronic for age <25 years, 48% signature symptom of acute CHIKV disease. This was followed for 25–44 years, 63% for 45–64 years, and 21% for ≥65 years; by fever (81%), generalized body ache (75%), headache (72%), P = .021). Aer ad ft justment for sex, and using the <25 years as Table 1. Demographic Characteristics of Study Participants Adjusted Variable Subcategory Number of Participants (%) Odds Ratio 95% CI P Value Sex .058 Male 64 (26.6) Reference Reference Female 176 (73.4) 1.68 0.87–3.26 Age Group (years) .0430 <25 40 (16.7) Reference Reference 25–44 109 (45.4) 1.17 0.53–2.58 45–64 71 (29.6) 2.20 0.93–5.18 ≥65 20 (8.3) 0.42 0.10–1.81 Ethnicity .5130 African Descent 84 (80.8) Reference Reference White 12 (5) 1.27 0.30–5.46 East Indian 5 (2.1) 0.58 0.07–4.50 Asian 2 (0.8) 0.00 0.00–∞ Other 27 (11.3) 1.61 0.64–4.03 Parish of Residence .6744 St. George’s 136 (57.1) Reference Reference St. Andrew 42 (17.5) 1.19 0.54–2.60 St. David 35 (14.5) 0.49 0.20–1.24 St. John 13 (5.42) 1.22 0.32–4.71 St. Patrick 11 (4.6) 0.84 0.25–2.86 St. Mark 2 (0.83) 0.65 0.04–11.19 Abbreviations: CI, confidence interval. Chronic Chikungunya Disease in Grenada • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. The Association of Acute Chikungunya-Disease Symptoms With Chronic CHIKV Arthralgia* Number of Participants With Adjusted Odds Acute Symptom Symptom (%) Adjusted P Value Ratio 95% CI Lower 95% CI Upper Fever 194 (80.8) .0442 2.26 1.02 4.99 Chills 159 (66.25) .1165 1.64 0.88 3.04 Generalized body ache 180 (75) .0244 2.24 1.11 4.53 Joint pains 219 (91.3) .0183 6.50 1.37 30.75 Muscle pains 149 (62.1) .0992 1.67 0.91 3.05 Bone pains 104 (43.3) .2315 1.42 0.80 2.52 Itchiness 117 (48.7) .4102 1.28 0.72 2.27 Headache 172 (71.6) .1096 1.71 0.89 3.30 Retro-orbital pain 88 (36.6) .0259 1.96 1.08 3.55 Dizziness 94 (39.1) .0563 1.77 0.98 3.18 Photosensitivity 79 (32.9) .0067 2.36 1.27 4.39 Stiff neck 72 (30.0) .0074 2.41 1.27 4.58 Red eyes 27 (11.25) .1349 2.04 0.80 5.17 Runny nose 31 (12.9) .1461 1.88 0.80 4.39 Earache 16 (6.6) .3039 1.88 0.56 6.24 Sore throat 60 (25.0) .0188 2.28 1.15 4.55 Cough 54 (22.5) .2007 1.60 0.78 3.28 Shortness of breath 40 (16.6) .4507 1.34 0.63 2.84 Loss of appetite 148 (61.6) .1309 1.58 0.87 2.87 Strange taste in mouth 87 (36.25) .0211 2.02 1.11 3.66 Nausea 83 (34.6) .0360 1.92 1.04 3.55 Vomiting 43 (17.9) .9542 0.98 0.46 2.06 Diarrhea 60 (25.0) .5868 1.20 0.63 2.29 Abdominal pain 56 (23.3) .1936 1.59 0.79 3.19 Rash 123 (51.3) .8208 1.07 0.59 1.93 Bloody nose 3 (1.2) .7240 0.64 0.05 7.87 Bleeding gums 9 (3.7) .7620 0.80 0.19 3.33 Bruising 5 (2.1) .2486 0.26 0.03 2.59 Impaired mental status 29 (12.1) .0004 7.85 2.51 24.55 Seizures 3 (1.25) .9882 0.00 0.00 ∞ Weakness in the extremities 146 (60.8) .0116 2.18 1.19 3.99 Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval. *Acute symptoms associated with risk of chronic CHIKV arthralgia are highlighted. chills (66%), muscle pain (62%), and other general symptoms of should be noted that indicators of dwelling conditions, ie, having febrile illness. It is interesting to note that, of these most com- an outdoor pit latrine (OR, 1.99; 95% CI, 0.83–4.80; P = .1249) mon symptoms, joint pain (P = .0183; OR, 6.5; 95% CI, 1.37– and/or a household floor of described as “other” in the question- 30.75), generalized body ache (P = .0244; OR, 2.24; 95% CI, naire (suggesting a dirt floor) (OR, 2.63; 95% CI, 0.46–15.02; 1.11–4.53), and weakness in the extremities (reported by 60.8% P = .2762), were more associated with chronic disease than edu- of patients) (P = .0116; OR, 2.18; 95% CI, 1.19–3.99) were asso- cational and occupational measures (Table 3), suggesting that a ciated with risk of subsequently developing chronic sequelae. poorer immediate environment increased the risk of persistent Other symptoms, such as fever, retro-orbital pain, photosensi- CHIKV disease sequelae. tivity, stiff neck, sore throat, and impaired mental state, were We hypothesized that mosquito avoidance behaviors were also associated with increased chronic disease risk (Table 2), al- likely to determine the frequency and intensity of CHIKV though this is likely due to these being indicative of increased exposure (ie, mosquito bites), and therefore may contribute to acute disease severity. the severity of acute infection, and thus have an influence on the e im Th pact of social economic status (SES) on the risk of devel- subsequent course of disease. However, we found that none of oping chronic CHIKV disease was assessed via a variety of proxy the various mosquito avoidance and repelling behaviors prac- measures of SES, pertaining to the participants’ occupation, edu- ticed by the participants reduced their risk of chronic disease cational status, living environment, and income (Table 3). Using (Figure 1). However, mosquito avoidance behaviors were not these measures, SES was not significantly implicated in a patient’s routinely nor consistently practiced (Figure 1), with most par- likelihood of developing chronic disease sequelae. However, it ticipants responding “never” to questions regarding the use of 4 • OFID • Heath et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Association of Proxy Measures of SES the Risk of Chronic CHIKV associated with increased risk of suffering from chronic CHIKV Arthralgia disease sequelae (P = .001). In particular, increased duration of joint pain specifically, during the acute syndrome, increased the Odds Adjusted P likelihood of suffering from persistent arthritis and arthralgia Variable Subcategory Ratio 95% CI Value (P ≥ .0001) in unadjusted analyses. Adjustment for sex and age Highest level of .874 education group yielded adjusted P values of .0061 and .0089, respectively Primary School Reference Reference (Table 4). Moreover, the adjusted OR for chronic disease per one Secondary School 0.69 0.29–1.65 category increase in duration of symptoms was 1.45 (95% CI, Tertiary College 0.91 0.38–2.20 1.14–1.84; P = .0025), and per 1 category increase in length of University 0.73 0.30–1.78 joint pain specifically was 1.33 (95% CI, 1.14–1.56; P = .0004). Undergraduate Professional Degree 2.89 0.36–22.99 Other studies have reported associations of body mass index Other Postgraduate 0.86 0.20–3.63 (BMI) with chronic CHIKV arthralgia. Thus, we calculated Other 0.81 0.04–15.50 BMI from the height and weight measurements of our study No. of rooms in 1.00 0.90–1.11 .961 participants, to allow for analysis of this factor and comparison House No. of people in 0.95 0.82–1.11 .534 of our data. Although initial unadjusted univariate analyses of house participants’ BMI associated obesity with the risk of chronic No. of children 1.06 0.85–1.32 .617 arthralgia (P = .036), aer m ft ultivariate adjustment for age and (<18) in house sex, we found that obesity was not associated with chronic House construc- .519 tion material CHIKV arthralgia in Grenada (P = .1045; OR, 1.68; 95% CI, Concrete (Wall) Reference Reference 0.90–3.16). Of note, however, high cholesterol did increase Wood (Board) 1.38 0.59–3.20 the risk of chronic arthralgia (OR, 0.39; 95% CI, 0.16–0.91; Concrete and Wood 1.44 0.71–2.92 P = .0304). No association was found between chronic arth- Floor Type Wood 0.93 0.51–1.70 .817 ralgia and any of the other comorbidities assessed in our co- Cement 0.98 0.54–1.79 .946 hort. Of all the domains of life assessed by the AIMS score, the Tile 0.97 0.55–1.72 .916 physical impact of chronic CHIKV disease (ie, the impact on Other 2.63 0.46–15.02 .2762 mobility, ability to walk and bend, and limb function) had the Bathroom Type Indoor Toilet Reference Reference .1249 highest average score of all the domains, indicating that all par- Pit Latrine 1.99 0.83–4.8 ticipants with persistent CHIKV disease experienced reduced Have air condi- 0.61 0.27–1.38 .233 tioning (Y/N) physical ability aer inf ft ection (Figure 2). Scores for the symp- Have a refrigerator 1.28 0.41–3.95 .671 tomatic (pain) domain of the scale were the widest ranging but, (Y/N) with the exception of the work domain, had the lowest average Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval; N, no; SES, social eco- impact score. The ae ff ct and social domains both scored, on nomic satus; Y, yes. average, higher than physical pain on the impact scale, indicat- ing that participants were debilitated psychologically and so- cially by their chronic CHIKV disease. The aspect of work was repellents (60.4% responding “never”), mosquito coils (65.8%), the lowest impacting in our participants. However, this domain and sleeping under mosquito nets (75%). In contrast, however, was mainly assessed by loss of work days and income, which, the controlling of mosquito breeding sites around the home was due to paid sick leave in Grenada, did not ae ff ct most people. practiced “always” by 45% of subjects. In addition, each domain of the arthritis impact scale was, to Increased frequency of mosquito bites missed the cutoff for varying degrees, positively associated with the duration of ini- significance in this study, but it was correlated with increased tial illness, and in particular duration of joint pain during acute risk of chronic CHIKV disease (P = .063). Chikungunya virus disease (Figure 3), suggesting that prolonged acute illness not infection is rarely asymptomatic, and being bitten by a virus-car- only increases likelihood of developing chronic arthralgia but rying mosquito usually manifests in observable illness . Thus, also increases the impact of chronic disease. an increase in the frequency of bites, particularly in an epidemic situation, will increase the likelihood of CHIKV disease. DISCUSSION e m Th ajority of participants (57.8%) reported that their acute illness had resolved within 1 week (Table 4), and a further 25.7% This study describes the widespread morbidity that the CHIKV of participants had recovered within 1–2 weeks. Smaller pro- epidemic had on the population of Grenada, and our data dem- portions of participants reported that their acute illness lasted onstrate that chronic CHIKV disease affects people across the for 3 (6.3%) and 4 weeks (5.1%). ethnic and socioeconomic spectrum. Using an unadjusted Cochran-Armitage trend test, the dur- Increasing age was found to be a significant risk factor for ation of symptoms during the initial acute illness was linearly chronic CHIKV arthralgia in our cohort, with those in the Chronic Chikungunya Disease in Grenada • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Measure of Vector Avoidance Behavior P-value Mosquito screens on windows at dwelling 0.169 Frequency of seeing mosquitoes in dwelling 0.683 80 Wear Repellent Frequency of bites 0.061 Wearing insect repellent 0.476 Use Coils Use of mosquito coils 0.742 Use of insect spray 0.907 Use Spray Sleep under a mosquito net 0.925 Sleeping Net Control of potential breeding sites at home 0.229 Collection of rainwater from roof 0.994 Control Breeding sites 60 Storage of rainwater in outdoor tanks 0.845 Tanks covered/have lid? 0.516 Never Occasionally Sometimes Often Always Figure 1. Analysis of the association of mosquito vector avoidance behaviors and the risk of chronic Chikungunya virus arthralgia. 25- to 44-year-old age group at the highest risk. This is in arthralgia than men [19, 33, 35–37]. A total of 35.4% of our concordance with several other studies conducted in similar study participants met our definition of persistent arthral- settings who have found age to be predictive of rheumatic gia, which strongly concurs with a recent meta-analysis on sequelae after CHIKV infection [15, 17, 19, 20, 22, 23, 32–34]. the incidence of chronic arthralgia performed by Rodríguez- We found that female gender increased the risk of chronic Morales et al. . Their analyses showed that in studies with arthralgia, although narrowly missing the cutoff for signifi- >200 participants, 34% of CHIKV-infected patients would go cance, which is in concordance with several studies that have on to develop chronic arthritis. This proportion is also similar shown females to be at higher risk for persistent arthritis/ to that recently reported by Feldstein et al. , in the US Virgin Islands. e p Th arish of participant’s residency was not found to be a risk Table 4. Association of Duration of Acute Symptoms and Acute Joint factor for CHIKV disease in Grenada. However, it should be noted Pain With the Risk of Chronic CHIKV Arthralgia that parish of residency is oen n ft ot where participants worked, Number of Adjusted P with many traveling into the capital of St. George’s each day. This Variable Participants Odds Ratio 95% CI Value is of relevance to CHIKV infection because Aedes spp are daytime Duration of Symptoms .0061 feeders. Nonetheless, the amount of time spent outdoors, either 0–3 days 35 Reference Reference as part of their occupation or outside of work, was not found to 4–7 days 105 0.74 0.32–1.73 be correlated with risk of chronic disease in this study. 1–2 weeks 61 0.92 0.37–2.30 Similarly, no proxy measure of SES was found to be sig- 3 weeks 15 1.11 0.29–4.22 4 weeks 12 4.69 4.69–28.73 nificantly implicated in increased risk of chronic arthralgia, Length of Acute Joint Pain .0089 although indicators of participants’ immediate living environ- 1 week 84 Reference Reference ment was more associated than educational and occupational 2 weeks 39 0.83 0.36–1.93 indicators. Previous studies that have examined environmen- 3 weeks 20 1.24 0.40–3.80 tal and social factors that impacted upon the manifestations of 4 weeks 15 3.88 0.94–16.04 1–3 months 23 2.59 0.90–7.46 CHIKV disease in small island settings have also described pri- 3–6 months 14 2.42 0.65–8.99 mary associations with housing conditions [39, 40]. The social- >6 months 24 6.76 1.74–26.32 ized healthcare system in Grenada may have minimized the Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval. impact of economic status on CHIKV disease outcome during 6 • OFID • Heath et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of participants 10 Physical Symptom A�ect Social Work Figure 2. Arthritis impact scores in subjects with Chikungunya virus-related persistent arthritis and arthralgia in each distinct life domain. Length Symptoms 0.8 0.6 Length Joint Pain 0.4 Physical 0.2 Symptom −0.2 Aect −0.4 Social −0.6 −0.8 Work −1 * Positive association is shown in blue, negative in red. Increasing size of a circle denotes increasing association. Adjusted p-value Domain Duration of symptoms Duration of joint pain Physical 0.0185 0.6799 Symptom 0.4611 0.2745 Aect 0.4097 0.43480 Social 0.7724 0.1325 Work 0.0011 0.2495 Figure 3. Correlation of duration of acute symptoms and initial joint pain with each life domain in arthritis impact quality-of-life assessment. Chronic Chikungunya Disease in Grenada • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Worsening sequelae Length Symptoms Length Joint Pain Physical Symptom Aect Social Work Table 5. Association of Comorbidities With the Risk of Chronic CHIKV several acute symptoms—including dizziness, retro-orbital pain, Arthralgia photosensitivity, stiff neck, sore throat, and altered mental state, which are suggestive of more severe illness—were found to be Comorbidity Odds Ratio 95% CI P Value associated with increased chronic disease risk. Disease severity Previous dengue infection 1.98 0.75–5.13 .1718 and the subsequent risk of arthritis/arthralgia has been corre- Asthma 0.95 0.45–2.00 .8945 lated with viral load during the acute phase . These observa- Respiratory illness 1.59 0.69–3.64 .2735 tions are informative for early recognition and management of Cardiovascular illness 1.33 0.44–4.04 .6095 Stroke 0.00 0.00–∞ .9886 patients at risk for developing persistent rheumatic symptoms. Hypertension 1.14 0.55–2.36 .7281 Weakness in the hands during acute illness was highly associ- High cholesterol 0.39 0.16–0.91 .0304 ated with the risk of persistent arthralgia in our study partici- Diabetes 1.65 0.53–5.17 .3894 pants. Previous studies of chronic CHIKV disease patients have Seizure disorders 1.79 0.10–30.94 .6878 demonstrated joint space narrowing in the distal joints upon Cancer 0.00 0.00–∞ .9849 radiographic imaging [43–45] and remarkable persistent arth- Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval. ritis of these joints , suggesting that disseminated infection and inflammation during acute illness increases the likelihood the outbreak, which may not be the case in countries with dif- of persistent arthralgia symptoms. Clinical management of acute ferent systems . This universal system also lends confidence symptoms, particularly inflammation, and the minimization of to estimates of the number of people infected with CHIKV in acute disease duration could reduce the incidence, morbidity, Grenada during the epidemic, because people are more likely to and economic impact of chronic CHIKV disease. seek medical advice and report their symptoms. Likewise, it is In addition to the physical restrictions persistent arthralgia perhaps unsurprising that educational level, as measured here had on “chronic” participants in this study, the AIMS assess- by years of schooling, was not implicated in risk of chronic arth- ment found that chronic CHIKV disease impacted psychologic- ralgia in our study, because school in Grenada is free and com- ally and socially on sufferers, even more so than did physical pulsory until age 16, mitigating gaps in education that may be a pain. These data are in support of several other studies that have risk factor in other countries where CHIKV is endemic. reported depression and/or depressed mood or a reduction in No mosquito avoidance behavior was found to be associated overall quality of life as a long-term consequence of CHIKV with decreased risk of disease (Table 2). However, we found that infection [22, 47–50]. Thus, medical follow up with chronic preventative measures, such as the wearing of repellent, were not CHIKV sufferers should include awareness of and support for commonly practiced by the majority of participants (Figure 3). potential depression and anxiety. In addition, this psychological In addition, traditionally used efforts targeted at combatting and sociological morbidity has implications for the development night time bites, eg, sleeping under a bed net and using mosquito of intervention programs in regions of high CHIKV incidence. coils in the home during the evening, are ineffective against day- This study is limited in that we were only able to follow up time feeding Aedes vectors. This lack of engagement in avoidance with patients from the outbreak database who were contactable. practices in high-risk populations, seemingly due to perceived This may have ae ff cted the data in terms of the demography of ineffectiveness, has been reported elsewhere , and it poses the study, because some patients on the database were foreign a challenge to public health authorities in strengthening com- students of St. George’s University, who were no longer on the munication, education, and outreach to increase the adoption of island. In addition, being contactable by telephone is an indi- protective behaviors in these populations to control the spread of cator of relative SES. Notwithstanding, as previously stated, CHIKV and similar arboviruses in future outbreaks. the ethnic and SES distribution of our study participants is re- e f Th requency of being bitten by mosquitoes narrowly flective of the permanent population of Grenada. Moreover, in a missed the threshold for significance. However, it is a limita- cross-sectional cohort study such as presented here, particularly tion of our study that, in an environment where mosquitoes when the long term-effects of a disease are being investigated, abound, and suffering bites is an everyday occurrence, self-re- it is likely that those people experiencing chronic sequelae are ported frequency of bites is largely subjective. In addition, be- more inclined to participate, and thus the incidence of chronic cause CHIKV is rarely asymptomatic, even a single bite by an CHIKV disease in the general population may be overestimated. infected vector is likely to manifest as febrile disease. In the However, as discussed above, we found that the proportion of context of an epidemic, however, the frequency of being bitten our cohort meeting our criteria for chronic disease was con- also raises questions regarding the implications of viral load on cordant with several studies of similar size [15, 17, 23, 35, 38]. disease severity. CONCLUSIONS e s Th everity of acute CHIKV disease has previously been reported to be predictive of recovery and long-term arthritis This study demonstrates that the significant morbidity of chronic and arthralgia symptoms [18, 21, 34, 42]. Similarly in our study, CHIKV disease affects people across all demographic and social 8 • OFID • Heath et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx234/4788106 by Ed 'DeepDyve' Gillespie user on 16 March 2018 15. Gérardin P, Fianu A, Michault A, et al. Predictors of Chikungunya rheumatism: strata and presents a significant physical, social, and economic a prognostic survey ancillary to the TELECHIK cohort study. Arthritis Res Ther burden to affected populations. Identification of risk factors for 2013; 15:R9. chronic disease after acute outbreaks, as presented herein, is im- 16. Murillo-Zamora E, Mendoza-Cano O, Trujillo-Hernández B, et al. Persistent arthralgia and related risks factors in laboratory-confirmed cases of Chikungunya perative for prevention, early intervention, and minimization of virus infection in Mexico. Rev Panam Salud Publica 2017; 41:e72. the impact of this potentially devastating disease. 17. Sissoko D, Malvy D, Ezzedine K, et al. Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl Trop Dis 2009; 3:e389. Supplementary Data 18. Borgherini G, Poubeau P, Jossaume A, et al. Persistent arthralgia associated with Supplementary materials are available at Open Forum Infectious Diseases Chikungunya virus: a study of 88 adult patients on Reunion Island. Clin Infect Dis 2008; 47:469–75. online. Consisting of data provided by the authors to benefit the reader, 19. Essackjee K, Goorah S, Ramchurn SK, et al. Prevalence of and risk factors for the posted materials are not copyedited and are the sole responsibility of chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after the authors, so questions or comments should be addressed to the corre- infection with Chikungunya virus. Postgrad Med J 2013; 89:440–7. sponding author. 20. Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, et al. Persistent chronic inflam- mation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol 2010; 184:5914–27. Acknowledgments 21. Larrieu S, Pouderoux N, Pistone T, et al. Factors associated with persistence of We would foremost like to express our gratitude to the people of Grenada arthralgia among Chikungunya virus-infected travellers: report of 42 French who participated in this study. Thanks also to the nursing staff at each of the cases. J Clin Virol 2010; 47:85–8. Parish health centers and the Grenadian Ministry of Health for facilitating 22. Schilte C, Staikowsky F, Staikovsky F, et al. Chikungunya virus-associated long- this research. term arthralgia: a 36-month prospective longitudinal study. PLoS Negl Trop Dis Disclaimer. e f Th unders had no role in the design, conduct or report- 2013; 7:e2137. ing of this work. 23. Elsinga J, Gerstenbluth I, van der Ploeg S, et al. Long-term Chikungunya seque- lae in Curaçao: burden, determinants and a novel classification tool. J Infect Dis Finanical support. This work was funded by the American Society 2017; 216:573–81. of Tropical Medicine and Hygiene and the American Committee on 24. LaBeaud AD, Noël TP, et al. Chikungunya in the Western Hemisphere: A review Arthropod-borne Viruses via the Robert E. Shope International Fellowship of the 2014 epidemic, the potential long-term impact, and research opportunities. in Infectious Diseases (to C. J. H.). In 60th Annual Caribbean Public Health Agency (CARPHA) Health Research Potential conifl cts of interest. All authors: No reported conflicts of Conference; 2015; St. George’s University, St. George’s, Grenada. interest. 25. Macpherson C, Noel T, Jungkind D, et al. Clinical, molecular and serological All authors have submitted the ICMJE Form for Disclosure of Potential outcomes of the Chikungunya outbreak in Grenada. In 60th Annual Caribbean Conflicts of Interest. Conflicts that the editors consider relevant to the con- Public Health Agency (CARPHA) Health Research Conference; 2015; St. George’s tent of the manuscript have been disclosed. University, St. George’s, Grenada. 26. Forde MS, Martin F, Mitchell G, Bidaisee S. 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