The Identification of Risk Factors for Chronic Chikungunya Arthralgia in Grenada, West Indies: A Cross-Sectional Cohort Study.

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 development 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 administered 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 suffering 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: These data demonstrate that chronic CHIKV affects 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.

Chikungunya virus (CHIKV) is an arthropod-borne virus (arbovirus), transmitted by Aedes albopictus and Aedes aegyptiae species mosquitoes [1]. Arthropod-borne viruses (arboviruses) comprise many of the most important “emerging” pathogens due to their geographic expansion and their increasing global health impact on naive populations. Chikungunya virus is a rapidly re-emerging pathogen that, over the last decade, has expanded its range across Africa and Asia and then emerged in Europe, the Pacific Region, and the Americas [2-5].

In 2013, CHIKV re-emerged in the America’s on the Caribbean Island of St. Martin, and it was first identified in Southeast Asia by the Asian genotype [6]. The rapid spread of the virus throughout the Caribbean was facilitated by an immunologically naive population and large numbers of travelers to the region from neighboring mainland countries and also travel between islands in the region.

Chikungunya virus causes both acute and chronic disabling illness. Initial week-long prostrating fevers are often followed by severe skeletal and joint pain, frank arthritis, and, more rarely, eye inflammation, vision loss, Guillain-Barre Syndrome, paralysis, vasculitis, encephalitis, hepatitis, and/or myopericarditis [7-9]. The term “chikungunya” means “that which bends up” in reference to the severe arthralgia associated with the acute phase of infection and the resulting posture of those afflicted.

To date, the precise mechanisms for CHIKV’s disabling sequelae remain to be fully elucidated unknown. Underlying comorbidities such as cardiovascular disease, hypertension, concomitant osteoarthritis, obesity, and diabetes have been identified as potentially increasing the severity of CHIKV disease [7, 8, 10–17]. In addition, age at the time of acute infection has been reported by several investigators to be predictive of persistent arthralgia after CHIKV infection [15, 17–23].

As the threat of CHIKV expansion looms, there is a specific need to study the determinants of severe human disease. The lessons learned will be valuable to assess risk and suitable therapies for severe disease.

Currently, there are no specific therapies or approved CHIKV vaccines. Ninety percent of those infected with CHIKV suffer joint pain, which can persist for years in up to 50% of patients [12]. Characterization of the risk factors and mechanisms underlying chronic disease is imperative to identify the determinants of severe human disease, assess risk, and ultimately develop risk control measures and specific therapies for this debilitating disease. In addition, syndromic surveillance may prove diagnostically valuable, in regions where CHIKV is endemic and laboratory confirmation of the disease is limited.

Our study site, Grenada, is the main island of a tri-island state of Grenada, Carriacou, and Petit Martinique in the southern Antilles. Between July and November of 2014, an explosive outbreak of CHIKV occurred in Grenada with even the most conservative estimates of attack rate at approximately 60% of the population affected [24-26]. In this study, we investigate the epidemiological, demographical, physical, and behavioral risk factors associated with development of CHIKV-related chronic arthralgia in Grenada.

METHODS

Participant Recruitment

Between November 2015 and January 2016, study participants were recruited from a health service database of patients who had had their blood tested for CHIKV during the outbreak between July and November of 2014 [24, 25]. Chikungunya virus infection had been confirmed by polymerase chain reaction and/or immunoglobulin M enzyme-linked immunosorbent assay as we have previously described [25]. The database included people who had presented at primary care facilities, hospitals, and also to St. George’s University Health Centre. All persons on this database were eligible for recruitment to our study. Healthcare in Grenada is provided free of charge to its citizens, and facilities include a General Hospital, larger local health centers in each Parish, and smaller health stations throughout the island, which are organized so that no household is more than 3 miles from a healthcare provider.

Participants were contacted via telephone and invited to attend a one-time appointment at one of the various healthcare facilities throughout the island. Home visit appointments were also offered to ensure maximum accessibility to the study.

Interview

In an in-person interview, informed consent (or parental consent for those aged <18 years) was obtained, and participants were administered questionnaires (Supplementary Figure 1) on the demographical, physical, environmental, behavioral, and social factors of their daily lives, and medical history, including any comorbidities, was also recorded. In particular, the symptoms suffered during their acute CHIKV illness, and any symptoms suffered since, were recorded. Subjects who reported persistent arthralgia, defined as suffering joint pains within the last month, were asked to complete the Arthritis Impact Measurement Scale (AIMS) questionnaire [27, 28], in order that the severity of their disease could be assessed. All interviews were conducted by 1 of 2 members of our field research team, to ensure consistency in technique and reporting.

Physical Exam

Study subjects then undertook a comprehensive physical examination administered by a single Grenadian registered nurse, again to ensure consistency and standardization of assessment. Height, weight, blood pressure, visual acuity, and reflex measurements were recorded. Current arthritis/arthralgia symptoms were documented, and extensive joint examinations were conducted to measure swelling, stiffness or restricted motion, and to verify reported symptoms.

Arthritis Severity Scoring

The severity of disease sequelae in “chronic” participants was quantified using the internationally validated AIMS score [27, 28]. The scale assesses the impact of arthritis/arthralgia on the participant’s functionality in various domains of life. The physical and symptom domains measure the impact of disease on the patient’s ability to move joints normally and their reported degree of pain, respectively. The affect and social domains of the scale assess the impact of arthralgia on the subject’s mood, sense of well being, social interactions, the pursuit of hobbies/leisure, and care of others.

Statistical Analysis

Demographic, ethnicity, physical, environmental, behavioral, and social factors were analyzed as they pertained to risk of suffering from persistent, chronic CHIKV-associated arthralgia. Subjects suffering from “chronic” arthralgia were defined as those that answered positively to the question “Have you suffered from joint pain since your initial CHIKV illness?” AND also answered “yes” to one of the questions; “Have you suffered joint pain in the last day/week/month?” Because our study was conducted 1 year after the end of the Grenadian outbreak, people answering positively to these questions have suffered symptoms within the chronic phase of the disease as classified by international consensus [29-31].

Initially, unadjusted univariate analyses were performed using Fisher’s exact test, to give crude associations of each variable or prognostic factor with the risk of chronic CHIKV arthralgia. The category boundaries for age group were as follows: <25 years, 25–44 years, 45–64 years, and ≥65 years. These were chosen to allow for comparison of data with other similar studies [15, 17, 23]. Subsequently, multivariate logistic regression models adjusting for both sex and age group were fitted to each of the other variables in turn for estimating adjusted odds ratios and associated 95% confidence intervals (CIs) for developing chronic CHIKV arthralgia status. For evaluating sex and age group, only those 2 variables were included in 1 logistic regression model. Wald χ2 tests were used to calculate P values for binary variables, and likelihood ratio χ2 tests were used for nominal variables, to give χ2 likelihood ratios and precision estimates.

For the variables of length of initial symptoms and length of initial joint pain, a Cochran-Armitage trend test was performed initially to test for associations of these with the risk of chronic joint pain. Subsequently, a multicategory logistic regression model was used to determine the odds ratio per category increase in duration.

RESULTS

A total of 240 participants were recruited to the study. Of these, 85 of the participants (35.4%) satisfied our criteria for suffering from chronic arthralgia and were administered the AIMS questionnaire to determine severity. The average time to follow up from initial presentation was 448 days (range, 391–556 days).

Of 240 participants, 64 (26.6%) were male and 176 (73.4%) were female. The age range of participants was 4–89 years, with both the mean and the median age being 40 years.

In our cohort, unadjusted estimates found that female sex did increase the risk of chronic CHIKV joint pain, although narrowly missing the threshold for significance (P = .058). However, when adjusted for age, this affect was reduced (P = .123; odds ratio [OR], 1.68; 95% CI, 0.87–3.26), suggesting that age was a more important predictor of chronic CHIKV arthralgia (Table 1).

Table 1.

Demographic Characteristics of Study Participants

Variable	Subcategory	Number of Participants (%)	Odds Ratio	95% CI	AdjustedP 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.

Indeed, unadjusted analysis of participant age demonstrated an association with the risk of chronic arthralgia. This association varied by age group (43% chronic for age <25 years, 48% for 25–44 years, 63% for 45–64 years, and 21% for ≥65 years; P = .021). After adjustment for sex, and using the <25 years as the reference group, the highest relative risk was in the 45- to 64-year-olds category (OR, 2.20; 95% CI, 0.93–5.18), followed by the 25–44 years group (OR, 1.17; 95% CI, 0.53–2.58), then the ≥65 years group (OR, 0.42; 95%, CI 0.04–11.19) (P = .043).

The ethnic distribution of participants in this study was representative of the demography of Grenada with 193 of 240 participants (80.8%) being of African descent. Of the other participants, 12 were white (5%), 5 were East Indian (2.1%), 2 were Asian (0.8%), and 27 subjects (11.3%) identified as “Other”. When adjusted for age and sex, no association was observed between ethnicity and chronic disease risk (P = .5130), and, in particular, African descent was not indicative of increased risk when compared with all other ethnic groups (P = .5761; OR, 0.81; 95% CI, 0.39–1.70) (Table 1).

St. George’s parish is the most urbanized, affluent, and densely populated parish in Grenada, and residents of this parish represented 138 of 240 (57%) of our study subjects (Table 1). No differences in the risk of developing chronic CHIKV arthralgia were detected in participants from St. George’s compared with any of the other less affluent, more rural, parishes (OR, 1.15; 95% CI, 0.65–2.05; P = .6273).

We have previously reported the characteristics of the patients seeking care at the time of the outbreak [25]. Among the participants in the current study, during acute illness, the most commonly recorded symptom was joint pain (Table 2), which was experienced by 91% of study participants and is a signature symptom of acute CHIKV disease. This was followed by fever (81%), generalized body ache (75%), headache (72%), chills (66%), muscle pain (62%), and other general symptoms of febrile illness. It is interesting to note that, of these most common symptoms, joint pain (P = .0183; OR, 6.5; 95% CI, 1.37–30.75), generalized body ache (P = .0244; OR, 2.24; 95% CI, 1.11–4.53), and weakness in the extremities (reported by 60.8% of patients) (P = .0116; OR, 2.18; 95% CI, 1.19–3.99) were associated with risk of subsequently developing chronic sequelae. Other symptoms, such as fever, retro-orbital pain, photosensitivity, stiff neck, sore throat, and impaired mental state, were also associated with increased chronic disease risk (Table 2), although this is likely due to these being indicative of increased acute disease severity.

Table 2.

The Association of Acute Chikungunya-Disease Symptoms With Chronic CHIKV Arthralgia

Acute Symptom	Number of Participants With Symptom (%)	Adjusted P Value	Adjusted Odds 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.

The impact of social economic status (SES) on the risk of developing chronic CHIKV disease was assessed via a variety of proxy measures of SES, pertaining to the participants’ occupation, educational status, living environment, and income (Table 3). Using these measures, SES was not significantly implicated in a patient’s likelihood of developing chronic disease sequelae. However, it should be noted that indicators of dwelling conditions, ie, having an outdoor pit latrine (OR, 1.99; 95% CI, 0.83–4.80; P = .1249) and/or a household floor of described as “other” in the questionnaire (suggesting a dirt floor) (OR, 2.63; 95% CI, 0.46–15.02; P = .2762), were more associated with chronic disease than educational and occupational measures (Table 3), suggesting that a poorer immediate environment increased the risk of persistent CHIKV disease sequelae.

Table 3.

Association of Proxy Measures of SES the Risk of Chronic CHIKV Arthralgia

Variable	Subcategory	Odds Ratio	95% CI	Adjusted P Value
Highest level of education				.874
	Primary School	Reference	Reference
	Secondary School	0.69	0.29–1.65
	Tertiary College	0.91	0.38–2.20
	University Undergraduate	0.73	0.30–1.78
	Professional Degree	2.89	0.36–22.99
	Other Postgraduate	0.86	0.20–3.63
	Other	0.81	0.04–15.50
No. of rooms in House		1.00	0.90–1.11	.961
No. of people in house		0.95	0.82–1.11	.534
No. of children (<18) in house		1.06	0.85–1.32	.617
House construction material				.519
	Concrete (Wall)	Reference	Reference
	Wood (Board)	1.38	0.59–3.20
	Concrete and Wood	1.44	0.71–2.92
Floor Type
	Wood	0.93	0.51–1.70	.817
	Cement	0.98	0.54–1.79	.946
	Tile	0.97	0.55–1.72	.916
	Other	2.63	0.46–15.02	.2762
Bathroom Type	Indoor Toilet	Reference	Reference	.1249
	Pit Latrine	1.99	0.83–4.8
Have air conditioning (Y/N)		0.61	0.27–1.38	.233
Have a refrigerator (Y/N)		1.28	0.41–3.95	.671

Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval; N, no; SES, social economic satus; Y, yes.

We hypothesized that mosquito avoidance behaviors were likely to determine the frequency and intensity of CHIKV exposure (ie, mosquito bites), and therefore may contribute to the severity of acute infection, and thus have an influence on the subsequent course of disease. However, we found that none of the various mosquito avoidance and repelling behaviors practiced by the participants reduced their risk of chronic disease (Figure 1). However, mosquito avoidance behaviors were not routinely nor consistently practiced (Figure 1), with most participants responding “never” to questions regarding the use of repellents (60.4% responding “never”), mosquito coils (65.8%), and sleeping under mosquito nets (75%). In contrast, however, the controlling of mosquito breeding sites around the home was practiced “always” by 45% of subjects.

Figure 1.

Analysis of the association of mosquito vector avoidance behaviors and the risk of chronic Chikungunya virus arthralgia.

Increased frequency of mosquito bites missed the cutoff for significance in this study, but it was correlated with increased risk of chronic CHIKV disease (P = .063). Chikungunya virus infection is rarely asymptomatic, and being bitten by a virus-carrying mosquito usually manifests in observable illness [8]. Thus, an increase in the frequency of bites, particularly in an epidemic situation, will increase the likelihood of CHIKV disease.

The majority of participants (57.8%) reported that their acute illness had resolved within 1 week (Table 4), and a further 25.7% of participants had recovered within 1–2 weeks. Smaller proportions of participants reported that their acute illness lasted for 3 (6.3%) and 4 weeks (5.1%).

Table 4.

Association of Duration of Acute Symptoms and Acute Joint Pain With the Risk of Chronic CHIKV Arthralgia

Variable	Number of Participants	Odds Ratio	95% CI	Adjusted P Value
Duration of Symptoms				.0061
0–3 days	35	Reference	Reference
4–7 days	105	0.74	0.32–1.73
1–2 weeks	61	0.92	0.37–2.30
3 weeks	15	1.11	0.29–4.22
4 weeks	12	4.69	4.69–28.73
Length of Acute Joint Pain				.0089
1 week	84	Reference	Reference
2 weeks	39	0.83	0.36–1.93
3 weeks	20	1.24	0.40–3.80
4 weeks	15	3.88	0.94–16.04
1–3 months	23	2.59	0.90–7.46
3–6 months	14	2.42	0.65–8.99
>6 months	24	6.76	1.74–26.32

Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval.

Using an unadjusted Cochran-Armitage trend test, the duration of symptoms during the initial acute illness was linearly associated with increased risk of suffering from chronic CHIKV disease sequelae (P = .001). In particular, increased duration of joint pain specifically, during the acute syndrome, increased the likelihood of suffering from persistent arthritis and arthralgia (P ≥ .0001) in unadjusted analyses. Adjustment for sex and age group yielded adjusted P values of .0061 and .0089, respectively (Table 4). Moreover, the adjusted OR for chronic disease per one category increase in duration of symptoms was 1.45 (95% CI, 1.14–1.84; P = .0025), and per 1 category increase in length of joint pain specifically was 1.33 (95% CI, 1.14–1.56; P = .0004).

Other studies have reported associations of body mass index (BMI) with chronic CHIKV arthralgia. Thus, we calculated BMI from the height and weight measurements of our study participants, to allow for analysis of this factor and comparison of our data. Although initial unadjusted univariate analyses of participants’ BMI associated obesity with the risk of chronic arthralgia (P = .036), after multivariate adjustment for age and sex, we found that obesity was not associated with chronic CHIKV arthralgia in Grenada (P = .1045; OR, 1.68; 95% CI, 0.90–3.16). Of note, however, high cholesterol did increase the risk of chronic arthralgia (OR, 0.39; 95% CI, 0.16–0.91; P = .0304). No association was found between chronic arthralgia and any of the other comorbidities assessed in our cohort. Of all the domains of life assessed by the AIMS score, the physical impact of chronic CHIKV disease (ie, the impact on mobility, ability to walk and bend, and limb function) had the highest average score of all the domains, indicating that all participants with persistent CHIKV disease experienced reduced physical ability after infection (Figure 2). Scores for the symptomatic (pain) domain of the scale were the widest ranging but, with the exception of the work domain, had the lowest average impact score. The affect and social domains both scored, on average, higher than physical pain on the impact scale, indicating that participants were debilitated psychologically and socially by their chronic CHIKV disease. The aspect of work was the lowest impacting in our participants. However, this domain was mainly assessed by loss of work days and income, which, due to paid sick leave in Grenada, did not affect most people.

Figure 2.

Arthritis impact scores in subjects with Chikungunya virus-related persistent arthritis and arthralgia in each distinct life domain.

In addition, each domain of the arthritis impact scale was, to varying degrees, positively associated with the duration of initial illness, and in particular duration of joint pain during acute disease (Figure 3), suggesting that prolonged acute illness not only increases likelihood of developing chronic arthralgia but also increases the impact of chronic disease.

Figure 3.

Correlation of duration of acute symptoms and initial joint pain with each life domain in arthritis impact quality-of-life assessment.

DISCUSSION

This study describes the widespread morbidity that the CHIKV epidemic had on the population of Grenada, and our data demonstrate that chronic CHIKV disease affects people across the ethnic and socioeconomic spectrum.

Increasing age was found to be a significant risk factor for chronic CHIKV arthralgia in our cohort, with those in the 25- to 44-year-old age group at the highest risk. This is in concordance with several other studies conducted in similar settings who have found age to be predictive of rheumatic sequelae after CHIKV infection [15, 17, 19, 20, 22, 23, 32–34]. We found that female gender increased the risk of chronic arthralgia, although narrowly missing the cutoff for significance, which is in concordance with several studies that have shown females to be at higher risk for persistent arthritis/arthralgia than men [19, 33, 35–37]. A total of 35.4% of our study participants met our definition of persistent arthralgia, which strongly concurs with a recent meta-analysis on the incidence of chronic arthralgia performed by Rodríguez-Morales et al. [35]. Their analyses showed that in studies with >200 participants, 34% of CHIKV-infected patients would go on to develop chronic arthritis. This proportion is also similar to that recently reported by Feldstein et al. [38], in the US Virgin Islands.

The parish of participant’s residency was not found to be a risk factor for CHIKV disease in Grenada. However, it should be noted that parish of residency is often not where participants worked, with many traveling into the capital of St. George’s each day. This is of relevance to CHIKV infection because Aedes spp are daytime feeders. Nonetheless, the amount of time spent outdoors, either as part of their occupation or outside of work, was not found to be correlated with risk of chronic disease in this study.

Similarly, no proxy measure of SES was found to be significantly implicated in increased risk of chronic arthralgia, although indicators of participants’ immediate living environment was more associated than educational and occupational indicators. Previous studies that have examined environmental and social factors that impacted upon the manifestations of CHIKV disease in small island settings have also described primary associations with housing conditions [39, 40]. The socialized healthcare system in Grenada may have minimized the impact of economic status on CHIKV disease outcome during the outbreak, which may not be the case in countries with different systems [17]. This universal system also lends confidence to estimates of the number of people infected with CHIKV in Grenada during the epidemic, because people are more likely to seek medical advice and report their symptoms. Likewise, it is perhaps unsurprising that educational level, as measured here by years of schooling, was not implicated in risk of chronic arthralgia in our study, because school in Grenada is free and compulsory until age 16, mitigating gaps in education that may be a risk factor in other countries where CHIKV is endemic.

No mosquito avoidance behavior was found to be associated with decreased risk of disease (Table 2). However, we found that preventative measures, such as the wearing of repellent, were not commonly practiced by the majority of participants (Figure 3). In addition, traditionally used efforts targeted at combatting night time bites, eg, sleeping under a bed net and using mosquito coils in the home during the evening, are ineffective against daytime feeding Aedes vectors. This lack of engagement in avoidance practices in high-risk populations, seemingly due to perceived ineffectiveness, has been reported elsewhere [41], and it poses a challenge to public health authorities in strengthening communication, education, and outreach to increase the adoption of protective behaviors in these populations to control the spread of CHIKV and similar arboviruses in future outbreaks.

The frequency of being bitten by mosquitoes narrowly missed the threshold for significance. However, it is a limitation of our study that, in an environment where mosquitoes abound, and suffering bites is an everyday occurrence, self-reported frequency of bites is largely subjective. In addition, because CHIKV is rarely asymptomatic, even a single bite by an infected vector is likely to manifest as febrile disease. In the context of an epidemic, however, the frequency of being bitten also raises questions regarding the implications of viral load on disease severity.

The severity of acute CHIKV disease has previously been reported to be predictive of recovery and long-term arthritis and arthralgia symptoms [18, 21, 34, 42]. Similarly in our study, several acute symptoms—including dizziness, retro-orbital pain, photosensitivity, stiff neck, sore throat, and altered mental state, which are suggestive of more severe illness—were found to be associated with increased chronic disease risk. Disease severity and the subsequent risk of arthritis/arthralgia has been correlated with viral load during the acute phase [20]. These observations are informative for early recognition and management of patients at risk for developing persistent rheumatic symptoms. Weakness in the hands during acute illness was highly associated with the risk of persistent arthralgia in our study participants. Previous studies of chronic CHIKV disease patients have demonstrated joint space narrowing in the distal joints upon radiographic imaging [43-45] and remarkable persistent arthritis of these joints [46], suggesting that disseminated infection and inflammation during acute illness increases the likelihood of persistent arthralgia symptoms. Clinical management of acute symptoms, particularly inflammation, and the minimization of acute disease duration could reduce the incidence, morbidity, and economic impact of chronic CHIKV disease.

In addition to the physical restrictions persistent arthralgia had on “chronic” participants in this study, the AIMS assessment found that chronic CHIKV disease impacted psychologically and socially on sufferers, even more so than did physical pain. These data are in support of several other studies that have reported depression and/or depressed mood or a reduction in overall quality of life as a long-term consequence of CHIKV infection [22, 47–50]. Thus, medical follow up with chronic CHIKV sufferers should include awareness of and support for potential depression and anxiety. In addition, this psychological and sociological morbidity has implications for the development of intervention programs in regions of high CHIKV incidence.

This study is limited in that we were only able to follow up with patients from the outbreak database who were contactable. This may have affected the data in terms of the demography of the study, because some patients on the database were foreign students of St. George’s University, who were no longer on the island. In addition, being contactable by telephone is an indicator of relative SES. Notwithstanding, as previously stated, the ethnic and SES distribution of our study participants is reflective of the permanent population of Grenada. Moreover, in a cross-sectional cohort study such as presented here, particularly when the long term-effects of a disease are being investigated, it is likely that those people experiencing chronic sequelae are more inclined to participate, and thus the incidence of chronic CHIKV disease in the general population may be overestimated. However, as discussed above, we found that the proportion of our cohort meeting our criteria for chronic disease was concordant with several studies of similar size [15, 17, 23, 35, 38].

CONCLUSIONS

This study demonstrates that the significant morbidity of chronic CHIKV disease affects people across all demographic and social strata and presents a significant physical, social, and economic burden to affected populations. Identification of risk factors for chronic disease after acute outbreaks, as presented herein, is imperative for prevention, early intervention, and minimization of the impact of this potentially devastating disease.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

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Table 5.

Association of Comorbidities With the Risk of Chronic CHIKV Arthralgia

Comorbidity	Odds Ratio	95% CI	P Value
Previous dengue infection	1.98	0.75–5.13	.1718
Asthma	0.95	0.45–2.00	.8945
Respiratory illness	1.59	0.69–3.64	.2735
Cardiovascular illness	1.33	0.44–4.04	.6095
Stroke	0.00	0.00–∞	.9886
Hypertension	1.14	0.55–2.36	.7281
High cholesterol	0.39	0.16–0.91	.0304
Diabetes	1.65	0.53–5.17	.3894
Seizure disorders	1.79	0.10–30.94	.6878
Cancer	0.00	0.00–∞	.9849

Abbreviations: CHIKV, Chikungunya virus; CI, confidence interval.