Introduction

Chikungunya, a mosquito-borne disease primarily transmitted by Aedes aegypti and Aedes albopictus, has emerged as a significant global health problem, particularly in Asian, African and the Americas [1,2]. Between 2011 and 2020, an estimated 19 million cases were reported worldwide, with approximately 80% occurring in Latin America and the Caribbean region [2].

Infection by the chikungunya virus (CHIKV, family Togaviridae, genus Alphavirus) has a wide spectrum of manifestations, ranging from asymptomatic or mild cases to severe and debilitating conditions, including neurological disorders and chronic arthralgia [3]. The prevalence of symptomatic chikungunya varies significantly across regions and populations, with an estimated rate of 75% (range: 63%−84%) [4]. The acute phase of chikungunya is primarily characterized by high fever (>39ºC), rash, headache, arthralgia and myalgia, symptoms that overlap with other arboviral infections, such as dengue [4].

Arthralgia is one of the most prominent symptoms of chikungunya, occurring in approximately 90% of cases. It is typically bilateral and symmetrical, predominantly affecting the joints of the hands, feet, knees and wrists [4,5]. Persistent arthralgia, defined as joint pain lasting beyond three months after the acute phase, is a major complication, affecting 30–60% of infected individuals [6–8]. A systematic review of 67 studies estimated the prevalence of chronic arthralgia at 44% after three months, declining to 34% after six months and 32% at twelve months [4].

The frequency of symptomatic chikungunya and persistent arthralgia post-infection, as well as the factors associated with these events, has shown high geographic heterogeneity and variation between studies [4,7]. Both events have been linked to a number of individual factors, including sociodemographic characteristics (e.g., advanced age and female sex) [9,10], comorbidities (diabetes, hypertension, ischemic heart disease, pre-existing joint disease), genetic polymorphisms and immunological factors [7,11–13]. Viral strain-related factors, such as the CHIKV lineage, have also been associated with chronic arthralgia. Specifically, the Asian lineage has been associated with a higher incidence of inapparent chikungunya infections [14], whereas the Indian Ocean lineage (a sublineage of the East/Central/South African [ECSA] strain) has been linked to chronic arthralgia [15].

Since its first detection in Brazil in 2014, CHIKV has caused severe recurrent epidemics nationwide. From 2013 to 2022, seven epidemic waves were recorded, with the Northeast region accounting for ~65% of confirmed cases being among the most affected [16]. To evaluate the long-term transmission patterns of CHIKV and other arboviruses, we conducted a population-based seroprevalence survey in Recife (2018–2019), a major urban center in Northeastern Brazil, three years after the city’s first major CHIKV epidemic (2016) [17]. The results showed an overall CHIKV, DENV and Zika (ZIKV) seroprevalence of 35.7%, 88.7% and 37.2%, respectively. Based on the estimated CHIKV seroprevalence estimate (35.7%, n = 2.070), we extrapolated that approximately 600.000 residents were infected between the virus’s emergence in 2015 and 2018/2019 survey period [17]. In this study, we estimated the prevalence of symptomatic CHIKV infection and persistent post-infection arthralgia, as well as investigated associated risk factors among the CHIKV-exposed participants in this survey.

Materials and methods

Results

A total of 760 survey participants were exposed to CHIKV. The median age was 38 years (range: 5–65), with a predominance of females (60.3%, 458/760), 54% (411/760) self-identifying as mixed-race (brown skin color) and 30.7% (175/760) reporting comorbidities. The seroprevalence of infection was 93.8% for DENV (n = 713; 95% CI: 91.9–95.3%) and 50.2% for Zika virus (n = 384; 95% CI: 46.9–54.1%) in the study population.

Of these, 532 met the symptomatic case definition criteria, resulting in a symptomatic chikungunya prevalence of 70% (95% CI: 66.7–73.2) and a symptomatic-to-asymptomatic ratio (SAR) of 2.16:1 (95% CI: 1.89:1–2.37:1).

The most frequently reported symptoms among symptomatic cases were arthralgia (93.8%), myalgia (91.3%), fever (89.8%), prostration (89.8%), and headache (81.4%). Rash, photophobia, eye pain, and edema were reported in approximately half of cases (Table 1).

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Table 1. Frequency distribution of the reported symptoms among cases of symptomatic chikungunya. Recife, Northeast Brazil, 2018-2019.

https://doi.org/10.1371/journal.pone.0328141.t001

Among participants reporting arthralgia (n = 499), over 70% experienced severe pain (VAS score ≥ 8), with a mean pain intensity of 8.3 ± 1.9 (median 9: range 1–10). The most frequently affected joints were those of the hands (89.9%), wrists (86.4%), feet (84.9%), ankles (83.9%), and knees (81.4%). Elbows and shoulders were involved in over half of cases (Table 1).

Pain intensity was significantly higher in those with arthralgia persisting >90 days (mean ± SD: 9.1 ± 1.5) compared to those with shorter symptom duration (7.9 ± 2.0; KW χ² = 54.61, p < 0.001). Similarly, females reported higher pain intensity than males (8.7 ± 0.1 vs. 7.6 ± 0.2; KW χ² = 30.37, p < 0.001), as did participants with comorbidities compared to those without (8.6 ± 0.15 vs. 8.2 ± 0.11; KW χ² = 6.71, p = 0.009).

In the univariable regression analysis, age group, sex, marital status, head of household income, education level, comorbidities, and prior DENV exposure (IgG anti-DENV) were associated with symptomatic chikungunya (p < 0.20) and were retained for multivariable analysis (Table 2). To address potential multicollinearity and explore latent structures among these variables, we performed a PCA. The data were suitable for PCA (Bartlett’s test: χ²(15) = 441.79, p < 0.001; KMO = 0.65).

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Table 2. Crude and adjusted prevalence rates (PR) of the association of sociodemographic and clinical characteristics with symptomatic chikungunya. Recife, Northeast Brazil, 2018-2019.

https://doi.org/10.1371/journal.pone.0328141.t002

A three-component structure, explaining 66.6% of the total variance, was identified: Component 1 (Sociodemographic Factor), that explained 31.4% of the variance and characterized by positive loadings for older age (0.55), prior DENV exposure (0.56), and a negative loading for being married/in a union (−0.62); Component 2 (Socioeconomic Status Factor), that explained 18.6% of the variance, was defined by a positive loading for higher income (0.73) and a negative loading for higher education level (−0.67) and; Component 3 (Biological Sex Factor), explaining 16.7% of the variance, that loaded almost exclusively on female sex (0.998).

In a multivariable logistic regression analysis model, both Components 1 and 3 were significantly independent predictors of symptomatic chikungunya. A one-standard-deviation increase in Component 1 was associated with 31% higher adjusted odds of symptomatic infection (aOR = 1.31, 95% CI: 1.17–1.46, p < 0.001). Similarly, Component 3 was associated with 34% higher odds per one-standard-deviation increase (aOR = 1.34, 95% CI: 1.15–1.57, p < 0.001). Component 2 was not significantly associated with the outcome (aOR = 1.16, 95% CI: 0.99–1.36, p = 0.062). This model showed acceptable goodness-of-fit (Hosmer-Lemeshow test: χ²(8) = 8.11, p = 0.423) and correctly classified 71.5% of cases (S1 File).

Following, a multivariable Poisson regression was performed to estimate the independent effect of each variable. The analysis confirmed that older age (≥36 years; aPR = 1.21 for 36–50 years and 1.19 for 51–65 years), female sex (aPR = 1.19; 95% CI: 1.08–1.32) and prior DENV exposure (aPR = 1.45; 95% CI: 1.03–2.04) were independently associated with an increased risk for symptomatic chikungunya. Conversely, higher household income was protective, with lower income categories showing significantly higher risk (≤2 wages: aPR = 1.34; > 2–4 wages: aPR = 1.37) (Table 2).

We next examined factors associated with chronic arthralgia (>90 days) among those who were symptomatic. From 499 symptomatic cases with arthralgia, 182 (36.5%; 95% CI: 32.4–40.8) reported chronic symptoms (>90 days). Variables associated with the outcome in univariable analysis (p-value <0.20) were age group, sex, head of the household income, comorbidities and severe acute joint pain (VAS ≥ 8) and were included in the multivariable model.

To address potential bias from missing data in head of the household income variable (n = 14, 2.8%), we performed multiple imputations using chained equation (MICE), generating five imputed datasets. The high quality of the imputation was supported by a low Fraction of Missing Information (FMI = 0.062) and a low Relative Variance Increase (RVI = 0.014). Poisson regression models were run on each imputed dataset and results were pooled for the final analysis.

In the adjusted model, older age, female sex, and severe joint pain during the acute phase of disease were independently associated with an increased risk of chronic arthralgia (Table 3). A dose-response association was observed for age compared to the reference group (5–19 years); the aPR was 2.39 (20–35 years), aPR = 4.10 (36–50 years), and aPR = 4.60 (51–65 years). Female sex was associated with 70% higher prevalence (aPR = 1.70; 95% CI: 1.29–2.25), and severe acute joint pain was associated with nearly three-fold higher risk (aPR = 2.91; 95% CI: 1.86–4.55). Conversely, a lower household income (≤2 minimum wages) was associated with a 33% lower prevalence of chronic arthralgia compared to the highest income group (aPR = 0.67; 95% CI: 0.50–0.90). Comorbidities (e.g., hypertension/diabetes) were associated with chronic arthralgia in unadjusted analysis (PR = 1.64, p < 0.01) but not in the adjusted model (Table 3).

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Table 3. Crude and adjusted prevalence rates (PR) of the association of sociodemographic and clinical characteristics with chronic arthralgia among symptomatic cases of chikungunya (n = 499). Recife, Northeast Brazil, 2018-2019.

https://doi.org/10.1371/journal.pone.0328141.t003

Discussion

In this study, we estimated the prevalence and analyzed factors associated with symptomatic chikungunya and chronic arthralgia in a population living in a hyperendemic arbovirus region, as evidenced by the high seroprevalence of DENV (93.8%) and ZIKV (50.2%).

Consistent with previous studies [4,26], the study showed a high burden of chikungunya morbidity, with 70% of study participants meeting criteria for symptomatic infection (symptomatic-to-asymptomatic ratio = 2.16:1) and a concerningly high prevalence (around 40%) of chronic arthralgia (>90 days), underscoring the significant long-term impact of CHIKV. In line with well-established clinical patterns [4,13,27], the most frequently reported symptoms were arthralgia (93.8%), myalgia (91.3%), fever (89.8%), and prostration (89.8%), with small joint, particularly the hands, wrists, and feet, most frequently affected.

Notably, over 70% of individuals who reported arthralgia in the acute phase informed severe pain, as indicated by a mean VAS score of 8.3 ± 1.9. Pain intensity was significantly higher in females, those who developed chronic arthralgia, and in individuals with comorbidities, which are groups previously established as being at risk for prolonged musculoskeletal symptoms [7,28]. Few studies have assessed joint pain intensity following CHIKV infection using the VAS [28–30]. While these studies reported moderate to severe, highlighting the clinical significance of the disease, the mean pain scores in our study population were higher than those previously documented. For instance, two cross-sectional studies, one conducted on Réunion Island (mean VAS = 5.8 ± 2.1) [29] and another in northeastern Brazil (mean VAS = 6.5 ± 2.0) [30], both reported lower pain intensity. In contrast, a prospective study of acutely ill patients admitted to hospitals in Mexico, a population likely representing more severe disease, reported higher pain scores than those in our study [28], supporting the evidence that pain intensity may reflect disease severity.

The prevalence of symptomatic chikungunya (70%) in our study population was high, aligning with rates reported in other regions [4,26]. Globally, studies have documented substantial variability in symptomatic chikungunya prevalence [4,9,14,26,31,32], suggesting that host- and virus-specific factors may shape local epidemiological patterns. Despite this variability, only three studies have analyzed risk factors, and their findings remain inconsistent [9,14,26], highlighting a critical evidence gap.

The multivariable regression analysis identified older age (>36 years), female sex, head of household income, and DENV exposure as independent factors for symptomatic chikungunya. PCA enriched this interpretation, showing the factors clustered into three latent profiles: a Sociodemographic Factor (combined older age, DENV exposure, and single marital status; aOR=1.31 per standard deviation (SD), a Socioeconomic Factor, and a distinct Biological Sex Factor (female sex; aOR=1.34 per SD. The converged findings from Poisson regression and PCA highlighted the multifactorial nature of symptomatic CHIKV infection, mainly driven by both demographic and biological sex.

The increased risk of symptomatic chikungunya with age aligns with studies from Nicaragua [14], and Brazil [31]. This trend may be explained by immunosenescence, a higher comorbidity burden, and cumulative exposure to the virus and mosquitos’ bites [33–35]. However, our findings contrast with reports from Malaysia [9] and the U.S. Virgin Islands [26]. These discrepancies may arise from differences in host genetics [36], circulating viral lineages [14], or pain perception [37].

Similarly, 20% higher in females than males (aPR = 1.19) align with studies reporting a higher frequency and severity of acute symptoms among females during CHIKV epidemics [7,28,38]. Underlying mechanisms may involve hormone-modulate immune responses [39], and established sex differences in pain perception [40]. However, it is important to note that some studies have found no significant sex-based differences [14,26], highlighting the role of other population-specific factors.

A key and novel finding was the independent association between DENV immunity and symptomatic infection (aPR = 1.45). The PCA further integrated this effect within a broader sociodemographic context of cumulative exposure (aOR=1.31) While antibody-dependent enhancement (ADE) is a postulated mechanism [41,42], in vitro evidence remains inconclusive for human disease and direct epidemiological evidence is still lacking. An alternative, non-exclusive explanation is that repeated mosquito bites in high-transmission areas modulate innate immunity, altering arboviral infections outcomes [43,44]. Based on these assumptions, we propose that this association may reflect broader effects of arthropod exposure, consistent with sociodemographic profile identified, rather than solely a virus-specific interaction. However, these finding merits investigation as it has profound implications for public health in co-endemic regions.

The multivariable analysis further identified lower income (≤4 minimum wages) as an independent risk factor for symptomatic CHIKV infection. Notably, households earning less than two minimum wages showed significantly higher prevalence of symptomatic cases. This association may reflect reduced healthcare-seeking behavior due to systemic barriers in healthcare access. While several studies have established links between socioeconomic status and Aedes-borne disease incidence [45,46], research specifically examining socioeconomic factors in relation to symptomatic chikungunya remains limited. Our findings are partially consistent with a Malaysian serological survey that identified higher education levels as a protective factor for symptomatic infection [9].

For the outcome chronic arthralgia, the final multivariable model confirmed established risk factors: older age (showing a clear dose-dependent effect), female sex (aPR = 1.70) and severe acute joint pain (aPR = 2.91). The strong association between older age and chronic arthralgia aligned with the literature [6,7,37] and may be explained by age-related immune dysregulation, leading to impaired viral clearance and prolonged inflammation [34], or cumulative joint vulnerability [47]. The association with female sex (aPR = 1.40) is well-documented [28,48] and may involve hormonal modulation of inflammation [39,49], leading to stronger inflammatory reactions [49], which may worsen joint pain and swelling. Psychosocial factors could also play a role in this sex difference. Women would report symptoms more frequently and exhibit greater healthcare-seeking behavior, leading to apparently higher disease severity in studies [40,50].

The finding that severe joint pain predicted chronic arthralgia is supported by previous studies [51] and may be related to a more robust inflammatory response or viral persistence [12]. However, the cross-sectional assessment of pain in our study requires caution; recall bias may influence this association as those with persistent pain may retrospectively report their acute-phase symptoms as more severe.

Interestingly, lower household income was associated with a reduced risk of chronic arthralgia (aPR = 0.67). This counterintuitive finding, which has been reported elsewhere [7,52], may reflect sociocultural normalization of pain and under-reporting in lower-income populations. Such under-reporting could mask a greater true burden of chronic morbidity within these groups.

Although studies generally indicate an inverse relationship between socioeconomic status and chronic pain, where those of lower status experience greater pain chronicity [53], emerging evidence suggests that social exclusion may correlate with reduced pain sensitivity, often described as ‘numbing’ [54].

The cross-sectional design and reliance on self-reported symptoms and retrospectively pain scoring, that potentially introduces recall and information bias, are key limitations of this study. Lack of biomarker measurements or other clinical exams, and potential unmeasured confounding factors limit causal inference. However, major strengths included the large, population-based population sample with laboratory-confirmed serostatus for CHIKV, ZIKV, and DENV, detailed clinical characterization (e.g., VAS pain scores, joint-specific data), the use of appropriate statistical models (Poisson regression) for common outcomes [25], and the application of PCA to identify latent risk profile and mitigate multicollinearity among explanatory variables. Furthermore, the study was conducted shortly after the first CHIKV epidemic amid low active DENV transmission [22,23], reducing the risk of misclassification bias between dengue and chikungunya cases.

In conclusion, this study highlights the high morbidity burden of chikungunya in a hyperendemic urban setting and identifies key demographic, clinical, and immunological risk factors. These findings underscore the need to prioritize public health interventions for higher-risk groups, such as older adults and women, while ensuring equitable access to care for chronic disability across all socioeconomic strata. Finally, the association between DENV immunity and increased risk of symptomatic CHIKV infection warrants further longitudinal studies to monitor specific immunological and genetic markers, which are needed to elucidate the possible underlying biological mechanisms.

Supporting information