Longitudinal analysis of post-acute chikungunya-associated arthralgia in children and adults: A prospective cohort study in Managua, Nicaragua (2014-2018)

Abstract

Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To characterize long-term chikungunya-associated arthralgia, we recruited 770 patients (105 0-4 years old [y/o], 200 5-9 y/o, 307 10-15 y/o, and 158 16+ y/o) with symptomatic chikungunya virus infections in Managua, Nicaragua, during two consecutive chikungunya epidemics (2014-2015). Participants were assessed at ~15 days and 1, 3, 6, 12, and 18 months post-fever onset. Following clinical guidelines, we defined participants by their last reported instance of arthralgia as acute (≤10 days post-fever onset), interim (>10 and <90 days), or chronic (≥90 days) cases. We observed a high prevalence of arthralgia (80-95%) across all ages over the study period. Overall, the odds of acute arthralgia increased in an age-dependent manner, with the lowest odds of arthralgia in the 0-4 y/o group (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.14-0.51) and the highest odds of arthralgia in the 16+ y/o participants (OR: 4.91, 95% CI: 1.42-30.95) relative to 10-15 y/o participants. Females had higher odds of acute arthralgia than males (OR: 1.63, 95% CI: 1.01-2.65) across all ages. We found that 23-36% of pediatric and 53% of adult participants reported an instance of post-acute arthralgia. Children exhibited the highest prevalence of post-acute polyarthralgia in their legs, followed by the hands and torso - a pattern not seen among adult participants. Further, we observed pediatric chikungunya presenting in two distinct phases: the acute phase and the subsequent interim/chronic phases. Thus, differences in the presentation of arthralgia were observed across age, sex, and disease phase in this longitudinal chikungunya cohort. Our results elucidate the long-term burden of chikungunya-associated arthralgia among pediatric and adult populations.

Fig 1. Prevalence of post-chikungunya-associated arthralgia over time, stratified by age range in years in Managua, Nicaragua (2014–2018).

Age trends for the prevalence of post-chikungunya-associated arthralgia depicted using a generalized additive model. A 95% confidence band is shown around the mean trend (A). The prevalence of arthralgia measured across days since fever onset and stratified by age range is depicted using a generalized additive model. Distributed marks at the top indicate the density of patient responses by day since fever onset. Participants were considered as having either acute (<10 days), interim (>10 and <90 days), or chronic (>90 days) disease (B).

Fig 2. Kaplan-Meier plot showing the proportion of participants reporting arthralgia over time in years in Managua, Nicaragua (2014–2018).

A Kaplan-Meier graph plotting the proportion of participants not reporting arthralgia (y-axis) against days since fever onset (x-axis). Ticks correspond to censoring events. Panels show the distribution of participants beginning 10 days post-fever onset and ending at the last reported data point based on the exclusion criteria (< 625 days post-fever onset), stratified by age range (A) and sex (B). The p-values were calculated using the log-rank test.

Fig 3. Reported polyarthralgia beyond the acute phase of chikungunya associated-arthralgia by body part and age in year in Managua, Nicaragua (2014–2018).

Cluster dendrogram depicting the relationship between occurrence of polyarthralgia across the different body parts, with the y-axis representing the underlying cluster distance calculated using the Manhattan distance method. The cophenetic distance correlation coefficient is 0.95; the higher the cophenetic distance correlation coefficient is, the more appropriately the dendrogram represents a hierarchical structure present in the original data (A). Age trends of the prevalence of arthralgia among clustered body groups (B) and individual body parts (C), including the 95% confidence intervals, visualized using shading corresponding to each respective color group and depicted using a generalized additive model.

Fig 4. Age trends in years for the percentage of chikungunya-associated arthralgia cases in each defined phase in Managua, Nicaragua (2014–2018).

Participants were considered as acute (<10 days), interim (>10 days and <90 days), or chronic (>90 days) phase arthralgia cases (A) or considered as either acute (<10 days) or post-acute (>10 days) phase arthralgia cases (B), based on their last instance of arthralgia. Graphs include the 95% confidence intervals, visualized using shading corresponding to each respective color group and depicted using a generalized additive model. The y-axis reflects, out of all participants with reported arthralgia, what percent had their last instance of arthralgia in each given phase.

Fig 5. Kaplan-Meier plot demonstrating the proportion of participants not experiencing arthralgia by diagnostic method and cohort.

A Kaplan-Meier graph plotting the proportion of participants not reporting arthralgia (y-axis) against days since fever onset (x-axis). Ticks correspond to censoring events. Panels show the distribution of participants beginning 10 days post-fever onset and ending at the last reported data point based on the exclusion criteria (<625 days post-fever onset), stratified by cohort (A) or CHIKV infection diagnostic method (B). The p-values were calculated using the log-rank test.