Cytokine and T cell responses in post-chikungunya viral arthritis: A cross-sectional study.

OBJECTIVE: To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy. METHODS: Participants with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry. RESULTS: Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05). CONCLUSION: Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy.

Regulatory T-cells and GARP expression are decreased in exercise-associated chikungunya viral arthritis flares.

Objective: Chikungunya virus (CHIKV) causes persistent arthritis, and our prior study showed that approximately one third of CHIKV arthritis patients had exacerbated arthritis associated with exercise. The underlying mechanism of exercise-associated chikungunya arthritis flare (EACAF) is unknown, and this analysis aimed to examine the regulatory T-cell immune response related to CHIKV arthritis flares. Methods: In our study, 124 Colombian patients with a history of CHIKV infection four years prior were enrolled and 113 cases with serologically confirmed CHIKV IgG were used in this analysis. Patient information was gathered via questionnaires, and blood samples were taken to identify total live peripheral blood mononuclear cells, CD4+ cells, T regulatory cells, and their immune markers. We compared outcomes in CHIKV patients with (n = 38) vs. without (n = 75) EACAF using t-tests to assess means and the Fisher's exact test, chi-squared to evaluate categorical variables, and Kruskal-Wallis tests in the setting of skewed distributions (SAS 9.3). Results: 33.6% of CHIKV cases reported worsening arthritis with exercise. EACAF patients reported higher global assessments of arthritis disease ranging from 0-100 (71.2 ± 19.7 vs. 59.9 ± 28.0, p=0.03). EACAF patients had lower ratios of T regulatory (Treg)/CD4+ T-cells (1.95 ± 0.73 vs. 2.4 ± 1.29, p = 0.04) and lower percentage of GARP (glycoprotein-A repetitions predominant) expression per Treg (0.13 ± 0.0.33 vs. 0.16 ± 0.24 p= 0.020). Conclusion: These findings suggest relative decreases in GARP expression may indicate a decreased level of immune suppression. Treg populations in patients with CHIKV arthritis may contribute to arthritis flares during exercise, though current research is conflicting.

Sleep Disturbances are a Significant Predictor of Chikungunya Arthritis Flare Severity.

OBJECTIVE: The primary objective of this research was to explore the link between sleep and flare pain associated with chikungunya virus (CHIKV) infection. The secondary objective was to investigate if cytokines and T regulatory (Treg) cells have an influence on this relationship. METHODS: A cross-sectional study was performed using data collected in Barranquilla, Colombia, which enrolled patients with and without chronic arthritis with a history of chikungunya infection. Flare severity was measured by a version of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) flare questionnaire adapted for CHIKV arthritis, including metrics for pain, difficulty with physical activity, fatigue, stiffness and difficulty maintaining social activities due to arthritis that contribute to flare severity. In addition, four sleep disturbance items, five inflammatory cytokine levels, four anti-inflammatory cytokine levels, and six Treg levels were measured. Then, multivariable linear regression models were used to test the direct and indirect effects of flare-pain on sleep disturbance, and to determine whether this relationship was mediated by cytokines or Tregs. Finally, the SAS CALIS procedure was used to test path models showing possible causal effects with mediators and confounds. RESULTS: The analysis showed that sleep disturbance is positively correlated with CHIKV arthritis flare pain, and that it is a significant predictor of flare severity after adjusting for demographic variables, cytokine, and T cell levels. Further, neither T cells nor cytokines mediate the pain/sleep relationship in CHIKV arthritis. CONCLUSION: There is a strong association between sleep disturbance and arthritis flare pain and severity; however, this relationship is not mediated by cytokines or T cells. Since this study is unable to determine causation, further research is needed to determine the mechanism underlying the relationship between sleep disturbances and CHIKV arthritis flares.

Chronic Joint Pain 3 Years after Chikungunya Virus Infection Largely Characterized by Relapsing-remitting Symptoms.

OBJECTIVE: To determine the frequency of chronic joint pain and stiffness 3 years after infection with chikungunya virus (CHIKV) in a Latin American cohort. METHODS: A cross-sectional followup of 120 patients from an initial cohort of 500 patients who reported joint pain 2 years after infection from the Atlántico Department, Colombia. Patients were clinically diagnosed as having CHIKV during the 2014-2015 epidemic, and baseline and followup symptoms at 40 months were evaluated in serologically confirmed cases. RESULTS: Of the initial 500 patients enrolled in the study, 482 had serologically confirmed chikungunya infection. From this group, 123 patients reported joint pain 20 months after infection, and 54% of those patients reported continued joint pain 40 months after infection. Therefore, 1 out of every 8 people who tested serologically positive for CHIKV infection had persistent joint pain 3 years after infection. Participants who followed up in person were predominantly adult (mean ± SD age 51 ± 14 yrs) and female (86%). The most common type of pain reported in these patients at 40 months post-infection was pain with periods of relief and subsequent reoccurrence, and over 75% reported stiffness after immobility, with 39% experiencing morning stiffness. CONCLUSION: To our knowledge, this is the first report to describe persistent joint pain and stiffness 40 months after viral infection. The high frequency of chronic disease highlights the need to develop prevention and treatment methods. Further studies should be conducted to understand the similarities between post-chikungunya joint pain and rheumatoid arthritis.

A Dengue Vaccine: Will It be Accepted and Is It Feasible? Lessons from Barranquilla, Colombia, and Merida, Venezuela.

With one vaccine on the market and others in clinical trials, policy makers in dengue endemic regions face the decision of whether to introduce a dengue vaccine in their communities. The World Health Organization (WHO) recommends that individualized assessments be conducted before any vaccine introduction to evaluate disease burden and the strength of current vaccination programs. This study seeks to aid in that decision-making process by examining the acceptability and feasibility of dengue vaccine introduction in Barranquilla, Colombia, and Merida, Venezuela. Surveys were administered February-June of 2018 for three groups: patients (n = 351), health professionals (n = 197), and government officials (n = 26). In Barranquilla, most respondents reported dengue to be a moderate-severe problem, that a dengue vaccine would be useful in their communities, and that their current vaccination programs could handle the addition of a new vaccine. In Venezuela, respondents were less likely to view dengue as a major concern and listed multiple barriers to not just dengue vaccine introduction, but to providing current vaccines as well. Further work is needed in Colombia to more objectively assess the country's readiness as a whole for a future dengue vaccine. As political and social unrest continues in Venezuela, however, future initiatives should focus on trust and capacity building. This study can serve as a framework for future assessments of the acceptability and feasibility of a dengue vaccine in both targeted areas and on larger scales.