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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 year old [y/o] children, 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. Author summary: Upon its emergence in the Americas in late 2013, chikungunya virus spread rapidly, leading to >2 million suspected autochthonous cases between 2014–2015. Much of what we know about chikungunya is derived from adult populations, leading to gaps in guidelines to treat pediatric chikungunya cases. To address these gaps, we assembled a large cohort of both pediatric (n = 612) and adult (n = 158) laboratory-confirmed (n = 682) or clinically/epidemiologically probable (n = 88) chikungunya cases from two distinct epidemics in 2014 and 2015 in Managua, Nicaragua, followed these patients over a two-year timeline, and analyzed chikungunya-associated arthralgia using rigorous statistical approaches. Our analysis demonstrates that the pediatric (0–15 years old [y/o]) population faces a previously unappreciated high burden of post-acute chikungunya-associated arthralgia. Further, we observed that post-acute arthralgia presents differently between pediatric and adult cases (16+ y/o). The difference between the two groups was evident when comparing distribution of polyarthralgia across the body parts and when analyzing the persistence of arthralgia >10 days post-fever onset. Using detailed longitudinal data, our findings provide insight into long-term chikungunya-associated arthralgia across age, sex, body parts, and the different phases of chikungunya. We believe these findings will inform clinical guidelines regarding chikungunya-associated arthralgia across all ages. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a mosquito-borne pathogen classified by the World Health Organization (WHO) as a public health emergency of international concern in 2016, and it is still identified as a priority disease. Although most infected individuals are asymptomatic or show mild symptoms, a risk of neurologic complications is associated with infection in adults. Additionally, infection during pregnancy is directly linked to microcephaly and other congenital malformations. Since there are no currently available vaccines or approved therapeutics for this virus, there is a critical unmet need in developing treatments to prevent future ZIKV outbreaks. Toward this end, we performed a large-scale cell-based high-content screen of 51,520 chemical compounds to identify potential antiviral drug candidates. The compound (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) was found to inhibit replication of multiple ZIKV strains and in different cell systems. SBI-0090799 did not affect viral entry or RNA translation but suppressed RNA replication by preventing the formation of the membranous replication compartment. Selection of drug-resistant viruses identified single-amino-acid substitutions in the N-terminal region of nonstructural protein NS4A, arguing this is the likely drug target. These resistance mutations rescued viral RNA replication and restored the formation of the membranous replication compartment. This mechanism of action is similar to clinically approved NS5A inhibitors for hepatitis C virus (HCV). Taken together, SBI-0090799 represents a promising lead candidate for the development of an antiviral treatment against ZIKV infection for the mitigation of severe complications and potential resurgent outbreaks of the virus. [ABSTRACT FROM AUTHOR]