High Rate of Subclinical Chikungunya Virus Infection and Association of Neutralizing Antibody with Protection in a Prospective Cohort in The Philippines

Abstract

BackgroundChikungunya virus (CHIKV) is a globally re-emerging arbovirus for which previous studies have indicated the majority of infections result in symptomatic febrile illness. We sought to characterize the proportion of subclinical and symptomatic CHIKV infections in a prospective cohort study in a country with known CHIKV circulation.Methods/FindingsA prospective longitudinal cohort of subjects ≥6 months old underwent community-based active surveillance for acute febrile illness in Cebu City, Philippines from 2012-13. Subjects with fever history were clinically evaluated at acute, 2, 5, and 8 day visits, and at a 3-week convalescent visit. Blood was collected at the acute and 3-week convalescent visits. Symptomatic CHIKV infections were identified by positive CHIKV PCR in acute blood samples and/or CHIKV IgM/IgG ELISA seroconversion in paired acute/convalescent samples. Enrollment and 12-month blood samples underwent plaque reduction neutralization test (PRNT) using CHIKV attenuated strain 181/clone25. Subclinical CHIKV infections were identified by ≥8-fold rise from a baseline enrollment PRNT titer <10 without symptomatic infection detected during the intervening surveillance period. Selected CHIKV PCR-positive samples underwent viral isolation and envelope protein-1 gene sequencing. Of 853 subjects who completed all study procedures at 12 months, 19 symptomatic infections (2.19 per 100 person-years) and 87 subclinical infections (10.03 per 100 person-years) occurred. The ratio of subclinical-to-symptomatic infections was 4.6:1 varying with age from 2:1 in 6 month-5 year olds to 12:1 in those >50 years old. Baseline CHIKV PRNT titer ≥10 was associated with 100% (95%CI: 46.1, 100.0) protection from symptomatic CHIKV infection. Phylogenetic analysis demonstrated Asian genotype closely related to strains from Asia and the Caribbean.ConclusionsSubclinical infections accounted for a majority of total CHIKV infections. A positive baseline CHIKV PRNT titer was associated with protection from symptomatic CHIKV infection. These findings have implications for assessing disease burden, understanding virus transmission, and supporting vaccine development.

Chikungunya Virus Infections Among Patients with Dengue-Like Illness at a Tertiary Care Hospital in the Philippines, 2012–2013

“…Furthermore, a study conducted in Cebu, in 2012-2013 found most CHIKV (Asian genotype) infections to be subclinical or only mildly symptomatic. 26 This suggests that the medically attended chikungunya cases in this study (which was also conducted in the Philippines and during a similar period) may represent only a small fraction of all CHIKV infections. It is also possible that the relative number of chikungunya cases misdiagnosed as dengue may be different with milder illnesses seen in primary care settings in the Philippines.…”

“…25 In another study by Yoon and others, a high rate of subclinical and symptomatic CHIKV infections was reported in a prospective community cohort in Cebu, Philippines, from 2012 to 2013 with a total incidence density of 12.22 CHIKV infections per 100 person-years. 26 These studies provide further evidence that chikungunya has re-emerged as an important disease in the Philippines as well as in Asia, 17,27 and highlights the importance of distinguishing symptomatic CHIKV infection especially in the background of hyperendemic DENV transmission. Here, we describe laboratory-confirmed CHIKV infections clinically diagnosed as dengue at a tertiary care hospital in the Philippines.…”

“…45,46 In our study, the CHIKV E1 gene sequences were Asian genotype, similar to those from CHIKVs collected in Cebu, in 2012 by Yoon and others. 26 Phylogenetic similarity between CHIKVs from the Philippines and those found recently in the Americas indicates that these viruses probably had the same origin. This genotype has been found in the Philippines since 1985 (Figure 1) indicating that the Asian genotype has been responsible for outbreaks in the Philippines for several decades.…”

“…Two CHIKV-positive acute blood samples were selected for envelope 1 (E1) gene sequencing based on a relatively strong CHIKV RT-PCR signal. E1 gene fragments were amplified and sequenced in accordance with methods previously described by Yoon and others 26 . AccessQuick RT-PCR System (Promega, Madison, WI) and PCR purification kit (Qiagen) were used for gene fragment amplification and purification, respectively.…”

The hidden burden of Chikungunya in central Mexico: results of a small-scale serosurvey

“…This is consistent with the range of 5 to 40% of asymptomatic CHKV infections previously described by other authors. [22][23][24] Although chikungunya, dengue, and zika are similar diseases that can be misclassified on clinical grounds, the severity of symptoms facilitates recognition of chikungunya and, therefore, the proportion of unapparent infections is typically lower than that in dengue (61% to 74%) or zika (80%). [25][26][27] Almost two fifths of the seropositive participants (39.5%) in our survey reported persistent pain, limited mobility, or lasting arthralgia.…”