Cyclical Patterns of Hand, Foot and Mouth Disease Caused by Enterovirus A71 in Malaysia

Abstract

Enterovirus A71 (EV-A71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (HFMD) in children. In Malaysia, since the first EV-A71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2-3 years for reasons that remain unclear. We hypothesize that this cyclical pattern is due to changes in population immunity in children (measured as seroprevalence). Neutralizing antibody titers against EV-A71 were measured in 2,141 residual serum samples collected from children ≤12 years old between 1995 and 2012 to determine the seroprevalence of EV-A71. Reported national HFMD incidence was highest in children <2 years, and decreased with age; in support of this, EV-A71 seroprevalence was significantly associated with age, indicating greater susceptibility in younger children. EV-A71 epidemics are also characterized by peaks of increased genetic diversity, often with genotype changes. Cross-sectional time series analysis was used to model the association between EV-A71 epidemic periods and EV-A71 seroprevalence adjusting for age and climatic variables (temperature, rainfall, rain days and ultraviolet radiance). A 10% increase in absolute monthly EV-A71 seroprevalence was associated with a 45% higher odds of an epidemic (adjusted odds ratio, aOR1.45; 95% CI 1.24-1.69; P<0.001). Every 10% decrease in seroprevalence between preceding and current months was associated with a 16% higher odds of an epidemic (aOR = 1.16; CI 1.01-1.34 P<0.034). In summary, the 2-3 year cyclical pattern of EV-A71 epidemics in Malaysia is mainly due to the fall of population immunity accompanying the accumulation of susceptible children between epidemics. This study will impact the future planning, timing and target populations for vaccine programs.

Fig 1. Monthly distribution of the number of HFMD cases in every state of Malaysia from 2008–2014.

Data were obtained from Ministry of Health, Malaysia.

Fig 2. Age-specific incidence rates of HFMD cases in Kuala Lumpur and Malaysia.

Incidence rates (per 1000 population) of HFMD cases in (A) Kuala Lumpur and (B) Malaysia, only available for 2011 to 2014, and obtained from Ministry of Health, Malaysia.

Fig 3. Age-specific seroprevalence and geometric mean titers of EV-A71 infection.

(A) Seroprevalence rates and (B) geometric mean titers of EV-A71 infection by age, in epidemic and non-epidemic years (P<0.05*; P<0.01**; P<0.001***).

Fig 4. Age-dependent seroprevalence rates of EV-A71 infection in Kuala Lumpur, Malaysia from 1995–2012 and EV-A71 genetic diversity.

(A) Seroprevalence rates of EV-A71 infection in 1–6 years (pre-school) and 7–12 years (primary school) age groups are shown. The asterisks indicate significant differences (P<0.05) in seroprevalence between the two age groups after Bonferroni correction for multiple comparisons across individual years. The black squares indicate reported EV-A71 epidemic years. The black line indicates the overall incidence rates of HFMD as reported by the Ministry of Health, Malaysia from 2007 (the statutory notification of HFMD was enforceable only from October 2006). (B) Bayesian Skyride plot estimating the genetic diversity of EV-A71 over time. (C) Maximum clade credibility tree based on VP1 sequences showing the EV-A71 subgenotypes present in Malaysia since the first epidemic in 1997. Posterior probability values are shown at the key nodes. EV-A71 BrCr from genotype A was used as the outgroup.