Severity and burden of hand, foot and mouth disease in Asia: a modelling study

Abstract

Background: Hand, foot and mouth disease (HFMD) affects millions of children across Asia annually, leading to an increase in implemented control policies such as surveillance, isolation and social distancing in affected jurisdictions. However, limited knowledge of disease burden and severity causes difficulty in policy optimisation as the associated economic cost cannot be easily estimated. We use a data synthesis approach to provide a comprehensive picture of HFMD disease burden, estimating infection risk, symptomatic rates, the risk of complications and death, and overall disability-adjusted life-year (DALY) losses, along with associated uncertainties.

Methods: Complementary data from a variety of sources were synthesised with mathematical models to obtain estimates of severity of HFMD. This includes serological and other data extracted through a systematic review of HFMD epidemiology previously published by the authors, and laboratory investigations and sentinel reports from Singapore's surveillance system.

Results: HFMD is estimated to cause 96 900 (95% CI 40 600 to 259 000) age-weighted DALYs per annum in eight high-burden countries in East and Southeast Asia, with the majority of DALYs attributed to years of life lost. The symptomatic case hospitalisation rate of HFMD is 6% (2.8%-14.9%), of which 18.7% (6.7%-31.5%) are expected to develop complications. 5% (2.9%-7.4%) of such cases are fatal, bringing the overall case fatality ratio to be 52.3 (24.4-92.7) per 100 000 symptomatic infections. In contrast, the EV-A71 case fatality ratio is estimated to be at least 229.7 (75.4-672.1) per 100 000 symptomatic cases. Asymptomatic rate for EV-A71 is 71.4% (68.3%-74.3%) for ages 1-4, the years of greatest incidence.

Conclusion: Despite the high incidence rate of HFMD, total DALY due to HFMD is limited in comparison to other endemic diseases in the region, such as dengue and upper respiratory tract infection. With the majority of DALY caused by years of life lost, it is possible to mitigate most with increased EV-A71 vaccine coverage.

Keywords: Epidemiology; Mathematical Modelling; Other Infection, Disease, Disorder, Or Injury; Paediatrics.

Figure 1

The severity pyramid structure for hand, foot and mouth disease (HFMD) (total, all aetiologies) and EV-A71 in particular. Bordered boxes are data sources, while boxes within the pyramids are estimated quantities. Pale yellow boxes represent the models and outcomes of submodel 1, the infection rate model. This model uses serological data and differential equations to estimate the rate at which infection must occur to match with observed seropositivity level of EV-A71. Blue boxes represent the data, model and outcomes of submodel 2, the symptomatic incidence rate model. This model uses surveillance data from Singapore to infer the incidence rate of HFMD and EV-A71-specific HFMD. Together with submodel 1, the estimated symptomatic rate of EVA71 (cyan box) can be calculated. The orange boxes represent the data and models of submodel 3: the hierarchical model, which is used to estimate indices that quantifies the higher-level severities of HFMD. CNS, central nervous system; MOH, Ministry of Health.

Figure 2

Data and results from the infection rate model (submodel 1). Left: seropositivity levels of EV-A71 with fitted curve. Red data points are from China, blue from Taiwan and orange from Singapore, green from Vietnam and brown from Thailand. The black line is the fitted model with 95% Bayesian credible intervals. Middle: required and observed rate of EV-A71 infection. The brown line shows the age-specific infection rate of EV-A71 implied from the seropositivity curve and is the required rate to get the observed seropositivity levels; the blue line shows the calculated average EV-A71 infection rate based on Singapore’s data from submodel 2. The difference between the two lines are the unobserved cases. Right: asymptomatic infection rate. Calculated from the percentage difference between the required and observed rates of infection in the middle.

Figure 3

Age and year trend of hand, foot and mouth disease (HFMD) symptomatic infection from the Incidence rate model (submodel 2). Left: the age effect. The black line reflects the overall proportion of incidence for each year of age, and red line represents the age effect for individual years from 2005 to 2012. Middle: the year effect. The black line is an index which reflects the number of notified cases for 2005–2012. The year effect for 2013–2015 is estimated from data (notified cases) obtained from the Weekly Infectious Disease Bulletin released by the Ministry of Health, Singapore, using linear regression. The year effect of EV-A71 (blue) is mathematically derived from the proportion of cases due to EV-A71 estimated by laboratory data (right). Right: laboratory data from Singapore’s surveillance system. This shows the proportion of cases due to each virus in each year from 2005 to 2015.

Figure 4

Data and results from the hierarchical model (submodel 3). Top: hand, foot and mouth disease (HFMD) severity for total HFMD. Bottom: HFMD severity for lab-tested EV-A71 cases. These were modelled in two separate hierarchical pyramid models. The median and 95% credible intervals for each individual paper are shown by the black dot and lines, respectively. All estimates at the individual level are based from a hyperparameter or a higher-level parameter. The vertices of the diamond show the median (also the red line) and 95% Bayesian credible Intervals. These represent the overall estimate for each severity index, where the estimates are linked together with a multiplicative relationship: P(D|C) = P(D|S) × P(S|H) × P(H|C). All parameters were estimated using a Bayesian hierarchical approach using Markov chain Monte Carlo. Case hospitalisation ratio estimate for EV-A71 cannot be calculated as studies on EV-A71 cases are almost performed exclusively from hospital data, and thus the lowest level is ‘hospitalised’ and not ‘cases’.