Cytokine and Chemokine Profiling in Patients with Hand, Foot and Mouth Disease in Singapore and Malaysia

Fiona Mei Shan Teo,Chia Yin Chong,Mia Tuang Koh,Anng Anng Wong,Justin Jang Hann Chu,Min Nyo,Natalie Woon Hui Tan,Yoke Fun Chan

doi:10.1038/s41598-018-22379-6

Abstract

Hand, foot and mouth disease (HFMD) is a prevalent contagious childhood disease typically associated with fever, oral lesions and limb exanthema. While HFMD is caused by a plethora of serotypes of viruses under the genus Enterovirus within the Picornaviridae family, Coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV-A71) are considered the main etiological agents. In recent years however, other viruses have also been isolated in considerable numbers from infected individuals in many regions, joining the legion commonly associated with HFMD. The present study investigated the cytokine and chemokine profiles of HFMD patients from Singapore and Malaysia for the first time. Comparative cohort studies of EV-A71-associated HFMD cases revealed that the Malaysia cohort had a distinct profile from the Singapore cohort, and this could be partly attributed by different EV-A71 genotypes. As the isolation of CV-A6, instead of CV-A16, had become prevalent in the Singapore cohort, it was also of particular interest to study the differential cytokine and chemokine profiles. Our data revealed that overlapping as well as unique profiles exist between the two major causative clinical isolates in the Singapore cohort. Having a better understanding of the respective immunological profiles could be useful for more accurate HFMD diagnosis, which is imperative for disease transmission control until multi-valent vaccines and/or broad-spectrum anti-viral drugs become available.

Highlights

In addition to Coxsackievirus A16 (CV-A16) and EV-A71, other serotypes such as CV-A4, CV-A5, CV-A6, CV-A7, CV-A9, CV-A10, CV-A24, Coxsackievirus B2 (CV-B2), CV-B3, CV-B4, CV-B5, EV-G18, EV-D70 and Echovirus 7 (E-7) are known to cause HFMD albeit in smaller numbers[3,8]
There were a total of 2 CV-A16-infected patients, 11 EV-A71-infected patients, 10 CV-A6-infected patients, and 9 healthy volunteers enrolled for the Singapore cohort, as well as 1 CV-A16-infected patient, 34 EV-A71-infected patients, and 1 CV-A6-infected patient enrolled for the Malaysia cohort
While EV-A71 remained as the major serotype isolated in both the Singapore and Malaysia cohorts, we observed a paradigmatic shift towards the CV-A6 serotype in the more recent recruitment from Singapore

Summary

Introduction

In addition to CV-A16 and EV-A71, other serotypes such as CV-A4, CV-A5, CV-A6, CV-A7, CV-A9, CV-A10, CV-A24, Coxsackievirus B2 (CV-B2), CV-B3, CV-B4, CV-B5, EV-G18, EV-D70 and Echovirus 7 (E-7) are known to cause HFMD albeit in smaller numbers[3,8] Some of these serotypes, are becoming more prevalent in the recent years, being capable of existing as the main circulating virus of HFMD outbreaks in some regions. Several independent studies had previously shown an association between elevated inflammatory cytokines and HFMD pathogenesis and progression[26,27,28,29,30,31,32,33,34,35,36,37,38,39] None of these studies has examined HFMD cases from Singapore and Malaysia. Previous studies have not analysed HFMD cases associated with CV-A6 infections, which was addressed in the present study

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Methods

Results