Hand foot and mouth disease: Enteroviral load and disease severity

In this article of EBioMedicine, Chunlan Song and colleagues studied 1109 children with hand, foot and mouth disease (HFMD) [[1]Song C Li Y Zhou Y et al.Enterovirus genomic load and disease severity among children hospitalised with hand, foot and mouth disease.EBioMedicine. 2020; https://doi.org/10.1016/j.ebiom.2020.103078Summary Full Text Full Text PDF Scopus (8) Google Scholar]. They demonstrated that the ones having throat swabs testing positive for a specific enterovirus serotype via RT-PCR had higher viral genomic loads, which correlated with four markers of clinical severity, namely admission to the ICU, CNS complications, LOS over five days and need for IVIG or steroids. This association was significant for patients infected with EV-A71 and less consistent for higher viral genomic loads of CV-A6. The authors observed a decline in viral load over time after illness onset of all HFMD associated enteroviruses. The association was statistically significant for CV-A6, CV-A10 and CV-A4, but not significant for CV-A2, CV-A16, or EV-A71. In the sensitivity analysis, however, the patients whose throat swabs tested negative for enteroviruses but whose stools tested positive for EV-A71 or CV-A16 were included, which allowed detection of a statistically significant difference, which is consistent with the results of previous studies [[2]Zhao SY Wang J Teng S et al.[Observation on intestinal viral shedding time of hand, foot and mouth disease induced by coxsackievirus A6].Zhonghua Er Ke Za Zhi. 2017; 55: 369-372PubMed Google Scholar]. This is one of the few and the largest investigations to study the association of enterovirus genomic loads among HFMD patients and their clinical severities. It is notable that less than 5% of the children in this study had an underlying medical condition, and none of the patients were immunocompromised. Enteroviruses are non-enveloped, positive-sense, single-stranded RNA viruses within the Picornaviridae family. This family includes more than 100 serotypes: Coxsackieviruses A (CV-A) and B (CV-B); polioviruses; numbered enteroviral serotypes (EV) and echoviruses. HFMD is generally a benign, self-limited, disease of children, although recent reports show CV-A6 can cause severe disease in adults [[3]Broccolo F Drago F Ciccarese G et al.Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: clinical presentation and phylogenesis of CV-A6 strains.J Clin Virol. 2019; 110: 1-6Crossref PubMed Scopus (19) Google Scholar]. Children under five years of age are the group most frequently diagnosed with HFMD due to enterovirus A, e.g. EV-A71, or Coxsackieviruses, e.g. CV-A16, CV-A6 or CV-A10, and rarely by CV-A4, CV-A2 or CV-A8 [[4]Ooi MH Wong SC Lewthwaite P et al.Clinical features, diagnosis, and management of enterovirus 71.Lancet Neurol. 2010; 9: 1097-1105Summary Full Text Full Text PDF PubMed Scopus (624) Google Scholar]. Although EV-A71 is responsible for most severe clinical cases, other serotypes have recently been reported to cause an increasing proportion of significant diseases [[5]Yang B Liu F Liao Q et al.Epidemiology of hand, foot and mouth disease in China, 2008 to 2015 prior to the introduction of EV-A71 vaccine.Euro Surveill. 2017; 22 (pii=16-00824)Crossref Scopus (75) Google Scholar,[6]Li Y Chang Z Wu P et al.Emerging enteroviruses causing hand, foot and mouth disease, China, 2010-2016.Emerg Infect Dis. 2018; 24: 1902-1906Crossref PubMed Scopus (44) Google Scholar]. Reports of epidemics of severe HFMD from east Asia have become frequent [[5]Yang B Liu F Liao Q et al.Epidemiology of hand, foot and mouth disease in China, 2008 to 2015 prior to the introduction of EV-A71 vaccine.Euro Surveill. 2017; 22 (pii=16-00824)Crossref Scopus (75) Google Scholar,[7]Solomon T Lewthwaite P Perera D et al.Virology, epidemiology, pathogenesis, and control of enterovirus 71.Lancet Infect Dis. 2010; 10: 778-790Summary Full Text Full Text PDF PubMed Scopus (969) Google Scholar]. Generally, HFMD causes only mild clinical signs, e.g. exanthema, and symptoms, e.g. fever, with recovery in a few days. In a minority of cases, however, central nervous system (CNS) symptoms develop, which can progress to cardiopulmonary complications and even death. Long term sequelae of survivors of such symptoms are common, especially following EV-71 infection [[4]Ooi MH Wong SC Lewthwaite P et al.Clinical features, diagnosis, and management of enterovirus 71.Lancet Neurol. 2010; 9: 1097-1105Summary Full Text Full Text PDF PubMed Scopus (624) Google Scholar]. Such severe systemic disorders include aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, pulmonary edema and cardiorespiratory collapse. It is believed that enteroviruses first replicate in the oropharyngeal cavity, especially the tonsils, and the bowel resulting in viremia [[7]Solomon T Lewthwaite P Perera D et al.Virology, epidemiology, pathogenesis, and control of enterovirus 71.Lancet Infect Dis. 2010; 10: 778-790Summary Full Text Full Text PDF PubMed Scopus (969) Google Scholar,[8]He Y Ong KC Gao Z et al.Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis.Am J Pathol. 2014; 184: 714-720Summary Full Text Full Text PDF PubMed Scopus (46) Google Scholar], dissemination and replication in mucous membranes and other organs, causing symptoms. Viral invasion of the CNS is rare, but it is thought to occur via migration of the virus along peripheral and cranial nerves to the CNS [[9]Wong KT Munisamy B Ong KC et al.The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways.J Neuropathol Exp Neurol. 2008; 67: 162-169Crossref PubMed Scopus (130) Google Scholar]. Although the findings of the current investigation differ from smaller studies from Vietnam and China, the larger sample size and use of four indicators of clinical severity increase its validity [[10]Nhan LNT Turner HC Khanh TH et al.Economic burden attributed to children presenting to hospitals with hand, foot, and mouth disease in Vietnam.Open Forum Infect Dis. 2019; 6 (ofz284)Crossref Scopus (14) Google Scholar]. This observation is especially true for the enteroviral genomic load of EV-A71 and these indicators. The authors acknowledge several limitations of their findings: 1. Long term sequelae of HFMD, which would be expected to be more frequent and severe in hospitalised patients, were not followed; 2. Quantitative RT-PCR was not used to measure viral load; 3. Throat swabs were only collected at a single time point for each subject; although viral genomic load appeared to decrease over time after symptom onset in throat swabs, collection at multiple time points would have been useful; 4. Although findings from hospitalised patients with HFMD have the most clinical significance, the data may not apply to less symptomatic, non-hospitalised patients. Although this study and others increase our understanding of the enterovirus-host relationship of HFMD, we have only candidate antivirals for its therapy [[7]Solomon T Lewthwaite P Perera D et al.Virology, epidemiology, pathogenesis, and control of enterovirus 71.Lancet Infect Dis. 2010; 10: 778-790Summary Full Text Full Text PDF PubMed Scopus (969) Google Scholar]. Therefore, future studies need to further investigate the pathophysiology of enterovirus infections, comparing hospitalised subjects to less severely affected patients, and follow the long term sequalae. The immune response of HFMD patients also needs better understanding in order to develop more specific antiviral therapies. Recently, two inactivated monovalent EV-A71 vaccines were licensed in China, and a monovalent CV-A16 vaccine and a bivalent EV-A71 and CV-A16 vaccine are under development. International trials, however, are needed to further assess efficacy, safety, durability and cross protection against related enteroviral types. Stephen K Tyring wrote the commentary. No conflicts of interest to declare. No funders were involved. Enterovirus genomic load and disease severity among children hospitalised with hand, foot and mouth diseaseHFMD clinical severities positively associate with viral genomic loads of EV-A71 in throat swabs. Specific antiviral drugs should be developed to reduce enterovirus load and to alleviate the clinical severities for HFMD cases. Full-Text PDF Open Access