Hand Foot Mouth Disease or Tomato flu- an Emerging Public Health Threat
Das T1 and Das NK2
1Scientist, ICAR-DFMD, Bhubaneswar
2BVO, Bisoi, Mayurbhanj, FARD, Government of Odisha
Corresponding author E mail id: tarenisahoo@gmail.com
Abstract
HFMD is a contagious febrile rash illness common in children below 5 years old. It is reported to be associated with fatal cardiopulmonary and neurological complications. HFMD is a major public health issues in Asia-Pacific region including India. Recent outbreak of tomato flu in India is a new variant of HFMD. The present article describes about etiopathology, transmission, diagnosis, control and prevention of DFMD.
Etiology
Hand Foot Mouth Disease is a viral disease caused by Enteroviruses under Picornaviridae family affecting children younger than 5 years old (Kimmis et al., 2018). Previously, Enterovirus A71 and Coxsackievirus A16 were the most common pathogen but recently, Coxsackievirus A6 and Coxsackievirus A10 are found to be emerging pathogen associated with HFMD (Esposito and Principi, 2018). This Coxsackie virus was first described in 1948 (Esposito and Principi, 2018; Robinson et al., 1958). Enterovirus (EV) A71 produces more severe disease as compared to Coxsackievirus (CV) A16 (Chang et al.,1999). During 2009-2010, CV-A16 (55%), CV-A6(38%), EV-71, CV-A10 and E-9 were reported to be associated with HFMD in Southern and Eastern India (Gopalkrishna et al., 2012). In recent outbreak in Vellore, Tamil Nadu, CV-A6 (75%) and CV-A16(255) were detected in HFMD cases (George et al., 2022).
Epidemiology
HFMD is a major public health issues in Asia-Pacific region including Malaysia, Vietnam, China, Taiwan, Singapore, Japan, Republic of Korea, Cambodia, Australia and India associated with major outbreaks and deaths (Chu et al., 2013). In Europe and America, large outbreaks have also been reported. In India, first HFMD was detected in Calicut, Kerala in 2003 (Sasidharan et al., 2005). In India, HFMD has also been reported in many other states like Karnataka, Tamil Nadu Jammu and Kashmir, Himachal Pradesh, Uttarakhand, Maharashtra, Odisha, West Bengal, Assam, Andaman Island etc. (Agarwal et al., 2015; Sarma et al., 2017; Palani et al., 2018; Borkakoty et al., 2020; Aggarwal et al., 2022; George et al., 2022). Tomato flu is a highly contagious febrile rash illness in young children with small tomato like red skin rashes/ blisters was first detected in Kollam district, Kerala on 6th May, 2022. Apart from Kerala, Haryana, Odisha and Tamil Nādu have also reported tomato flu (Chavda et al., 2022). It was later confirmed via PCR and sequencing that tomato flu in Kerala was caused by CA16, one of the commonest viral pathogens associated with HFMD (Tang et al., 2022).
HFMD is a contagious disease common in children below 5 years old. Adolescents and adults are occasionally affected with this disease. HFMD susceptibility and severity is associated with age, sex, hygiene, social contact, high temperature(>280C) and humidity (>60%) etc. (Esposito and Principi, 2018). Mortality was reported more among children below 2 years old and males are found to develop symptoms compared to females. In temperate Asia, HFMD is more common during late spring and early summer and in tropical and sub-tropical Asia, HFMD has been reported more during late spring and fall (Esposito and Principi, 2018; Palani et al., 2018).
Transmission
HFMD is transmitted from human to human through direct body contact, contact with respiratory droplets, nasal and throat secretion, blister fluid, stool or close contact with contaminated toys, utensils, table surfaces etc. Contaminated environment like playground, hospital visit, public place visit, shopping, eating outside etc. and finger sucking, lack of access to clean water and infrequent washing of hand are other risk factors associated with HFMD (Xie et al., 2015).
Clinical signs
The incubation period is 3-5 days. Clinical signs vary from asymptomatic to symptomatic. It includes fever, chills, cough, cold, sore throat, abdominal pain, diarrhea, vomiting, malaise, myalgia, loss of appetite, pruritis, skin eruptions on hand and feet, vesicles and ulcers in the mouth. Different rashes like papular, maculopapular, erythematous, vesicular and pustular have been described to be present on different body parts including hands, legs, mouth (palate, buccal mucosa, tongue, lip, gum), buttock, trunk, face and neck (Palani et al., 2018). It is usually self-limiting. But in some cases, HFMD has been associated with severe neurological and cardiopulmonary complications which can be fatal. Coxsackievirus A16 causes large vesicle formation and central nervous system disease, Enterovirus A71produces petechial and papular rashes and Coxsackievirus A6 causes nail shedding (Aswathyraj et al., 2016).
Pathology
HFMD virus uses different cellular receptors like scavenger receptor B2, P-Selectin glycoprotein ligand-1 and Sialic acid glycan for its pathogenesis in host cells. EV-71 infection resulted in elevation of cytokines and chemokines like IL-6, IFN-γ and MIG in cerebrospinal fluid and elevation of IL-1β, IL-6, IL-8, IP-10, IL-10, TNF-α, MCP-1 etc. in plasma with resulting severe pulmonary oedema (https://doi.org/10.1086/591462). Qin et al., 2019 identified various immunological and metabolic predictors of severe HFMD. Lower number of eosinophils, blood sodium and chloride, blood creatine kinase, and increased blood neutrophils, alkaline phosphatase, globulin, IgG etc. are predictors of severe HFMD. In an experimental study, mice developed fore and hind limb paralysis on third day after intraperitoneal inoculation with CV-A16 strain and histopathology revealed muscle necrosis, infiltration of inflammatory cells, ventricular dilation, hemorrhage and neuronal degeneration in brain (Tikute et al., 2019). Necrotizing fasciitis has also been reported in HFMD affected children (Smith and Scott, 2019). Histopathology of biopsy sample discovered more necrotic keratinocytes in the upper third of epidermis and more neutrophilic infiltration in the epidermis and dermal infiltrate (Boer-Auer and Metze, 2019). The reported histopathological findings of central nervous system mainly hippocampus, brain stem, cerebellar dentate nucleus, spinal cord in severe infection are neuronophagia, perivascular cuffing, cytolysis, focal oedema etc. and in lungs, interstitial pneumonia, neurogenic pulmonary oedema and hemorrhages. Cardiopulmonary failure has been linked to brain stem encephalitis and autonomic nervous system dysregulation. (https://apps.who.int/iris/handle/10665/207490). Viral epidydimo-orchitis was also reported to be associated with HFMD (Lella et al., 2022).
Diagnosis
Rapid and early diagnosis of HFMD is required for proper clinical management and for avoiding any future complications. Throat, vesicle and rectal swab samples or stool are appropriate clinical specimens for virus detection. Virus isolation is a traditional and time-consuming method. Human rhabdomyosarcoma cells and Vero cells can be used for isolation of EV-71 and CA16. Molecular techniques like RT-PCR, Nested RT-PCR, Multiplex RT-PCR Real Time RT-PCR, Sequencing are useful for rapid diagnosis of HFMD from clinical samples. Conventional neutralization tests and indirect immunofluorescent assay (IFA) are useful in diagnosis of HFMDV (https://apps.who.int/iris/handle/10665/207490 ). Loop mediated isothermal amplification assay (LAMP) has also been developed to detect HFMD from clinical samples with high sensitivity and specificity (Chen et al., 2021).
Control and prevention
Early accurate diagnosis and proper clinical management can reduce future cardiopulmonary and nervous complications in HFMD affected children. The prevention and control measure should be followed along with proper treatment for reducing virus transmission and severity of disease. Proper and effective surveillance system, good personal hygiene and sanitation like frequent hand washing with soap, avoiding thumb sucking and nail chewing etc., improving health care facilities and clinical management services, assisting schools and childcare centers during outbreak, improving laboratory facilities, establishing network system for exchange of knowledge and information, establishing intersectoral collaboration and proper disease monitoring are important effective HFMD prevention and control measures (https://apps.who.int/iris/handle/10665/207490). Disinfecting contaminated surfaces or objects with diluted chlorine containing bleach is also useful during HFMD outbreak.
As effective treatment or antiviral drugs are not always available, effective vaccination is always a best way to prevent and control HFMD. Inactivated monovalent Enterovirus-A71 are now available in some countries to reduce EV-A71 associated HFMD burden. As major serotypes like CV-A6, CV-A16, CV-A10, CV-A5, CV-A2 are emerging, development of effective multivalent vaccine is crucial for reducing burden of such life-threatening disease with high economic significance associated with multiple serotypes (Meng et al., 2020). A promising broad spectrum HFMD Tetravalent virus like particle vaccine against CV-A6, CV-A16, CV-A10 and EV-A71 and β-propiolactone inactivated trivalent vaccine CVA6, CVA10 and CVA16 has been developed with promising result (Lim et al., 2018; Zhang et al., 2018).
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