Hand, Foot, and Mouth Disease (HFMD) in India: A Review on Clinical Manifestations, Molecular Epidemiology, Pathogenesis, and Prevention

HFMD is a childhood viral disease initiated by enteroviruses (EVs). Symptoms are initiated with mild-to-moderate fever of short duration followed by oral and skin lesions. Skin lesions are papulovesicular which appears on palms/soles of feet, hands, knees, and elbows. Oral lesions appear as vesicles producing multiple small superficial ulcers. Disease is usually mild illness but sometimes progresses in severe form as meningitis, encephalitis, and polio-like paralysis. Etiological agents of the disease belong to Picornaviridae family. The causative viral agents are from genus human enterovirus (HEV) such as enterovirus-A 71 (EV-A71), coxsackievirus –A6 (CV-A6), CV-A10, CV-A16. Coxsackievirus A-16 (CV-A16) and enterovirus A-71 (EV-A71) are the major etiological agents of this disease, among children reported globally. In India, studies conducted on HFMD cases revealed CV-A16 as a major EV type and under circulation over a period of time. Molecular studies of different CV-A16 isolates and the viral kinetic studies conducted on organ tissues of experimental mouse model with complete VP1 gene sequencing revealed presence of B1c sub genotype which is currently in circulation. Genetic changes observed at nucleotide and amino acid level in vital organs of experimental infected mice model might predict some targets and can act as markers of virulence. Mice infected with CV-A16 strains revealed progressive pathological changes in mice organs. Major affected organs were to be as brain, heart, intestine, and skeletal muscles. The present review focuses on HFMD caused by CV-A16 with epidemiological, molecular, pathogenesis and need of antivirals against the disease.

[1]  Ying Zhang,et al.  Pathogenic analysis of coxsackievirus A10 in rhesus macaques , 2022, Virologica Sinica.

[2]  V. Mahajan,et al.  Hand, Foot and Mouth Disease: A Single Centre Retrospective Study of 403 New Cases and Brief Review of Relevant Indian Literature to Understand Clinical, Epidemiological, and Virological Attributes of a Long-Lasting Indian Epidemic , 2022, Indian dermatology online journal.

[3]  V. Gopalkrishna,et al.  Epidemiological and molecular characteristics of circulating CVA16, CVA6 strains and genotype distribution in hand, foot and mouth disease cases in 2017 to 2018 from Western India , 2020, Journal of medical virology.

[4]  P. Wangikar,et al.  Pathological and molecular studies on Coxsackie virus A‐16 isolated from hand, foot, and mouth disease cases in India: Approach using neonatal mouse model , 2019, Journal of medical virology.

[5]  D. Damle Oral acyclovir for severe hand, foot and mouth disease , 2018 .

[6]  S. Esposito,et al.  Hand, foot and mouth disease: current knowledge on clinical manifestations, epidemiology, aetiology and prevention , 2018, European Journal of Clinical Microbiology & Infectious Diseases.

[7]  S. Esposito,et al.  Hand, foot and mouth disease: current knowledge on clinical manifestations, epidemiology, aetiology and prevention , 2018, European Journal of Clinical Microbiology & Infectious Diseases.

[8]  J. Bailly,et al.  Large-scale HFMD epidemics caused by Coxsackievirus A16 in Bangalore, India during 2013 and 2015. , 2017, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[9]  V. Gopalkrishna,et al.  Genetic characterization of enterovirus strains identified in Hand, Foot and Mouth Disease (HFMD): Emergence of B1c, C1 subgenotypes, E2 sublineage of CVA16, EV71 and CVA6 strains in India. , 2017, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[10]  P. Liu,et al.  Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014 , 2015, Reviews in medical virology.

[11]  S. Blomqvist,et al.  Genome Sequence of Coxsackievirus A6, Isolated during a Hand-Foot-and-Mouth Disease Outbreak in Finland in 2008 , 2014, Genome Announcements.

[12]  Qingwei Liu,et al.  A murine model of coxsackievirus A16 infection for anti-viral evaluation. , 2014, Antiviral research.

[13]  Zhenglun Liang,et al.  Coxsackievirus A16 , 2014, Human vaccines & immunotherapeutics.

[14]  Z. Ku,et al.  Active immunization with a Coxsackievirus A16 experimental inactivated vaccine induces neutralizing antibodies and protects mice against lethal infection. , 2013, Vaccine.

[15]  S. Kar,et al.  An outbreak of hand, foot and mouth disease in bhubaneswar, Odisha , 2013, Indian Pediatrics.

[16]  Junzhi Wang,et al.  A Neonatal Mouse Model of Coxsackievirus A16 for Vaccine Evaluation , 2012, Journal of Virology.

[17]  S. Chandy,et al.  Virological Investigation of Hand, Foot, and Mouth Disease in a Tertiary Care Center in South India , 2012, Journal of global infectious diseases.

[18]  S. Chitambar,et al.  Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. , 2012, Journal of medical microbiology.

[19]  Qingwei Liu,et al.  Construction and characterization of an infectious clone of coxsackievirus A16 , 2011, Virology Journal.

[20]  K. Chua,et al.  Hand foot and mouth disease due to enterovirus 71 in Malaysia , 2011, Virologica Sinica.

[21]  Feng Ruan,et al.  Risk Factors for Hand, Foot, and Mouth Disease and Herpangina and the Preventive Effect of Hand-washing , 2011, Pediatrics.

[22]  K. Yuen,et al.  Human enterovirus 71 and hand, foot and mouth disease , 2010, Epidemiology and Infection.

[23]  T. Hara,et al.  Rhombencephalitis and Coxsackievirus A16 , 2009, Emerging infectious diseases.

[24]  K. Goh,et al.  Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007. , 2009, Annals of the Academy of Medicine, Singapore.

[25]  Gulhima Arora,et al.  Hand foot and mouth disease: emerging epidemics. , 2008, Indian journal of dermatology, venereology and leprology.

[26]  Luan-Yin Chang Enterovirus 71 in Taiwan. , 2008, Pediatrics and neonatology.

[27]  Yong Zhang,et al.  Molecular epidemiological analysis of echovirus 19 isolated from an outbreak associated with hand, foot, and mouth disease (HFMD) in Shandong Province of China. , 2007, Biomedical and environmental sciences : BES.

[28]  T. Solomon,et al.  Human enterovirus 71 disease in Sarawak, Malaysia: a prospective clinical, virological, and molecular epidemiological study. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[29]  A. Luchs,et al.  Echovirus 4 associated to hand, foot and mouth disease. , 2006, Revista do Instituto de Medicina Tropical de Sao Paulo.

[30]  H. Lei,et al.  A Mouse-Adapted Enterovirus 71 Strain Causes Neurological Disease in Mice after Oral Infection , 2004, Journal of Virology.

[31]  A. Bruu Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses and Newer Enteroviruses , 2003 .

[32]  Kow-Tong Chen,et al.  An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. , 1999, The New England journal of medicine.

[33]  T. Yeh,et al.  Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[34]  D. Fleming,et al.  Epidemiological, virological, and clinical features of an epidemic of hand, foot, and mouth disease in England and Wales. , 1996, Communicable disease report. CDR review.

[35]  J. Galama,et al.  General primer-mediated polymerase chain reaction for detection of enteroviruses: application for diagnostic routine and persistent infections , 1992, Journal of clinical microbiology.

[36]  M. Ferson,et al.  Outbreak of Coxsackievirus A16 hand, foot, and mouth disease in a child day-care center. , 1991, American journal of public health.

[37]  Y. Ishimaru,et al.  Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. , 1980, Archives of disease in childhood.

[38]  E. H. Lennette,et al.  Propagation and isolation of group A coxsackieviruses in RD cells , 1975, Journal of clinical microbiology.

[39]  E. H. Lennette,et al.  An apparently new enterovirus isolated from patients with disease of the central nervous system. , 1974, The Journal of infectious diseases.

[40]  E. H. Lennette,et al.  Fatal infection in an infant associated with Coxsackie virus group A, type 16. , 1963, The New England journal of medicine.

[41]  F. Doane,et al.  Report of an outbreak of febrile illness with pharyngeal lesions and exanthem: Toronto, summer 1957; isolation of group A Coxsackie virus. , 1958, Canadian Medical Association journal.

[42]  S. Lal,et al.  Hand-foot-and-mouth disease in calicut , 2005, Indian journal of pediatrics.

[43]  K. Goh,et al.  An outbreak of hand, foot, and mouth disease in Singapore. , 1982, Bulletin of the World Health Organization.

[44]  J. M. Joseph Laboratory diagnosis of viral diseases. , 1971, Maryland state medical journal.