Hand-foot-mouth disease (HFMD) is an infectious disease, commonly affects children below five years of age. The disease is so named because of its characteristic clinical presentations of vesicular rash in hand, foot and mouth.
AGENT
HFMD is caused by several viruses of Picornaviridae family and genus Enterovirus. The genus Enterovirus consists of 12 species; nine enteroviruses (Enterovirus A–F, J and H) and 3 Rhinovirus (Rhinovirus A–C).
Human enteroviruses belong to the Enterovirus species A–D. Coxsackievirus A16 (CVA16), and Enterovirus 71 (EV 71) are the two major genes of HFMD. Both EV71 and CVA16 belong to the species Enterovirus A. Other enteroviruses that are also associated with the causation of HFMD are CVA6, CVA9, CVA10, echoviruses and several coxsackie B viruses.
The members of enterovirus are small, non-enveloped, single stranded, positive sense RNA viruses. The genome is translated as a large polyprotein which is composed of four capsid proteins (VP1-VP4) and seven non-structural proteins (2A–C and 3A–D). VP1 is the major surface protein. It contains neutralizing epitopes, used as the major protein for genomic analysis and candidate antigen for vaccine preparation.
HFMD OUTBREAKS
During the last 10 years, the disease has emerged in Asia Pacific region with several large outbreaks in China, Singapore, Hong Kong, Korea, Vietnam, Japan, Malaysia, Taiwan and Thailand. In China, a major outbreak occurred in Anhui province in 2008, after which the disease has affected more than 12 million cases and 3000 deaths. HFMD is now a notifiable disease in many of these countries. Outbreaks have been reported due to EV71, CVA16 and recently due to CVA6. Outbreaks due to EV71 and CVA6 are associated with more severe cases with high rate of mortality.
Changing etiology pattern has been noted in some countries, where one agent remains predominant for one or more years and then gets replaced with another agent in subsequent years.
In India, the first outbreak of HFMD was reported in 2003 from Calicut, followed by in 2007 from West Bengal and thereafter from several other states. So far all the outbreaks have reported mild form of disease. CVA16 has been confirmed to be the causative agent in one of the outbreak.
HFMD disease can occur at any time of the year. However, the disease more commonly shows a seasonal peak during the late spring and early summer; April to August with a peak at May or June. In some years, two peaks are observed; major one during April to August and minor peak during September to October.
PATHOGENESIS
Virus is present in oropharyngeal secretion, vesicular fluid and excreted in feces of the infected person. Transmission of virus occurs primarily through person-to-person or through feco-oral route by (i) direct contact with infected oral or vesicular fluid, (ii) contact with infected droplets or fomites or (iii) ingestion of contaminated water.
Virus causing HFMD initially gets implanted in the oropharynx or ileum, from where it reaches the regional lymph nodes. Replication of virus at this site leads to viremia which causes seeding of virus to skin, mucous membrane, CNS, and other tissues. Replication at these sites leads to major viremia and clinical manifestations.
CLINICAL FEATURES
The incubation period varies from 2 to 7 days. The disease affects mostly children of below 5 years of age and adults are rarely affected. The symptoms start with general manifestations of fever, malaise, loss of appetite and sore throat.
After 1–2 days of fever, lesions initially appear in the oral cavity. Lesions in hand and feet can occur simultaneously or after the appearance of lesions in the oral cavity. Along with hand and feet, the other sites of lesions are knee, elbow and buttocks. Lesions are painful and pruritic. To begin with, these are maculopapular in nature which progresses to become vesicular with erythematous border. Symptoms in most of the cases subside within 7–8 days.
COMPLICATIONS
Complications are more commonly seen with EV71 and CVA6. In general, coxsackievirus A16 causes mild disease, whereas complications are more common due to EV71. Complications in EV71 cases occur in 20–30% of cases and mostly associated with neurological and cardiopulmonary manifestations such as meningitis, meningoencephalitis, encephalitis, acute flaccid paralysis, pulmonary hemorrhage, and myocarditis.
Coxsackie AV6 has also been associated with a relatively severe course of disease as compared to the classical cases of HFMD and considered to be a more virulent strain. In pediatric patients, CVA6 has been reported to cause severe form of skin lesions in the form of vesiculobulous, erosive and purpuric lesions. In adults with CVA6 purpuric lesions in palm and sole may resemble secondary syphilis.
LAB DIAGNOSIS
The diagnosis of HFMD is mainly based on the typical clinical presentation. Laboratory confirmation is required in atypical presentation and for genetic analysis of the strains. Confirmations of etiological agent though not important for individual patient but is helpful from a larger perspective in order to understand the molecular epidemiology of virus and to predict the severity of the outbreak.
Throat swab, vesicular fluid, stool samples are required for isolation of virus and viral genome detection by RT-PCR. Serum sample is required for detection of antibodies. Samples for virus isolation and RT-PCR should be transported at 4°C to the laboratory.
Molecular detection: Diagnosis of enterovirus infection by molecular method is presently the most commonly used practice for patient diagnosis and confirmation of outbreaks. Detection of viral RNA can be done by RT-PCR directly from clinical samples or from culture supernatant. Primers are available both pan enterovirus genome and for type specific viruses like CA16 and EV71.
Isolation: Isolation of enterovirus is done by cell culture system or suckling mice host. No single cell line support the growth of all types of enteroviruses. Various cell lines, such as human rhabdomyosarcoma (RD), HEp-2, human colorectal cancer cell line (Caco-2), and human pulmonary adenocarcinoma cell line (A549) have, therefore, been recommended for isolation of the HFMD agent. Appearance of cytopathic effect is confirmed by presence of viral antigen or RNA by immunofluorescence or PCR using type specific antisera and primer, respectively.
Serology: Demonstration of four-fold change in the antibody titer by complement fixation or neutralization can diagnose the acute disease.
Neutralization assay based on the inhibition of cytopathic effect by serial dilution of patient’s sera is the conventional method used for measurement of antibody titer against enteroviruses. The method is not used for patient diagnosis and mostly used for seroprevalence assay or retrospective confirmation of outbreak.
Presently IgM ELISA is commonly used for diagnosis. The test is available for CVA16 and EV71. IgM antibody detection is positive in around 50% of cases during the first few days of illness which increases to near 100% towards 8th day onwards. The test is commonly used these days as this is convenient and rapid. However, high antigenic similarities between different enteroviruses can lead to false positives.
VACCINE
Three Enteroviruses, 71 vaccines have been developed in China, of which one has got the licensure in December 2015 and the other two have completed phase III clinical trial.
All the three vaccines are inactivated vaccine prepared from the whole virus (EV71 C4 genotype) grown on cell culture using the principles used for the preparation of polio vaccine.
The vaccine that has been licensed by China Food and Drug Administration (CFDA) is the first EV71 vaccine to get the licensure. It has been manufactured by Chinese Academy of Medical Sciences. Vaccine has shown 97% efficacy in preventing infection by EV71 in a large clinical trial which included more than 12,000 children. Vaccine is given intramuscularly in two doses at six months and second dose after
الاكثر قراءة في الفايروسات
اخر الاخبار
اخبار العتبة العباسية المقدسة
