Recent outbreaks

14 April - July 1997, Sarawak, Malaysia

• a mixed outbreak of hand, foot and mouth disease, and a syndrome including encephalitis, acute flaccid paralysis, myopericarditis and acute pulmonary oedema that claimed the lives of 47 infants and children, whose ages ranged from 4 months to 6 years
• Enterovirus 71, Coxsackievirus B5 and a "new" adenovirus were implicated as the cause(s) of the outbreak
• the source of the infections remains unclear

April 1998 and continuing, Taiwan

• Enterovirus 71 and a mutant strain of Coxsackievirus A8 or A9 have been implicated in the current outbreak of hand, foot and mouth disease and a syndrome similar to that encountered in Malaysia last year
• 38 infants and children, all <6 years, have died as of 15 June 1998
• >200 victims have been hospitalized, >200,000 children have already been infected, and >500,000 children are likely to be infected by fall

May 1998 and continuing, Hong Kong

• on 10 June 1998, the Department of Health posted the following statement on its homepage: "According to hospital clinicians and the primary care doctors in both public and private sectors, there is no unusual rise in enterovirus activity like hand, foot and mouth disease."
• however, information obtained through personal communication with private practitioners and paediatricians suggested the contrary, both sources indicating a recent upsurge of hand, foot and mouth disease in local children since May and cases are still showing up in both public and private sectors
• educational pamphlets prepared by the Department of Health on hand, foot and mouth disease have been circulating in nurseries and kindergartens since June, suggesting that the public health authority might have been giving conflicting messages to the public regarding the current situation in Hong Kong
• "Information on Enteroviruses for Doctors" can be found at the following website: http://www.info.gov.hk/dh/new/bulletin/10-06-98.htm, which includes figures of enterovirus isolates at the Government Virus Unit from 1994 to May 1998

Virology

• 5 major groups of enteroviruses, the first 4 are termed NPEV
  

  	23 Group A Coxsackieviruses (serotypes A1-A22, A24)
  	6 Group B Coxsackieviruses (serotypes B1-B6)
  	31 Echoviruses (serotypes 1-9, 11-27, 29-33)
  	4(newer) Enteroviruses (serotypes 68-71)
  	3 Polioviruses (serotypes 1-3)

• Hepatitis A virus (previously Enterovirus 72) is no longer classified as an enterovirus because of significant genetic diversity at VPI locus which is characteristic of enteroviruses by viral RNA sequencing

Epidemiology

• ubiquitous, infections occur worldwide
• humans are the only known natural host
• infections and clinical attack rates typically highest in children <10 years of age
• higher prevalence in tropical regions, among lower socioeconomic groups, under overcrowding conditions, and where hygiene is poor
• most common in summer and early fall in temperate climates, seasonal pattern absent or less evident in the tropics
• incubation period generally 3-6 days, 12-72 hours for Coxsackievirus A24 and Enterovirus 70
• routes of transmission
  predominantly enteric transmission, faecal-oral or oral-oral (e.g. via sharing of teats or baby pacifiers among infants)
  • faecal viral shedding and period of communicability can continue for 6-12 weeks after onset of primary infections
  • viral particles can contaminate water and food, and may survive on environmental surfaces for periods long enough to allow transmission from fomites
  • infants in diapers appear to be the most efficient transmitters
  
  direct or indirect contact with respiratory droplets (e.g. Coxsackievirus A21)
  • respiratory shedding occurs 2-3 days before onset of clinical disease, is usually limited to a week or less, but can be up to 3 weeks after onset
  
  direct or indirect contact with infected tears (e.g. Coxsackievirus A24 and Enterovirus 70
  • spread via fingers and fomites
  
  perinatal or vertical transmission in newborns
• both community and nosocomial outbreaks can occur, and disruption of transmission may be difficult to attain within a short period

Clinical diseases

• the majority of enterovirus infections in children are asymptomatic
• clinical manifestations are protean, wide spectrum of both common and uncommon diseases among infants and children
• secondary household contacts may develop more severe disease as a result of exposure to a higher viral load (inoculum size)
• immunocompromised patients, especially those with humoral immunodeficiencies, can develop persistent CNS infection lasting for several months or more

Acute nonspecific febrile illness

• most common presentation of symptomatic enteroviral infection
• common cause of fever without an apparent focus or localizing sign among infants, especially during the summer and fall
• some infants will also have irritability, lethargy, poor feeding, vomiting, diarrhoea, abdominal pain, or signs of upper respiratory tract infection suggestive of common cold or pharyngitis
• infants usually recover within 2-10 days without complications

Exanthem and / or enanthem

• characteristic papulovesicular exanthem and stomatitis of hand, foot and mouth disease (HFMD) is associated with Coxsakieviruses A4, A5, A9, A10, A16, B2 and B5, and Enterovirus 71 (EV71)
• epidemic HFMD is usually caused by Coxsackievirus A16, and less often EV71
• petechial exanthem is associated with Echovirus 9
• erythema multiforme is associated with Coxsackieviruses A10, A16 and B5, Echovirus 6 and Polioviruses
• some infected children will develop a nonspecific skin rash
• characteristic pharyngeal ulcers of herpangina (vesicular pharyngitis) is associated with Coxsackieviruses A1-A10, A16 and A22, febrile convulsions occurred in 5% of cases in one series

Conjunctivitis

• acute haemorrhagic conjunctivitis (AHC) is a highly contagious infection characterized by ocular pain, pruritus, photophobia, watery discharge, eyelid swelling and subconjunctival haemorrhages
• Enterovirus 70 was the cause of the original pandemic of AHC in the late 60's and early 70's, also widely referred as "Apollo 11 disease" after the NASA space mission of 1969
• a variant of Coxsackievirus A24 also causes epidemic AHC
• incubation period is as short as 12-72 hours

Epidemic myalgia / epidemic pleurodynia / Bornholm disease / Devil's grippe

• associated with Coxsackieviruses B1-B3, B5 and B6, and Echoviruses 1 and 6
• incubation period usually 3-5 days
• characterized by acute paroxysmal spasmodic pain localized in chest or abdomen, aggravated by movement or breathing, usually accompanied by fever and frequently by headache
• pain tends to be more abdominal than thoracic in infants and young children, may be misdiagnosed as acute appendicitis
• most patients recover within 1 week of onset, but relapses do occur
• localized epidemics or similar illness in multiple family members are characteristic
• important to differentiate from more serious medical or surgical conditions
• no fatalities have been reported

Pericarditis / Myocarditis / Myopericarditis

• associated with cardiomyotropic Coxsackieviruses B1-B5, occasionally Coxsackieviruses A1, A4, A9, A16 and A23, and other enteroviruses
• enteroviruses account for 1/3 to 1/2 of all sporadic acute cases, and for virtually all cases during epidemics
• clinically indistinguishable from disease caused by other cardiotropic viruses (e.g. adenoviruses, influenza A virus, mumps virus)
• occurrence mainly sporadic, fatalities occur in only 5% of diagnosed cases, but institutional outbreaks with high case-fatality rates in newborns have been described in maternity units

Aseptic meningitis

• enteroviruses account for >90% of community-acquired cases of viral meningitis in a recently completed study in Baltimore
• more commonly associated with group B Coxsakieviruses (e.g. B2, B5) and Echoviruses (e.g. 4, 6, 9, 11, 16, 30)
• group A Coxsackieviruses (e.g. A2-A4, A7, A9-A10) cause fewer than 5% of cases
• naturally occurring (wild type) Polioviruses only an important cause of the past, so called "nonparalytic poliomyelitis"
• rare cases of vaccine-associated meningitis occur among both recipients of oral polio vaccine and close contacts of vaccinees
• only a minority of infants <3 months will have clinical manifestations of neurologic disease
• 10% have acute CNS complications such as seizures, obtundation or increased ICP

Encephalitis / Meningoencephalitis

• enteroviruses account for 10-20% of cases of encephalitis of proven viral aetiology
• associated with Coxsackieviruses B2, B4 and B5, Echoviruses 3, 4, 6 and 11, and Enterovirus 71
• group A Coxsakieviruses have been conspicuous among the agents isolated from infants and children with focal enteroviral encephalitis
• clinical manifestations range from mental status changes to coma and decerebration, partial complex seizures, hemichorea and acute cerebellar ataxia, findings that in some cases suggest a diagnosis of herpes simplex encephalitis

Myelitis / Encephalomyelitis

• NPEV rarely cause polio-like acute flaccid paralysis (AFP) that is clinically and pathologically indistinguishable from classical poliomyelitis
• myelitis caused by NPEV is less severe, muscle weakness (residual paralysis) is less likely to persist and bulbar involvement is less common
• associated with Coxsackieviruses A4, A7 and A9, Coxsackievirus B4, Echovirus 6, 9 and 16, and Enterovirus 71
• EV71 is known to have been responsible for large outbreaks of AFP involving hundreds of individuals, mostly children
• laboratory diagnosis of all AFP cases should routinely include tests capable of detecting NPEV, in particular, EV71 once the primary objective of poliovirus eradication by 2000 has been achieved

Neonatal infections

• neonates are at risk of serious and sometimes fatal diseases resulting from vertically transmitted (during perinatal period) or nosocomially acquired enterovirus infections
• group B Coxsackieviruses and Echoviruses are responsible for the vast majority of neonatal diseases
• the unique susceptibility to perinatal enterovirus infections, which extends to about 10 days of age, is based in part on the immunologic immaturity of the human infant, and in part on other host factors
• the outcome is strongly influenced by the presence or absence of passively acquired maternal antibody specific for the infecting enterovirus serotype
• the timing of maternal infection in relation to development of protective maternal IgG antibody, and delivery of the infant, may be the most critical prognostic factor
• clinical disease can range from nonspecific febrile illnesses to exanthems, bacterial-like sepsis with or without DIC, pneumonia, myocarditis, hepatitis, pancreatitis, adrenalitis, aseptic meningitis, encephalitis and disseminated infection
• the most severe manifestations are usually limited to infants younger than 10 days of age
• neonatal myocarditis is usually caused by Coxsackieviruses B2-B5, mortality rate is generally reported to be 30-50%
• neonatal hepatitis is associated with Echoviruses, in particular, Echovirus 11 which causes fulminant hepatic failure and severe coagulopathy within 2-3 days of onset, mortality rate is 80% even with intensive care and after heroic blood component replacement therapy
• perinatal pneumonitis is associated with Echovirus 6, 9 and 11, has a high mortality rate, and onset of symptoms within hours of birth in some neonates indicates prenatal exposure

Miscellaneous diseases

• parotitis (summer "mumps")
• pneumonitis
• hepatitis
• pancreatitis
• orchitis

Diagnosis

Clinical

• only AHC, HFMD and herpangina can be diagnosed clinically with relative ease and certainty
  a large proportion of enteroviral infections requires laboratory investigation for definitive diagnosis

Laboratory

• not all symptomatic enteroviral infections can be diagnosed with current technology
• specimen quality of utmost importance, highest rate of isolation for throat swabs, nasopharyngeal aspirates, stool and rectal swabs
• specimens should be obtained from any other suspected sites of clinical involvement (e.g. eye swabs, CSF, pericardial fluid etc.)
• specimen storage and transport ideally require appropriate medium and refrigeration at 4°C, repeated freezing-thawing or drying diminishes viral recovery
• cell culture techniques as routine procedure for viral isolation
• sensitivity of viral isolation varies by serotype
• viral isolation from any specimen except faeces usually can be considered causally related to compatible clinical disease
• isolation of poliovirus requires further differentiation of vaccine strain from wild type virus with nucleic acid probe or polymerase chain reaction (PCR)
• suckling mouse inoculation may be used for recovery of some group A Coxsackieviruses
• PCR for entrovirus RNA in CSF is usually more sensitive than viral isolation, but not freely available currently
• acute and convalescent sera (preferably 4 weeks after onset) should be stored frozen and paired for serological diagnosis
• rise in titre of virus-specific neutralizing antibody can be considered diagnostic especially during community outbreaks

Treatment

• no effective specific antiviral therapy currently exists
• the severity of disease and poor outcome has raised interest in the use of maternal plasma and IVIG ( Ig/kg ) to Echovirus 11-infected neonates with hepatitis and coagulopathy, anecdotal reports describe successful outcome but case numbers too small for assessment of real clinical benefit
• the putative efficacy of corticosteroids, alone or in combination with cyclosporin or azathioprine, in treating enteroviral myopericarditis have been discredited by recent studies, but a study showed that high dose IVIG administration resulted in improved left ventricular function and survival among 21 children, compared with 25 historical controls
• IVIG containing high antibody titre to specific infective enterovirus may be beneficial for treatment of life-threatening infections in neonates and immunocompromised patients

Prevention and control

• immunization
  apart from polioviruses, there are no effective vaccines against enteroviruses
• personal hygiene
  hygienic handwashing of utmost importance
  - after changing diaper
  - in between diapering or eye care of infants in nursery
  - after handling excreta like stool and respiratory secretions, including articles soiled therewith
  - after going to toilet
  - before preparing meals or handling food
  - before feeding
  - before examining individual patients in eye clinics
• avoid sharing of teats and pacifiers among infants
  avoid sharing of towels and handkerchieves
  strict asepsis in eye clinics
• environmental hygiene
  sanitary disposal of diapers and excreta like stool and respiratory secretions
  crowd reduction
  ventilation
  adequate chlorination of swimming pools, spas and jacuzzis
• isolation of mildly infected children at home
  avoid contact with other children, in particular, neonates until illness is over
  attendance at nursery, childcare centre, kindergarten or school is not advisable before full recovery
• isolation of hospitalized patients
  contact / enteric precautions are indicated for the duration of hospitalization
• individuals, including health care workers, with suspected enterovirus infections should be excluded from visiting or providing direct patient care in maternity and nursery units, and from contact with infants and pregnant women near term or in labour

Dr. Leung Chi Wai Paediatric Infectious Disease Unit Department of Paediatrics Princess Margaret Hospital