ENTEROVIRUS 71 INFECTIONS AT A CANADIAN CENTER
Enterovirus infections are very common infections in infants and children. They cause a wide spectrum of diseases including myelitis, encephalitis, aseptic meningitis, myocarditis, pericarditis, respiratory illnesses, gastroenteritis, acute hemorrhagic conjunctivitis, arthritis and exanthems. The severity varies from life-threatening to mild or asymptomatic illness.
Enterovirus 71 was first described in 1974, 1 and outbreaks have since been reported around the world. It is associated with hand, foot and mouth disease, but it is its association with neurologic syndromes such as fatal encephalitis, acute flaccid paralysis, rhombdencephalitis and aseptic meningitis that have been the distinguishing hallmark of many outbreaks. 2–9
Our understanding of the epidemiology and clinical profile of enterovirus 71 is limited because most studies are prompted by outbreaks and also because the ability to identify this enterovirus easily has been limited. 10 The aim of this study was to describe the epidemiology and clinical presentation of children infected with enterovirus 71 who were seen during a 1-year period at a tertiary care pediatric facility in Canada.
Specimens for viral isolation were collected in viral transport medium (nasopharyngeal aspirates) or sterile containers (cerebrospinal fluid, stool). Specimens were inoculated onto: human embryonic lung fibroblasts, rhesus monkey kidney cells and A549 cells. When a cytopathic effect was evident, the enterovirus was identified by immunofluorescence on cells scraped from the monolayer. An initial screen using a mouse anti-enterovirus monoclonal antibody pool (including antibodies directed against coxsackie viruses B1 to B5 and a pool of echoviruses (DAKO Diagnostic Canada, Inc., Mississauga, Ontario, Canada) was done. If this was negative, a mouse anti-enterovirus monoclonal antibody blend for detection of enteroviruses 70 and 71 was used (Chemicon International, Temecula, CA). Positive isolates were tested individually with enterovirus 70 and 71 immunofluorescent reagents (Chemicon). Hospital charts of all patients from whom enterovirus 71 was isolated between January, 1998, and December, 1998, were reviewed.
During the study period there were 20 cultures positive for enterovirus 71 from 20 patients (12 male and 8 female). The patients had a median age of 4.5 months (range, 5 weeks to 5 years). Ninety-five percent of the infections occurred during the summer and fall seasons with a peak in September. Enterovirus 71 was isolated from 12 nasopharyngeal aspirates, 4 throat swabs, 3 stools and 1 palate swab.
The clinical spectrum of patients with enterovirus 71 infections included 10 children with aseptic meningitis (including 2 cases of meningoencephalitis and 1 case of encephalitis), 7 with respiratory illness (asthma exacerbation, bronchiolitis, pneumonia, cough, apnea), 1 case each with hand, foot and mouth disease, fever without focus and postinfectious cerebellitis. The mean peak temperature was 38.8°C rectally, and fever remained for an average of 4.2 days. Eighteen patients were hospitalized with an average length of stay of 4.2 days.
Meningitis. The 10 children with meningitis had a median age of 6.5 months (range, 5 weeks to 24 months). Nine had an erythematous macular or papular rash, 7 had anorexia, 6 were irritable, 5 were lethargic and 4 vomited. Other findings were truncal ataxia in one patient, an atypical febrile seizure in another and a right Bell’s palsy in a third patient. Meningeal signs were rare. The mean peak temperature was 39°C and fever lasted an average of 5 days (range, 1 to 8 days). The mean CSF leukocyte count was 280 white blood cells/μl (range, 25 to 874) with an average of 64% neutrophils and 34% mononuclear cells. The mean cerebrospinal fluid concentrations of glucose and protein were 3.4 mmol/l and 0.6 g/l, respectively.
All patients were hospitalized with an average length of stay of 5.7 days. In addition one patient who had had an upper respiratory infection 1 week before admission presented with headache, vertigo, ataxia and horizontal nystagmus. A nasopharyngeal aspirate grew enterovirus 71. It was thought that the illness could possibly represent a postinfectious cerebellitis.
Respiratory illness. There were two cases with bronchiolitis, two cases of pneumonia, one asthma exacerbation, one case of chronic cough and aspiration and one case of apnea. The median age of this group was 4 months (range, 7 weeks to 21 months). Three patients also had gastroenteritis symptoms including anorexia, vomiting and diarrhea. Approximately one-half (three of seven) of these patients had fever with a peak mean temperature of 38.5°C lasting an average of 1.6 days (range, 1 to 3). The mean hospital duration was 2.1 days (range, 0 to 7). One case presented to the emergency room after an acute life-threatening event when the infant became apneic and cyanotic with a fixed gaze after a feeding. Enterovirus 71 was isolated from a nasopharyngeal aspirate. Whether infection was directly related to this incident or not is unclear.
Other presentations. Hand, foot and mouth syndrome was diagnosed in a 6-week-old infant who had a fever of 39.4°C; vesicles on arms, soles of feet and palate; irritability; poor feeding; and diarrhea. A 3-month-old infant who presented with fever with no focus had a peak temperature of 39.1°C and petechiae on the face and chest.
Enterovirus 71 has been associated with outbreaks involving significant neurologic disease. Large outbreaks of acute paralysis in Hungary, Bulgaria, Australia, Hong Kong, Japan and the United States have been attributed to enterovirus 71. 2–4, 8, 9 The paralytic disease, clinically indistinguishable from poliomyelitis, is characterized by asymmetric motor weakness ranging in severity from weakness of one limb to quadriplegia. In about one-third the central nervous system disease is preceded by nonspecific symptoms such as fever, headache, sore throat and anorexia. Of 149 patients with paralysis in Bulgaria, 44 children died, 4 many with bulbar symptoms. A recently described outbreak of enterovirus 71 in Taiwan emphasized the severe neurologic complications in children including brain stem encephalitis, which had a fatality of 14%. 5, 6
In contrast to the outbreaks of fatal encephalitis and acute flaccid paralysis, our patients all had relatively mild illnesses. One-half were diagnosed with aseptic meningitis and about one-third had respiratory illness. Eighteen patients were hospitalized, yet the average length of stay was 4 days and most patients improved rapidly.
Enteroviral meningitis is usually mild, lasts <1 week and has a good prognosis. This is consistent with our findings of enterovirus 71 aseptic meningitis. All patients had fever with a peak mean temperature of 39°C lasting an average of 5 days. Associated vomiting, anorexia and rashes were common. Hand, foot and mouth syndrome frequently occurs with enterovirus 71 infection. Only two of our nine patients with a rash had associated lesions on their hands, feet and mouths.
Of interest in our series was the number of cases associated with respiratory illness. This was a slightly younger group and the respiratory diseases were, for the most part, mild and self-limited. Length of hospitalization was considerably shorter for this group. It is possible that as a result of the mild clinical picture associated with enterovirus 71 respiratory illness, the true involvement of enterovirus 71 in respiratory disease remains unknown. Also, because enteroviruses are shed for weeks after primary infections, it is difficult to say whether they caused the respiratory symptoms in our patients.
In conclusion our patients with enterovirus 71 infection had a wide spectrum of illnesses that were generally mild. We did not see significant neurologic disease. It remains to be seen whether the introduction of easier diagnostic methods allows the clinician to widen the spectrum of illnesses caused by this virus.
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