Keywords enterovirus infection - asymptomatic aseptic meningitis - prematurity - simultaneous
infection - triplets
Enteroviruses are nonenveloped, single-stranded, positive-sense viruses in the Picornaviridae
family and include poliovirus, coxsackievirus groups A and B, echoviruses, and the
numbered enteroviruses. To date, more than 100 serotypes have been identified.[1 ] Primarily enteroviruses are spread person-to-person by the fecal-oral route; respiratory
and vertical transmission occur less frequently. The pathophysiology of enterovirus
infection is illustrated in [Fig. 1 ]. Intrauterine infection is rare, but often fatal.[2 ]
[3 ] Postnatal enterovirus infection tends to be more common, and more serious, when
acquired at younger ages. Sixty to seventy percent of neonates diagnosed with enterovirus
infection in the first 10 days of life are infected at the time of delivery.[4 ] Of those infected in the first month of life, up to 25% may have serious disease.[4 ] However, most severe enteroviral infections occur in the first 2 weeks of life,
manifestations of which may include overwhelming sepsis-like syndrome,[5 ] meningoencephalitis, cardiovascular collapse, myocarditis,[6 ] pneumonia, hepatitis, and/or coagulopathy.[4 ]
[7 ]
[8 ] Risk factors for severe disease in neonates include absence of neutralizing antibody,
maternal illness in the perinatal period, prematurity, onset in the first few days
of life, and infection with more virulent viruses.[7 ] Family members, hospital staff, and other caregivers also transmit infection to
newborns, especially during the peak season.[4 ] Outbreaks of necrotizing enterocolitis-like gastrointestinal infection in the newborn
intensive care nursery have been reported.[9 ]
Figure 1 The pathophysiology of enterovirus infection.
Infection is most prevalent in young children and symptomatic infection (disease)
is more frequent in males, in the summer months (in temperate regions), and in crowded
conditions. In older infants and children, common manifestations of enteroviral infection
include nonspecific febrile illness, gastroenteritis, herpangina, pharyngitis, hand
foot and mouth disease, other exanthemata, upper respiratory tract infection (URTI),
and conjunctivitis.[10 ] Among those beyond the neonatal period, infection in the first months of life tends
to be more severe (and more frequently results in hospitalization).[11 ]
[12 ]
[13 ] Sepsis-like syndrome (including multiorgan failure), hepatitis, myopericarditis,
paralysis, and central nervous system (CNS) involvement are among the more serious
manifestations of enterovirus-caused disease in older infants and children.[10 ] Enteroviral infection has been implicated in cases of sudden infant death syndrome
in at least one study, as well.[14 ] However, even in the first month of life, 79% of infected neonates are asymptomatic.[15 ]
Case Report
Ten-week-old male triplets were born at 31 weeks' gestation following a pregnancy
complicated by preterm labor and growth failure of triplet B. Cesarean delivery occurred
when their mother had impending hypertensive crisis. Following an unremarkable 1-month
stay in the newborn intensive care unit, they were sent home in August with their
parents, a 20-month-old brother who attended daycare, and the grandparents. Their
mother and brother were sick with URTI and the grandmother had acute gastroenteritis
and bronchitis. All three triplets developed URTI ~2 weeks before readmission to the
hospital.
At 10 weeks of age, one of the triplets (triplet C) was found to be fussier than usual
with increased spitting up. His temperature was 101 F. He was admitted, evaluated,
and treated for serious bacterial infection due to his prematurity and fever. His
physical examination was normal except for fever and fussiness. His sibling (triplet
B) also felt warm to touch and was found to have a temperature of 100.6 F. He was
similarly evaluated later the same day and treated for serious bacterial infection.
His physical examination was completely normal at the time of admission except for
fever. Triplet A was admitted later the same day due to the cerebrospinal fluid (CSF)
results of the other two triplets. At the time of admission and throughout his hospitalization,
he was afebrile and had a normal examination. Important features of the clinical course
of the triplets and the CSF findings are summarized in [Table 1 ].
Table 1
Clinical and Cerebrospinal Fluid Features of the Triplets
Maximum Temperature
Cerebrospinal Fluid Findings
Glucose (mg/dL)
Protein (mg/dL)
Red Blood Cells (Per µL)
White Blood Cells (Per µL)
Polymorpho-nuclear Leukocytes
(%)
Lymphocytes (%)
Monocytes (%)
Triplet A
98.6
44
102
19
773
20
60
20
Triplet B
100.6
37
96
321
11
25
57
17
Triplet C
101.0
44
58
8
445
35
10
55
All three triplets were initially treated with ampicillin and cefotaxime until bacterial
cultures of blood, urine, and CSF were negative. Triplet B required one bolus of crystalloid
and a brief course of supplemental oxygen therapy for episodes of bradycardia, which
resolved promptly. Enterovirus polymerase chain reaction (PCR) testing was positive
on CSF from all three newborns. They recovered completely and remain healthy more
than a decade later.
Discussion
Aseptic meningitis is the most common CNS infection and enteroviruses are the most
commonly identified etiology.[16 ]
[17 ] In a cohort of 227 children aged less than 24 months with enteroviral aseptic meningitis,
63.5% were less than 8 weeks old and 84.1% were less than 16 weeks old.[16 ] The most common symptoms were fever in 88% and irritability in 79%. Thirty percent
had symptoms of URTI. Evidence of meningeal irritation was noted in only 8.7%, however.[16 ] Asymptomatic enteroviral meningitis has not been reported, to the best of our knowledge.
The CSF profiles of bacterial and viral meningitis may overlap, particularly during
the earliest stages of viral meningitis, before a mononuclear predominance is established.
In a series of 17 patients with enterovirus meningitis aged less than 2 months, 62.5%
demonstrated a predominance of polymorphonuclear leukocytes in the CSF and 64% had
hypoglycorrhachia.[18 ] In the aseptic meningitis cohort of 227 patients, median white blood count was 103/mm3 (with a range of 0 to 4050/mm3 ) with median neutrophil percentage of 26% (range 0 to 100%).[16 ] The median CSF protein concentration was 67 mg/dL (range 6 to 550 mg/dL) and median
glucose concentration was 52 mg/dL (range 24 to 122 mg/dL).[16 ] It is interesting that triplet A, who was fever free and asymptomatic, had the highest
CSF protein and the most white blood cells present in the CSF.
The etiologic diagnosis of viral meningitis requires positive identification of a
virus from CSF or other site.[17 ] Although virus culture was the gold standard diagnostic test, PCR for enterovirus
detection performed on CSF is a sensitive, specific, rapid, and readily available
method for the diagnosis of enteroviral meningitis.[19 ] Treatment for aseptic meningitis caused by enterovirus infection is essentially
supportive, although the Collaborative Antiviral Study Group is conducting a randomized,
placebo-controlled therapeutic trial of the antiviral, pleconaril, for severe neonatal
enteroviral infection.[4 ]
Aseptic meningitis is an unusual complication of enteroviral infection, resulting
from seeding of the CNS during primary or secondary (major) viremia ([Fig. 1 ]). One case of intrauterine infection of twins whose mother developed chorioamnionitis
at 34 weeks' gestation documented enterovirus in the CSF of both premature neonates.[2 ] Although concurrent enteroviral aseptic meningitis in family members has been reported
rarely,[20 ] simultaneous disease acquired postnatally in twins or triplets has not (to the best
of our knowledge). Antibody-mediated immunity is of primary importance in protection
against enteroviral infection, and these premature siblings likely lacked transplacental
antibody to their virus type. Both the uncommon occurrence of enteroviral aseptic
meningitis (relative to all enterovirus infection in humans) and the rarity of concurrent
aseptic meningitis in family members suggest that host genetic factors must play an
as yet undefined role in the progression of enteroviral infection to involve the CNS.
