Coxsackievirus B5 Infection and Aseptic Meningitis in Neonates and Children Robert Marier, MD; William Rodriguez, MD; Robert J. Chloupek, MD; Carl D. Brandt, PhD; Hyun Wha Kim, MD; Robert S. Baltimore, MD; Clarence L. Parker; Malcolm S. Artenstein, MD

metropolitan Washington, DC, an outaseptic meningitis in children was recognized in the summer and fall of 1972. Age-specific attack rates were highest in In

break of

children less than 1 year of age. The incidence of cases showed two peaks: one in July and another in October. Coxsackievirus B5 was associated with cases occurring in July, August, and September, but was not implicated in the October cases. Seventy-six percent of the confirmed coxsackievirus B5 infections in aseptic meningitis patients occurred in infants less than 2 months old. Specific meningeal symptoms were less frequently observed in these young infants, although viral isolations were more common (13 of 15) compared to patients over 2 months of age (four of 19). Analysis of reported coxsackievirus B5 infections in Washington, DC, and the United States as a whole suggests a five- or six-year periodicity.

outbreaks of coxsackievi¬ rus B5 occurred in the United States during the summer and fall of

Major

Received for publication Feb 4,1974; accepted Aug 14. From the Center for Disease Control (Dr. Marier); Children's Hospital National Medical Center (Drs. Rodriguez, Brandt, and Kim); and Walter Reed Army Institute of Research (Drs. Chloupek, Baltimore, and Artenstein, and Mr. Parker), Washington, DC. During this study, Dr. Marier was an Epidemic Intelligence Service officer, Center for Disease Control, assigned to the District of Columbia Department of Human Resources, and is now with the Yale University School of Medicine, New Haven, Conn. Dr. Rodriguez is a Minority Access to Research fellow. Reprint requests to Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, DC 20012 (Dr. Artenstein).

1972.' Coxsackievirus B5 infections prevalent in the metropolitan Washington, DC, area during the summer of 1972, and aseptic men¬ ingitis associated with this agent was were

common.

A wealth of factual knowledge ac¬ cumulated in the past 25 years has elucidated the epidemiologie, clinical, and laboratory features of coxsack¬ ievirus infections.2 Thus, the poten¬ tial for group coxsackieviruses to cause severe disseminated infections in newborns is well known.3 Their po¬ tential to cause less severe illness in this age group has also been recog¬ nized.4·5 The outbreak described in the current report emphasizes this fea¬ ture. In addition, enterovirus sur¬ veillance conducted at both a local and national level suggests a perio¬ dicity of coxsackievirus B5 infections. IDENTIFICATION OF CASES

the second week of July several newborns with men¬ 1972, ingitis were admitted to the Walter Reed Army Hospital in Washington, DC. Because of the young age of these infants, the initial clinical diag¬ nosis of neonatal sepsis prompted the use of antibiotics in therapy. How¬ ever, the clinical course, the failure to incriminate bacterial organisms, the occurrence of an increasing number of similar cases in the community

During

and, lastly, the recovery of coxsack¬ ievirus B5 from clinical specimens suggested that these patients were the harbingers of an epidemic in the community. Accordingly, hospitals in the area were alerted, measures to prevent transmission in nurseries were instituted,1 and surveillance and data collection procedures were estab¬ lished. New cases of aseptic men¬ ingitis in nine area hospitals were tabulated weekly. Four of the hospi¬ tals surveyed were civilian hospitals with large pediatrie services; the other five were military general hos¬ pitals. The hospitals served an area that included the nearby Virginia and

Maryland populations. In addition, reported to the Bureau of Dis¬

cases ease

bia

Control of the District of Colum¬

Department of Human Resources

included in the tabulations. Other health care surveys have indi¬ cated that the hospitals surveyed would have provided inpatient care for 98% of the pediatrie population in the District of Columbia. Only infant and childhood illness was surveyed. Criteria for the diagnosis of aseptic meningitis were these: (1) no prior antibiotic therapy, (2) cerebrospinal fluid (CSF) white blood cell (WBC) count greater than 10/cu mm, (3) negative CSF cultures for bacteria, (4) fever, (5) one of the following: lethargy, irritability, nuchal rigidity. were

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MATERIALS AND METHODS viral isolation submitted Army Institute of Re¬ search (WRAIR) were either inoculated immediately or frozen at -70 C until tested. Virus isolation and identification procedures at WRAIR were those previ¬ ously described," and used Rhesus monkey kidney, human embryonic fibroblast, or kidney monolayers, along with typing antisera obtained from commercial sources. Neutralizing antibody studies on acute and convalescent sera were performed with a challenge strain obtained from the CSF of one of the current patients. Specimens submitted to the Center for Disease Con¬ trol were frozen at -30 C until tested. The prevalence of coxsackievirus B5 infections in the community during the epidemic pe¬ riod was determined by reviewing the records of subjects whose nasal, oropharyngeal, and anal swab specimens were studied as part of ongoing virologie sur¬ veillance at Children's Hospital National Medical Center (CHNMC).'·8

Specimens for

to the Walter Reed

RESULTS Epidemiologie Studies Between June 3 and Oct 28,1972, a total of 104 patients less than 15 years old with aseptic meningitis were observed in metropolitan Wash¬ ington, DC (Fig 1). The incidence of cases peaked during the week of July 22, fell to a low point during Septem¬ ber, and then reached a second peak

21. Eightyfour of the cases occurred prior to Oct 1, and 20 occurred thereafter. There were some striking differences be¬ tween cases associated with each of these peaks: 38% of cases occurring between June and September were in infants less than 2 months of age, and 50% were in children less than 1 year old; only 5% of cases occurring in Oc¬ tober were in infants less than 2 months old, and 15% were in children less than 1 year old (Fig 2). Second, coxsackievirus B5 was isolated from 17 of 34 patients associated with the first epidemic peak, but in none of eight patients who were tested dur¬ ing the second peak. Indeed, cox¬ sackievirus B5 was not identified in metropolitan Washington, DC, after

during the week of Oct

September. There

was no

geographic or family

clustering of coxsackievirus B5 cases. Fifty percent of all aseptic men¬ ingitis patients were District of Co-

residents, 20% were Virginia residents, and 30% were Maryland lumbia

residents. The attack rate for summer and fall aseptic meningitis in District of Columbia residents less than 15 years old was 28 cases per 100,000 population per year, while for sum¬ mer cases alone the rate was 21 per

100,000 population. Age-specific

at¬

tack rates for the District of Colum¬ bia cases only are shown in Table 1. Rates for the coxsackievirus-B5-associated summer epidemic are plotted separately in that table. For the en¬ tire group of patients, ages ranged from 1 day to 15 years. The youngest patients were 1, 2, and 7 days old. There were two patients 2 weeks old and 18 patients 3 or 4 weeks old. There was no clear evidence of noso¬ comial nursery infection. Seventy percent of the patients were boys. Blacks and whites were equally affected.

Table

Clinical Characteristics The symptoms and signs of men¬ ingitis were in large measure deter¬ mined by the patient's age, and were typical of those expected in aseptic meningitis. Children over 2 months of age often had vomiting and nuchal ri¬ gidity. Of the infants less than 2 months of age, fever, irritability, and vomiting were the major presenting symptoms. A maculopapular rash was

reported

in 11

patients.

Laboratory data for all the aseptic meningitis cases are shown in Table 2. Separate analysis of the data for 17 patients with proved coxsackievirus B5 infection and for the October cases did not show differences. Labo¬ ratory findings were also related to the patient's age: CSF WBC count, protein level, lactic dehydrogenase (LDH) level, and peripheral WBC

count

significantly (P < .05) poly-

were

higher,

and the percentage of

1.—Age-Specific Attack Rates of Aseptic Meningitis Summer Outbreak Only

Summer & Fall Outbreaks

Population*

No. of Cases

100,000

0-1 >l-4 5-9 10-14

14,745 44,990 64,219 65,000 188,954

14 13 14 11 52

95 29 22 17 28

Totals *

Rate/

No. of Cases 13 10

Rate/

Age, yr

100,000 88 22 14 12 21

40

According to 1970 census.

Fig

1. -Incidence

1972.

by week of aseptic meningitis in Washington, DC, June through October

O ALL CASES

BCOXSACKIE

20

UNO

Bs

ISOLATED

VIRUS ISOLATED

18

16 14

12 10

8 6 4

2 10 17 241 I JUNE

8 15 22 29l 5 12 19 AUGUST JULY WEEK ENDING

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26> 2

9

16 23

SEPTEMBER

301

14 21 28 OCTOBER

7

morphonuclear cells (PMNs) in the CSF and peripheral WBC count were significantly lower in the younger age group. In general, the laboratory findings were typical for aseptic men¬ ingitis; for example, a 6-week-old girl had a CSF pleocytosis of 348 WBCs per cubic millimeter, with 47% PMNs; CSF glucose level was 53 mg/100 ml. Peripheral WBC count was 15,000/cu

% OF CASES 60

J 50

SUMMER OUTBREAK

HI FALL

OUTBREAK

mm, with 40% PMNs. The CSF LDH

40

level

was 27 units. Coxsackievirus B5 isolated from her CSF, throat, and stool specimens. There were, however, several cases in infants that were not so easily distinguished from those with bacterial meningitis. For example, a 3-week-old boy had a CSF WBC count of 960/cu mm, with 75% PMNs. The CSF glucose and protein levels were 48 and 80 mg/100 ml, respectively. Peripheral WBC count was 20,000/cu mm, with 55% PMNs. Coxsackievirus B5 was isolated from his CSF, throat, and stool specimens. A CSF LDH level determination was not obtained on this patient.

was

30

20

IO

500 CSF PMNs, % 50 CSF protein level, 120 CSF glucose level, mg/100 ml 40 28 CSF LDH level, units

Coxsackievirus B5 infection and aseptic meningitis in neonates and children.

In metropolitan Washington, DC, an outbreak of aseptic meningitis in children was recognized in the summer and fall of 1972. Age-specific attack rates...
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