Viral meningitis in Pediatric Population

Case Presentation• A 29-day-old male infant was brought to the office with a h/o tympanic

fever 100.0 F X2days. He was eating well and had no other symptoms. No fever during the office visit, and the physical examination was normal. Discharged with a diagnosis of a viral illness. Two days later, he developed a temperature of 103.0 F. He was mildly anorectic, more irritable and more somnolent. He had no cough, vomiting or diarrhea.

• The prenatal history: remarkable for maternal first-trimester primary genital herpes simplex virus (HSV) infection, mother tested negative for group B streptococcus. No history of IV drug use. She had not traveled out of the country and had no known exposure to ticks, cats or undercooked meat.

• The patient had been delivered by cesarean section because of probable reactivation of maternal genital HSV infection.

Case(cont.)• PE: rectal temperature of 99.6 F; pulse, 174 bpm; respiration, 40 per

minute; and BP, 97/41 mm Hg. The infant was fussy but consolable and in no acute distress. Physical examination was remarkable only for a clear nasal discharge. His lungs were clear, and the heart examination was normal. He had no bulging fontanelle, rash, petechiae, vesicular lesions, hepatosplenomegaly or neurologic abnormalities.

• The CSF:RBC= 15 per mL and WBC= 1,295 per mL, with a differential of 1 percent neutrophils, 32 percent lymphocytes and 67 percent monocytes. The cerebrospinal fluid glucose level was 35 mg per dL (1.94 mmol per L), with a serum glucose level of 110 mg per dL (6.1 mmol per L) and a cerebrospinal fluid protein measurement of 79 mg per dL (0.79 g per L). CBC: WBC=13,600 per mL, with a differential of 32 percent neutrophils, 61 percent lymphocytes and 2 percent monocytes.

Case(cont.)• Because of the patient's age and the maternal history of genital HSV

infection, the infant was admitted to the hospital, and cefotaxime (Claforan), ampicillin and acyclovir (Zovirax) were administered. Clinical improvement was apparent within the first 48 hours.

• After bacterial cultures were negative for 72 hours, therapy with cefotaxime and ampicillin was discontinued.

• After cerebrospinal fluid culture for HSV was negative for seven days and the polymerase chain reaction (PCR) test of the cerebrospinal fluid was negative, therapy with acyclovir was discontinued. Stool culture grew coxsackie B virus. The infant recovered and was reaching appropriate developmental milestones at six months of age.

Viral meningitis• Inflammation of leptomeninges• Often referred as aseptic meningitis• Usually self-limited clinical course, with complete recovery

over 7-10 days• more protracted course with meningoencephalitis or

meningomyelitis

Etiology• One third of cases: no causative agents identified• 85%- Enteroviral meningitis• 5%- Arboviruses• 4%- Herpes Family Viruses: HSV-1/HSV-2/VZV/EBV/CMV/Human Herpes

Virus-6• Rare: Mumps (1:100,000),Lymphocytic Choriomeningitis,

Adenovirus,Measles, HIV• Nonviral causes of aseptic meningitis: tuberculosis, fungi,

mycoplasma,Lyme borelliosis;chemical meningitis(post-neurosurgery),neoplasm, granulomatous disorders

• Note: consider partially-treated bacterial meningitis as a possible etiology for the aseptic nature of meningitis (pt on antibiotics for AOM/sinusitis, with meningitis and CSF findings identical to viral meningitis)

Signs and Symptoms of Meningitis in Infants

• Fever or hypothermia (temperature may also be normal) • Poor feeding • Irritability or lethargy; paradoxical irritability • Seizures • Rash (petechial, vesicular, macular) • Tachypnea or apnea• Jaundice• Meningeal signs may be absent; Bulging fontanelle (late)• Vomiting or diarrhea • Altered sleep pattern

CSF

• Cell counts with differential, Gram stain, glucose , protein and bacterial cultures.

• Some fluid should be saved if further diagnostic studies are needed.

• Viral cultures (needs 7 days to grow).• PCR: same-day results for several viruses: HSV, CMV, HIV and

enteroviruses.

• Latex antigen tests for Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis and group B streptococcus may be useful(especially if patients received antibiotics and have negative Gram stains and cultures).

CT, MRI (head)

• Indicated to help identify causative agents.• Calcifications: cytomegalovirus, toxoplasmosis,

rubella and HSV • Abscesses: Staphylococcus aureus, Citrobacter

diversus, Proteus mirabilis and other bacteria

Typical Cerebrospinal Fluid Values in Newborns and Young Infants

Normal term newborn Normal infant* Bacterial meningitis Viral Meningitis WBC < 22 /mL < 7/mL 200 -100,000/mL 25-1,000/ mL

Neutrophils < 60% < 10% 80 to 100% < 50%

Glucose > 60% of serum > 50% of serum < 40% of serum > 40% of serum

Protein 20-170 mg/ dL < 40 mg/ dL 100 to 500 mg/dL 50 to 100 mg/dL • Information from Lipton JD, Schafermeyer RW. Evolving concepts in pediatric bacterial

meningitis--part I: pathophysiology and diagnosis. Ann Emerg Med 1993;22:1602-15, and Griffith BP, Booss J. Neurologic infections of the fetus and newborn. Neurol Clin 1994;12:541-64.

Note!

• Although cerebrospinal fluid values may help to differentiate bacterial from viral etiologies, culture is still the gold standard.

• Cerebrospinal fluid values for bacterial and aseptic meningitis may overlap

• All newborns and young infants should receive antibiotic therapy if cerebrospinal fluid values are abnormal or meningitis is suspected.

• Empirical antiviral therapy (Acyclovir) should be added if the history, physical examination and laboratory findings suggest a possible viral etiology

Etiologies of Bacterial Meningitis in Newborns and Young Infants

• < 1 month of age: GBS /Enterobacteriacea/Listeria monocytogenes

• 1-3 months: GBS/S.Pneumoniae/H.influenzae/N.Meningitidis/Enterobacteriaceae

• >3months: S.pneumoniae/Haemophilus influenzae/Neisseria meningitidis/Neonatal Pathogens

• The widespread use of the H. influenzae type b (Hib) vaccine has caused a dramatic decrease in the incidence of this disease (from 2.9 cases per 100,000 in 1986 to 0.2 cases per 100,000 in 1995).

Morbidities and Mortality• Incidence of bacterial meningitis in newborns=0.3/1000 live births

(industrialized countries)• Incidence of HSV meningitis= 0.02-0.5/1000 live births.• In developed countries, the greater mortality from neonatal bacterial

meningitis from declined from 50% in 1970s to <10% in the late 1990s. • Morbidities related to neonatal bacterial meningitis -significant source of

disability. • Cerebral palsy: 8.1%, learning disability 7.5%, seizures 7.3%, and hearing

problems 25.8%. • HSV meningitis: Mortality 15%. • Both HSV-1 and HSV-2 carry the same risk of mortality, HSV-2 is more

commonly associated with higher morbidities (cerebral palsy, mental retardation, seizures, microcephaly and ophthalmic defects).

EnterovirusesPicornaviridae family (“pico”=small; “rna”=RNA)

• 85% cases of viral meningitis;• Echoviruses/coxsakieviruse A and B/ polioviruses/ and the numbered

enteroviruses.• Nonpolio enteroviruses=nearly as prevalent as rhinoviruses (common cold)• Coxsackievirus B alone = more than 60% of meningitis cases in children

younger than age 3yo• In summer and fall; acute onset, last 1-2weeks;fecal-oral and respiratory

route; associated symptoms:pharyngitis/pleurodynia/rash/pericarditis. • Expectant mothers infected with Coxsackievirus B may remain minimally

symptomatic, but their infants acquire infection perinatally =potential fatal illness, targeted mainly toward heart.

• Enteroviruses 70 &71 (strong neurotropism):meningoencephalitis, poliolike paralitic syndromes, Guillain-Barre syndrome, aseptic meningitis

• If Enterovirus is a possibility, CSF is to be sent for this viral culture.

HSV• Known for ages: Ancient Greeks and Romans coined the term “herpes”

meaning to creep or crawl.• Double-stranded DNA, enveloped, Herpesviridae Family (divided into

alpha, beta, gamma).• HSV1 &2 both belong to alpha subfamily, genus Simplexvirus.• Short replication cycle,ability to destroy infected cells,latent infection• HSV affects 1,500 to 2,000 neonates each year. • Of these, 4 percent acquire the virus congenitally, 86 percent during

delivery and 10 percent postnatally.• Risk: timing of maternal seroconversion; highest: onset of maternal

primary herpes is near the time of labor. • HSV-1= m/c cause of sporadic encephalitis; HSV-2=aseptic meningitis.• Devastating in neonatal patient, with high mortality and morbidity

Presentation of neonatal HSV infection• Incubation=4-21 day, so exhibit signs btw 6 and 21 days postnatally• Three patterns:• 1= localized HSV with herpetic lesions of the skin, eye or mouth (SEM); if

left untreated, 75% progress to more extensive infection• 2= generalized herpes sepsis, resembles bacterial sepsis, with alterations

in temperature, and lethargy, respiratory distress, anorexia, vomiting and cyanosis.

• 3= localized central nervous system infection (meningitis or encephalitis), with irritability, bulging fontanelle, seizures, paralysis or coma;

• Generalized or localized seizures =m/c symptoms, so diagnosis of herpes infection must be entertained in any infant presenting with seizures with no underlying etiology

• When HSV infection is a possibility, samples of the cerebrospinal fluid should be sent for HSV culture and PCR, surface culture for HSV and blood for LFT to be done, empiric Acyclovir to be started.

• Possible infection with cytomegalovirus, syphilis, toxoplasmosis, Lyme disease and tuberculosis may be evaluated with diagnostic tests such as PCR, specific antibody titers and acid-fast stains. Cytomegalovirus is the most common congenital infection. Approximately 40,000 infants born in the United States have cytomegalovirus infection, and 20 percent of these infants experience significant morbidity or mortality.

Practical approach

• All febrile newborns birth-28 days should be hospitalized • All should receive empiric antibiotics, usually gentamicin/third

generation cephalosporin and ampicillin.• Acyclovir is not recommended routinely but should be

considered in febrile neonates with risk factors for neonatal HSV. – Risk factors include primary maternal infection esp with

vaginal delivery, prolonged rupture of membranes, the use of fetal scalp electrodes, skin, eye or mouth lesions, seizures, and CSF pleocytosis or elevated CSF RBC’s.

1. A 6-day-old infant is brought to the emergency department in August with a 1-day history of decreased feeding, decreased activity, tactile fever, and rapid breathing. He was born at term by normal spontaneous vaginal delivery and weighed 3,742 g. His mother reports that she had a nonspecific febrile illness 1 week before delivery for which she received no treatment. Her group B Streptococcus screen was positive at 36 weeks' gestation, and she received two doses of ampicillin (>4 hours apart) during labor. The baby received no antibiotics and was discharged at 48 hours of age. Physical examination today reveals a toxic, lethargic infant who is grunting and has a temperature of 39.4°C, heart rate of 180 beats/min, and respiratory rate of 60 breaths/min. His lungs are clear, with subcostal retractions. He has a regular heart rhythm with gallop, his pulses are thready, his capillary refill is 4 seconds, and his extremities are cool.

Of the following, the MOST likely cause of this baby's illness is A. Early-onset group B Streptococcus infection B. Echovirus 11 infection

C. Herpes simplex virus infectionD. Hypoplastic left heart syndromeE. Respiratory syncytial virus infection

2. A 4-year-old boy presents to the emergency department with a 2-day history of fever, decreased activity, and vomiting and a complaint of increasing headache today. The light has been bothering his eyes. He attends day camp and participates in swim class 5 days/week. On physical examination, the sleepy but arousable boy has a temperature of 39.5°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, and blood pressure of 80/50 mm Hg. His throat is erythematous, and he has neck pain with flexion. The remainder of his physical examination findings are normal. Cerebrospinal fluid (CSF) analysis reveals a white blood cell count of 0.32x103/mcL (0.32x109/L) (80% neutrophils, 20% lymphocytes), protein of 55 mg/dL, and glucose of 45 mg/dL.

Of the following, the additional test on the CSF that is MOST likely to confirm the cause of this child's illness is:

A. Arbovirus polymerase chain reaction panelB. Bacterial cultureC. Enterovirus polymerase chain reactionD. Herpes simplex virus polymerase chain reactionE. Viral culture

3. A term newborn is delivered to a mother who has had a 5-day history of a nonspecific gastroenteritis, some loose stools, generalized malaise, and low-grade fever. The infant had a seizure at 6 hours of age and is ill, with an inspired oxygen requirement of 0.40, some petechiae, and oozing from the umbilicus and phlebotomy sites. He is irritable on neurologic examination.

Laboratory findings include:– White blood cell count, 7.5x103/mcL (7.5x109/L)– Platelet count, 90.0x103/mcL (90.0x109/L)– Hematocrit, 45% (0.45)– Aspartate aminotransferase, 240.0 U/L– Alanine aminotransferase, 300.0 U/L– Fibrinogen, 90.0 mg/dL (2.6 mcmol/L)– Prothrombin time, 20 seconds– Partial thromboplastin time, 60 seconds– Internationalized Normalized Ratio (INR), 1.80– Serum glucose, 90.0 mg/dL (5.0 mmol/L)

A lumbar puncture reveals 35 white blood cells, with 50% polymorphonuclear cells and 50% mononuclear cells; 1 red blood cell; glucose of 60.0 mg/dL (3.3 mmol/L); and protein of 100 mg/dL (1,000 g/L). No organisms are seen on cerebrospinal fluid (CSF) Gram stain.

Of the following, a TRUE statement about this patient's meningitis is that

A. Gram-negative organisms are unlikely to be causativeB. Group B streptococcal meningitis is likely to be the causeC. Infection likely is related to maternal enteroviral infectionD. The abnormal CSF glucose and protein values indicate

bacterial meningitisE. The abnormal liver function test results and CSF cell counts

indicate herpes simplex virus infection

4. You admitted a patient to the hospital yesterday who had acute onset of fever (temperature of 103.0°F [39.4°C]), a petechial rash, meningismus, and shock. She required blood pressure support and mechanical ventilation during the night. As per the protocol for your hospital, you placed this child into respiratory isolation upon admission. Today you are told that her blood culture is growing Neisseria meningitidis. The nurse taking care of her asks you how long the child needs to remain in respiratory isolation.

Of the following, the BEST answer is until the child:A. Completes 1 day of antimicrobial therapyB. DefervescesC. Is clinically stable D. Is extubated E. Is proven not to have meningitis