Deciphering bacterial meningitis

July 1, 2016

The introduction of conjugated vaccines has decreased the incidence of bacterial meningitis in children, amounting to one of the biggest public health successes in the practicing pediatrician’s career.

The introduction of conjugated vaccines has decreased the incidence of bacterial meningitis in children, amounting to one of the biggest public health successes in the practicing pediatrician's career. In fact, the median age of patients successfully treated for bacterial meningitis has increased from younger than age 5 years to age 42 years and older. Improvements have been seen in every age group, except in those aged younger than 2 months. Cases of meningitis from strains of bacteria not covered by vaccination and drug-resistant strains, however, remain a concern for clinicians managing pediatric patients.

Etiology, epidemiology, and risk factors

The most common cau ses of bacterial meningitis are Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b (Hib; rarely a cause since the development of a vaccine), group B Streptococcus (GBS), and Listeria monocytogenes.1-3 Etiology depends on the age of the patient (Table 1).3,4 Introduction of the conjugate Hib vaccine in the 1990s almost eliminated Hib in countries in which it was introduced and decreased the overall incidence of meningitis by nearly 55%.3 This was followed by the introduction of the heptavalent pneumococcal vaccine (PCV7) in 2000, which reduced pneumococcal meningitis by nearly 60% in children aged younger than 2 years.3-5

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In the years between 1998 and 2007, herd immunity continued to drop the rate of meningitis by more than 30%, from a rate of 2 cases per 100,000 to 1.38 cases per 100,000.3,6 Despite these advances, however, case fatality rates did not change and rates of pneumococcal disease from strains not covered by the PCV7 strain began to emerge. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced, but S pneumoniae remains the most common cause of bacterial meningitis for children aged older than 1 month.3

More recently, introduction of a vaccine targeting N meningitidis serogroup C disease significantly reduced invasive meningococcal disease. In Canada, the serogroup C vaccination led to a decrease in incidence from 0.07 to 0.25 per 100,000 (depending on the province) to fewer than 0.05 per 100,000 per year, a reduction of 14% per year. It is estimated that this annually decreases the burden of N meningitidis serogroup C by 75 to 85 invasive meningococcal disease cases and 10 to 12 deaths.7

For the United States, the Immunization Action Coalition reports that the incidence during 2005 to 2011 was 0.3 cases per 100,000 population and decreased to an incidence of 0.18 cases per 100,000 population in 2013.8 Serogroups B, C, and Y were equally responsible for reported cases. Two quadrivalent conjugated meningococcal vaccines (MenACWY-DT and MenACWY-CRM197) are licensed in the United States, and another is licensed in Europe (MenACWY-TT).9 In the United States, there are programs for both infant and child, as well as adolescent immunization.

Despite the shifting incidence of meningitis, patients aged younger than 2 months still have the highest incidence of bacterial meningitis primarily associated with the different etiologies (Table 1).3,4 In this age group, GBS and Escherichia coli are responsible for 70% to 80% of cases. Although routine maternal GBS and intrapartum antibiotic treatment have decreased early-onset GBS disease by 86%, the incidence of late-onset disease has not changed.3

Risk factors for pediatric meningitis, which also vary by age, are presented in Table 2.10-12

Differential diagnosis

A number of different diseases can mimic meningitis, and not all children presenting with signs and symptoms of meningitis have the disease. In a review of 650 children undergoing a lumbar puncture, there were many diseases found to mimic meningitis symptoms such as pneumonia, otitis media, pharyngitis, and gastroenteritis. In this review study, neck stiffness was twice as likely (50% vs 25%) and a positive Brudzinski test was 3 times as likely in patients diagnosed with meningitis.13,14 Viral illness, sinusitis, and migraine were common causes of headache, with no cases of bacterial meningitis in 2 studies of patients presenting to an emergency department with headache.15,16 Although 30% of patients presenting to an emergency department with signs of meningismus had meningitis, 8% had pneumonia and 46% were diagnosed with upper respiratory tract infection or other self-limiting illnesses.17

Other causes of meningitis also can mimic bacterial meningitis such as viruses, fungi, mycobacteria, and parasites. Retropharyngeal abscess is a relatively common infectious disease process that mimics meningitis. Other infectious mimickers include brain abscess, subdural or epidural abscess, and encephalitis.3

NEXT: Presentation

 

Presentation

The clinical features of bacterial meningitis are often nonspecific and can vary by age. The younger the child, the less likely he or she will present with classic symptoms of fever, headache, and meningeal signs. A neonate or young infant may only present with apnea, bulging fontanel, diarrhea, fever, irritability, lethargy, poor feeding, temperature instability, or vomiting.18 Symptoms are variable, however, and the patient may have fever, hypothermia, or euthermia. Parents may describe their infant as fussy, jittery, or inconsolable.3 Seizure may be a presenting sign in 20% to 50% of cases of Hib meningitis (less in other etiologies), but neck stiffness is uncommon.

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In older children, changes in mentation, fever, headaches, nausea, photophobia, and vomiting may be present. Symptoms may evolve over several days or a period of hours.3 Seizure may be the sole presenting sign in patients with pneumococcal meningitis. A positive Kernig or Brudzinski sign has low sensitivity for meningitis, and their absence does not rule out meningitis.18 Rash and petechiae are present in about 50% of cases of invasive disease due to N meningitidis. Symptoms of bacterial meningitis presenting in neonates and older children are listed in Table 3.3,18 Table 4 shows how different signs may display in different age groups.14,19

NEXT: Diagnosis

 

Diagnosis

Blood cultures, a complete blood count, and electrolytes should be obtained. White blood cell (WBC) counts can be normal, high, and may be low in neonates. More than 80% of patients (the percentage is higher for Hib and lower for other causes) not pretreated with antibiotics will have positive blood cultures with bacterial meningitis. Procalcitonin levels will be elevated in bacterial meningitis, but these cannot distinguish between bacterial and viral meningitis. If petechiae or low platelet counts are present, disseminated intravascular coagulation should be considered and worked up. Syndrome of inappropriate antidiuretic hormone (SIADH) is suggested by a low sodium level and other testing.3

A lumbar puncture (LP) should be obtained unless contraindicated in patients because of:

·      Hemodynamic instability,

·      Increased intracranial pressure,

·      Coagulopathy, or

·      Neurologic findings indicating a mass lesion.

Computed tomography (CT) is not routinely needed prior to LP. The CT findings not apparent on physical exam are unlikely to change clinical management.20 Patients with coma, papilledema, and focal neurologic findings should have a CT prior to LP. The need for CT, however, should not delay obtaining blood cultures or antibiotic administration. Patients without these findings do not need a CT prior to LP.21,22 If CT is obtained, LP should be performed after CT if there are no contraindications.

The spinal fluid should be sent for:

·      WBC count and differential;

·      Glucose;

·      Total protein; and

·      Gram stain and bacterial culture.

In the bacterial meningitis patient not treated with antibiotics before presentation, elevated WBCs, low glucose, and elevated protein in the spinal fluid are suggestive of bacterial meningitis. Spinal fluid normals are based on the patient’s age. Occasionally, cerebrospinal (CSF) fluid may appear normal when the spinal tap is performed very early in a child’s illness.

The spinal tap results can be altered following a traumatic tap, making it difficult to diagnose bacterial meningitis. Following a traumatic tap, cell counts are difficult to interpret. The easiest formula is to subtract 1 to 2 CSF WBCs for every 1000 CSF red blood cells (RBCs)/mm3. This formula and the formula comparing the ratio of CSF WBCs to CSF RBCs to blood WBCs to blood RBCs, however, should be interpreted with caution and likely empiric antibiotics should be started pending culture results.3

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Pretreatment with antibiotics decreases likelihood of a positive CSF culture. Reports demonstrate a positive culture result in bacterial meningitis with oral and parenteral antibiotics of only 71% and 66%, respectively. Parenteral antibiotics sterilize the CSF within a couple of hours, but antimicrobial pretreatment does not impact the ability to diagnose bacterial meningitis using cell counts, protein, and glucose.3,23-25

Although latex agglutination tests are available to assist in making a diagnosis, these rarely alter the treatment plan and the tests are not needed in most instances.10 In fact, such testing is no longer routinely recommended for antibiotic-pretreated patients.3

NEXT: Empiric antibiotics

 

Empiric antibiotics

The goal is to administer antibiotics as early as possible once the diagnosis of bacterial meningitis is considered. Although adverse outcomes are not associated with duration of symptoms prior to treatment, delay of antibiotic administration is associated with poor outcomes.26,27 Empiric antibiotic therapy should target likely pathogens based on the patient’s age, underlying health conditions, and local efficacy and susceptibility patterns. Antibiotic choices should have good penetration into CSF and have bactericidal properties.3,28

Empiric antibiotics for bacterial meningitis in the neonatal period are primarily ampicillin plus gentamicin or ampicillin plus cefotaxime. The latter regimen is more common when clinicians are concerned about increasing resistance of E coli to ampicillin. Once an organism is identified, the antibiotic coverage can be tailored for the infant.3,28

Empiric antibiotics for bacterial meningitis outside the neonatal period include vancomycin (because of cephalosporin-resistant pneumococci) plus either cefotaxime or ceftriaxone. Vancomycin can be discontinued if the etiology of bacterial meningitis is susceptible to penicillin or cephalosporins. Rifampin may be added in certain situations for pneumococcal meningitis, and the pediatrician should consider consultation with an infectious diseases specialist.3,28

In children with significant allergic reactions to penicillins and cephalosporins, vancomycin plus rifampin or vancomycin plus meropenem are options for initial therapy.3,28

Antibiotics may be discontinued when blood and CSF cultures are negative in patients with an unremarkable CSF in which bacterial meningitis is ruled out. Children with positive blood cultures and an abnormal CSF, but a negative CSF culture, are often treated as if the CSF culture were positive. If both CSF and blood cultures are negative but the child had an abnormal CSF evaluation, consultation with a pediatric infectious diseases expert is recommended.3,28

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Total duration of antibiotic therapy will depend on the patient’s age and bacterial etiology. For uncomplicated neonatal meningitis with GBS or S pneumoniae, a 14- to 21-day course of treatment is usually sufficient. Outside the neonatal period, the usual course of treatment for uncomplicated bacterial meningitis is 10 to 14 days for S pneumoniae and 7 days for N meningitidis.3,28

Dexamethasone therapy

Steroids are believed to decrease neurologic complications in bacterial meningitis by decreasing inflammatory response and modulating mediators that are released when initial antibiotics result in the lysis of cell walls.29 However, dexamethasone therapy outside of treatment for H influenzae (for which it is clearly indicated) remains controversial. The evidence of benefit in pneumococcus or meningococcus is less clear, and no recommendation can be made currently. There is also a potential concern that steroids may decrease the effectiveness of vancomycin by decreasing inflammation and further reduce its already suboptimal CSF penetration.3,28

The American Academy of Pediatrics (AAP) Committee on Infectious Diseases recognizes the benefit of dexamethasone therapy in H influenzae type b meningitis. The AAP committee says clinicians can consider its use in bacterial meningitis in patients aged older than 6 weeks after considering the risks and benefits. If used, dexamethasone should be administered with the first dose of antibiotics because it has no benefit if administered more than 1 hour after the antibiotic.3,28

Complications

Among survivors of bacterial meningitis, 50% are reported to have at least 1 complication at 5 years. The most commonly cited bacterial cause associated with complications is H influenzae. Complications may be categorized as intellectual/behavioral deficits (78%), neurologic (14%), hearing loss (7%), and vision loss (3%).30,31

Examples of intellectual and behavioral deficits include:

·      Cognitive impairment,

·      Academic limitations, and

·      Attention-deficit/hyperactivity disorder.

Intellectual disability (intelligence quotient [IQ]<70) is noted in 4% of survivors of bacterial meningitis, and studies have found lower IQ scores in survivors of bacterial meningitis compared with their siblings.30,31 In a report of 130 survivors evaluated at a single center (average age, 8 and 6 years following meningitis episode), children experiencing meningitis did worse than age-matched controls on assessments of fine motor function, IQ scores, and tests of school behavior, neuropsychologic function, and auditory figure-ground differentiation, even though the children with meningitis performed in the average range.32-34 Onset of meningitis before age 12 months is associated with poor performance on tests requiring language and executive skills 12 years after disease onset.33

The complications can extend well into adulthood. In a British cohort, survivors of meningitis at age 16 years were more likely to have attended special education (at a rate of 4 times the national average); more than 3 times as likely to not pass a General Certificate of Secondary Education (GCSE; an internationally recognized certificate in a particular subject); and twice as likely to not pass core subjects (eg, basic English, math, foreign language) on a GCSE.35 Similarly, a Danish cohort reported lifelong impairment, with meningitis cases less likely than controls to complete high school, attain higher education, or achieve economic self-sufficiency.36 Finally, mood problems, behavioral problems, socialization problems, thought problems, and attention problems are reported in multiple studies years after the initial treatment of meningitis.30,37

The pediatrician needs to be aware of the educational issues that may be facing survivors of bacterial meningitis so that parents and teachers can be on the lookout for problems and intervene as necessary and as early as possible.38 Commonly reported neurologic complications include spasticity, motor deficits, and seizure disorder. 

NEXT: Conclusions

 

Generalized seizures are more likely to occur at disease onset, while partial seizures are more likely to occur at several days of hospital admission. Seizures occurring early in the course that are easily controlled are not likely to lead to neurologic sequelae. Seizures occurring later in the course of treatment or that are more difficult to control are more likely to be associated with permanent neurologic sequelae.38 Hemiparesis or quadriparesis is generally associated with some sort of intracranial pathology (eg, cerebral edema), which can generally resolve over time.39

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Hearing loss can be either transient or permanent. It is important to screen for hearing loss after meningitis. Risk factors for hearing loss at presentation include:40

·      S pneumoniae infection, 2 to 3 times greater compared with other etiologies;

·      Ataxia;

·      Symptoms for several days prior to admittance; and

·      Absence of petechiae.

Interestingly, complications such as hemiparesis and subdural empyema seem to have increased in frequency after the introduction of PCV13.41

Conclusion

Meningitis remains a significant burden in the pediatric age group, and complications may lead to lifelong impairment. It is important for the pediatrician to not only understand how bacterial meningitis can be prevented through vaccinations but also to understand its risks, workup, and treatment.

 

 

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38. Marlow N, Johnson S. What the teacher needs to know. Arch Dis Child. 2007;92(11):945.

39. Kim KS. Bacterial meningitis beyond the neonatal period. In: Cherry JD, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ, eds. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia, PA: Elsevier Saunders; 2014:425.

40. Koomen I, Grobbee DE, Roord JJ, Donders R, Jennekens-Schinkel A, van Furth AM. Hearing loss at school age in survivors of bacterial meningitis: assessment, incidence, and prediction. Pediatrics. 2003;112(5):1049-1053.

41. Olarte L, Barson WJ, Barson RM, et al. Impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in US children. Clin Infect Dis. 2015;61(5):767-775. 

Dr Bass is chief medical information officer and associate professor of medicine and of pediatrics, Louisiana State University Health Sciences Center–Shreveport. The author has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.