Meningitis in Pediatric Patients and the Value of Multiplex PCR Syndromic Testing

Meningitis is an inflammation of the protective membranes (meninges) around the brain and spinal cord, usually due to an infection in the surrounding fluid. However, there are also non-infectious causes of meningitis, including injuries, cancer, and certain drugs. Treatment of meningitis differs depending on the underlying cause.

Pediatric Bacterial Meningitis is Associated with High Morbidity and Mortality

The incidence of acute community-acquired bacterial meningitis (ABM) in children has declined in median- and high-income countries with prevention efforts such as vaccination and intrapartum group B Streptococcus (GBS) prophylaxis. However, the disease continues to have high rates of neurological morbidity and mortality.¹

According to the CDC, in the United States, there were about 350 cases of meningococcal disease in 2017, and the groups most at risk are children under 1 year old, and those who are between the ages of 16 and 23. Despite its relative rarity in the United States, meningitis has a fatality rate of 10-15%, and up to 1 in 5 survivors will have long-term disabilities, including loss of limb(s), deafness, nervous system problems, and brain damage.²

Meningococcal disease is particularly serious and can be deadly within hours. Because of the high level of risk associated with meningitis, prompt diagnosis and administration of effective antimicrobial therapy are critical.³

Symptoms and Causes of Meningitis in Children

The most common meningitis symptoms in children include fever, headache, and stiff neck. Additional symptoms may include nausea, vomiting, photophobia, and altered mental status. Symptoms in babies may differ or be difficult to notice, but can include being slow or inactive, irritability, vomiting, feeding poorly, or bulging in the anterior fontanelle. Clinicians may also assess reflexes in young children.⁴

Multiple types of pathogens can cause bacterial meningitis, but the five that are most common are Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus agalactiae (group B Streptococcus, also called GBS), and Listeria monocytogenes. In a global review of the burden of meningitis, S. pneumoniae and N. meningitidis were the predominant pathogens across all age groups.⁵

Premature infants, newborns, and babies under 2 months old are at the greatest risk for bacterial meningitis in children. The most common pathogen for this group is GBS, accounting for about 40% of early-onset neonatal meningitis cases. Among children after the neonatal period, S. pneumoniae and N. meningitidis are the most common causes for community-acquired bacterial meningitis, followed by GBS and other gram-negative organisms.⁶

Challenges in the Diagnosis and Management of Pediatric Meningitis

Clinicians face numerous challenges when it comes to the management of patients with meningitis, including the similarity of symptoms to other illnesses, lack of sensitivity and/or specificity in traditional diagnostic tools, and the development of antimicrobial resistance. Additionally, there are severe complications of infectious meningitis to contend with, which can include sepsis, neurologic sequelae, and death.

Lumbar puncture for cerebrospinal fluid (CSF) analysis, as well as Gram stain and culture, are used to help clinicians make a diagnosis. However, normal CSF values for protein, glucose, and WBC vary with the patient’s age, and the normal values for infants are poorly defined. The sensitivity and specificity of Gram stain and culture are also variable. Additionally, antibiotic pre-treatment has been associated with lower sensitivity of CSF and blood cultures (but did not affect the sensitivity of the CSF Gram stain).⁶

Infants with bacterial meningitis can be especially challenging to diagnose because they can have negative blood cultures and normal CSF parameters, despite infection.⁷

Viral meningitis (also called aseptic meningitis) in children presents additional challenges, although it tends to have good clinical outcomes. Often, patients with aseptic meningitis are admitted to the hospital and receive unnecessary empiric antibiotics, which increases the length and cost of hospital stay.⁵ Reviewing data for patients under the age of 17, one study found that 92.2% received empiric antibiotics—but about two thirds had a viral etiology.⁸

Distinguishing between bacterial and viral etiologies is important—both from an immediate treatment perspective and for managing antimicrobial resistance in the long term. However, traditional methods of meningitis testing may fail to identify a pathogen and can take several days to complete. Given the urgency of prompt diagnosis and treatment for patients with meningitis—especially meningococcal disease—these failures or delays may contribute to adverse outcomes.

Clinically Actionable Results Through Syndromic Multiplex PCR Testing

Infectious Diseases Society of America (IDSA) guidelines for meningitis state that, “CSF cultures may take >48 hours for organism identification and are positive in 70-85% of patients with bacterial meningitis who have not received prior antimicrobial therapy; therefore, rapid diagnostic tests should be considered to determine the bacterial etiology of meningitis.”⁹

Definitive diagnosis of infection etiology requires laboratory confirmation. Traditional methods of meningitis testing rely on growing organisms in culture, which can be slow and ineffective. When a patient is facing a potentially life-threatening infection, as in the case of meningitis, speed and accuracy become extremely important to clinical outcome.

BioFire^® FilmArray^® Panels use a syndromic testing approach to simultaneously target multiple pathogens with overlapping signs and symptoms. In one test, the BioFire^® FilmArray^® Meningitis/Encephalitis (ME) Panel targets 14 of the most common bacteria, viruses, and fungi associated with central nervous system infections—with accurate results in about an hour. Syndromic testing with multiplex PCR provides results in a clinically actionable timeframe, which can be lifesaving and help guide appropriate therapy.

In children, use of the BioFire ME Panel increased pathogen detection by 2.3x,¹⁰ shortened the time to diagnosis from initial presentation to the Emergency Department by 4 days, and reduced length of hospital stay by 2 days.¹¹ In addition, there was a reduction in length of antimicrobial therapy for both acyclovir (an antiviral) and antibiotics.¹² These same clinical benefits that the BioFire ME Panel helps provide can also contribute to cost savings for hospitals and healthcare systems.

Positive and Negative Meningitis PCR Test Results May Help Guide Antimicrobial Therapy

Although meningitis is relatively rare, its morbidity and mortality risks make it a medical emergency. However, unnecessary antimicrobial use increases risk of toxicity, raises healthcare costs, and contributes to the development of antimicrobial resistance.¹³

Striking the appropriate balance in antimicrobial use can be especially challenging with patients who may be facing a life-threatening infection. According to IDSA guidelines for meningitis, “PCR may be useful for excluding the diagnosis of bacterial meningitis, with the potential for influencing decisions to initiate or discontinue antimicrobial therapy.”⁹ The ability to exclude meningitis in pediatric patients is important, and both negative and positive PCR results from the BioFire ME Panel may inform the initiation or discontinuation of antimicrobial therapy.

References:

Hasbun, R., Wootton, S., Rosenthal, N., Balada-Llasat, J., Chung, J., Duff, S., Bozzette, S., Zimmer, L. and Ginocchio, C., 2019. Epidemiology of Meningitis and Encephalitis in Infants and Children in the United States, 2011–2014. Pediatric Infectious Disease Journal, 38(1), pp.37-41.
gov. 2021. Meningococcal Disease: Technical and Clinical Information | CDC. [online] Available at: https://www.cdc.gov/meningococcal/clinical-info.html.
gov. 2021. Meningococcal Disease Diagnosis and Treatment | CDC. [online] Available at: https://www.cdc.gov/meningococcal/about/diagnosis-treatment.html.
gov. 2021. Signs and Symptoms of Meningococcal Disease | CDC. [online] Available at: https://www.cdc.gov/meningococcal/about/symptoms.html.
Oordt-Speets, A., Bolijn, R., van Hoorn, R., Bhavsar, A. and Kyaw, M., 2018. Global etiology of bacterial meningitis: A systematic review and meta-analysis. PLOS ONE, 13(6), p.e0198772.
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Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review | Antimicrobial Resistance & Infection Control | Full Text (biomedcentral.com)