SGEM#319: Is it Aseptic Meningitis or More Than This?

Date: February 12th, 2021 Guest Skeptic: Dr. Dennis Ren is a paediatric emergency medicine fellow at Children’s National Hospital in Washington, DC. Reference: Mintegi S et al. Clinical Prediction Rule for Distinguishing Bacterial from Aseptic Meningitis. Pediatrics 2020 Case: A 4-year-old immunized girl presents to the emergency department (ED) with a fever and rhinorrhea for the past four days. Her parents report that she has been complaining of a headache and seems more tired and sleepy in the past day. On exam, she is febrile to 38.5 ºC, appears tired, with meningismus on examination but answers questions appropriately. She does not have any petechiae or purpura on skin exam. You explain that you must obtain some blood for laboratory work and perform a lumbar puncture (LP) because you are concerned that she has meningitis. Her nervous parents agree to the LP. Her cerebrospinal fluid appears clear and preliminary cerebrospinal fluid (CSF) results show a pleocytosis with 16 white blood cells per µL without any red blood cells. Her parents ask you whether or not she will have to stay in the hospital or receive antibiotics. Background: Vaccines cause adults. Supporting this position is that since the introduction of conjugate vaccines the incidence of life-threatening bacterial meningitis has decreased. The first conjugate vaccine introduced was the haemophilus influenzae type b (Hib) vaccine. This vaccine has a reported efficacy of 98% (Makwana and Riordan 2007). The success of conjugate vaccines is that most cases of pediatric meningitis are now aseptic (viral cause). It is important to distinguish between bacterial vs aseptic meningitis. This is because bacterial meningitis is associated with serious morbidity and mortality and requires prompt antibiotic treatment; aseptic meningitis is self-limited and requires only supportive care. Patients with suspected bacterial meningitis require hospital admission with empiric antibiotics pending culture results (Sáez-Llorens and McCracken 2003). There is no single variable that can help discriminate between bacterial vs. aseptic meningitis.  Combinations of variables have been tried in the past as part of clinical scoring systems such as the Bacterial Meningitis Score (BMS) to identify children with CSF pleocytosis at low risk for bacterial meningitis (Nigrovic et al 2002). However, BMS did not take into account C-reactive protein and procalcitonin levels that have shown promise in risk stratifying febrile children at risk for bacterial infection (Van den Bruel et al 2011). Additionally, BMS has missed a few cases of bacterial meningitis. Specifically, 2 out of 1714 patients categorized as very low risk for bacterial meningitis had bacterial meningitis (sensitivity 98.3%, NPV 99.9%). Both patients missed were younger than 2 months old (Nigrovic et al 2007). The study we are reviewing today aimed to develop and validate a more accurate scoring system called the Meningitis Score for Emergencies (MSE) to distinguish between bacterial vs. aseptic meningitis in children 29 days to 14 years old with CSF pleocytosis based on four objective lab criteria. Clinical Question:  Can a clinical decision tool using laboratory data help distinguish between bacterial from aseptic meningitis in children 29 days to 14 years old with cerebrospinal fluid pleocytosis? Pleocytosis- CSF WBC ≥10 cells per µL. Corrected for presence of CSF RBCS (1:500 leukocytes to erythrocytes in peripheral blood) and CSF protein (every 1000-cell increase on CSF RBCs per mm3, CSF protein increased by 1.1 mg/dL) Bacterial meningitis defined as patient with either identification of bacterial pathogen in CSF culture and/or Neisseria meningitides or Streptococcus pneumoniae on polymerase chain reaction and either positive blood culture or blood PCR result for N meningitides or S pneumoniae Aseptic meningitis defined as CSF pleocytosis and negative CSF and blood bacterial cultures and negative Neisseria meningitidesor Streptococcus pneumoniae on polymerase chain reaction Reference: Mintegi S et al. Clinical Prediction Rule for Distinguishing Bacterial from Aseptic Meningitis. Pediatrics 2020 Population: Children between 29 days and 14 years old with a diagnosis of meningitis across 25 Spanish emergency departments. Exclusion: Children <29 days old, critically ill, with purpura, not previously healthy or treated with antibiotics within 72 hours before lumbar puncture. Intervention: Retrospective derivation and prospective validation of Meningitis Score for Emergencies (MSE) for distinguishing bacterial vs. aseptic meningitis using procalcitonin >1.2 ng/mL, CSF protein >80 mg/L, CSF absolute neutrophil count >1000 cells per mm3, and C-reactive protein >40 mg/L. The four laboratory components were given different points if present and zero points if absent. So, if the procalcitonin was elevated you got 3 points, 1 point for elevated CRP, 1 point for elevated ANC and 2 points for elevated CSF protein (max score 7). Comparison: Bacterial meningitis score (Pediatrics 2002), validated (JAMA 2007) The BMS had 5 components: four are laboratory and one is clinical (seizure at or before presentation). Each of these components were also given a different number of points if present and zero points if absent. The BMS is available on MDCalc. Outcome: Accuracy of clinical decision support tool in distinguishing bacterial vs aseptic meningitis in children with CSF pleocytosis. (sensitivity, specificity, negative predictive value, positive predictive value, and likelihood ratios). Authors’ Conclusions: “The meningitis score for emergencies (MSE) accurately distinguishes bacterial from aseptic meningitis in children with CSF pleocytosis.” Quality Checklist for Clinical Decision Tools: The study population included or focused on those in the ED. Yes The patients were representative of those with the problem. Unsure All important predictor variables and outcomes were explicitly specified. Yes This is a prospective, multicenter study including a broad spectrum of patients and clinicians (level II). No Clinicians interpret individual predictor variables and score the clinical decision rule reliably and accurately. Yes This is an impact analysis of a previously validated CDR (level I). No For Level I studies, impact on clinician behavior and patient-centric outcomes is reported.  N/A The follow-up was sufficiently long and complete. Unsure The effect was large enough and precise enough to be clinically significant. Unsure Key Results: The final study included 1,009 patients between 29 days and 14 years of age. There were 819 patients assigned to the derivation group while 190 were assigned to the validation group. Slightly over 1/3 were female with mean age of 2 years. The vast majority (91%) had aseptic meningitis and only 9% had bacterial meningitis. Of those with meningitis, 80% had either N meningitides (41.3%) or S pneumonia (38.5%). Other organisms included: Group B Strep 5.5%, Strep pyogenes 4.3%, Enterococcus faecalis, H influenzae (2.2% each) and E. coli, Listeria monocytogenese, Salmonella typhimurium, Strep bovis, Kingella kingae, Fusobacterium necrophorum (1.1% each). Validation Group MSE ≥1: Sensitivity 100%, specificity  77.4%, NPV 100%, PPV 46.3%, LR+ 4.4 and LR- 0 Derivation and Validation Group MSE ≥1: Sensitivity 100%, specificity 83.2%, NPV 100%, PPV 37.4%, LR+ 5.95 and LR- 0. No patients with bacterial meningitis were missed with the MSE. Two patients with bacterial meningitis were missed with the BMS. 1-month-old with Streptococcus agalactiae meningitis although BMS is used for patients >2 months 3-year-old with meningococcal meningitis 1) Procalcitonin Testing: Procalcitonin is the cool new kid on the block when it comes to detecting bacterial infections. Procalcitonin testing may not be available at all hospitals limiting applicability of this new scoring tool. 2) Age: Similar to the Bacterial Meningitis Score (BMS) study, this study did not include any patients <29 days old. Unlike the BMS study that included patients up to age 19, this study does not include any patients over the age of 14. It is difficult to determine whether the incidence of aseptic vs bacterial meningitis in the age group >14 to 19 years would have affected the accuracy of the MSE. 3) Derivation vs Validation Sets: Out of a total of 1,509 eligible patients, 500 were excluded: 414 from derivation group, 86 from validation group. Proportionately, 50 patients (12%) with bacterial meningitis were excluded from the derivation group while 28 patients (32%) with bacterial meningitis were excluded from the validation set. This may suggest that the groups were uneven in their relative distribution of bacterial vs aseptic meningitis. When comparing the characteristics between patients in the final derivation and validation groups, there was also a higher percentage of bacterial meningitis in the validation set compared to the derivation set (16.3% vs 7.4%). 4) CSF Gram-Stain: The authors made a decision to not include CSF Gram-stain in the score despite it being positive in 75% of cases of bacterial meningitis and positive CSF Gram-stain having specificity >97%. They state that this is due to limitations of availability of performing Gram-stain 24/7 in all EDs but recommend that a child with CSF pleocytosis and positive Gram stain should be put on antibiotics regardless of MSE score. 5) Geography: One of the limitations mentioned by the authors is that this study population is drawn purely from Spanish emergency departments. The prevalence of bacterial meningitis differs worldwide so this scoring tool would need external validation in different counties and in rural vs urban areas.