Serum Procalcitonin Level and Other Biological Markers to Distinguish Between Bacterial and

Aseptic Meningitis in Children

A European Multicenter Case Cohort StudyDubos, F, M.D., et al. Archives of Pediatric Adolescent Medicine 2008; 162 (12): 1157-

1163.

Journal ClubKate Messing, M.D.December 18, 2008

Background

• Acute meningitis in children is predominantly aseptic meningitis and does not require specific treatment.

• Bacterial meningitis occurs in about 5% of all meningitis cases and carries significant risks including severe neurological sequelae and death, especially when specific treatment is delayed.

Background Continued

• In the ED, it can be very difficult to distinguish between aseptic and bacterial meningitis, and in many cases antibiotics are started immediately and are continued until cultures are negative for 48 to 72 hours.

• This assures rapid treatment of children with bacterial meningitis however also exposes many children with aseptic meningitis to IV antibiotics and hospital admission.

Background Continued

• Tests that are included in the workup of bacterial vs. aseptic meningitis in the ED include:

– CRP level.– WBC count.– Neutrophil Count.– Blood Culture.– CSF: (protein level, glucose level, WBC count,

neutrophil count, culture).– ** These tests combined do not offer 100%

sensitivity with high specificity for distinguishing between bacterial and aseptic meningitis.

Procalcitonin (PCT)

• The precursor of the hormone calcitonin, is produced under normal conditions in the C cells of the thyroid gland.

• In healthy subjects, PCT levels are < 0.1 ng/mL or undetectable.

• Increased serum PCT level has been found in some cases to be one of the most sensitive and specific markers for discriminating between bacterial and aseptic meningitis.

Objective

• To better distinguish between bacterial meningitis and aseptic meningitis in the ED and help to limit unneeded antibiotic administration and subsequent hospital admission.

• “To validate procalcitonin (PCT) level as the best biological marker to distinguish between bacterial and aseptic meningitis in children in the emergency room.”

Study Design

• Secondary analysis of retrospective multi-center hospital-based cohort studies.

• 6 pediatric emergency departments or ICUs of tertiary care centers in 5 European countries.

Patients

• Inclusion Criteria (overall 198 patients):– Ages: 29 days to 18 years old.– Admitted for bacterial or aseptic meningitis and

had measurements of the main inflammatory markers (including PCT) in blood and in CSF in the ED.

• Exclusion Criteria:– Patients having any known neurosurgical disease,

known immunosuppression, traumatic lumbar puncture (CSF RBC cell count of > 10,000/μL), or previously treated meningitis, or were referred from another hospital because of diagnosis of meningitis.

– Patients with missing data.

Definitions

• Bacterial Meningitis:– Acute onset of meningitis (CSF WBC

count of ≥ 7/μL) and documented positive bacterial infection in CSF or Blood culture.

• Aseptic Meningitis:– Acute onset of meningitis and the

absence of any bacterial meningitis criteria.

Data Collection

• Lab data was retrospectively extracted from existing databases or medical files in each center and sent to one main center.

• At each center, the PCT level was determined by the same standardized test (Lumitest PCT; Brahms Diagnostica, Berlin, Germany).

Results

• Centers varied widely for inclusion dates and prevalence of bacterial meningitis.

Results Continued

• Of the 198 patients: 96 (48%) were found to have bacterial meningitis and 102 (52%) had aseptic meningitis.

• 34 patients were admitted to the ICU, including 10 with aseptic meningitis.

• Main microorganisms identified: N. meningitidis (n = 45), Strep. Pneumoniae (n = 32), H. influenzae (n = 7), and Group B Streptococcus (n = 4).

Results Continued

• The distribution of all blood and CSF labs differed significantly between patients with bacterial vs. aseptic meningitis.

Results Continued

• The PCT of 0.5 ng/mL or higher showed the best sensitivity (99%, 95% CI: 97-100%) and specificity (83%, 95% CI: 76-90%) of all of the biological markers.

• The results did not change when they considered only patients not admitted to the ICU.

Results Continued

• There was one case of a 21 month old male with bacterial meningitis and a PCT level less than 0.5 ng/mL :– Caused by N. meningitidis.– Initial PCT value was lower than the

level of detection.

Conclusion

• A high serum PCT level is the best biological predictor, with the best sensitivity and specificity, for distinguishing between bacterial and aseptic meningitis in children presenting to the emergency department.

• Although the sensitivities and specificities for CRP level, CSF protein level, and CSF neutrophil count were also good, they were significantly lower than the PCT level in patients with bacterial meningitis.

Conclusion

• “Although PCT level is probably the best biological predictor currently available to distinguish between bacterial and aseptic meningitis, it cannot be used alone with 100% sensitivity and good specificity.”

Critical Appraisal

• Was the study a randomized trial?• No:

• Retrospective cohort study.– Patient’s were from 6 different European

Centers.– Centers were found from a Literature Search and

chosen if they had previously reported on a cohort of patients with meningitis and PCT measurement.

Critical Appraisal

• Are there efficacious treatments for the disorder?– Yes:

• Bacterial Meningitis Treatment:– Early diagnosis and treatment are very important.– Appropriate antimicrobial therapy and supportive

measures.• Aseptic Meningitis Treatment:

– Treatment for viral meningitis is mostly supportive. – Rest, hydration, antipyretics, and pain or anti-

inflammatory medications can be given as needed.

Critical Appraisal• Does the current burden of suffering warrant

screening?– Yes:

• If we were able to better predict and diagnose bacterial meningitis earlier, this could lead to better outcomes for patients.

• Also, could decrease the number of children exposed to antibiotics unnecessarily.

• Before the 1990s, Hib was the leading cause of bacterial meningitis

• The prevalence of bacterial meningitis has been reduced.

• Today, Neisseria meningitidis and Streptococcus pneumoniae are the leading causes of bacterial meningitis and continue to have significant morbidity and mortality if not diagnosed and treated early.

Critical Appraisal

• Does the screening test have high sensitivity and specificity?

• Yes: PCT Level: sensitivity (99%, 95% CI: 97-100%) and specificity (83%, 95% CI: 76-90%).

• Receiver-Operating Curve:– PCT level had AUC of 0.98,

significantly higher than that for other biological markers (p = 0.001).

Critical Appraisal

• Can the health system cope with the screening program?– Yes:• Adding another test to the work-up for

meningitis initially would not be a huge burden on the health system.• If it allowed earlier predictability of

bacterial meningitis in children, it could improve our care for these children.• Currently, however, University of Chicago

does not have a lab or send out lab for procalcitonin.

Critical Appraisal

• Will positive screenees comply with further assessment and intervention?– Yes:

• An initial PCT level drawn will most likely not be a burden on the patient or their families.

• It is doubtful that parents would decline medical care if their child requires further medical intervention and support from the hospital.

Overall Conclusions• Weakness:

– Retrospective, cohort study.– Unable to use test with certainty (one child with

undetectable PCT level and bacterial meningitis).• Strength:

– Interesting topic, not a lot of data on the subject related to bacterial meningitis.

• However, there will most likely never be just one test that will determine if physicians use or not use antimicrobial therapy in these cases.

• It is important to remember to look at the patient and use clinical judgment on whether or not to start treatment and admit the patient to the hospital or not.

References

Dubos, F. Serum Procalcitonin Level and Other Biological Markers to Distinguish Between Bacterial and Aseptic Meningitis in Children: A European Multicenter Cohort Study. Archives of Pediatric and Adolescent Medicine, 2008; 162 (12): 1157 – 1163.

van Rossum, AMC, et al. Procalcitonin as an early marker of infection in neonates and children. Lancet Infectious Disease, 2004; 4: 620-630.

Thank you and thanks especially to Dr. Marcinak and Dr. Quinlan!

Have a great day!