PEDIATRICS Vol. 105 No. 2 February 2000, pp. 316-319

Cerebrospinal Fluid Findings in Aseptic Versus Bacterial Meningitis

Barbara Negrini, MD, Kelly J. Kelleher, MD, MPH, and Ellen R. Wald, MD

From the Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

	ABSTRACT

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Background.  Aseptic meningitis is often reported to be characterized by a mononuclear cell predominance in the cerebrospinal fluid (CSF), whereas bacterial meningitis is characterized by a polymorphonuclear (PMN) cell predominance. In contrast, other studies suggest that PMNs can be the most prevalent cell in early aseptic meningitis followed by a shift to mononuclear cells within 24 hours. These contradictory reports may lead to uncertainty in the diagnosis and treatment of meningitis.

Objectives.  To assess 1) the characteristics of the CSF differential in aseptic versus bacterial meningitis, 2) the influence of duration of illness on the CSF differential, and 3) the role of the CSF differential in discriminating between aseptic versus bacterial meningitis.

Methods.  A retrospective chart review was conducted of all cases of meningitis in children >30 days of age hospitalized during the peak months for enteroviral meningitis (April to October) between 1992 to 1997. Cases of aseptic meningitis were defined as having at least 20 white blood cells/mm³ and the absence of bacterial growth on culture. Patients were excluded if they received antibiotic therapy within the previous 5 days. Cases of bacterial meningitis were defined as having a positive culture of the CSF or the presence of a CSF pleocytosis with positive cultures of the blood. CSF variables including white blood cell differential and time from the onset of symptoms to the performance of a lumbar puncture were analyzed. PMNs were considered to be predominant when the percentage of neutrophils added to juvenile forms was >50% of cells.

Results.  One hundred fifty-eight cases of meningitis were reviewed: 138 were aseptic and 20 were bacterial. The patients ranged in age from 30 days to 18 years; 61% were male. Fifty-seven percent of cases of aseptic meningitis had a PMN predominance. The percentage of PMNs in the CSF in patients with aseptic meningitis was not statistically different for patients who had a lumbar puncture performed either within or beyond 24 hours of the onset of symptoms. Fifty-one percent of the 53 patients with aseptic meningitis and duration of illness >24 hours had a PMN predominance. The ability of a PMN predominance to differentiate between aseptic and bacterial meningitis was assessed. The sensitivity of a PMN predominance for aseptic meningitis is 57% whereas the specificity is 10%. The positive predictive value of a PMN predominance for aseptic disease is 81% but the negative predictive value is 3%. Alternative definitions of PMN predominance from 60% to 90% were not useful as a clinical indicator of bacterial disease.

Conclusions.  The majority of children with aseptic meningitis have a PMN predominance in the CSF. The PMN predominance is not limited to the first 24 hours of illness. Because the majority of children with a PMN predominance during enteroviral season will have aseptic disease, a PMN predominance as a sole criterion does not discriminate between aseptic and bacterial meningitis.  Key words:  meningitis, aseptic, cerebrospinal fluid analysis, PMN predominance, children.

The differentiation between bacterial and aseptic meningitis is based on both clinical findings and analysis of the cerebrospinal fluid (CSF). Viral infections are the most common cause of aseptic meningitis. The term aseptic meningitis will be used to describe both proven and presumed cases of viral meningitis. Standard textbooks describe the typical CSF findings in aseptic meningitis as a pleocytosis of between 20 and 1000 white blood cells (WBCs) comprised mainly of lymphocytes.^1-3 Although several studies have documented that polymorphonuclear (PMN) cells can predominate early in the course of aseptic meningitis,^4-6 a high percentage of PMNs raises a concern that the meningitis may be caused by a bacterial agent.

During recent seasonal outbreaks of enteroviral disease, a predominance of PMNs in the CSF seemed to be the rule rather than the exception. We hypothesized that a predominance of PMNs in patients with aseptic meningitis is more common than previously documented and is not limited to the first 24 hours of illness. This review was conducted to assess the characteristics of the CSF findings in children with aseptic meningitis and to examine the influence of duration of illness on these findings. By comparing these characteristics in children with aseptic meningitis to the CSF findings in children with bacterial meningitis, the ability of CSF parameters, particularly the predominance of PMNs, to differentiate between aseptic and bacterial disease can be determined.

	METHODS

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A retrospective chart review was conducted of all patients outside of the neonatal age group hospitalized at the Children's Hospital of Pittsburgh with a diagnosis of meningitis from April to October, the months with the peak incidence for enteroviral disease, in the years 1992 to 1997. Cases of aseptic meningitis were defined as patients with a pleocytosis in the CSF of at least 20 WBC/mm³ and the absence of any bacterial growth on culture of the CSF. Cases were excluded for the following reasons: age <30 days, receipt of antibiotics within 5 days before the lumbar puncture was performed, concurrent bacterial infection (including a parameningeal focus), neurosurgical procedure before the onset of meningitis, presence of a shunt within the central nervous system, or presence of a known immunodeficiency. Cases of bacterial meningitis were defined by either a positive culture from the CSF or a pleocytosis in the CSF and a positive blood culture for a bacterial pathogen.

Data collected on each patient included demographic information, duration of illness before presentation to the hospital, and CSF parameters. The duration of prodromal illness was defined as the number of hours between the onset of the first symptom noted by the patient or parent and performance of the lumbar puncture. Symptoms included fever, headache, irritability, lethargy, nasal congestion, cough, vomiting, diarrhea, or change in feeding pattern. Because the onset of symptoms was often recorded in the medical record as occurring during a particular part of the day (morning, afternoon, evening), the number of hours of the prodromal illness was rounded to the nearest multiple of 12. If there was an acute deterioration during the prodromal phase, that time was also noted as a potential indicator of a progression from viremia or bacteremia to meningeal infection. PMNs were considered to be predominant when the percentage of neutrophils added to juvenile forms was >50%.

Statistical Analysis

Because the data were not normally distributed, statistical comparisons between groups were performed using the nonparametric Mann-Whitney U test. For categorical variables, the Pearson ² test was used to assess between group differences.

	RESULTS

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One hundred fifty-eight cases of meningitis were reviewed. One hundred thirty-eight cases were categorized as aseptic meningitis and 20 were categorized as bacterial meningitis. The patients ranged in age from 30 days to 18 years; the median age for patients with aseptic meningitis was 2.8 months and the median for patients with bacterial meningitis was 11.0 months (P = NS). Sixty-four percent of the cases of aseptic meningitis and 45% of the cases of bacterial meningitis occurred in boys (P = NS).

CSF characteristics are summarized in Table 1. Because the distributions of the data were significantly skewed, both mean and median data are presented. Positive cultures for enterovirus from the CSF were obtained from 11 patients; 35 additional patients had viral cultures performed that were negative and the remaining 92 cases did not have viral cultures performed. The rapid recovery of patients with aseptic disease suggests that other serious causes of meningitis such as tuberculosis, rickettsial, or fungal infections were unlikely. There was no statistically significant difference in the CSF characteristics between the 11 patients with proven enteroviral meningitis and the 127 patients with a presumed viral cause. The number of cases per year ranged from 10 to 36, but the proportion of patients with a PMN predominance was not statistically different between the different years.

Streptococcus pneumoniae was isolated from the CSF of 11 patients and Haemophilus influenzae was isolated from the CSF of 6 children. Three children had a positive blood culture and a pleocytosis in the CSF even though the cultures of the CSF were sterile. In each of these children, antibiotics had been administered before the lumbar puncture was performed. Two of these cases yielded S pneumoniae and 1 grew Escherichia coli.

Table 2 shows the percentage of cases of both aseptic and bacterial meningitis that had a predominance of PMNs. These data were used to assess the ability of PMN predominance alone to discriminate between the 2 types of meningitis. The sensitivity of a PMN predominance to identify patients with aseptic meningitis is 57% whereas the specificity is 10%. The sensitivity of a PMN predominance to identify patients with bacterial meningitis is 90% with a specificity of 43%. The positive predictive value (PPV) of a predominance of PMNs for aseptic meningitis is 81% and the negative predictive value is 3%. For bacterial meningitis, the PPV of a PMN predominance is 19% and the negative predictive value is 97%.

Alternative thresholds of PMN values, ranging from 60% to 90% of the CSF pleocytosis, were examined to determine if a different definition of PMN predominance would be helpful in distinguishing bacterial and aseptic disease. A receiver operating characteristics curve was constructed using the sensitivity and specificity values of PMN percentage to predict bacterial disease. The results showed the area under the curve was 0.74 (P = .0005) which suggests that PMNs are related to bacterial meningitis but does not suggest a useful threshold level of clinical significance. The PPV for bacterial meningitis at various thresholds remained low. Even at a level of 90% of PMNs in the CSF, the PPV was only 25%.

An acute deterioration during the course of the prodromal illness was noted in the medical record in 18 patients with aseptic meningitis. These patients had a median percentage of PMNs of 79% with an average duration of prodromal symptoms of 131 hours, which was significantly longer than the rest of the cohort. The average duration of their period of deterioration before the lumbar puncture was performed was 21 hours. The median age for this group was 5.2 years whereas children without a marked period of deterioration had a median age of 2.3 months. However, there were no statistically significant differences between this group and the rest of the cohort with respect to CSF variables.

The distribution of the percentage of PMNs versus the time from the onset of symptoms in aseptic meningitis, excluding the 18 patients with an acute deterioration, is shown in Fig 1. This demonstrates that many patients have a PMN predominance, even when the lumbar puncture was performed >24 hours from the onset of symptoms. Among patients with aseptic meningitis who had a lumbar puncture performed within the first 24 hours of symptoms, 57% had a PMN predominance; 51% of those who had a lumbar puncture after 24 hours had a PMN predominance.

View larger version (8K): [in this window] [in a new window]   Fig. 1.   Percentage of polymorphonuclear cells versus time from onset of symptoms to lumbar puncture in aseptic meningitis.

	DISCUSSION

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Our data show that the majority of children with aseptic meningitis (57%) had a predominance of PMNs during enteroviral season. The median percentage of PMNs in all cases of aseptic meningitis was 59%. The cases were selectively concentrated during seasonal outbreaks of enteroviral disease as an attempt to isolate the CSF response to viral agents. Patients with enteroviral meningitis, proven by a positive culture, had a median percentage of PMNs of 57%. These findings are in contrast to several studies that have reported that lymphocytes predominate in aseptic disease.^7-9 However, none of these studies addressed the timing of the performance of the lumbar puncture in the course of the illness. Standard pediatric textbooks reflect this literature by stating that aseptic meningitis is usually characterized by a mononuclear predominance, but early in the course of disease, the spinal fluid may be characterized primarily by PMNs.^1,2,10

There are several other studies which support our findings and report a higher rate of PMN predominance in patients with aseptic meningitis. In 1962, Lepow and colleagues⁴ described 407 patients with aseptic disease in which two thirds had a PMN predominance. These data were difficult to interpret, however, because many of the patients received antibiotics before the lumbar puncture was performed and, accordingly, may represent individuals with partially treated bacterial disease. More recently, Chiou and colleagues⁵ reported that 62.5% of a series of 25 infants with coxsackie B meningitis had a PMN predominance. Finally, Harrison and Risser⁶ showed that in a group of 9 children, all had a PMN predominance on their initial lumbar puncture. Our data differs from the latter 2 studies because it included 6 different years. Potentially, different enteroviruses could produce varying inflammatory responses in the CSF thereby altering the WBC differential. As in the more recent studies, our data does not include any cases of partially-treated bacterial meningitis.

In previous studies, the percentage of PMNs in patients with aseptic meningitis has been interpreted in the context of the time between onset of symptoms and the performance of the lumbar puncture. Our data show that 51% of patients who had a lumbar puncture performed >1 day from the onset of their illness maintained a PMN predominance. Even at 48 hours and beyond, many patients with aseptic meningitis still had a PMN predominance. Our data are supported by Harrison and Risser⁶ who found that 88.9% of their patients maintained a predominance of PMNs in the CSF when a repeat lumbar puncture was performed after 5 to 8 hours. However, these data differ from several previous studies which suggest a rapid shift from PMN to mononuclear cells.^11-13

It is unclear when the meninges actually become infected in patients for whom there is a prolonged duration of symptoms before the performance of the lumbar puncture. The 18 children who had a long prodromal phase were excluded from Fig 1 because the timing of the onset of their meningitis is unclear. This group consisted of patients who were significantly older than the cohort of patients with aseptic meningitis as a whole. This finding may reflect a tendency to perform lumbar punctures earlier in the course of illness in infants compared with older children.

When confronted with an individual child with meningitis, the clinician must make treatment decisions, based at least in part, on the evaluation of the CSF. Because bacterial meningitis is almost always characterized by a PMN predominance, many patients with a high percentage of PMNs in the CSF are started on antibiotics pending the results of bacterial cultures. It is appropriate to initiate antibiotic therapy when the patient seems significantly ill or the CSF characteristics are ambiguous. However, our data suggest that PMN predominance, as a sole criterion, is a poor diagnostic marker of disease type. In our population, the PPV of a PMN predominance for aseptic disease is high at 81% whereas the PPV for bacterial disease is only 19%. This suggests that, during the peak season for aseptic meningitis, a patient with a PMN predominance in the CSF is actually more likely to have aseptic than bacterial meningitis. This conclusion is also true for a PMN predominance of 90% in the CSF because the PPV remains too low to influence clinical decisions. These results are similar to those reported by Spanos et al¹⁴ who, in a study of 422 patients with meningitis, showed that the percentage of PMNs had significant overlap for both bacterial and viral cases and could not be used as a diagnostic tool.

This study has several limitations. The retrospective chart review required interpretation of the initiation of symptoms. When the timing of symptoms was not specifically recorded in the medical record, the onset was rounded to the nearest 12-hour period. Although this limits the precision of our data, the vague report of onset of symptoms is typical of that encountered by the clinician. Unfortunately, it is not routine practice in our institution to obtain viral cultures in cases of suspected aseptic meningitis. To increase the likelihood that the aseptic cases would be caused by enteroviruses, data collection was limited to the summer and fall seasons. Accordingly, our conclusions will be most useful to the clinician in outbreaks of enteroviral disease occurring in the usual season.

	CONCLUSION

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In summary, our data demonstrate that PMN predominance occurred in the majority of cases of aseptic meningitis. In contrast to previous studies, this was not limited to patients who presented within 24 hours from the onset of symptoms. As a sole criterion, PMN predominance at any level from 50% to 90% is not useful in distinguishing bacterial from aseptic disease. This information should allow clinicians to feel more confident of the diagnosis of aseptic meningitis even if a PMN predominance is found after several days of symptoms especially if other clinical and laboratory evidence support this diagnosis.

	FOOTNOTES

Received for publication May 5, 1999; accepted Aug 6, 1999.

Reprint requests to (B.N.) Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213. E-mail: negrinb{at}chplink.chp.edu

	ABBREVIATIONS

CSF, cerebrospinal fluid; WBC, white blood cell; PMN, polymorphonuclear; PPV, positive predictive value.

	REFERENCES

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