This study evaluated the clinical and laboratory characteristics of infants ≤90 days old with meningitis who presented to the hospital with a fever. We also investigated whether initial C-reactive protein levels and white blood cell counts were reliable predictors of bacterial meningitis.
The medical records of 1,151 infants aged ≤90 days who visited our hospital with a fever between October 2009 and October 2019 were retrospectively evaluated.
Of the 1,151 patients, 274 (23.8%) had meningitis (bacterial, n=7; viral, n=206; pleocytosis in the cerebrospinal fluid, n=136). Thirty-seven viral meningitis patients (18.0%) had a positive polymerase chain reaction result without pleocytosis in the cerebrospinal fluid. The patients without pleocytosis were significantly younger. Among the patients with only pleocytosis, 46 had a urinary tract infection, 22 had other viral infections, and the etiology was unknown in 68. Among patients with urinary tract infections, infants without pleocytosis were younger than those with pleocytosis. Low white blood cell counts (<5,000/mm3) were more frequently found in bacterial meningitis patients (n=7) than in viral meningitis patients. Furthermore, there were normal C-reactive protein levels (42.9%) and no pleocytosis (20%) in some cases of bacterial meningitis.
Our findings show that meningitis is not uncommon among infants ≤90 days old who were brought to the hospital with complaints of fever. Furthermore, younger patients may not have cerebrospinal fluid pleocytosis, even if they have bacterial meningitis. Therefore, the patient’s condition should be monitored closely and, if necessary, a re-examination should be considered.
Fever is the most common symptom indicative of serious infections among young infants, including neonates [
Central nervous system infections, such as bacterial or viral meningitis, frequently occur in young infants due to immature humoral and cellular immunity. Depending on the age at diagnosis, type of identified organism(s), and delay in treatment, central nervous system infections can lead to several acute comorbidities, severe complications, and long-term disabilities, ranging from hearing loss to a permanent motor or cognitive impairment [
Clinical signs and symptoms of central nervous system infections are often nonspecific in young infants. These symptoms include fever, hypothermia, food retention, skin lesions, irritability, or general malaise [
In addition, serum C-reactive protein (CRP) levels, WBC count, and procalcitonin are commonly used inflammatory biomarkers in the blood. However, there is no consensus regarding their ability to distinguish between bacterial and viral meningitis [
In this study, we aimed to describe the biochemical characteristics of CSF, blood, and urine in febrile infants ≤90 days old with meningitis. Furthermore, we compared the characteristics of the laboratory results in patients with meningitis after dividing them into two groups based on the presence or absence of pleocytosis in the CSF.
The medical records of 1,172 patients of age less than 90 days who visited Inje University Sanggye Paik Hospital with a complaint of fever between October 2009 and October 2019 were retrospectively evaluated. The study protocol was approved by the Institutional Review Board of Inje University Sanggye Paik Hospital (2020-03-015). The requirement for informed consent was waived due to the retrospective nature of the study.
Patients <35 weeks gestational age (n=7) and those with underlying conditions (n=14), including Cornelia de Lange syndrome (n=1), cerebral infarction (n=2), periventricular leukomalacia (n=1), Prader-Willi syndrome (n=1), congenital cytomegalovirus infection (n=1), and congenital hypothyroidism (n=1), were excluded. Data regarding age, gestational age, sex, clinical characteristics, diagnosis, and all laboratory profiles, including blood, CSF, urine, and sputum were collected from all the patients.
For all included patients, all blood laboratory tests including initial WBC and CRP level checks were performed immediately after visiting the hospital. The peak CRP was defined as the highest numerical value by comparing all tests performed during hospitalization, including the initial CRP.
For all the included patients (n=1,151), LP is usually performed after the initial blood test following which the platelet level is confirmed. In our study, LP was performed on 867 patients (74.3%). Of those 867 patients, 281 did not undergo CSF analysis due to traumatic tap or insufficient sample quantity, and one patient had a positive result for virus polymerase chain reaction (PCR) of enterovirus. Patients with traumatic LP were excluded from the CSF analysis. The detailed results are described in
All patients who received the LP were tested for bacterial culture and underwent real-time multiplex PCR (Seegene Inc., Seoul, Korea) for six types of viruses—cytomegalovirus, human herpesvirus 6, Epstein-Barr virus, herpes simplex viruses 1 and 2, and varicella-zoster virus—or Reverse Transcriptase PCR for enteroviruses (Seegene Inc.).
Bacterial meningitis was defined as bacterial growth in the CSF. Viral meningitis was defined as either a positive PCR result or patients with age-adjusted CSF pleocytosis with a negative CSF culture or PCR results for a virus without UTIs or bacteremia. Coinfections were defined as meningitis accompanied by bacteremia, UTI, or other viral infections.
CSF pleocytosis was defined as a CSF WBC count >22 WBCs/mm3 if the patient was <4 weeks old; >15 WBCs/mm3 if the patient was between 4 and 7 weeks of age; and >5 WBCs/mm3 if the patient was ≥8 weeks old. UTI was diagnosed as a urine culture (collected by urethral catheterization) with more than 100,000 colony-forming units/mL [
Patients with various types of meningitis were compared and analyzed based on the presence or absence of pleocytosis in the CSF.
Continuous variables, including age and CRP, are expressed as the mean±standard deviation and were compared using t-tests. Categorical variables, including sex and age group, were compared using a chi-square test or Fisher’s exact test. The comparison between the viral meningitis group and bacterial meningitis was performed a nonparametric test, Mann-Whitney U test. All statistical analyses were performed using IBM SPSS Statistics for Windows version 25.0 (IBM Corp., Armonk, NY, USA). Statistical significance was defined as a
During the study period, 1,151 infants (630 [54.74%] males and 521 [45.26%] females) were included. The cause of infection was identified in 724 (432 [59.67%] males and 292 [40.33%] females). LP was performed on 867 patients: meningitis (n=274, 23.8%); UTI (n=180); bacteremia (n=24); and other viral infections (n=347). The remaining 503 patients with unexplained fever were suspected of having a viral infection and they recovered without complications (
Of the 274 meningitis patients, 158 (57.7%) were males and 116 (42.3%) were females. The mean age at symptom onset was 52.85±23.42 days (range, 1 to 90). Fifty-nine (21.5%) infants were ≤30 days old, 94 (34.3%) were 31 to 60 days old, and 121 (44.2%) were 61 to 90 days old. Seven patients had bacterial meningitis (Group B
Among the patients with bacterial meningitis, except for two patients with traumatic tap who could not be included in the analysis, 80% (4/5) had pleocytosis and 20% (1/5) had non-pleocytosis CSF. One patient who had non-pleocytosis with the initial WBC count and initial CRP in a normal range was later diagnosed with GBS meningitis. In addition, another patient with traumatic tap had CSF non-pleocytosis (CSF red blood cell count, >20,000/mm3; CSF WBC, 3/mm3). Therefore, 28.6% (2/7) of bacterial meningitis patients had non-pleocytosis.
A comparison of the bacteremia patients with and without pleocytosis in the CSF revealed that a significantly large proportion of patients without pleocytosis underwent LP <24 hours after the onset of fever (10/11, 90.9%; chi-square test,
Of the 191 children diagnosed with viral meningitis without traumatic tap, 81.7% (156/191) had CSF pleocytosis and 18.3% (35/191) had CSF non‐pleocytosis (
There were no patients with bad prognosis from viral meningitis. However, one of the patients with bacterial meningitis died and one suffered from subdural empyema, but is developing normally without any sequelae.
Among the patients with UTIs, 7.8% had coinfection with PCR-positive viral meningitis, 25.6% had reactive pleocytosis in the CSF, and one patient (0.5%) had a co-infection with bacterial meningitis. A comparison of the patients with UTI with and without pleocytosis in the CSF revealed that younger patients had a low rate of pleocytosis occurrence (56.23±20.41 days vs. 67.61±13.59 days, t-test
When comparing bacterial meningitis with viral meningitis, there were more cases of WBC count <5,000/mm3 in patients with bacterial meningitis (chi-square test,
It is challenging to differentiate between severe infection and benign viral infections among infants aged ≤90 days reporting with a fever. Of the severe infections in young infants, central nervous system infections are the most serious as they may lead to long-term morbidities. However, the most common infection of the central nervous system is aseptic meningitis. In a study of young infants with acute meningitis, almost 80% of infants were found to have aseptic meningitis [
Of the 191 children diagnosed with viral meningitis without traumatic tap, 18.3% had CSF non‐pleocytosis. In particular, infants with CSF non‐pleocytosis were younger than those with CSF pleocytosis, suggesting a negative correlation with age (
Previous studies also showed some cases of enteroviral meningitis without pleocytosis [
The mechanism of meningitis with non-pleocytosis in infants is still unclear. Seiden et al. [
In our study, the mean time interval from onset to LP was significantly shorter in viral meningitis without pleocytosis. These results suggest that sufficient time may be needed for CSF pleocytosis to develop. In other words, in the early stages of central nervous system infections, results may indicate non-pleocytosis if sufficient time has not passed to allow pleocytosis to develop [
Our study showed that 7.8% of UTI patients had coinfection with PCR-positive viral meningitis, 25.6% had reactive pleocytosis in CSF, and one patient (0.5%) had bacterial meningitis (
Meningitis may not always be accompanied by pleocytosis. Pleocytosis can be related to age, the interval from symptom onset to LP, and peripheral WBC counts. A comparison between viral meningitis and bacterial meningitis revealed that there were more cases of WBC count <5,000/mm3 in patients with bacterial meningitis (chi-square test,
Excluding herpes simplex virus infections, most viral meningitis is known to be non-fatal. However, some cases of enterovirus, human herpesvirus 6 infections, and parechovirus [
This study has some limitations. As our work is retrospective in nature, a generalization of the results may not be appropriate. We did not obtain data of CSF examinations in all the included infants. Therefore, further prospective studies are necessary.
In conclusion, we showed that meningitis is not uncommon among infants ≤90 days old who have come to the hospital with a fever. Furthermore, younger age may be negatively correlated with CSF pleocytosis in meningitis. Our results indicate initial CRP levels may not be reliable predictors of bacterial meningitis and that initial leukopenia may be more dependable. Analysis of CSF or inflammatory markers in the peripheral blood is insufficient to diagnose meningitis and to also differentiate between viral and bacterial source, and therefore, PCR tests for various viruses and bacteria may be necessary. Meningitis patients <90 days old have non-specific symptoms and signs and often do not have CSF pleocytosis. It is crucial to closely monitor the patient's condition by analyzing whether the laboratory findings and clinical symptoms are consistent.
No potential conflict of interest relevant to this article was reported.
Conceptualization: SJY. Data curation: KUC. Formal analysis: KUC. Writing-original draft: KUC. Writing-review & editing: KUC and SJY.
We would like to thank Ho Hyeong Jo for his time and useful comments. This work was supported by the 2019 Inje University research grant.
Flow diagram depicting the selection of the study population.
Flow diagram illustrating the strategy to identify the cause of fever.
Clinical characteristics of febrile infants with meningitis (n=274)
Characteristic | Value |
---|---|
All patients | 274 |
Age (day) | 52.85±23.42 (1–90) |
Age group (day) | |
0–30 | 59 (21.5) |
31–60 | 94 (34.3) |
61–90 | 121 (44.2) |
Sex, male:female | 158 (57.7):116 (42.3) |
Bacterial meningitis |
7 |
Group B |
5 |
|
2 |
Viral meningitis with virus PCR positive in CSF |
130 |
Type of virus in cases with positive PCR in CSF | |
Human herpesvirus-6 meningitis | 1 |
Enteroviral meningitis | 129 |
Type of viral meningitis excluding patients without CSF analysis | 113 |
Viral PCR (+) in CSF with pleocytosis | 76 |
Viral PCR (+) in CSF without pleocytosis | 37 |
Traumatic tap | 16 |
Viral PCR (+) without CSF analysis | 1 |
Only pleocytosis in CSF | 136 |
Unknown pleocytosis | 68 |
Reactive in urinary tract infection | 46 |
Reactive in other viral infection | 22 |
Reactive in bacteremia | 1 |
Urinary tract infection with viral meningitis (virus PCR positive) | 14 |
Values are presented as mean±standard deviation (range) or number (%).
PCR, polymerase chain reaction; CSF, cerebrospinal fluid.
This test includes
This test includes cytomegalovirus (CMV), human herpes virus 6 (HHV6), Epstein-Barr virus (EBV), herpes simplex virus 2 (HSV2), varicella-zoster virus (VZV), herpes simplex virus 1 (HSV1), and enterovirus.
Comparison of viral meningitis with and without pleocytosis in cerebrospinal fluid
Variable | With pleocytosis (n=156) | Without pleocytosis (n=35) | Multivariate analysis | |
---|---|---|---|---|
Male | 84 | 12 | 0.04 |
|
Female | 72 | 23 | ||
Age (day) | 54.18±22.23 | 39.20±22.64 | 0.00 |
|
Exp(B)=1.07 | ||||
(1.04–1.10) | ||||
Age group (day) | ||||
<60 | 86 | 29 | 0.00 |
|
>60 | 70 | 6 | ||
Time interval from onset to LP (day) | 0.84±1.09 | 0.43±0.82 | 0.04 |
|
<24 hours | 67 (42.95) | 24 (68.57) | 0.01 |
|
CSF WBC (/mm3) | 182.94±277.05 | 3.94±4.26 | 0.00 |
|
CSF protein (mg/dL) | 78.01±34.15 | 70.27±27.05 | >0.05 | |
Exp(B)=1.04 | ||||
(1.01–1.06) | ||||
CSF glucose (mg/dL) | 49.39±12.56 | 55.11±11.02 | 0.01 |
|
Exp(B)=0.96 | ||||
(0.93–0.10) | ||||
Peripheral blood | ||||
WBC (/mm3) | ||||
<5,000 | 6 | 3 | >0.05 | |
>15,000 | 49 | 3 | 0.01 |
|
Mean | 12,792.56±5,357.56 | 9,134.57±3,507.66 | 0.00 |
|
Exp(B)=1.00 | ||||
(1.00–1.00) | ||||
Initial CRP (mg/dL) | 1.10±1.64 | 1.06±1.02 | >0.05 | |
Peak CRP (mg/dL) | 1.40±2.61 | 1.45±1.46 | >0.05 |
Values are presented as mean±standard deviation or number (%).
LP, lumbar puncture; CSF, cerebrospinal fluid; WBC, white blood cell; CRP, C-reactive protein.
Comparison between viral meningitis and bacterial meningitis patients
Variable | Viral meningitis |
Bacterial meningitis (n=7) | Comparison |
---|---|---|---|
Age (day) | 53.00 (1–90) | 27.00 (2–74) | 0.03 |
Sex | >0.05 | ||
Male | 103 | 5 | |
Female | 103 | 2 | |
Time interval from onset to LP (day) | 1.00 (0–7) | 0.00 (0–1) | >0.05 |
<24 hours | 100 (48.54) | 6 (85.71) | >0.05 |
CSF WBC (/mm3) | 40.00 (0–1,360) | 230.00 (2–1,970) | >0.05 |
CSF protein (mg/dL) | 74.65 (19–501.2) | 111.40 (60.3–566.6) | >0.05 |
CSF glucose (mg/dL) | 49.00 (29–127) | 52.30 (7.6–85.7) | >0.05 |
Initial white blood cell count | |||
<5,000/mm3 | 10 (4.83) | 2 (28.57) | 0.01 |
>15,000/mm3 | 53 (25.60) | 2 (28.57) | >0.05 |
Median | 11,125 (1,540–27,120) | 10,210 (1,790–31,810) | >0.05 |
Initial C-reactive protein | 0.5 (0.3–11.3) | 1.0 (0.3–13.9) | 0.02 |
Peak C-reactive protein | 0.6 (0.3–14.7) | 12.9 (6.8–26.7) | 0.00 |
Values are presented as median (range) or number (%).
LP, lumbar puncture; CSF, cerebrospinal fluid; WBC, white blood cell.
Viral meningitis with viral polymerase chain reaction in cerebrospinal fluid (n=130)+reactive pleocytosis with other viral infection (n=22)+unknown pleocytosis in cerebrospinal fluid (n=68)–reactive pleocytosis with urinary tract infection (n=14).