ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10081-1443 |
A Study on the Utility of Lumbar Puncture as a Diagnostic Marker for Meningitis in Neonatal Sepsis
1,3,4Department of Neonatology, Cloudnine Hospital, Bengaluru, Karnataka, India
2Department of Neonatology, Cloudnine Hospital, Bengaluru, Karnataka, India; Department of Neonatology, Notre Dame University, Perth, Australia
Corresponding Author: Kishore Kumar, Department of Neonatology, Cloudnine Hospital, Bengaluru, Karnataka, India; Department of Neonatology, Notre Dame University, Perth, Australia, Phone: +91 9900155001, e-mail: drkishore@cloudninecare.com
Received: 19 January 2024; Accepted: 11 August 2024; Published on: 05 November 2024
ABSTRACT
Objectives: The primary outcome was to study the utility of lumbar puncture (LP) in neonatal sepsis, and the secondary outcome was to study the clinical profile of the neonates with sepsis in a comparison of practices between two units.
Methods: This is a retrospective comparative study conducted at two tertiary neonatal intensive care units (NICUs) during the period from January 2017 to January 2020. All neonates with C-reactive protein (CRP)-positive sepsis admitted to the NICU were included. Those with suspected sepsis but CRP-negative were excluded. The eligible medical records were reviewed, and data were recorded into a structured pro forma at both centers. The data from both units were analyzed.
Results: Data from a total of 252 neonates were analyzed. Unit 1 (U1) had 29% blood culture-proven sepsis, of which 69% were late-onset, whereas at unit 2 (U2) it was 17.1%, of which 85% were late-onset and the remaining were early-onset. The incidence of meningitis was 3% in U1 and 1.9% in U2. Of these, 83% were associated with late-onset sepsis and only 17% with early-onset sepsis. Most of these neonates had the same organism in blood and cerebrospinal fluid (CSF).
In those with meningitis, the highest CRP was <100 mg/L in 67% and >200 mg/L in 43% in U1, while all had a CRP <100 mg/L in U2. A receiver operating characteristic (ROC) curve plotted for CRP and culture-positive meningitis showed a CRP cutoff >80 mg/dL with a specificity of 84.9% and sensitivity of 66.7% for considering LP in sepsis.
Conclusion: Lumbar puncture, being an invasive procedure, could be reserved only for those babies with culture-positive sepsis or with symptoms of meningitis or severe sepsis. This study suggests a CRP >80 mg/L as an indication for LP in neonatal sepsis.
Keywords: C-reactive protein, Critical care, Lumbar puncture, Neonates, Sepsis
How to cite this article: Mathew J, Kumar K, Gaonkar S, et al. A Study on the Utility of Lumbar Puncture as a Diagnostic Marker for Meningitis in Neonatal Sepsis. Pediatr Inf Dis 2024;6(4):115–119.
Source of support: Nil
Conflict of interest: None
INTRODUCTION
Neonatal sepsis can be either proven sepsis or suspected sepsis. Clinically, it is a challenge to distinguish sepsis from sepsis with meningitis in neonates. Sepsis and meningitis have nonspecific clinical features, and meningitis may present without specific symptoms along with sepsis. The incidence of meningitis in neonatal sepsis has varied from 0.3 to 3% in various studies and is 0.5% according to the Indian National Neonatal Database report for the year 2000.1 Studies from the United Kingdom (UK) and India reported an incidence of meningitis associated with late-onset sepsis (LOS) to be 3–30%.2 The need for lumbar puncture (LP) in neonates with suspected sepsis is justified, considering the morbidity and mortality associated with a missed or delayed diagnosis of meningitis. Early recognition of infants at risk for poor prognosis would be helpful in prompt management. On the other hand, the drawbacks of performing a LP in neonates must be considered. Lumbar puncture is an invasive procedure that carries risks of its own.3,4 Therefore, it is challenging to decide which neonate, as part of the septic workup, needs one. National Institute for Health and Care Excellence (NICE) CG149 recommendations suggest considering LP to evaluate for meningitis in early-onset sepsis (EOS) in neonates with C-reactive protein (CRP) level >10 mg/L, but the evidence for this is poorly defined.5 We conducted this study to compare practices of two units regarding the use of LP, as there are no clear guidelines stating the need for LP as part of the workup of neonatal sepsis and to propose a possible best practice. The primary outcome was to study the utility of LP in sepsis, and the secondary outcome was to study the clinical characteristics of the neonates with sepsis.
METHODS
This is a retrospective comparative study conducted at two tertiary neonatal intensive care units (NICU) in India during the period from January 2017 to January 2020. The Institutional Ethics Committee approved the study, and a waiver of written informed consent was obtained. Neonates with CRP-positive sepsis (≥10 mg/L) admitted to the NICU were included. Those with suspected sepsis but CRP-negative and infants older than 28 days at admission were excluded. Only infants with positive blood cultures, clinical features of meningitis, severe sepsis, and/or CRP levels greater than 50 mg/L were subjected to LP by Unit 1 (U1). At unit 2 (U2), LP was performed in all neonates with CRP values ≥10 mg/L. At both centers, LP was deferred in newborns with sepsis who were hemodynamically unstable. Lumbar puncture was done before the start of any intravenous antibiotics. The medical and laboratory records of the eligible neonates were reviewed, and relevant data including maternal risk factors, gestational age (GA), gender, birth weight, onset of infection (early/late onset), associated comorbidities, cerebrospinal fluid (CSF) analysis, CSF and blood cultures, duration of antibiotics, hospital stay, and outcomes were recorded in a structured proforma at both centers.
Statistical Analysis
Statistical analysis was done using R software version 4.1.0. Categorical variables were presented as counts and percentages. Receiver operating characteristics (ROC) curve was constructed to find a cutoff value for the highest CRP among those with CSF culture positivity.
RESULTS
We analyzed the data of a total of 252 neonates (U1–100, U2–152) across both units, as described in Table 1. Both units are comparable in all aspects, with >90% of babies being intramural and <10% being extramural. There was a male predominance of neonates, with a ratio of 1.4:1. Around 32% of neonates admitted to U1 were in the GA groups of greater than 37 weeks and 30–34 weeks, whereas U2 had 45% neonates greater than 37 weeks. U1 had 12% extreme preterm babies, and U2 had 16%. Most of the neonates (37%) at U1 were between 1.5 and 2.5 kg, whereas at U2, most neonates (39%) were greater than 2.5 kg. Both units had about 18% of babies with birth weights <1 kg.
| Baseline characteristics of the study population | U1 n (%) |
U2 n (%) |
|---|---|---|
| Sex | ||
| Male | 57 (57%) | 95 (63%) |
| Female | 43 (43%) | 57 (38%) |
| GA at birth (weeks) | ||
| <28 | 12 (12%) | 25 (16%) |
| ≥28 to <30 | 10 (10%) | 7 (5%) |
| ≥30 to <34 | 31 (31%) | 31 (20%) |
| ≥34 to <37 | 15 (15%) | 20 (13%) |
| ≥37 | 32 (32%) | 69 (45%) |
| Birth weight distribution (kg) | ||
| <1 | 18 (18%) | 28 (18%) |
| 1–1.49 | 19 (19%) | 22 (14%) |
| 1.5–2.5 | 37 (37%) | 41 (27%) |
| 2.51–4.5 | 25 (25%) | 60 (39%) |
| >4.5 | 1 (1%) | 1 (1%) |
Unit 1 had 29% blood culture-proven sepsis, of which 69% were late onset, whereas at U2, it was 17.1%, with 85% being late onset and the remaining early onset. The common maternal risk factors among early-onset culture-positive babies were preterm labor, preterm premature rupture of membranes (PPROM), and chorioamnionitis. LP was performed for 24% of the neonates in U1 and for 89% in U2. Only 7% of babies with sepsis had seizures in U1, and 11.5% in U2. U1 used antibiotics for <14 days in the majority (52%), while U2 used antibiotics for 7–21 days in 70%. Duration of hospital stay and outcomes in these babies are shown in Table 2. CRP levels were between 51 and 100 mg/L in 48% of cases in U1 and between 10 and 50 mg/L in 35%.
| Baseline characteristics of the neonates with proven sepsis | U1 (total = 29) n (%) |
U2 (total = 26) n (%) |
|---|---|---|
| Antibiotic duration | ||
| <7 days | 5 (17%) | 1 (4%) |
| 7–14 days | 10 (34%) | 8 (31%) |
| 14–21 days | 6 (21%) | 10 (38%) |
| >21 days | 8 (28%) | 7 (27%) |
| Hospital stay (in days) | ||
| 0–30 | 16 (55%) | 15 (57%) |
| 31–60 | 12 (41%) | 3 (12%) |
| 61–90 | 0 (0%) | 6 (23%) |
| >90 | 1 (4%) | 2 (8%) |
| Outcome | ||
| Discharged | 18 (62%) | 18 (69%) |
| DAMA | 3 (10%) | 3 (12%) |
| Death | 8 (28%) | 5 (19%) |
The incidence of meningitis was 3% in U1 and 1.9% in U2. The overall incidence of meningitis across both units was 2.3%. Of the six newborns with meningitis, 83% were associated with LOS and only 17% with EOS. Most of these neonates had the same organism in both blood and CSF, as seen in Table 3. Only 1 (of 6, 16%) neonate who had meningitis had a negative blood culture. Additionally, 3.9% had CSF biochemistry suggestive of meningitis but were culture-negative. Among neonates with negative CSF cultures but with biochemical parameters suggestive of meningitis, 70% had suspected sepsis, and only 30% were blood culture-positive.
| Baby number | EOS/LOS | Organism in blood culture | Organism in CSF culture |
|---|---|---|---|
| 1 | LOS | MSSA | MSSA |
| 2 | Suspect LOS | No growth | K. pneumoniae |
| 3 | LOS | MRSA | MRSA |
| 4 | LOS | E. coli | E. coli |
| 5 | EOS | E. faecalis | Coagulase negative Staph |
| 6 | LOS | E. coli | E. coli |
Among those neonates with meningitis, the highest CRP was <100 mg/L in 67% and greater than 200 mg/L in 33% (43%) in U1, whereas all had a CRP <100 mg/L in U2. A ROC curve plotted for CRP and culture-positive meningitis showed a CRP cutoff greater than 80 mg/dL with a specificity of 84.9% and sensitivity of 66.7%, 95% CI, 78.2–90.2, for considering LP in sepsis, as seen in Figure 1. In this study population, only 15% in U1 and 6.5% in U2 had any form of surgical intervention. CRP levels in neonates with blood and/or CSF culture-positive infections are shown in Table 4.
Fig. 1: Receiver operating characteristics curve for highest CRP cutoff CSF culture positive
| CRP (mg/L) | U1 | U2 | ||||
|---|---|---|---|---|---|---|
| No. of blood C/S positive | No. of LP done | No. of CSF C/S positive | No. of blood C/S positive | No. of LP done | No. of CSF C/S positive | |
| 10–50 | 11 | 11 | 1 | 9 | 104 | 1 |
| 51–100 | 14 | 11 | 1 | 8 | 19 | 2 |
| 101–200 | 1 | 1 | 0 | 5 | 8 | 0 |
| >200 | 3 | 1 | 1 | 4 | 4 | 0 |
| Total | 29 | 24 | 3 | 26 | 135 | 3 |
| Positivity rate | 3/29 (10.3%) | 3/24 (12.5%) | 3/26 (11.5%) | 3/135 (2.2%) | ||
In the outcome measures of the study population, 79% were discharged, 12% died, and 9% were discharged against medical advice in U1. U2 had 86% discharges, 7% deaths, and 7% discharges against medical advice. The difference was statistically significant (p = 0.037).
DISCUSSION
According to the National Neonatal Perinatal Database 2002–2003, the most prevalent pathogen causing neonatal sepsis among intramural newborns in India is Klebsiella pneumoniae, with an incidence of only 2.3%. Meningitis was seen in 0.3% of neonates. There was a reported incidence of 32.2% sepsis and 19.6% meningitis in extramural babies.1 The incidence of neonatal sepsis in this study across both units was 21.8%, and the incidence of meningitis among those with sepsis was 9%. In blood, Staphylococcus epidermidis was the most often found organism, followed by Escherichia coli and K. pneumoniae. The most common organism in CSF was Staphylococcus aureus. Among those with meningitis, 17% were associated with EOS and 83% with LOS.
The American Academy of Pediatrics (AAP) recommends performing an LP for neonates with EOS (usually <72 hours old) if the blood culture is positive, the clinical history or laboratory data strongly suggest bacterial sepsis, or if the newborn does not improve with antibiotics.6 While guidelines advise against performing LP on neonates who do not exhibit ”signs” of a systemic infection and instead reserve LP for those who do, signs of a systemic infection in newborns can be subtle, such as irritability, poor feeding, or a high-pitched cry, causing some variability in the clinical diagnosis.7,8 To provide a quantitative tool, NICE published CG149 guidelines in England and Wales, which recommend that an LP be ”considered” if the baby has a CRP concentration of 10 mg/L or above, the blood culture is positive, or the baby does not respond to antimicrobial therapy.9 Some have criticized the use of a CRP cutoff of 10 mg/L; a 2014 UK study revealed low adherence to this protocol.7
It is simple to understand why the AAP did not propose a laboratory-marker cutoff for performing an LP, given the varied causes and responses of CRP elevations in neonates across different gestations and the absence of evidence of CRP alterations in neonatal meningitis.6 The rationale behind the NICE guideline development group’s (GDG) decision to set a CRP cutoff of greater than 10 mg/L for an LP is interesting to comprehend. The findings of elevated CRP observed in newborn sepsis served as their foundation. Their decision was based on the higher chance of sepsis rather than specifically meningitis, as their evidence examined different CRP cutoffs ranging from 2.5 to 10 mg/L for the diagnosis of sepsis in babies aged under 12 hours to up to 10 days old.10-12 Certainly, the GDG took note of the possibility that the incidence of meningitis in bacteremic infants may rise up to 23%.13,14
By choosing a specific CRP cutoff for their LP criterion, the NICE GDG attempted to ensure that all neonates with meningitis were included. Since these criteria were not very specific, they were modified to only ”consider” an LP if the CRP was greater than 10 mg/L or if all other criteria were met. This gave physicians greater discretion to reduce the number of unwarranted LPs. Yet, 11.1% of cases of neonatal meningitis were left out. We also used the same cutoff but observed that in U2, where all hemodynamically stable neonates had an LP, the incidence of meningitis was only 6 out of 152 (3.9%), whereas in the other unit, which used additional factors to decide on LP, the incidence of meningitis was almost the same, 3 out of 100 (3%). In light of the above, adopting a universal CRP cutoff for consideration of an LP may not seem prudent; the choice should be made based on multiple factors, including clinical, microbiological, and laboratory markers like CRP.5
Infection in neonates can cause varied CRP responses. Repeat assessments are necessary in the early stages of the disease because CRP synthesis is delayed during the early inflammatory response and has low sensitivity.15 A CRP response can be impeded by hypoxia, severity of disease, prematurity, and comorbidities.16 Furthermore, CRP is not very specific because it can also increase as a result of noninfective conditions.17 Pro-inflammatory cytokines from the mother, such as IL-6, have the ability to cross the placenta and induce CRP production in the neonate.18
Few studies have been conducted on CRP rises in neonatal meningitis because the incidence of the condition is low, and those that have been done involve small numbers. The sensitivity of a CRP cutoff greater than 10 mg/L has been shown to be 76.3% in one study, and a CRP cutoff greater than 40 mg/L has been shown to be 72.7% at 24 hours.19,20 Based on the highest CRP level within 4 days around the LP, a UK study reported a CRP cutoff greater than 10 mg/L with a sensitivity of 88.9%. Specificity was determined by a single-unit analysis and was 78.8%. Our ROC curve shows a specificity of 84.9% and sensitivity of 66.7% for a CRP cutoff of greater than 80 mg/dL for performing LP in sepsis.
Hisamuddin et al.21 showed that the sensitivity and specificity of CRP in the diagnosis of acute neonatal sepsis were 76.92 and 53.49%, respectively, while it had a positive predictive value of 80% and a negative predictive value of 48.94%. Overall, neonatal sepsis was diagnosed with 70.07% diagnostic accuracy using CRP. They concluded that while CRP estimation can be useful in the diagnosis of neonatal sepsis, it cannot serve as the sole marker.17 Monitoring the response to treatment in infected newborns, determining the length of antibiotic therapy, and identifying potential complications can all be aided by serial CRP levels.22,23
Up to 30% of neonates with positive blood cultures will also have a positive CSF culture concurrently.24 Our study had 17.2% of neonates with concurrently positive CSF culture. However, 15–38% of infants with confirmed meningitis can have a negative blood culture.25-27 Meningitis may go undiagnosed if a method is used to assess newborns for meningitis only after bacteremia has been proven. Among asymptomatic babies with risk conditions, the incidence of meningitis is quite low.16
The rate of LP in the Kingston study was 2.76%, which used a rigid cutoff of greater than 10 mg/L. In the UK, the rate of LP performed was 1.37% after the introduction of the 2012 CG149 guidelines.5 Our rate of LP performed was 63% across both units together, with U1 performing LP in only 24% of newborns and U2 performing LP in 88% of newborns with raised CRP, as mentioned in the methodology.
In the study by Kumar et al.,3 only five babies (3.3%) out of those suspected of having clinical sepsis were found to have meningitis. Meningitis was not present in any of the clinically normal babies with high-risk obstetric factors. Additionally, 22.9% of LPs were traumatic, 26.3% had insufficient fluid for a thorough study, and 37% had inconclusive results. Our data showed only 0.8% meningitis in babies with suspected sepsis.
Important factors contributing to the utility of LP include the clinical setting and the probability of meningitis. When we compared our practices, U1 performed LP mainly in babies with CRP greater than 10 mg/L and severe sepsis but who were hemodynamically stable, or if the babies had clinical features suggestive of meningitis. U2 performed LP in all babies above the stated CRP cutoff, excluding only those who were hemodynamically unstable or had severe thrombocytopenia. The CSF positivity rate in U1 was 12.5%, considering LP was performed only when clinically warranted, while it was 2.22% in U2, confirming the poor yield of routine LP with a very low incidence of meningitis, as shown in Table 2. Although the yield is low in babies with clinical sepsis, no reliable clinical or laboratory markers exist to identify which babies may develop meningitis, thus there remains a gray area that needs to be explored.
To discuss the drawbacks of performing an LP,28,29 hypoxia and respiratory arrest due to incorrect positioning, pain and discomfort, difficulty obtaining the necessary samples, headache or irritability, and spinal hematoma or abscess are possible complications associated with LP. Lower GAs increase these risks. It has been reported that in the neonatal period, the incidence of ”traumatic” LP (LP; CSF red cells greater than 500/mm) is 35–46%.4 A traumatic LP affects the interpretation, diagnosis, and treatment of the underlying illness and adds to the risk of complications, including compromise of respiratory function. LP can also lead to hemodynamic instability when performed on a critically ill newborn.3
The above literature helps us understand that, in newborns who are clinically normal but have unfavorable obstetric circumstances, routine LP may not be necessary. However, since the presence of Gram-negative bacilli or fungi in the CSF will influence the choice of treatment, babies with suspected LOS should undergo an LP right away.30 We observe that among neonates with CSF CS negative but biochemical parameters suggestive of meningitis, most have clinical EOS (7 out of 10, 70%), and only 3 of these are blood culture positive. Thus, in EOS, LP could potentially be deferred in neonates whose blood cultures are negative. Conversely, in those with CSF CS positive, 83% (5 out of 6) had LOS and were blood culture positive with the same organism found in both blood and CSF. This reinforces the need for LP in LOS with positive growth in blood and CSF.
We compared two units, which had similar outcomes despite differing practices. U1 performed LP only in neonates with positive blood cultures and/or clinical features of meningitis, severe sepsis, and/or CRP greater than 50 mg/L. U2 performed LP for all neonates with CRP greater than 10 mg/L. This suggests that an invasive procedure like LP could be avoided unless clinically necessary, as both practices yielded similar outcomes, as mentioned in the results of our study.
The comparative nature of this study, examining two units with slightly different approaches regarding the use of LP in the management of neonatal sepsis, is one of its key strengths. Limitations of the study include its retrospective design and the small cohort of neonates from two centers. Further, similar larger randomized controlled trials would be beneficial to establish a standard, indicative CRP cutoff level.
CONCLUSION
Routine LP, being an invasive procedure, may not be required in all neonates with raised CRP. It could be reserved for those with culture-positive sepsis or symptoms of meningitis or severe sepsis. In babies who are blood culture positive, there are no reliable clinical or laboratory markers to predict which will have meningitis, and therefore, these babies warrant a LP. This study suggests using a CRP greater than 80 mg/L as an indication for LP in neonatal sepsis.
Clinical Significance
Objective clinical and laboratory parameters can help in determining the real need for an invasive procedure like LP in the management of neonatal sepsis.
ACKNOWLEDGMENTS
We sincerely thank Dr Arvind Shenoi for critically reviewing the manuscript and providing guidance throughout the work on this article. We also thank Dr Arun Kumar for his assistance with the statistical analysis of data and review of the manuscript.
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