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The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Pitfalls in the diagnosis of in neonates and young infants: the role of

Luca Bedetti, Lucia Marrozzini, Alessandro Baraldi, Elisabetta Spezia, Lorenzo Iughetti, Laura Lucaccioni & Alberto Berardi

To cite this article: Luca Bedetti, Lucia Marrozzini, Alessandro Baraldi, Elisabetta Spezia, Lorenzo Iughetti, Laura Lucaccioni & Alberto Berardi (2018): Pitfalls in the diagnosis of meningitis in neonates and young infants: the role of lumbar puncture, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2018.1481031 To link to this article: https://doi.org/10.1080/14767058.2018.1481031

Accepted author version posted online: 23 May 2018.

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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Pitfalls in the diagnosis of meningitis in neonates and young infants: the role of lumbar puncture

Luca Bedetti, MDa; Lucia Marrozzini, MDa; Alessandro Baraldi, MDa; Elisabetta Spezia, MDa; Lorenzo Iughetti, MDa,b; Laura Lucaccioni, MDc; Alberto Berardi MDc;

Affiliations: a Scuola di Specializzazione in Pediatria, Università di Modena e Reggio Emilia, Modena, Italy b Unità Operativa di Pediatria, Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell’Adulto, Azienda Ospedaliero-Universitaria Policlinico, Modena; Italy c Unità Operativa di Terapia Intensiva Neonatale, Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell’Adulto, Azienda Ospedaliero-Universitaria Policlinico, Modena; Italy

Correspondence to:Luca Bedetti, Scuola di Specializzazione in Pediatria, Università di Modena e Reggio Emilia, Modena, Italy, Via del Pozzo, 71 - 41124 Modena (MO), Italy Phone: +39 347 3667447. e-mail: [email protected]

Keywords: meningitis, infections, neonate, young infant, paediatric practice

Running head:

Contributors AllLu mauthorsbar pu madencture substantive in neonates intellectual and young icontributionsnfants to the published study and approved the final manuscript as submitted.

Funding None declared

Competing interests None declared JUST ACCEPTED Abstract

Meningitis occurs frequently in neonates and can lead to a number of acute, severe complications and long-termdisabilities. An early diagnosis of neonatal meningitis is essential to reduce mortality and to improve outcomes. Initial clinical signs of meningitis are often subtle and frequently overlap with those of , and current haematologic tests do not distinguish sepsis from meningitis. Thus, lumbar puncture remains the gold standard for the diagnosis of meningitis in infants, and this procedure is recommended in clinical guidelines. Nevertheless, in clinical practice, lumbar puncture is frequently deferred or omitted due to concerns regarding hypothetical adverse events or limited experience of the performer. Future studies should assess whether a combination of clinical findings and select haematological tests at disease onset can identify those neonates with the highest risk of meningitis who should undergo lumbar puncture. Furthermore, clinicians should be convinced that the actual benefits of an early diagnosis of meningitis far outweigh the hypothetical risks associated with lumbar puncture.

JUST ACCEPTED INTRODUCTION

Neonates and young infants (0-90 days) are the most susceptible to infections; sepsis and meningitis occur more frequently during the first month of life than during later periods1. Sepsis can be classified as early onset sepsis (EOS), presenting from birth to day 3 and reflecting vertical transmission, or as late onset sepsis (LOS), from day 4 to 89, mostly reflecting horizontal transmission2. The main mechanism of meningitis development is primary bacteraemia with secondary spread to the ; for this reason, meningitis frequently overlaps with sepsis in neonates.

Incidence rates of neonatal meningitis are lower in high-income countries than in low-income countries (0.3 vs 0.8-6.1/1000 live births),3 partly due to the decline in early onset meningitis because of widespread intrapartum prophylaxis for preventing group B

EOS4,5. Nevertheless, group B streptococcus remains a leading cause of both sepsis and meningitis in high-income countries2,6. Neonatal meningitis can cause a number of acute, severe complications (, stroke, intracerebral thrombosis, haemorrhage and brain )7 and long- termdisabilities(neurodevelopmental or sensory neural impairment)8. An early diagnosis of neonatal meningitis is essential for correct therapy and to reduce mortality and complications.

Lumbar puncture (LP) is currently the best way to confirm the diagnosis3. However, the indications for LP vary across studies1,9. Clinicians are sometimes reluctant to perform an LP, potentially because of concerns regarding the potential risks of adverse events during the procedure (i.e., hypoxia or bradycJUSTardia) or further comp licACCEPTEDations (see below). However, these potential risks, even if they are real, have not been precisely defined in large prospective studies, particularly with regard to neonates of younger gestational age. Perhaps because of these uncertainties, the rate of performing an LP seems to vary across gestational ages, and rates of LP are lower in neonates of younger gestational age10,11. WHEN TO SUSPECT MENINGITIS IN INFANTS WITH SEPSIS

Clinical signs

The diagnosis of meningitis remains challenging because the initial signs are often subtle and overlap with those of sepsis. The suspicion of meningitis is greater in the presence of , irritability, , bulging fontanel, abnormal consciousness, hypotonia and tremors12.

Signs of meningitis may also vary according to birth weight. Crebs and Costa13 compared clinical signs in 34 neonates with birth weights <2500 g and in 53 neonates with birth weights >2500 g and found that apnoea (20.6%), (17.6%) and abdominal distension (23.5%) were predominant in neonates <2500 g, whereas irritability (45.3%), seizures (41.5%) and bulging fontanel (30.2%) were the most frequent clinical findings in neonates >2500 g.

Laboratory tests

Attempts have been made to identify blood indicators to rule out meningitis in sick infants. However, none of the currently available tests are sufficiently accurate to exclude bacterial meningitis without performing an LP. C-reactive protein (CRP). A retrospective cohort study including 97 new-borns with culture- negative EOS14 evaluatedthe immature-to-total (I/T) ratio, CRP at 12 and 24 hours, and LP. CRP >40 mg/L and an I/T ratio >0.3 had poor sensitivity (70-73% and 18-70%, respectively) and specificity (28-45% and 63-76%, respectively) for confirming meningitis. The authors concluded that these are not valid screening tests for diagnosing meningitis in patients with culture- negative EOS. JUST ACCEPTED Procalcitonin (PCT). ThePCT assay is currently an excellent laboratory test for diagnosing serious bacterial infections in young infants. The diagnostic value of PCT >0.3 ng/ml (specificity 78%, sensitivity 90%) is greater than that of CRP >20 mg/L (specificity 75%, sensitivity 75%)15. Unfortunately, no studies have compared PCT levels in septic neonates with and without meningitis. White b lood c ell (WBC) count. Total WBC count has little value in the diagnosis of neonatal meningitis16. Bonsu17 demonstrated that no WBC count intervals or cut-off points are sufficiently accurate to guide the decision to perform an LP; otherwise, there is a risk of missing a substantial proportion of meningitis cases. Martinez18 found that in young infants with fever without a source, haematological tests (leukocyte count, absolute neutrophil count, CRP and/or PCT levels) were performed in 92% of 21- to 90-day-old infants who appeared well, whereas 19% of these infants underwent an LP. LP was more likely to be performed in infants with abnormal blood tests than in infants with entirely normal blood tests (29% vs 14%). However, no infants had confirmed bacterial meningitis, suggesting that the decision to perform an LP should not be based on laboratory test results only. Blood culture (BC). In daily practice, someone performs an LP on the basis of BC results. By studying

90 cases of EOS, Berardi10 found that an LP was performed in only 32% of neonates; furthermore, LP was performed even less often among new-borns with birth weights <1500 g (13% of cases).Stoll19 retrospectively evaluated >9000 very low birth weight (VLBW) neonates with suspected late onset meningitis and found that LP was more likely to be performed in infants with a positive BC than in those with a sterile BC (66% vs 34%). Notably, meningitis was more likely in neonates with a positive BC than in those with a sterile BC (7.2% vs 1.5%, p<.001), but ~1/3 of those with meningitis had a sterile BC. False negative BC results are frequent (due to insufficient blood samples), whereas meningitis may occur in some (up to ~50%) neonates with a sterile BC16,20. Therefore, if an LP is performed on the basis of BC results, cases of meningitis can be missed, and the diagnosis is delayed until the BC results are available21. Because are frequently given at disease presentation, these drugs could inhibit the growth of in cerebral spinal fluid (CSF) culture. Meningitis and CSF parameters. Normal CSF white cell count and glucose levels are similar in preterm and full-term neonates, while CSF protein values are significantly higher in preterm neonates and decrease withJUST age (table 1)22. It is controversial ACCEPTED whether the diagnosis of meningitis can entirely rely on CSF parameters; in fact, no single CSF value can confirm the diagnosis. CSF parameters vary widely among neonates with bacterial meningitis (ranges: WBC count, 0 to 15900/mm3; glucose, 0 to

199 md/dL; protein, 41 to 1964 mg/dL). WBC count <8/mm3 has the highest sensitivity (97%), while

CSF glucose value <20 mg/dl has the highest specificity (98%)15. CSF culture: CSF culture is the gold standard for confirming bacterial meningitis and identifying the pathogen23. However, antibiotic treatment is frequently initiated before performing an LP, which affects CSF parameters. Children pre-treated for 12 hours had lower rates of positive CSF cultures (84% vs 58%), higher CSF glucose levels (median, 29 mg/dl vs 49 mg/dl), and lower CSF protein levels (median, 174 mg/dl vs 121 mg/dl) than non-pre-treated children. In contrast, CSF Gram-positive rates and CSF WBC count are not affected by antibiotics24. Meningitis and bacterial polymerase chain reaction. Compared to standard cultures, molecular methods have increased sensitivity for diagnosing bacterial meningitis (78.1 vs 90.6%)25, and polymerase chain reaction is useful for diagnosing group B streptococcal meningitis in neonates and young infants26. Molecular methods yield results more rapidly than BC, and they have a role when antibiotics are given before LP27.

Meningitis and cytokine levels. Ye28 studied cytokine levels in blood and CSF and the blood/CSF ratio in children younger than 10 years with bacterial meningitis and children with viral encephalitis, epilepsy, febrile seizures or no complications/diseases. CSF WBC count had low sensitivity (70%) and good specificity (93%), while CSF IL-6 levels >38.2 pg/mL had 100% sensitivity and 91.0% specificity. The combination of CSF IL-6 and the CSF/blood IL-6 ratio had the best sensitivity (100%) and specificity (97%) in discriminating bacterial meningitis. Data concerning neonates are unavailable.

Meningitis and ultrasound diagnosis

Spinal ultrasound could improve the diagnosis and follow-up of neonatal meningitis. Echogenicity and trabeculations have high specificity (100%) and low sensitivity (59%) for the diagnosis of meningitis29, whereas pulsation of the spinal cord and nerve roots has good specificity (85%) and moderate sensitivity (76%). The authors suggest that spinal ultrasound follow-up could be used to monitor disease seJUSTverity and treatment e fficACCEPTEDacy without the need for additional invasive procedures.

LUMBAR PUNCTURE

When to perform LP: selective or universal approach?

The gold standard for confirming bacterial meningitis is a positive CSF culture30. Delaying treatment until signs and symptoms of meningitis are obvious carries the risk of preventable mortality, whereas treating neonates with antibiotics presumptively on the basis of subtle signs or risk factors alone results in overtreatment31. Some clinicians may choose to perform LPs in the sepsis workups for all neonates but are sometimes forced to defer the procedure in cases of critical clinical conditions. Performing an LP in infants younger than 90 days of age is challenging for physicians, and the variability in performing LP is well documented1.9. Patrick32 found that full-term new-borns in teaching and children’s hospitals and those in urban areas were significantly more likely to undergo LP for suspected EOS than new-borns in rural areas and non-teaching hospitals. These results indicate inconsistent application of available clinical guidelines. It is controversial whether LP should be performed with a universal or a selective approach in suspected EOS and LOS. At the Kaplan Medical Centre33, a selective approach was applied in VLBW infants with suspected LOS. The decision to perform am LP was made by an experienced senior physician who considered the clinical state evaluation and presence of risk factors. LP was performed in 71% of suspected LOS cases, and meningitis was diagnosed in 1.4% of infants. An analysis of the rates of complications at 18 months of age between infants who did or did not undergo LP did not show significant differences, with no evidence of missed or partially treated meningitis. Even if this selective strategy seems safe and advisable, it is poorly standardized and susceptible to individual interpretation. In contrast, LP in asymptomatic neonates at risk for EOS is not recommended34.

LP in young infants with respiratory distress syndrome or urinary tract infections

None of 203 new-born infants less than 24 hours old investigated for respiratory distress syndrome had a positive CSF culture35. Weiss36 came to similar results in a study of preterm infants with respiratory signs on the first day of life: 4 of 374 patients had a positive CSF culture, and only one had a negative BC.JUST Thus, the authors concluded ACCEPTED that infants with isolated respiratory signs deserve a selective approach regarding undergoing an LP, and an abnormal neurological examination should be considered. More recent data from Stefanski37 showed that the incidence of meningitis in children younger than 1 year of age with bronchiolitis was zero. Urinary tract infection in infants younger than 90 days of age is rarely associated with meningitis; thus, routine LP is not recommended in this population. Viullermine38 studied 75 infants with a urinary tract infection, and none had coexisting culture-proven meningitis. Positive urinalysis has a high negative predictive value for meningitis (98.2%) in infants 30 to 90 days of age39, but it probably needs further investigation in neonates.

How to perform LP

LP in young infants is sometimes difficult to perform; however, experienced clinicians40 and, in our experience, nurses who maintain the baby in the best position may have a higher success rate. A successful LP should avoid blood contamination to obtain reliable CSF parameters. A minimum of 30 drops (1.5 ml) is required to perform all routine laboratory tests (CSF parameters and viral and bacterial cultures). Local anaesthetics should be administered to reduce pain, and sedation with benzodiazepine (usually midazolam) is sometime required41.

LP can be performed in at least four positions (Figure1)42. Oncel43 found that the sitting position with flexed legs (and abdominal compression) provides the widest interspinous spaces, thereby increasing the LP success rate in neonates. However, an early study44 evaluated hypoxemia during LP in neonates aged 0-24 hours (mean gestational age, 34 weeks) in three positions (sitting without abdominal compression and lateral with or without abdominal compression) and found that mean transcutaneous

PO2 was significantly lower during LP in the lateral position with abdominal compression; therefore, positions in which the legs do not compress the abdomen are recommended for LP. On the basis of these conflicting results, it is difficult to suggest the best position for performing LP. Furthermore, the correct site to tap can be found by palpating from the superior iliac crest to the midline, reaching the L3-L4 or L4-L5 interspaces. Recent trials suggest that ultrasound assistance may minimize the number of attemptsJUST45. ACCEPTED

Indications to perform LP

“Too sick to tap” and “risk of complications” are cited daily in neonatal units as reasons to defer LP19, and in our experience, an additional reason is “the baby was too well to suspect meningitis”. According to NICE guidelines46, every child and young person with suspected meningitis should undergo an LP unless any contraindications are present. In addition, US guidelines34 recommend that “LP can be deferred in any infant who is critically ill or who is likely to have cardiovascular or respiratory compromise during the procedure”, but LP should be performed in young infants with suspected sepsis unless meningitis can be excluded clinically17,34. LP should be performed in neonates who can safely undergo the procedure; have a positive BC and abnormal laboratory markers and clinical signs; and do not respond to therapy34. LP seems to be mandatory in febrile neonates aged less than 21 days who do not appear well18. However, clinical guidelines do not provide indications for every situation, and the decision whether to perform LP is often left to clinicians.

LP contraindications and complications

Unfortunately, most contraindications and complications of LP (table 2) are from studies carried out in paediatric patients, with limited data regarding neonates. Stoll et al. found no change in the risk of death among VLBW infants who underwent LP (10% vs 10%)19, whereas mortality was significantly increased in neonates with confirmed meningitis (23%) compared to those without meningitis (9%, p .001). A fearful complication is brain herniation resulting from different pressures between the cranial and spinal compartments47. However, it is unknown whether these paediatric complications occur at the same (or perhaps lower) rates in neonates.

Traumatic and unsuccessful LP

LP may fail after a traumatic tap or when the CSF volume is insufficient. Nigrovic found that factors associated with failure were younger age, inability to palpate and visualize the lumbar spinous processes,JUST limited clinician experience, ACCEPTED no use of local anaesthetics and troubled patients48. A retrospective review carried out in an Academic level-4 NICU49 confirmed that 75% of LPs performed by residents were traumatic (>1,000 red blood cells/mm3). Glatstein50 studied infants younger than

2 years of age and found that the rates of traumatic LP (defined as >400 red blood cells/mm3) were 26.2% and 12.5% in the sitting and lying positions, respectively. The rates of unsuccessful LP (failure to obtain CSF) were 24% after a single LP and 50% after multiple attempts; traumatic LP was not affected by the duration of the procedure or, in contrast to the results reported by Nigrovic48, by physician experience or sedative use. Ultrasonographic support is under study, but more data are necessary to recommend its widespread use51,52. Neal40 found that the rates of first successful LP in infants under six months of age were 58% and 31% with and without bedside spine ultrasonography, respectively; these rates increased to 75% and 44%, respectively, after three attempts.

CONCLUSIONS

Currently, LP remains essential to confirm meningitis, but further data are welcome to reinforce the concept that the actual benefits of an early meningitis diagnosis far outweigh the hypothetical risks associated with LP. In the future, a combination of clinical findings and select laboratory tests upon disease presentation could help identify neonates with the highest risk of meningitis and those who should undergo an LP.

References

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Table 1. CSF findings in preterm and term infants in Neonatal Intensive Care Unit. Preterm Infants Value

Term Infants

≤ 7 days > 7 days all ≤ 7 days > 7 days all

CSF WBC, cells/µL

All infants

Median (IQR) 3 (1-7) 3 (1-4) 3 (1-6) 3 (1-6) 2 (1-4) 3 (1-6)

95th percentile 18 12 16 23 32 26

Antibiotic-unexposed

95th percentile 17 10 11 31 53 32

CFS protein, mg/dL

All infants

Median (IQR) 116 93 (69-122) 104 78 (60-100) 57 (42-77) 74 (54-96) JUST(93-138) ACCEPTED(79-131)

95th percentile 213 203 203 137 158 137

Antibiotic-unexposed

95th percentile 195 136 195 136 284 136

CSF glucose, mg/dL All infants

Median (IQR) 53 (43-65) 47 (40-58) 49 (42-62) 50 (44-56) 52 (45-64) 51 (44-57)

5th percentile 33 33 33 35 38 36

Antibiotic-unexposed

5th percentile 33 35 33 33 33 33

Adapted from “Cerebrospinal fluid reference ranges in term and preterm infants in the neonatal intensive care unit”22. CSF, cerebral spinal fluid; IQR, interquartile range.

Table 2. Contraindications and complications of LP

Controindications53 Complications

• Haemodinamical instability Common54:

• Severe respiratory distress syndrome • Headache

• Increased intracranial pressure • Mild local pain at the puncture site

• Underlying coagulopathies Rare41,47,54:

• Skin infection on the site of the tap • epidural, subdural or subarachnoid haemorrhage • Status epilepticus JUST ACCEPTED• Osteomyelitis • Abnormal anatomy of spinal cord • epidural abscess or discitis • Spinal Epidural Abscess • bleeding

• backache transient dysaesthesia

• brain herniation Table 2. Contraindications and complications of LP

Controindications53 Complications

• Haemodinamical instability Common54:

• Severe respiratory distress syndrome • Headache

• Increased intracranial pressure • Mild local pain at the puncture site

• Underlying coagulopathies Rare41,47,54:

• Skin infection on the site of the tap • epidural, subdural or subarachnoid haemorrhage • Status epilepticus • Osteomyelitis • Abnormal anatomy of spinal cord • epidural abscess or discitis • Spinal Epidural Abscess • bleeding

• backache transient dysaesthesia

• brain herniation

JUST ACCEPTED JUST ACCEPTED