RESUMEN

Objetivo:

Determinar la incidencia y las características clínicas, bacteriológicas y del líquido cefalorraquídeo de la meningitis neonatal en hospitales de Lima.

Materiales y métodos:

Se realizó un estudio observacional, multicéntrico en seis hospitales de la ciudad de Lima, con una vigilancia epidemiológica durante un año.

Resultados:

La incidencia acumulada hospitalaria fue de 1,4 casos por mil nacidos vivos. Fueron incluidos 53 casos de meningitis neonatal, 34% (18/53) fueron tempranos y 66% (35/53) tardíos. Los factores maternos asociados fueron líquido amniótico meconial e infección de tracto urinario. El 58,8% (30/51) presentó controles prenatales insuficientes. El factor neonatal más asociado fue sepsis. Los principales síntomas fueron fiebre, irritabilidad, hipoactividad y dificultad respiratoria. En el líquido cefalorraquídeo (LCR) se destacó la pleocitosis, sin predominio de polimorfonucleares (PMN), hipoglucorraquia y proteinorraquia. Los patógenos aislados con mayor frecuencia fueron Escherichia coli y Listeria monocytogenes.

Conclusiones:

La incidencia hospitalaria de meningitis neonatal fue de 1,4 por mil nacidos vivos, siendo diez veces mayor en prematuros. La dificultad respiratoria fue el síntoma más frecuente en la forma temprana, mientras que la fiebre e irritabilidad en la forma tardía. El LCR mostró pleocitosis sin predominio de PMN. Los gérmenes más frecuentes fueron Escherichia coli y Listeria monocytogenes. La ventriculitis e hidrocefalia fueron las complicaciones neurológicas más comunes.

Palabras clave:
Meningitis; Neonato; Prematuro; Líquido Cefalorraquídeo; Perú

ABSTRACT

Objective:

To determine the incidence and the clinical, bacteriological and cerebrospinal fluid characteristics of neonatal meningitis in Lima hospitals.

Materials and methods:

An observational, multicenter study was conducted in six hospitals in the city of Lima during 1 year of epidemiological surveillance.

Results:

The cumulative hospital incidence was 1.4 cases per 1000 live births. A total of 53 cases of neonatal meningitis were included, 34% (18/53) were early and 66% (35/53) late. The associated maternal factors were meconium-stained amniotic fluid and urinary tract infection. Insufficient prenatal check-ups were found in 58.8% (30/51). The most associated neonatal factor was sepsis. The main symptoms were fever, irritability, hypoactivity and respiratory distress. Pleocytosis in cerebrospinal fluid (CSF) was significant, without predominance of polymorphonuclear lymphocytes (PMN), hypoglycorrhagia and proteinorrhagia. The most frequent pathogens isolated were Escherichia coli and Listeria monocytogenes.

Conclusions:

The hospital incidence of neonatal meningitis was 1.4 per 1000 live births, being ten times higher in preterm infants. Breathing difficulty was the most frequent symptom in the early stage, while fever and irritability in the late stage. CSF showed pleocytosis without predominance of PMN. The most frequent germs were Escherichia coli and Listeria monocytogenes. Ventriculitis and hydrocephalus were the most common neurological complications.

Keywords:
Meningitis; Newborn; Premature; Cerebrospinal Fluid; Peru

INTRODUCTION

Neonatal meningitis (NM) is a devastating disease, known to exist for over a century. Early publications emphasized its clinical rarity and cumbersome diagnostic process ¹1. Bell WE, McCormick WF, Murillo PL. Meningitis neonatales. Infecciones neurológicas en el niño. 2 ed. Barcelona: Salvat; 1979.^,22. Ziai M, Haggerty RJ. Neonatal meningitis. N Engl J Med. 1958;259(7):314-20. doi: 10.1056/NEJM195808142590702.
https://doi.org/10.1056/NEJM195808142590... . However, over time it has been reported on every continent, and despite scientific and technological advances, it remains a public health problem ³3. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... .

Incidence of NM varies considerably. In developed countries, it is estimated to be around 0.3 cases per 1,000 live births, while in developing countries this incidence can be as high as 6.1 cases per 1,000 live births ³3. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... . With the new methods, detection has improved and lethality has decreased; however, morbidity remains high (20-60%) ⁴4. Holt DE. Neonatal meningitis in England and Wales: 10 years on. Arch Dis Child - Fetal Neonatal Ed. 2001;84(2):85F-89..

In Peru, Oliveros reported 0.47 cases per 1,000 live births in 1993 ⁶6. Oliveros Donohue MA, Ramos Pianezzi R, León Cueto JL, Mazzini Pérez-Reyes J, Van Oordt, Bellido J, Livia Becerra C. Meningitis neonatal en la UCI del Hospital Edgardo Rebagliati Martins (IPSS) 1986-88. Diagnóstico. 1993;32(4/6):73-7.. However, in recent years an upward trend has been observed, ranging from 0.9 to 1.5 cases per 1,000 live births ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342...

6. Oliveros Donohue MA, Ramos Pianezzi R, León Cueto JL, Mazzini Pérez-Reyes J, Van Oordt, Bellido J, Livia Becerra C. Meningitis neonatal en la UCI del Hospital Edgardo Rebagliati Martins (IPSS) 1986-88. Diagnóstico. 1993;32(4/6):73-7.^-77. Lazo E, Guillén D, Zegarra J. Meningitis neonatal en el Hospital Nacional Cayetano Heredia. Rev Peru Pediatr. 2008;61(3):157-164.. This incidence could be greater in our population due to the high frequency of maternal-perinatal factors, such as insufficient prenatal control, sepsis, immaturity due to prematurity and factors inherent to neonatal intensive care ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... .

NM is classified in 2 types, early and late ⁸8. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013.. Early NM starts within the first 72 hours and is related to contamination through the birth canal with bacteria such as Escherichia coli, Streptococcus group B and Listeria monocytogenes⁹9. Devi U, Bora R, Malik V, Deori R, Gogoi B, Das JK, et al. Bacterial aetiology of neonatal meningitis: A study from north-east India. Indian J Med Res. 2017 Jan;145(1):138-143. doi: 10.4103/ijmr.IJMR_748_15.
https://doi.org/10.4103/ijmr.IJMR_748_15... ^,1010. Pérez RO, Lona JC, Quiles M, Verdugo MÁ, Ascencio EP, Benítez EA. Sepsis neonatal temprana, incidencia y factores de riesgo asociados en un hospital público del occidente de México. Rev Chil Infectol. 2015;32(4):447-452.. After 72 hours, late NM is associated with germs from the hospital environment, such as coagulase-negative Staphylococcus and gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Enterobacter spp.) ⁹9. Devi U, Bora R, Malik V, Deori R, Gogoi B, Das JK, et al. Bacterial aetiology of neonatal meningitis: A study from north-east India. Indian J Med Res. 2017 Jan;145(1):138-143. doi: 10.4103/ijmr.IJMR_748_15.
https://doi.org/10.4103/ijmr.IJMR_748_15...

10. Pérez RO, Lona JC, Quiles M, Verdugo MÁ, Ascencio EP, Benítez EA. Sepsis neonatal temprana, incidencia y factores de riesgo asociados en un hospital público del occidente de México. Rev Chil Infectol. 2015;32(4):447-452.^-1111. Zea-Vera A, Turin CG, Ochoa TJ. Unificando los criterios de sepsis neonatal tardía: propuesta de un algoritmo de vigilancia diagnóstica. Rev Peru Med Exp Salud Pública. 2014;31(2):358-63..

NM is a health emergency, and as soon as it is suspected, empirical antibiotic treatment should be indicated ¹²12. Perlman JM, Cilio M. Neonatal Meningitis: Current Treatment Options. Neurology. Neonatology Questions and Controversies. Third Edition. Phyladelphia: Elsevier; 2019.. However, diagnosis is complex due to the low specificity of signs and symptoms and the difficulty of isolating the germs by culture. So, when risk factors are detected, clinical suspicion is the only alternative ²2. Ziai M, Haggerty RJ. Neonatal meningitis. N Engl J Med. 1958;259(7):314-20. doi: 10.1056/NEJM195808142590702.
https://doi.org/10.1056/NEJM195808142590... ^,88. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013..

Given the scarce information on NM in our country regarding aspects such as its frequency, impact on morbimortality and the prevalence of the pathogens involved ⁹9. Devi U, Bora R, Malik V, Deori R, Gogoi B, Das JK, et al. Bacterial aetiology of neonatal meningitis: A study from north-east India. Indian J Med Res. 2017 Jan;145(1):138-143. doi: 10.4103/ijmr.IJMR_748_15.
https://doi.org/10.4103/ijmr.IJMR_748_15... ^,1212. Perlman JM, Cilio M. Neonatal Meningitis: Current Treatment Options. Neurology. Neonatology Questions and Controversies. Third Edition. Phyladelphia: Elsevier; 2019., it is extremely important to know the epidemiological and clinical profile of the disease. For this reason, the objective of the study was to estimate the incidence, associated factors, clinical aspects and cerebrospinal fluid (CSF) characteristics, etiology, and complications of NM in hospitals in the city of Lima.

MATERIALS AND METHODS

Design and population

Multi-center case series study carried out between 2017 and 2018, with the aim of carrying out hospital epidemiological surveillance of NM for 12 consecutive months in Lima hospitals, without intervening in the diagnosis and treatment processes.

To be included in the study, hospitals had to have neonatal units, neonatal physicians, specialized nursing staff, specialists in neurology or neuropediatrics, neuroimaging equipment and a clinical laboratory suitable for processing general analysis and cytochemical and bacteriological examination of CSF. For this purpose, 12 hospitals were selected, from which 6 met the inclusion criteria: Hospital Cayetano Heredia (HCH), Hospital Nacional Docente Madre Niño San Bartolomé (HSB), Hospital Nacional Arzobispo Loayza (HNAL), Instituto Nacional Materno Perinatal (INMP), Hospital Nacional Guillermo Almenara Irigoyen (HNGAI) and Hospital Nacional Daniel Alcides Carrión (HNDAC). All were level III health facilities.

A research team was organized with physicians representing each of the six hospitals, who were trained in the process of inclusion, follow-up and collection of clinical and laboratory data. All centers had a neonatologist and a neurologist. A new-case alert system was developed. The possibility of a case, was recorded, communicated and confirmed by the representant of each hospital. The monitoring and data collection continued until discharge. An ad hoc clinical file was created, with data about filiation, sex, age, gestational age, prenatal, birth and postnatal data, CSF characteristics and bacteriological data. There was no interference in management decisions. In all hospitals the objectives of the project were presented to the pediatric medical team.

In order to estimate hospital incidents, the number of births during the observation period was recorded, according to the perinatal register and statistics office of each hospital. Finally, premature births were recorded by gestational age and sex.

Variables

All full-term infants under 28 days or pre-term infants under 44 weeks corrected gestational age were entered into the study. The inclusion criteria for all cases of NM were infants who were symptomatic or at risk of infection; pleocytosis ≥ 30 leukocytes/μL in CSF, diagnosis and care at the hospital of birth. The hospital follow-up concluded with the discharge of the patient. Neonates with severe cerebral malformations and spinal dysraphism were excluded.

NM categorization was confirmed (germ identified), probable (high bacterial suspicion), and possible (low bacterial suspicion) ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... ^,1111. Zea-Vera A, Turin CG, Ochoa TJ. Unificando los criterios de sepsis neonatal tardía: propuesta de un algoritmo de vigilancia diagnóstica. Rev Peru Med Exp Salud Pública. 2014;31(2):358-63.. NM was confirmed when the germ was identified in the CSF, by culture, polymerase chain reaction (PCR), coagglutination or blood culture. Probable NM was defined by hypoglycorrhachia (glycorrhachia ≤50% of serum glucose or absolute glycorrhachia of ≤40 mg/dL) and hyperproteinuria (proteinuria ≥60 mg/dL) ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... ^,88. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013.. Cases of possible NM had any level of glycorrhachia or proteinorrhachia or normal biochemical values. The viruses were identified by PCR or viral indirect immunofluorescence (viral IIF) in the CSF. The fungi were identified by CSF culture/PCR. In the case of lumbar punctures (LP), a leukocyte was discounted for every 500 red blood cells in CSF.

Early MN was defined as, confirmed, probable or possible cases diagnosed before 72 hours of age. Late NM was defined as cases diagnosed after 72 hours of age⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... ^,88. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013.. Early neurological complications were defined within the first seven days of detection. The complications considered were hydrocephalus, ventriculitis, subdural effusion and cerebral infarction, identified by cerebral ultrasound or cerebral magnetic resonance.

In order to measure the burden of disease, out-of-hospital cases were recorded. Out-of-hospital cases are defined as cases of NM born in other hospitals and admitted during the study period.

A set of prenatal, natal and postnatal variables were recorded and analyzed. Numerical variables were: maternal age, antenatal control, gestational age, birth weight; and categorical variables were: maternal urinary infection, maternal fever, chorioamnionitis, presence of meconium amniotic fluid, pre-eclampsia / eclampsia, asphyxia, intraventricular hemorrhage, sepsis, anemia, meconium aspiration, fever, respiratory distress, hypoactivity, irritability, vomiting. Likewise, CSF characteristics and germ frequencies, treatment, complications and lethality were recorded and analyzed.

Ethical considerations

The identity of the patients was protected by numerical codes. The project was also approved by the Institutional Ethics Committee of Universidad Peruana Cayetano Heredia and by the ethics committees of each of the participating hospitals.

Statistical Analysis

The information was collected and stored in a Microsoft Excel 2016 © database. The accumulated incidence during one year of observation in each hospital was determined. The project started in several successive months in 2017 and ended sequentially in 2018. The cumulative incidence was estimated from the sum of confirmed cases, probable cases and possible cases divided by the number of live births. Out-of-hospital cases were not considered for the incidence calculation.

The frequencies of clinical and laboratorial variables are presented for early, late and out-of-hospital NM. Numerical variables were summarized with medians and their interquartile range. Logistic regression was performed to determine the influence of some factors on early meningitis with respect to late meningitis, by analyzing all cases. Homogeneity was determined by the Levene and Forsythe-Browne tests. The only few missing data were from the prenatal control variable, so no replacement technique was necessary.

RESULTS

Patient Enrollment

The project started in 2017. Given that the enrollment in hospitals was carried out gradually, the study was completed in 2018. During this period a total of 38,513 live neonates were registered in the six hospitals, of which 51 patients were included who developed 53 cases of NM, one patient presented three episodes of NM. From the reported cases, 41.5% (22/53) were neonates who, having left the hospital in good condition, were readmitted on suspicion of an infectious process. During the study period, seven out-of-hospital cases were admitted (Figure 1), considered only for the profile of clinical, etiological and laboratorial analysis.

The average maternal age was 27.2 years and parity was 2.3 per woman. The number of prenatal controls was also insufficient in 58.8% (30/51) of the mothers. From the neonates, 54.7% (29/53) were born prematurely before 37 weeks. The population studied was homogeneous among the hospitals included.

Epidemiological characteristics

The hospital incidence was 1.4 cases per 1,000 live births, with a wide variation among hospitals, from 0 to 3.2 cases per 1,000 live births. HCH and HNDMNSB had the highest incidence. In pre-term infants under 37 weeks, the NM incidence was 7.5 cases per 1,000 live births and 0.7 cases per 1,000 live full-term births (Table 1).

The male/female ratio was 1.4; males represented the 58.3% (35/60) and females 41.7% (25/60). The majority of patients were from northern Lima at 42% (25/60), mainly from the districts of San Martín de Porres and Los Olivos, followed by districts of eastern Lima at 15% (9/60). Figure 2 shows that the cases came from areas surrounding the hospitals.

From the total, 34% (18/53) were early NM cases and 66% (35/53) were late NM cases. Cases of confirmed NM were 58.5% (31/53), of which 25.8% (8/31) were early and 74.2% (23/31) late. Bacterial NM occurred in 87.1% (27/31) of the confirmed cases and viral NM in 12.9% (4/31). Probable NM was 22.6% (12/53) of the total of cases and possible NM was 18.9% (10/53). Regarding outpatients, 4 had confirmed NM, 2 had probable NM and 1 had possible NM.

Clinical characteristics

For early NM, the associated prenatal factors were meconial amniotic fluid (38.9%), urinary tract infection (33.3%), maternal fever (27.8) and chorioamnionitis (22.2%). However, in the late NM, these factors did not seem to have a major influence (Table 2).

Sepsis was the most important factor related to NM; and according to the NM types, 50% (9/18) were early meningitis cases, 20% (7/35) were late meningitis cases and 42.9% (3/7) were of out-of-hospital meningitis cases. The average age for the onset of symptoms in early NM cases was 0.9 days; 18.6 days in late NM; and 11.9 days in the out-of-hospital cases. Symptoms such as respiratory distress, were more common in the early NM. In late NM, fever, irritability and hypoactivity predominated (Table 2). Table 5 shows the risk factors associated with early NM in relation to late NM.

Cytochemical and bacteriological characteristics of the CSF

On average, 2.5 and 2 LPs were performed for early and late NM, respectively. In most cases of early NM, the LP was performed on the first day of hospitalization; and in cases of late NM, it could take until the third day of illness.

In Table 3, the cytochemical characteristics of the CSF are presented. The median value for pleocytosis was 225 leukocytes/μL for early NM and 202 leukocytes/μL for late NM, the median value for polymorphonuclears (PMN) was of 57% and 30%, respectively. Hypoglycorrhachia was similar in both types of meningitis and hyperproteinorrhachia was higher in early NM. In the out-of-hospital type, there was less pleocytosis and more glycorrhachia (Table 3).

A total of 35 germs were identified, including bacteria, viruses and a case of Candida albicans. In all clinical types, Escherichia coli and Listeria monocytogenes predominated. In 17.1% (6/35) of the cases the germ was isolated both in blood culture and in the CSF. Escherichia coli was found in four of those cases, group B Streptococcus and coagulase negative Staphylococcus, in one case each. Cases of influenza B, coronavirus and adenovirus were identified by indirect immunofluorescence (IIF). In a single case, PCR was performed, isolating herpes virus VI (Table 4).

Treatment and special conditions

Treatment schedules were highly variable. The mean duration for cases of early NM was 21 days and 19.5 days for late meningitis. Before the first LP was performed, 62% of children received antibiotics. The most commonly used drugs were ampicillin (60%), cefotaxime (38%), vancomycin (28%), meropenem (33%) and gentamicin (22%), in different schedules.

In the specific analysis of late meningitis, not including outpatients, two groups were differentiated (Figure 1). In the first group, 86.7% (13/15) of patients were pre-term infants, 46.6% (7/15) had respiratory distress, most were diagnosed at seven days of age, and their CSF was characterized by increased pleocytosis. In the second group, 75% (15/20) were full-term infants, fever and irritability were the most frequent symptoms and the diagnosis was made within the first two days of hospitalization.

Three patients had special presentations. One had minor pleocytosis and urinary-related bacteremia by Escherichia coli; another had normal initial cytochemistry, but with a CSF culture positive for Escherichia coli that later developed pleocytosis; and the third one had three episodes of meningitis (recurrent) by extended-spectrum beta-lactamase-producing Escherichia coli.

Complications and lethality

At least one neurological complication was observed in 25% (15/60) of the cases, from which, 73.3% (11/15) were pre-term infants. Early and late neurological complications were ventriculitis and hydrocephalus respectively.

From the cases with late NM, 95.2% (40/42) were discharged with favorable evolution, early NM had a favorable evolution in 77.8% (14/18) of the cases. Four cases were referred to a hospital with a higher complexity level. Two neonates died (3.3%), one presenting early NM and the other, the late type.

DISCUSSION

NM had a hospital incidence of 1.4 cases per 1,000 live births, with a higher risk in pre-term than in full-term infants. The wide variability in incidence leads to the suspicion that diagnostic protocols for NM were not standarized across hospitals. A variety of causal germs, mostly bacteria, were identified, with the frequency of Eschericha coli and Listeria monocytogenes being particularly noteworthy.

We present a larger NM clinical scenario than those known. In this scenario the early type is related to birth conditions and the late type is related to prolonged stay of pre-term infants in neonatal units ⁹9. Devi U, Bora R, Malik V, Deori R, Gogoi B, Das JK, et al. Bacterial aetiology of neonatal meningitis: A study from north-east India. Indian J Med Res. 2017 Jan;145(1):138-143. doi: 10.4103/ijmr.IJMR_748_15.
https://doi.org/10.4103/ijmr.IJMR_748_15... . We provide a new viewpoint, derived from the community, which occurs more in full-term infants near the second week, related to a higher proportion of viral agents.

Neonatal meningitis is an under-diagnosed and under-recorded prevalent disease in our country ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... ^,1313. Medina, María del Pilar. Frecuencia de enfermedad neurológica en recién nacidos. Rev Peru Pediatr. 2007;60(1):11-9.. In 2016, Zea et al., noted that LP is often deferred in confirmed sepsis ¹⁴14. Zea-Vera A, Turín CG, Rueda MS, Guillén-Pinto D. Uso de la punción lumbar en la evaluación de sepsis neonatal tardía en recién nacidos de bajo peso. Rev Peru Med Exp Salud Pública. 2016;33(2):278-282.. Likewise, in a similar population it has been observed that medical criteria may vary depending on the level of medical specialization ¹⁵15. Vera S. Variabilidad del criterio para indicar la punción lumbar en las unidades de cuidados intensivos neonatales [tesis de bachiller]. Lima: Facultad de Medicina, Universidad Peruana Cayetano Heredia; 2018..

We present an epidemiological surveillance study according the management protocols of each hospital. The incidence of 1.4 per 1,000 live births is an average value worldwide ³3. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... , and is initially taken as a reference. This value will have to be adjusted in the future when the diagnostic criteria are standardized. However, the high incidence in premature infants alerts us about the need for vigilance in neonatal units ^{(2, 16)}.

This study was characterized by the inclusion of cases with defined pleocytosis. This was made to meet the inflammatory criteria for meningitis, classified as confirmed, probable and possible, according to the definition of neonatal sepsis. Therefore, more positive isolates were found in blood cultures. Less were found to be positive in blood and CSF cultures, and only a few cases were observed solely in CSF culture. We believe that PCR could have helped to reduce the number of probable and possible cases, and to identify cases of pleocytosis as just an inflammatory phenomenon ⁸8. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013.^,99. Devi U, Bora R, Malik V, Deori R, Gogoi B, Das JK, et al. Bacterial aetiology of neonatal meningitis: A study from north-east India. Indian J Med Res. 2017 Jan;145(1):138-143. doi: 10.4103/ijmr.IJMR_748_15.
https://doi.org/10.4103/ijmr.IJMR_748_15... ^,1717. Marcilla C, Martínez A, Carrascosa M, Baquero M, Alfaro B. Meningitis víricas neonatales. Importancia de la reacción en cadena de la polimerasa en su diagnóstico. Rev Neurol. 2018; 67:484-490..

All known risk factors for neonatal sepsis are related to NM ¹²12. Perlman JM, Cilio M. Neonatal Meningitis: Current Treatment Options. Neurology. Neonatology Questions and Controversies. Third Edition. Phyladelphia: Elsevier; 2019.^,1818. Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017;390(10104):1770-80. doi: 10.1016/S0140-6736(17)31002-4.
https://doi.org/10.1016/S0140-6736(17)31... . For the early type, peripartum fever and incomplete prenatal controls were found to be risk factors. These factors suggest the risk of microbial invasion from the vaginal flora, the subsequent placental inflammatory response, initiation of labor and consequently sepsis and meningitis ⁸8. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013.. However, other clinical and sociocultural factors may not be considered.

Classically, NM is divided into early and late according to its mechanism of contamination¹²12. Perlman JM, Cilio M. Neonatal Meningitis: Current Treatment Options. Neurology. Neonatology Questions and Controversies. Third Edition. Phyladelphia: Elsevier; 2019.^,1616. Coto GD, López JB, Fernández B, Fraga JM, Fernández JR, Reparaz R, et al. Meningitis neonatal. Estudio epidemiológico del Grupo de Hospitales Castrillo. An Pediatr. 2002;56(6):556-63.^,1919. Zhao Z, Yu J-L, Zhang H-B, Li J-H, Li Z-K. Five-Year Multicenter Study of Clinical Tests of Neonatal Purulent Meningitis. Clin Pediatr (Phila). 2018;57(4):389-97. doi: 10.1177/0009922817728699.
https://doi.org/10.1177/0009922817728699... . However, we have identified a third group of patients who come from their homes, from the community environment, are term infants, febrile and irritable with less pleocytosis, contaminated with common respiratory tract agents, both bacterial and viral, and in some cases by germs that colonize maternal secretions.

The age of symptoms onset for both types of NM was found to be within the expected ranges, 0.9 days for early NM cases and 18.6 days for late NM cases. This was found to be in accordance with other series, and clearly associated with the type of birth and neonatal unit stay ¹²12. Perlman JM, Cilio M. Neonatal Meningitis: Current Treatment Options. Neurology. Neonatology Questions and Controversies. Third Edition. Phyladelphia: Elsevier; 2019.^,1616. Coto GD, López JB, Fernández B, Fraga JM, Fernández JR, Reparaz R, et al. Meningitis neonatal. Estudio epidemiológico del Grupo de Hospitales Castrillo. An Pediatr. 2002;56(6):556-63.^,2020. Olmedo I, Pallas CR, Miralles M, Simón de las Heras R, Rodriguez J, Chasco A. Meningitis neonatal: Estudio en 56 casos. An Esp Pediatr. 1997; 46:189-194.. The group of children of out-of-hospital origin also behaved as late NM at 11.9 days.

The symptoms were more frequent in early NM than in the late type, being very nonspecific and related to sepsis. Among them, respiratory difficulty stood out in 70% of early cases, perhaps due to lung immaturity in the premature group or to respiratory acidosis ³3. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... ^,1212. Perlman JM, Cilio M. Neonatal Meningitis: Current Treatment Options. Neurology. Neonatology Questions and Controversies. Third Edition. Phyladelphia: Elsevier; 2019.^,1616. Coto GD, López JB, Fernández B, Fraga JM, Fernández JR, Reparaz R, et al. Meningitis neonatal. Estudio epidemiológico del Grupo de Hospitales Castrillo. An Pediatr. 2002;56(6):556-63.. In late NM more neurological symptoms were observed ¹1. Bell WE, McCormick WF, Murillo PL. Meningitis neonatales. Infecciones neurológicas en el niño. 2 ed. Barcelona: Salvat; 1979.^,33. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... . However, identification of these symptoms depends on the experience of the examiner ¹⁴14. Zea-Vera A, Turín CG, Rueda MS, Guillén-Pinto D. Uso de la punción lumbar en la evaluación de sepsis neonatal tardía en recién nacidos de bajo peso. Rev Peru Med Exp Salud Pública. 2016;33(2):278-282.^,2121. Garges HP. Neonatal Meningitis: What Is the Correlation Among Cerebrospinal Fluid Cultures, Blood Cultures, and Cerebrospinal Fluid Parameters?. Pediatrics. 2006;117(4):1094-100.. Maternal fever, sepsis, and respiratory distress were three factors found to be more likely to develop in early NM than in the late type. These were probably generated by maternal infections, urinary tract infections and chorioamnionitis ¹1. Bell WE, McCormick WF, Murillo PL. Meningitis neonatales. Infecciones neurológicas en el niño. 2 ed. Barcelona: Salvat; 1979.^,88. Volpe J. Bacterial and Fungal Intracranial Infections. Neurology of the Newborn. Fifth Edition. Philadelphia: Saunders Elsevier; 2013.. It will remain for future studies to ensure the diagnosis of chorioamnionitis by pathological examination of the placenta.

In most cases, more than one LP was carried out, following international guidelines. Given that NM is a difficult to diagnose multi-symptomatic disease caused by many aggressive agents, the guidelines recommend that the LP be performed prior to the use of antibiotics. It is also recommended that a new control should be performed within 48-72 hours, especially if there is no clinical improvement, with the purpose of reducing the bacterial load or achieving sterilization of the CSF ¹⁴14. Zea-Vera A, Turín CG, Rueda MS, Guillén-Pinto D. Uso de la punción lumbar en la evaluación de sepsis neonatal tardía en recién nacidos de bajo peso. Rev Peru Med Exp Salud Pública. 2016;33(2):278-282.^,2121. Garges HP. Neonatal Meningitis: What Is the Correlation Among Cerebrospinal Fluid Cultures, Blood Cultures, and Cerebrospinal Fluid Parameters?. Pediatrics. 2006;117(4):1094-100.^,2222. Greenberg RG, Benjamin DK, Cohen-Wolkowiez M, Clark RH, Cotten CM, Laughon M, et al. Repeat lumbar punctures in infants with meningitis in the neonatal intensive care unit. J Perinatol. 2011;31(6):425-429. doi: 10.1038/jp.2010.142.
https://doi.org/10.1038/jp.2010.142... .

In both clinical types, moderate pleocytosis without PMN predominance was noted, they also presented hypoglycorrhachia and proteinorrhachia. This particular characteristic has already been observed in other national studies ⁶6. Oliveros Donohue MA, Ramos Pianezzi R, León Cueto JL, Mazzini Pérez-Reyes J, Van Oordt, Bellido J, Livia Becerra C. Meningitis neonatal en la UCI del Hospital Edgardo Rebagliati Martins (IPSS) 1986-88. Diagnóstico. 1993;32(4/6):73-7.^,77. Lazo E, Guillén D, Zegarra J. Meningitis neonatal en el Hospital Nacional Cayetano Heredia. Rev Peru Pediatr. 2008;61(3):157-164., perhaps, bacteriological factors, sample processing and patient’s immunological conditions are involved. In bacterial NM, hypoglycorrhachia and proteinorrhachia are common findings. These are explained by glucose consumption and increased detritus, their persistence for more than two weeks has been associated with poor prognosis ²³23. Tan J, Kan J, Qiu G, Zhao D, Ren F, Luo Z, et al. Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein. PLoS One. 2015 Oct 28;10(10):e0141620. doi: 10.1371/journal.pone.0141620.
https://doi.org/10.1371/journal.pone.014... . However, these indicators may be aggravated by the presence of intracranial hemorrhage. Also, on rare occasions, the first LP may not demonstrate pleocytosis, and a second sample may be required within 12 to 24 hours²¹21. Garges HP. Neonatal Meningitis: What Is the Correlation Among Cerebrospinal Fluid Cultures, Blood Cultures, and Cerebrospinal Fluid Parameters?. Pediatrics. 2006;117(4):1094-100..

The microbiological behavior of NM has varied regarding time and different geographical areas²2. Ziai M, Haggerty RJ. Neonatal meningitis. N Engl J Med. 1958;259(7):314-20. doi: 10.1056/NEJM195808142590702.
https://doi.org/10.1056/NEJM195808142590... ^,33. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... ^,1616. Coto GD, López JB, Fernández B, Fraga JM, Fernández JR, Reparaz R, et al. Meningitis neonatal. Estudio epidemiológico del Grupo de Hospitales Castrillo. An Pediatr. 2002;56(6):556-63.^,2424. Collaborative Study Group for Neonatal Bacterial Meningitis. A multicenter epidemiological study of neonatal bacterial meningitis in parts of South China. Zhonghua Er Ke Za Zhi Chin J Pediatr. 2018;56(6):421-428. doi: 10.3760/cma.j.issn.0578-1310.2018.06.004.
https://doi.org/10.3760/cma.j.issn.0578-...

25. Berardi A, Lugli L, Rossi C, China MC, Vellani G, Contiero R, et al. Infezioni da Streptococco B Della Regione Emilia Romagna. Neonatal bacterial meningitis. Minerva Pediatr. 2010;62(3 Suppl 1):51-4.^-2626. Bentlin MR, Ferreira GL, Rugolo LMS de S, Silva GHS, Mondelli AL, Rugolo Júnior A. Neonatal meningitis according to the microbiological diagnosis: a decade of experience in a tertiary center. Arq Neuropsiquiatr. 2010;68(6):882-887.. Streptococcus agalactie stands out mainly in developed countries and gram-negative bacteria in non-developed countries ³3. Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial Meningitis in the Infant. Clin Perinatol. 2015;42(1):29-45. doi: 10.1016/j.clp.2014.10.004.
https://doi.org/10.1016/j.clp.2014.10.00... ^,2424. Collaborative Study Group for Neonatal Bacterial Meningitis. A multicenter epidemiological study of neonatal bacterial meningitis in parts of South China. Zhonghua Er Ke Za Zhi Chin J Pediatr. 2018;56(6):421-428. doi: 10.3760/cma.j.issn.0578-1310.2018.06.004.
https://doi.org/10.3760/cma.j.issn.0578-... . In this series, Eschericha coli and Listeria monocytogenes were the prevalent germs in both types of NM, followed by a variety of gram-negative and gram-positive bacteria, fewer virus cases and one case of Candida albicans, all described in different case series.

NM by Eschericha coli has been known for many decades ¹1. Bell WE, McCormick WF, Murillo PL. Meningitis neonatales. Infecciones neurológicas en el niño. 2 ed. Barcelona: Salvat; 1979.^,22. Ziai M, Haggerty RJ. Neonatal meningitis. N Engl J Med. 1958;259(7):314-20. doi: 10.1056/NEJM195808142590702.
https://doi.org/10.1056/NEJM195808142590... to be a part of early neonatal sepsis cases. It can also cause late NM, usually associated with severe acute and mid-term complications such as hydrocephalus, subdural effusions, cerebral infarctions and abscesses²2. Ziai M, Haggerty RJ. Neonatal meningitis. N Engl J Med. 1958;259(7):314-20. doi: 10.1056/NEJM195808142590702.
https://doi.org/10.1056/NEJM195808142590... ^,2727. Zhu M-L, Mai J-Y, Zhu J-H, Lin Z-L. Clinical analysis of 31 cases of neonatal purulent meningitis caused by Escherichia coli. Zhongguo Dang Dai Er Ke Za Zhi Chin J Contemp Pediatr. 2012;14(12):910-912.. In recent years, the increased frequency of beta-lactamase strains and their antimicrobial resistance has being notable ²⁴24. Collaborative Study Group for Neonatal Bacterial Meningitis. A multicenter epidemiological study of neonatal bacterial meningitis in parts of South China. Zhonghua Er Ke Za Zhi Chin J Pediatr. 2018;56(6):421-428. doi: 10.3760/cma.j.issn.0578-1310.2018.06.004.
https://doi.org/10.3760/cma.j.issn.0578-... ^,2626. Bentlin MR, Ferreira GL, Rugolo LMS de S, Silva GHS, Mondelli AL, Rugolo Júnior A. Neonatal meningitis according to the microbiological diagnosis: a decade of experience in a tertiary center. Arq Neuropsiquiatr. 2010;68(6):882-887.. Therefore, their presence in this series alerts about early identification and treatment.

Listeria monocytogenes is a pathogen that has become more important in Peruvian series in recent years ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... ^,77. Lazo E, Guillén D, Zegarra J. Meningitis neonatal en el Hospital Nacional Cayetano Heredia. Rev Peru Pediatr. 2008;61(3):157-164.. It has been observed to be 5-20% ²⁶26. Bentlin MR, Ferreira GL, Rugolo LMS de S, Silva GHS, Mondelli AL, Rugolo Júnior A. Neonatal meningitis according to the microbiological diagnosis: a decade of experience in a tertiary center. Arq Neuropsiquiatr. 2010;68(6):882-887. of the early and late types reported, and it usually produces a moderate or severe disease, according to some international and national reports. However, its infectious mechanism is not clearly identified, but it is understood that the invasion is by genitourinary route and related to the maternal intestinal flora.

The lethality rate by NM in national reports has been decreasing over time. In 1993, Oliveroset al. reported 20% death in a series of 24 cases ⁶6. Oliveros Donohue MA, Ramos Pianezzi R, León Cueto JL, Mazzini Pérez-Reyes J, Van Oordt, Bellido J, Livia Becerra C. Meningitis neonatal en la UCI del Hospital Edgardo Rebagliati Martins (IPSS) 1986-88. Diagnóstico. 1993;32(4/6):73-7., and in 2017, Lewis reported 3.8% in a series of 53 patients ⁵5. Lewis G, Schweig M, Guillén-Pinto D, Rospigliosi ML. Meningitis neonatal en un hospital general de Lima, Perú, 2008 al 2015. Rev Peru Med Exp Salud Pública. 2017; 34:233-8. doi: 10.17843/rpmesp.2017.342.2297.
https://doi.org/10.17843/rpmesp.2017.342... . Such decrease may be related to early diagnosis and treatment. However, the frequency of neurological complications was 25%, and the high morbidity in premature infants (75%) was noteworthy ²⁸28. Ouchenir L, Renaud C, Khan S, Bitnun A, Boisvert A-A, McDonald J, et al. The Epidemiology, Management, and Outcomes of Bacterial Meningitis in Infants. Pediatrics. 2017;140(1):1-8. Pediatrics. 2017 Jul;140(1). doi: 10.1542/peds.2017-0476.
https://doi.org/10.1542/peds.2017-0476... ^,2929. Krebs VLJ, Costa GAM. Clinical outcome of neonatal bacterial meningitis according to birth weight. Arq Neuropsiquiatr. 2007;65(4b):1149-1153.. Consequently, the use of cerebral ultrasound as a diagnostic tool for hydrocephalus, ventriculitis and cerebral infarction is very important in premature infants ³⁰30. Gupta N, Grover H, Bansal I, Hooda K, Sapire JM, Anand R, et al. Neonatal cranial sonography: ultrasound findings in neonatal meningitis-a pictorial review. Quant Imaging Med Surg. 2017 Feb;7(1):123-131. doi: 10.21037/qims.2017.02.01.
https://doi.org/10.21037/qims.2017.02.01... .

Not including certain variables such as prenatal steroid use, intrauterine infections, histological chorioamnionitis, invasive procedures, recording of sepsis cases without meningitis, antimicrobial sensitivity and resistance, community contacts, and not involving more hospitals are among the main limitations of this study. However, the strengths of the study were to demonstrate that NM is frequent, that pre-term infants are at greater risk, that the disease can present itself in different ways and that a wide spectrum of causal infectious agents exists. With these considerations we contribute to the national knowledge of this disease.

In conclusion, the hospital incidence of NM was 1.4 cases per 1,000 live births, and even higher in premature infants. Respiratory distress was the most frequent symptom for early NM, while fever and irritability were the most frequent symptoms of late NM. Moderate pleocytosis, with hypoglycorrhachia and proteinorrhachia, was noted in the CSF. The most frequent pathogens isolated were Eschericha coli and Listeria monocytogenes. The most common neurological complications were ventriculitis and hydrocephalus. A new pathogenic scenario for NM is proposed, it consists of three infection types: vertical infection, by vaginal flora germs; nosocomial infection, by contamination in neonatal units; and infection from the community by common germs.

A national epidemiological surveillance study of NM is recommended. This study should standardize diagnostic criteria (clinical, cytochemical, culture, PCR), neuroimaging criteria (ultrasound and resonance) and criteria for identification of perinatal risk factors.

Acknowledgement:

To all physicians and nurses in the neonatal departments of the participating hospitals.

References

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