Prognostic factors related to sequelae in childhood bacterial meningitis: Data from a Greek meningitis registry

Bacterial meningitis (BM) is a life-threatening disease, often related with serious complications and sequelae. During the last decades the disease epidemiology has changed dramatically in the countries that adopted the conjugate vaccines against Haemophilus influenza type b (Hib), Neisseria meningitidis and Streptococcus pneumoniae. However the impact of these vaccines on the disease epidemiology needs to be further investigated during the next few years. Infants and children who survive bacterial meningitis suffer neurological and other sequelae, including hearing impairment, adversely affecting academic performance [1]. The incidence rate (IR) of residual abnormalities in post meningitic children is approximately 15% (with a range of 10% to 30%) [2]. As previously reported the mean annual incidence rate of BM in Greece throughout a period of 32 years has been estimated to be 16.9/100,000 children, for meningococcal meningitis 8.9/100,000 children, for pneumococcal meningitis 1.3/100,000 children, for Hib meningitis before conjugate vaccine 2.5 per 100,000 and for Hib meningitis after conjugate vaccine 0.4 per 100,000 children [3].

Knowledge about factors associated with poor prognosis could be valuable in selecting patients for more intensive monitoring and treatment, in order to further improve outcome. Several risk factors associated with sequelae in childhood BM have been identified in previous studies, such as the specific organism causing the disease, duration of illness before admission, presence of convulsions, focal neurologic deficits, depressed level of consciousness or absence of petechiae on admission and low cerebrospinal fluid (CSF) glucose [4‐6]. However, findings of various studies are conflicting or inconclusive, either due to the limited number of patients or due to differences in statistical analysis (univariate vs multivariate analysis).

The aim of this study was to present among others the clinical and laboratory characteristics of a significantly large population of children presenting with BM, and to identify independent prognostic factors for sequelae, by applying a multivariable analysis approach.

The present study examined clinical, laboratory and general characteristics of children with acute BM in order to identify independent predictors of sequelae. Currently presented information has been extracted from an established meningitis registry derived from an extensive series of patients collected prospectively over a period of 32 years in a tertiary children's hospital [3].

Findings regarding epidemiological trends with respect to etiology of BM, from 1974 to 2005 in Greece, have been discussed extensively elsewhere [3]. From our study, clinico-laboratory findings of these patients largely support what is currently known about childhood BM [8]. Presenting signs and symptoms depended significantly on the age of the patient. Infants less than one years of age presented more commonly with seizures, bulging fontanelle, grunting and poor feeding as expected for such an age group. However this age group presented less commonly with coma. Toddlers and children greater than two years of age manifested more often with meningeal signs, headache, vomiting and haemorrhagic rash. Fever however was common for all age groups, therefore it can be concluded that fever is independent of age. It would also be feasible to suggest that our population with fever may be somewhat lower than it should be due to the admission of antipyretics by parents prior to hospital admission.

The introduction of the Hib vaccine at the end of period B is apparent as the rate of children presenting with seizures, bulging fontanelle, grunting, meningeal signs, shock and coma reduced significantly in period C compared to periods A and B. Improved socioeconomic conditions resulted in increased public awareness about the disease, improved availability of medical services, early recognition of signs and symptoms by caregivers and health professionals and prompt referral to tertiary medical centres. All of these changes are reflected in a reduction by more than 12 hours of the interval between the onset of symptoms to hospital admission, from period A to period C in the current study. When considering our study group, 71.3% of Hib meningitis cases were < 2 years of age, while patients < 5 years of age showed a reduction of 92.5% for the incidence rate of Hib meningitis with the introduction of Hib conjugate vaccine during period C (post Hib era) [3]. Hence, it can be concluded that the reduction in the rates of seizures, bulging fontanelle and grunting - all related to infantile meningitis - is largely attributed to the introduction and usage of Hib conjugate vaccine. Moreover, an outbreak of serogroup C meningococcal disease that occurred in Greece in the years 1996-1997 increased the mean age of children affected from BM during period C, and was also responsible for the increased rate of haemorrhagic rash in the same period [9].

The case fatality rate estimated in the present study of 3.8% is comparable to rates from other developed countries (4.8%) as reported in the meta-analysis by Baraff et al [10]. On the other hand, the currently estimated rate of sequelae overall (3.3%), is lower when compared to other reports in the literature, which ranges from 8% to 37% - with an average around 15% to 17.5% [1, 11‐16]. Such a variation may be attributed to the differences in the criteria adopted in each study in the selection of its study population defined by e.g. age, pathogen type, disease severity and even definition of sequelae. Nevertheless, we believe that the sequelae rates estimated in our study are possibly underestimated, due to incomplete update of the registry forms by the attending physicians, which is a known weakness of disease registries. The present study supports the current literature with respect to sequelae being less common in meningococcal meningitis. N.meningitis in our study showed to be more common but with lower rates of sequelae. This leads to an underestimation of sequelae in our series when compared to other studies where Hib was predominant cause of meningitis. This could partially explain the lower estimates of sequelae rates in our study.

Another factor that might have influenced the low rate of sequelae in the present study is the extensive use of corticosteroids in our hospital for BM from the mid 70s, almost 20 years before the first prospective double-blind studies that supported the use of dexamethasone in childhood BM [17].

According to previous reports, hearing impairment of any type is expected to develop in 5.6% to 30.6% of patients with bacterial meningitis, while severe, profound or bilateral hearing loss is expected to occur in 1.0 to 5.1% of patients [10, 14, 18‐21]. These findings are in agreement with the current study as 23 out of 2,235 children (1.0%), developed severe hearing loss.

Analyses of a large number of variables were found to correlate with sequelae. Some of these variables that have not been previously reported include the absence of headache (related with septicemia and meningitis rather than meningitis alone), bulging fontanelle, grunting and poor feeding on admission (physical signs encountered in infants), vomiting on admission and a positive blood culture or CSF gram stain. Moreover, presence of meningeal signs, bulging fontanelle, grunting or poor feeding on the 3^rd day of hospitalization (indicating the occurrence of complications or sequelae such as ventriculitis or hydrocephalus) or absence of petechiae on the 3^rd day could be used as prognostic factors.

Furthermore, multivariate statistical analysis was applied in order to control the confounding influence of other variables and to assess the independent effect of risk factors on the outcome. Presence of seizure on admission and on the 3^rd post-admission day increased the risk of sequelae significantly (OR = 5.36 and OR = 17.80 respectively). Many authors report similar findings, while some correlate atypical convulsions with later sequelae [5, 11, 12, 16, 22‐24]. According to our findings the occurrence of seizures on admission were strongly associated with the development of seizure disorder as a sequelae (RR = 4.61), while the RR increased to 12.75 when seizures occurred on the 3^rd day. Current data demonstrate that late seizures are stronger predictors of seizure disorder.

Low CSF glucose was found to be an important prognostic factor for the development of sequelae (OR = 5.18), in agreement with other studies that correlated low CSF glucose with increased risk of hearing loss, with increased risk of death or epilepsy, or with lower ratio of CSF and blood glucose with increased risk of sequelae [6, 23, 25]. High CSF protein considered to be an indicator of CSF inflammation, was found to independently predict the occurrence of sequelae (OR = 3.97), as previously reported [16]. Positive blood culture is reported for the first time as a prognostic factor for sequelae in children suffering from BM (OR = 2.66). Blood cultures are not considered to be extremely invasive to patients and results are available during the first few days of hospital stay.

On multivariate analysis, either isolation of N. Meningitidis or presence of hemorrhagic rash were predictors of a favourable outcome regarding sequelae. Similar findings have been reported in a study on risk factors for meningococcal disease, another on the prognosis of hearing loss, while Biesheuvel et al. incorporated the absence of petechiae in a prediction rule for neurological sequelae after childhood bacterial meningitis [5, 6]. Similarly the role of pneumococcal meningitis as a prognostic factor for sequelae in BM has also been well documented [5, 6, 12]. No independent relationship was found between young age, duration of symptoms, presence of shock or CSF WBC and sequelae.

In the present study certain combinations of prognostic factors such as seizures, absence of petechiae, low CSF glucose, high CSF protein and a positive blood culture have a significantly increased risk for sequelae. Similarly, absence of petechiae/ecchymoses and use of anti-epileptics for > 2 days have been used in a prognostic scoring system for sequelae in childhood BM [5].

Although current study focuses on short term effects of BM in children, several studies have pointed out the presence of long term neurobehavioural effects. Academic, intellectual and executive ability may be negatively influenced in these children, as they are found to perform worse compared to their peers [11, 26].

Our study concentrates on the prognostic factors associated with meningitis disease in Greece only. One of the main advantages of this study is that, by engaging a total of 2,477 children, it turns out to be one of the biggest cohorts of children affected with bacterial meningitis. Such a high number of patients allows for safe conclusions to be drawn, supported by relatively narrow confidence intervals in the statistical analysis. Moreover, due to the extended period that the meningitis was in operation, we were able to delineate long-term changes in the clinical and laboratory characteristics of childhood BM. On the other hand, long duration of the study was related with one limitation being the lack of homogeneity in the data of the registry forms. The use of antibiotic therapy prior to bacterial confirmation of meningitis may also affect the results of this study giving an under-representation of confirmed cases. Moreover, a possible limitation of the study is the percentage of missing values ranging from 0.4% to 35% in different variables without having any indication that they were created systematically. However, we have to acknowledge that missing values is a weakness of the analysis.

In conclusion, current data indicate that sequelae can be predicted by a combination of seizures, absence of hemorrhagic rash, low CSF glucose, high CSF protein and a positive blood culture. Etiology is critical for the prognosis of sequelae in childhood BM. Late findings, including a combination of bulging fontanelle and seizures on the 3^rd day also correlate with increased sequelae. These risk factors may be of value in selecting patients for more intensive therapy and in identifying possible candidates for new treatment strategies.

We would like to thank all pediatricians who participated in the collection of data by filling the Registry Form. Moreover, we would like to thank Dr J Economides who performed hearing screening in children with bacterial meningitis.