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Predicting sequelae and death after bacterial meningitis in childhood: A systematic review of prognostic studies

  • Rogier CJ de Jonge1, 2Email author,
  • A Marceline van Furth1,
  • Merel Wassenaar3,
  • Reinoud JBJ Gemke1 and
  • Caroline B Terwee3
BMC Infectious Diseases201010:232

DOI: 10.1186/1471-2334-10-232

Received: 11 April 2010

Accepted: 5 August 2010

Published: 5 August 2010

Abstract

Background

Bacterial meningitis (BM) is a severe infection responsible for high mortality and disabling sequelae. Early identification of patients at high risk of these outcomes is necessary to prevent their occurrence by adequate treatment as much as possible. For this reason, several prognostic models have been developed. The objective of this study is to summarize the evidence regarding prognostic factors predicting death or sequelae due to BM in children 0-18 years of age.

Methods

A search in MEDLINE and EMBASE was conducted to identify prognostic studies on risk factors for mortality and sequelae after BM in children. Selection of abstracts, full-text articles and assessment of methodological quality using the QUIPS checklist was performed by two reviewers independently. Data on prognostic factors per outcome were summarized.

Results

Of the 31 studies identified, 15 were of moderate to high quality. Due to substantial heterogeneity in study characteristics and evaluated prognostic factors, no quantitative analysis was performed. Prognostic factors found to be statistically significant in more than one study of moderate or high quality are: complaints >48 hours before admission, coma/impaired consciousness, (prolonged duration of) seizures, (prolonged) fever, shock, peripheral circulatory failure, respiratory distress, absence of petechiae, causative pathogen Streptococcus pneumoniae, young age, male gender, several cerebrospinal fluid (CSF) parameters and white blood cell (WBC) count.

Conclusions

Although several important prognostic factors for the prediction of mortality or sequelae after BM were identified, the inability to perform a pooled analysis makes the exact (independent) predictive value of these factors uncertain. This emphasizes the need for additional well-conducted prognostic studies.

Background

Bacterial meningitis (BM) is a severe infection of the central nervous system which occurs especially in children <5 years of age. Although the occurrence of negative consequences of BM in developed countries is strongly reduced by vaccination strategies, antibiotic treatment and good care facilities, BM is still responsible for substantial morbidity and mortality in both developing and developed countries [13].

The mortality rate is approximately 5%, and the long-term morbidity, mainly consisting of persistent neurological sequelae, is 15% [2, 46]. Sensorineural hearing loss, seizures, motor problems, hydrocephalus and mental retardation [4, 710], as well as more subtle outcomes like cognitive, academic and behavioral problems are observed in post-meningitis children [5, 11].

In pediatric care, the goal must be to prevent these sequelae as much as possible. Therefore, early recognition of children with BM with high risk for the development of sequelae is mandatory [5, 1215]. For this reason, several studies have developed prediction models or have proposed prognostic factors for mortality or morbidity in children after BM [59, 1237]. The aim of the present study was to systematically review the available evidence regarding prognostic factors predicting death or sequelae due to BM in children aged 0-18 years in both developing and developed countries.

Methods

Literature selection

A systematic search of MEDLINE and EMBASE until March 20th 2009 was conducted to identify prognostic studies on mortality or various sequelae after BM in children. The search focused on BM using terms for the 10 most common causative pathogens according to the Netherlands Reference Laboratory for Bacterial Meningitis [38]. These pathogens are listed in Apendix 1. Tuberculoid meningitis or rare forms of BM were excluded. The search was refined using MeSH terms and text words on: morbidity, mortality, cause of death, survival rate, survival, prognos*, predict*, course*, cohort* longitudinal, cohort studies, follow-up, followup, follow up, follow-up studies. The search strategies used for Medline and Embase are included in Appendix 2. All abstracts found were screened by two reviewers independently (RdJ and MW). Those potentially eligible for inclusion were read in full text by the same two reviewers independently and subsequently discussed during a consensus meeting. Reference lists of each of the selected publications were checked to retrieve relevant publications which had not been identified by the computerized search.

The publications had to meet the following inclusion criteria, which were defined prior to the search:

- The study aimed to identify prognostic factors on mortality or various sequelae due to BM. Only studies designed as prognosis studies were included. Studies designed to analyze an associative model were excluded.

- The study was designed as a longitudinal cohort study, with at least one follow-up measurement. Both prospective and retrospective studies were included.

- BM had occurred at 0-18 years of age.

- Results were published in English as full report articles in international journals from January 1960 until March 20th 2009.

Quality Assessment

The assessment of the methodological quality was performed using the Quality In Prognosis Studies (QUIPS) tool, designed for systematic reviews of prognostic studies through international expert consensus (Table 1) [39]. This assessment was performed independently by two authors (RdJ and MW). Disagreements between both authors were discussed during a consensus meeting.
Table 1

Used (adapted) QUIPS list for scoring methodological quality of prognosis studies

Criteria

Score

 

+

+/-

-

1. Study participation

   

   • Target population

3

1.5

0

   • Sampling frame

3

1.5

0

   • Inclusion criteria

3

1.5

0

   • Baseline study population

3

1.5

0

   • Adequate study participation

3

1.5

0

2. Study attrition

   

   • Proportion of population available for analysis

5

2.5

0

   • Outcome and prognostic factor information on those lost to follow up

5

2.5

0

   • Reasons and potential impact of subjects lost to follow up

5

2.5

0

3. Measurement of prognostic factors

   

   • Definition of prognostic factor

5

2.5

0

   • Valid and reliable measurement of prognostic factor

5

2.5

0

   • Method and setting of prognostic factor measurement

5

2.5

0

4. Measurement of outcomes

   

   • Definition of outcome

5

2.5

0

   • Valid and reliable measurement of outcome

5

2.5

0

   • Method and setting of outcome measurement

5

2.5

0

5. Statistical analysis and presentation

   

   • Presentation of analytical strategy

5

2.5

0

   • Model development strategy

5

2.5

0

   • Reporting of results

5

2.5

0

The QUIPS contains six categories assessing (1) bias due to patient selection, (2) attrition, (3) measurement of prognostic factors, (4) outcome measurement, (5) confounding on statistical analysis, and (6) confounding on presentation. The items on confounding were considered irrelevant for our study because in studies regarding prognosis, the design to predict a specific outcome based on a combination of several possible prognostic factors, confounding is not an issue. The remaining 17 items of the five categories were each scored to assess the quality of the included study. High quality ('+') was scored when there was low risk of bias, moderate quality ('+/-') with moderate risk, and low quality ('-') when there was high risk of bias.

To strengthen the discriminative capacity of the QUIPS we developed a scoring algorithm. All five categories were given a maximum of 15 points each, equally divided over all items per category. For all items we assigned 5 points in case of low risk of bias and 2.5 and 0 in case of moderate and high risk of bias, respectively. Except for category 1 (patient selection bias) which contained five instead of three items. Here we assigned 3 points in case of low risk of bias and 1.5 and 0 in case of moderate and high risk of bias, respectively. A total score, with a maximum of 75 points, was calculated by summing up the scores per item. A priori, we chose to consider ≥60 points (≥80% of the maximum attainable score) as high quality, between 45 and 60 points (≥60% of the maximum attainable score) as moderate/high quality and <45 points as low quality studies.

Data extraction and analysis

Of the selected studies, data were extracted regarding study population (age at infection, country), causative pathogen, design (prospective or retrospective), duration of follow-up, method of analysis (uni- or multivariate), outcome measures and independent statistically significant prognostic factors from multivariate analysis or, if not available, from univariate analysis (p < 0.05). To facilitate interpretation and comparison of the results, data were categorized per outcome: (1) hearing loss, (2) mortality, (3) neurological sequelae, or (4) poor outcome when the original study made no distinction between mortality and neurological sequelae. Both short- and long-term outcomes were included.

This review did not aim to analyze original study data, therefore only the data presented in the manuscripts was used. Authors were not approached for insight in their data.

Analysis of prognostic factors

Due to heterogeneity in study design, study population and analyses of the included studies, no quantitative analysis was performed. Instead, the prognostic factors predictive for mortality or sequelae after BM were summarized per outcome category. Prognostic factors reported in different papers on the same cohort were counted once. Due to the large variety in proposed factors found, only those factors found significant (p < 0.05) in more than one study of moderate/high quality were presented.

Results

Selection of studies

Figure 1 presents a flow chart of the study selection. The search strategy yielded 6,963 citations. Of these, 43 articles seemed to fulfill the inclusion criteria and were retrieved in full text. Two additional articles were identified by checking the reference lists. Review of these 45 articles resulted in exclusion of 14 articles not meeting the inclusion criteria. Eleven studies were excluded based on design (one letter, one validation study and nine presenting an association model instead of a prognostic model), one study dealt with diagnosis (prediction of meningitis instead of sequelae), and two studies were excluded because no differentiation was made between viral or aseptic and BM for outcome measurement. Finally, 31 articles were included and assessed on methodological quality.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2334-10-232/MediaObjects/12879_2010_Article_1212_Fig1_HTML.jpg
Figure 1

Selection and number of publications.

Methodological quality

The results of the quality assessment are presented in Table 2. The overall quality score ranged from 17 to 62.5 points with a median score of 43.5. Based on our cutoff of ≥60 and ≥45 points, respectively, one article was classified as high quality, 14 articles were classified as moderate/high quality and 16 articles as low quality studies.
Table 2

Results of quality assessment of studies on mortality or sequelae after bacterial meningitis.

Study

Study participation

Study attrition

Measurement of prognostic factors

Measurement of outcomes

Statistical analysis and presentation

Quality score

(points)

Quality:

+ = high

+/- = moderate

- = low

Koomen et al., 2004 [5]

15

12.5

10

12.5

12.5

62.5

+

Lovera et al., 2005 [33]

13.5

7.5

12.5

10

12.5

56

+/-

Roine et al., 2008 [35]

15

10

7.5

7.5

15

55

+/-

Oostenbrink et al., 2002 [21]

15

7.5

10

10

12.5

55

+/-

Pelkonen et al., 2009 [6]

12

10

12.5

7.5

12.5

54.5

+/-

Forsyth et al., 2004 [18]

10.5

10

7.5

15

10

53

+/-

Biesheuvel et al., 2006 [24]

12

7.5

10

10

12.5

52

+/-

Pagliano et al., 2007 [19]

12

5

12.5

10

12.5

52

+/-

Koomen et al., 2003 [7]

15

7.5

10

7.5

10

50

+/-

Woolley et al., 1999 [9]

12

5

7.5

12.5

12.5

49.5

+/-

Klinger et al., 2000 [31]

13.5

7.5

7.5

10

10

48.5

+/-

Singhi et al., 2007 [15]

13.5

5

5

12.5

12.5

48.5

+/-

Kornelisse et al., 1995 [8]

10.5

5

10

10

12.5

48

+/-

Fakhir et al., 1992 [27]

12

7.5

7.5

12.5

7.5

47

+/-

Akpede et al., 1999 [16]

10.5

7.5

10

10

7.5

45.5

+/-

Kaaresen et al., 1995 [29]

13.5

7.5

7.5

5

10

43.5

-

Kutz et al., 2006 [14]

13.5

5

7.5

7.5

10

43.5

-

Pikis et al., 1996 [20]

13.5

7.5

7.5

7.5

7.5

43.5

-

Pomeroy et al., 1990 [34]

15

5

5

10

7.5

42.5

-

Wasier et al., 2005 [37]

10.5

5

7.5

7.5

10

40.5

-

Grimwood et al., 1996 [12]

7.5

5

7.5

12.5

7.5

40

-

Edwards et al., 1985 [17]

10.5

7.5

7.5

10

2.5

38

-

Letson et al., 1992 [32]

10.5

5

5

10

7.5

38

-

Chao et al., 2008 [26]

12

2.5

5

7.5

5

32

-

Johnson et al. 2007 [28]

12

2.5

5

7.5

5

32

-

Bortolussi et al., 1978 [25]

10.5

5

2.5

7.5

5

30.5

-

Antilla et al., 1994 [22]

7.5

2.5

7.5

7.5

2.5

27.5

-

Kirimi et al., 2003 [30]

7.5

5

7.5

2.5

5

27.5

-

Valmari et al., 1987 [36]

4.5

2.5

5

5

7.5

24.5

-

Herson et al., 1977 [13]

4.5

2.5

5

2.5

5

19.5

-

Bhat et al., 1987 [23]

4.5

2.5

2.5

2.5

5

17

-

Studies of moderate/high quality scored well on patient selection, outcome measurement, statistical analysis and presentation, and relatively well on prognostic factor measurement. However, many moderate/high quality studies scored poor on attrition. Studies classified as low quality scored relatively well on patient selection, but poor on all other categories. A poor score on prognostic factor measurement was often due to the fact the studies did not mention all factors considered in their analysis but presented only those factors found significant.

Study characteristics

Table 3 summarizes the study characteristics of all included publications. Studies were grouped by outcome categories and ranked by quality. Of all 31 included studies, four studies focused on hearing loss, four on mortality, five on neurological sequelae ranging from mild to severe, and another 12 studies focused on poor outcome. The remaining six studies focused on both mortality and neurological sequelae, for which results were presented separately. Therefore, these studies were included more than once. The majority of all studies (n = 21) had a retrospective study design and 22 were conducted in developed countries. Sixteen studies performed a multivariate analysis. Although Klinger et al. [31] performed a multivariate analysis, we reported the prognostic factors based on their univariate analysis, since this study reported several models for different time intervals which was more difficult to compare with other results. There was considerable variation among studies with respect to population size (37 - 716 patients) and follow-up duration (from moment of hospital discharge up to 23 years later). Studies also varied with respect to age at infection (0-17, of which three studies considered specifically neonatal/infant age) and type of causative pathogen studied (varying from describing all types (n = 17), to those only studying a specific microorganism (n = 9; mainly Streptococcus pneumoniae)) or more than one but not all microorganisms (n = 5; mainly concerning all microorganisms; however, excluding Haemophilus influenzae type B (HiB)).
Table 3

Study characteristics of studies on prediction of sequelae after bacterial meningitis.

Study

Score (quality)

Design

Developed or developing (Country)

N

Age at infection

Pathogen

Follow-up duration

Outcome:

Analysis

Significant prognostic factors

From multivariate analysis

Or from univariate analysis with p < 0.05

Forsyth et al., 2004 [18]

53 (+/-)

Prospective

Developing (Malawi)

343

2 months - 13 yr

All

1 and 6 months after discharge

Hearing loss

Univariate

Coma, positive CSF Gram stain, a low peripheral WBC count, high CSF protein level, associated neurological sequelae

Koomen et al., 2003 [7]

50 (+/-)

Retrospective

Developed (The Netherlands)

628

0 - 9.5 yr (mean 2.4yr)

Non Hib

 

Hearing loss

Multivariate

History of symptoms >2 days, absence petechiae, low CSF glucose level, causative pathogen (S. pneumoniae), ataxia

Woolley et al., 1999 [9]

49,5 (+/-)

Retrospective

Developed (UK)

432

Median 7.7 months

All

6 months intervals for at least 1 yr (range 1-5 yr)

Hearing loss

Multivariate

Male sex, increased ICP, low CSF glucose level, causative pathogen (S. pneumoniae), presence nuchal rigidity

Kutz et al., 2006 [14]

43,5 (-)

Retrospective

Developed (USA)

171

3 months 17 yr (mean 3.8 yr)

All

During hospitalization (longer if necessary)

Hearing loss

Univariate

Long duration hospitalization, cranial nerve neuropathy, low CSF glucose level, high CSF protein level,

seizures (not significant in case of S. pneumoniae)

Lovera et al., 2005 [33]

56 (+/-)

Retrospective

Developing (Paraguay)

72

35 days - 15 yr (mean 48 months)

S. pneumoniae

During hospitalization

Mortality

Univariate

Age <12 months, coma, seizures, prolonged duration of seizures >48 h, low CSF WBC count, high CSF protein (albumin) level, low CSF glucose level, low peripheral WBC count, low Hb

Roine et al., 2008 [35]

55 (+/-)

Prospective

Developing (6 countries in Latin America)

654 total cohort, 332 included in analysis

Median 8 months in patients who died, median 12 months in survivors (not otherwise reported)

all

During hospitalization

Mortality

Multivariate

Impaired consciousness, poor peripheral circulation, high CSF protein level

Pelkonen et al., 2009 [6]

54,5 (+/-)

Retrospective

Developing (Angola)

403 total cohort, 290 included in analysis

Median 9.0 months

All

During hospitalization

Mortality

Multivariate

Impaired consciousness, severe dyspnea, convulsions during hospitalization

Kornelisse et al., 1995 [8]

48 (+/-)

Retrospective

Developed (The Netherlands)

83

3 days- 12.3 yr (median 8 months)

S. pneumoniae

During hospitalization

Mortality

Univariate

Comatose level of consciousness, shock, respiratory distress, low peripheral WBC count, low serum sodium level, high CSF protein level

Fakhir et al., 1992 [27]

47 (+/-)

Retrospective

Developing (India)

247

1 month - 14 yr

N. meningitidis

During hospitalization

Mortality

Univariate

Illness duration <12 h, hypotension, peripheral circulatory failure, coma (disturbed sensorium), rash duration <12 h, rash extent widespread, fever >40°C, absent neck rigidity, low peripheral WBC count, low ESR, low platelet count

Akpede et al., 1999 [16]

45,5 (+/-)

Prospective

Developing (Nigeria)

109

>1 month - 15 yr

All

During hospitalization (after discharge?)

Mortality

Univariate

Seizures, coma, shock

Wasier et al., 2005 [37]

40,5 (-)

Retrospective

Developed (France)

49

1 - 108 months (median 17 months)

S. pneumoniae

1-12 yr (mean 5 yr)

Mortality

Multivariate

High PRISM II score, low peripheral WBC count, low platelet count

Chao et al., 2008 [26]

32 (-)

Retrospective

Developing (Taiwan)

37

3 months - 11 yr (mean 37 months)

S. pneumoniae

 

Mortality

Univariate

Coma, shock, mechanical ventilation (endotracheal tube intubation), hyponatremia, low CSF WBC count, low CSF glucose level, low CSF/blood glucose ratio

Johnson et al., 2007 [28]

32 (-)

Retrospective

Developing (Nigeria)

71

<16 yr

All

During hospitalization

Mortality

Univariate

Respiratory distress, purulent/turbid CSF appearance, high CSF protein level, low CSF glucose level

Bortolussi et al., 1978 [25]

30,5 (-)

Retrospective

Developed (Canada)

52

Neonates (<1 month)

All

During hospitalization

Mortality

Univariate

low peripheral WBC count, thrombocytopenia, low birth weight <2500 g

Study

Score (quality)

Design

Developed or developing (Country)

N

Age at infection

Pathogen

Follow-up duration

Outcome: sequelae

Analysis

Significant prognostic factors

From multivariate analysis

Or from univariate analysis with p < 0.05

Koomen et al., 2004 [5]

62,5 (+)

Retrospective

Developed (The Netherlands)

182

0 - 9.5 yr

(mean 2.4yr)

Non- Hib

4.0 - 10.4 yr post meningitis (average 7.4 yr)

Neurological sequelae

Academic & behavioural limitations

Multivariate

male gender, low birth weight ≤3000 g, low educational level father, causative pathogen (S. pneumoniae), low CSF WBC count, delay >6 h start antibiotics, dexamethasone use ≤2 days, anticonvulsive treatment of seizures, prolonged fever >9 days

Pelkonen et al., 2009 [6]

54,5 (+/-)

Retrospective

Developing (Angola)

403 total cohort, 249 survivors, 200 included in analysys

Median 9.0 months

All

During hospitalization

Severe neurological sequelae

Multivariate

History of symptoms >3 days, impaired consciousness, convulsions during hospitalization

Biesheuvel et al., 2006 [24]

52 (+/-)

Retrospective

Developed (The Netherlands)

88 (derivation)

628 (validation)

0.9 - 5.8 yr (mean 2.8 yr) (derivation) and 0 - 9.5 yr (mean 1.9 yr) (validation)

Non Hib

 

Neurological sequelae

Both mild and severe

Multivariate

Seizures (atypical convulsions), absence petechiae/ecchymoses, low body temperature <40°C, high body temperature/fever >40°, causative pathogen (S. pneumoniae), use of anti epileptic drugs >2 days

Singhi et al., 2007 [15]

48,5 (+/-)

Prospective

Developing (India)

80

2 months - 12 yr (mean 31.4 months)

All

12-44 months after discharge (mean 27.5 months)

Neurological sequelae

Both mild and severe

Multivariate

coma, cranial nerve palsy, absent deep tendon reflexes

Kornelisse et al., 1995 [8]

48 (+/-)

Retrospective

Developed (The Netherlands)

83

3 days- 12.3 yr (median 8 months)

S. pneumoniae

Hospital duration

Neurological sequelae

Both mild and severe

Univariate

High clinical severity score (Herson & Todd score), vomiting, shock, low peripheral WBC count, low CSF WBC count, low CSF glucose level

Akpede et al., 1999 [16]

45,5 (+/-)

Prospective

Developing (Nigeria)

109

>1 month - 15 yr

All

During hospitalization (after discharge?)

Neurological sequelae

Both mild and severe motor and sensory sequelae

Univariate

Young age ≤2 yr, seizures, coma, prolonged fever >7 days, antibiotic treatment, focal nerve deficits, abnormal posturing, abnormal muscle tone

Pikis et al., 1996 [20]

43,5 (-)

Retrospective

Developed (Greece)

47

1 month - 14 yr (mean 2.6 yr)

S. pneumoniae

4- 23 yr (mean 12.4 yr)

Neurologic sequelae

Both mild and severe

Multivariate

Coma, high peripheral WBC count

Pomeroy et al., 1990 [34]

42,5 (-)

Prospective

Developed (USA)

185

1 month - 14 yr (median 10 months)

All

1,3,6,12, months after discharge and yearly up to 6 yr

Neurologic sequelae

Both mild and severe

Univariate

Seizures, low CSF glucose level

Chao et al., 2008 [26]

32 (-)

Retrospective

Developing (Taiwan)

37

3 months - 11 yr (mean 37 months)

S. pneumoniae

 

Neurological sequelae

Both mild and severe lasting >6 months

Univariate

Focal neurological signs, seizures

Study

Score (quality)

Design

Developed or developing (Country)

N

Age at infection

Pathogen

Follow-up duration

Outcome: poor outcome

Analysis

Significant prognostic factors

From multivariate analysis

Or from univariate analysis with p < 0.05

Lovera et al., 2005 [33]

56 (+/-)

Retrospective

Developing (Paraguay)

72

35 days - 15 yr (mean 48 months)

S. pneumoniae

During hospitalization

Mortality & neurological sequelae

Univariate

Young age <12 months, coma, seizures, seizure duration >48 h, low CSF WBC count, high CSF protein (albumin) level, low CSF glucose level, low peripheral WBC count, low Hemoglobin

Oostenbrink et al., 2002 [21]

55 (+/-)

Retrospective

Developed (The Netherlands)

93

1 month - 15 yr (median 2.8 yr)

Non Hib

0.6 yr

Mortality & neurological sequelae

Multivariate

male gender, seizures (atypical convulsions), low body temperature, causative pathogen (S. pneumoniae)

Roine et al., 2008 [35]

55 (+/-)

Prospective

Developing (6 countries in Latin America)

642 total cohort, 356 included in analysis

Median 7 months in patients whith positive outcome measure died, median 14 months in patients without (not otherwise reported)

all

During hospitalization

Mortality & severe neurological sequelae

Multivariate

Impaired consciousness, history of symptoms >48 h, high CSF protein level, low peripheral WBC count

Roine et al., 2008 [35]

55 (+/-)

Prospective

Developing (6 countries in Latin America)

641 total cohort, 296 included in analysis

Median 7 months in patients whith positive outcome measure died, median 18 months in patients without (not otherwise reported)

all

During hospitalization

Mortality & all neurological sequelae

Multivariate

Impaired consciousness, convulsions before admission, poor peripheral circulation, low CSF glucose level, low peripheral WBC count

Pagliano et al., 2007 [19]

52 (+/-)

Prospective

Developed (Italy)

64

1 month -14 yr (median 26 months)

S. pneumoniae

8 weeks

Mortality & neurological sequelae

Multivariate

ICU admission, low CSF WBC count, penicillin nonsusceptibility

Klinger et al., 2000 [31]

48,5 (+/-)

Retrospective

Developed (Canada)

101

Neonates 1-28 days

All

1 yr

Mortality & neurological sequelae

Univariate

Hypotension, coma, inotrope, seizure duration >12 h, status epilepticus, low CSF/blood glucose level, low peripheral WBC count, abnormal neurological examination at discharge, ventilation, no. of anticonvulsants

Klinger et al., 2000 [31]

48,5 (+/-)

Retrospective

Developed (Canada)

101

Neonates 1-28 days

All

1 yr

During hospitalization,

Mortality & neurological sequelae

*multivariate analysis

* For different time schedules during and after hospital admission not presented here

Akpede et al., 1999 [16]

45,5 (+/-)

Prospective

Developing (Nigeria)

109

>1 month - 15 yr

All

Possibly after discharge in neurologic clinic

Mortality & neurological sequelae

Univariate

Young age ≤2 yr, seizures, coma, shock, prolonged fever, >7 days antibiotic treatment, no meningeal signs, focal nerve deficits, abnormal posturing, abnormal muscle tone

Kaaresen et al., 1995 [29]

43,5 (-)

Retrospective

Developed (Norway)

92

Median 1.9 yr

(range 1 month - 13.8 yr)

All

Hospital duration and mean 6 weeks afterwards, or longer if necessary

Mortality & neurological sequelae

Multivariate

History of symptoms >48 h, seizures, high body temperature,>38 °C, peripheral vasoconstriction, low CSF WBC count

Grimwood et al., 1996 [12]

40 (-)

Prospective

Developed (Australia)

138

3 months - 14 yr

All

Mean 6.7 yr post meningitis (range 5.3-9.3 yr)

Mortality & neurological sequelae

Multivariate

Young age ≤12 months, long symptom duration before diagnosis >24 h, seizures >72 h, focal neurological signs

Edwards et al., 1985 [17]

38 (-)

Retrospective

Developed (USA)

51

Infants (not further described)

Group B streptococcus

Mean 6 yr (range 3.3- 9.0 yr

Mortality & neurological sequelae

Univariate

Coma, hypotension (BP <40 mm Hg), low peripheral WBC count, low PMN, high CSF protein level

Letson et al., 1992 [32]

38 (-)

Retrospective

Developed (USA)

53

3.5 weeks - 30 months (mean 8 months

H. influenzae b

S. pneumoniae

Mean 35 months

Mortality & neurological sequelae

Multivariate

Seizures, male gender, low CSF glucose level

Anttila et al., 1994 [22]

27,5 (-)

Prospective

Developed (Finland)

143

Mean 30 months range 3 months - 15 yr

All

During hospitalization, at discharge and at 2 weeks, 3,6,12 months

Mortality & neurological sequelae

Univariate

Low body temperature, coma, neck rigidity, leaving supine position

Kirimi et al., 2003 [30]

27,5 (-)

Prospective

Developing

(Turkey)

48

2 months - 13 yr

all

Hospital duration

Mortality & neurological sequelae

Univariate

Fever >36-48 h after admission, coma 6-48 h after admission, anaemia, prolonged anaemia >3 days, low CSF WBC count, high CRP level, high CSF WBC count >3 days, low CRP level >3 days, antibiotic treatment

Valmari et al., 1987 [36]

24,5 (-)

Retrospective

Developed (Finland)

123 developing model

98 validation model

1 month- 14 yr

mean 30 months developing model

mean 20 months validation model

all

Mean 2 months

Mortality & neurological sequelae

Multivariate

Male sex, low CSF glucose level, low CSF WBC count, otitis media, low Hb, low serum potassium level, positive CSF gram stain, focal neurological signs, low peripheral WBC count, low CSF granulocyte %, low platelet count, neck rigidity, absence petechiae, duration of symptoms >48 h

Herson et al., 1977 [13]

19,5 (-)

Retrospective

Developed (USA)

73

6 weeks - 5 yr

H. influenzae b

Hospital duration,

Residual morbidity: 3 months - 2 yr

Mortality & neurological sequelae

Univariate

Coma, low body temperature, seizures, shock (BP <60 mm Hg), young age <12 months, low CSF WBC count, low Hb, low CSF glucose level, prolonged symptom duration

Bhat et al., 1987 [23]

17 (-)

Prospective

Developing (India)

256

Non neonatal (not further described)

all

 

Mortality & neurological sequelae

Univariate

Duration of illness prior to therapy >7 days, low body temperature, coma, associated illness, low peripheral WBC count, purulent/turbid CSF appearance, high CSF WBC count, high CSF protein level, low CSF glucose level, neck rigidity, distension of abdomen, no meningeal signs, positive gram stain, positive culture, type of causative pathogen

Studies are grouped by outcome categories and ranked by quality.

Prognostic factors

Table 4 summarizes the most important prognostic factors for sequelae and death after BM per type of outcome. For mortality and various sequelae together, 75 different possible prognostic factors were identified as significant by the included studies. Many of these factors might be of influence for the prediction of sequelae. However, it is implausible that all of them will be (equally) important. And due to poor study quality, factors not predictive for sequelae or death might have been found as prognostic factors. We therefore considered only those factors found significant in more than one study of moderate/high quality as evidence for being potentially important factors. Results from univariate and multivariate analyses are presented separately. Factors reported in studies of low quality are reported combined and not per type of outcome.
Table 4

Summary of prognostic factors.

Prognostic factor

Moderate/high quality studies with multivariate analysis

Moderate/high quality studies with univariate analysis

Low quality studies with multivariate analysis

Low quality studies with univariate analysis

 

Hearing loss

Mortality

Neurological sequelae

Poor outcome

Hearing loss

Mortality

Neurological sequelae

Poor outcome

All outcomes

All outcomes

History of symptoms >48 h

1x

  

1x

    

1x

 

Coma/impaired consciousness

 

2x

2x

2x

1x

4x

1x

3x

1x

6x

Seizures

 

1x

2x

2x

 

2x

1x

2x

2x

4x

Shock/hypotension

     

3x

1x

2x

 

3x

Peripheral circulatory failure

 

1x

 

1x

 

1x

   

1x

Severe respiratory distress

 

1x

   

1x

   

1x

Prolonged fever (>7 days)

  

1x

   

1x

1x

  

Seizures >12 h after admission

     

1x

 

2x

1x

 

Low peripheral WBC count

   

2x

1x

3x

1x

2x

2x

3x

Low CSF WBC count

  

1x

1x

 

1x

1x

1x

2x

3x

Low CSF glucose level

2x

  

1x

 

1x

1x

1x

2x

6x

High CSF protein level

 

1x

 

1x

1x

2x

 

1x

 

4x

S. pneumonia as causative pathogen

2x

 

2x

1x

      

Young age

     

1x

1x

2x

1x

1x

<1 years

     

1x

 

1x

1x

1x

<2 years

      

1x

1x

  

Male gender

1x

 

1x

1x

    

2x

 

Fever >40°C

  

1x

  

1x

    

Absence of petechiae

1x

 

1x

     

1x

 
In total, 17 factors were regarded as showing some evidence of importance in the prediction of sequelae or mortality after BM.
  • For hearing loss, the factors S. pneumoniae as a causative pathogen and a low cerebrospinal fluid (CSF) glucose level showed some evidence of being important (i.e. reported in more than one moderate/high quality study).

  • For mortality, coma and seizures were found to be predictive, next to shock, peripheral circulatory failure, severe respiratory distress, a low peripheral white blood cell (WBC) count and a high CSF protein level.

  • For neurological sequelae in general, coma, seizures, prolonged fever for at least seven days and a low CSF (WBC) count were considered important risk factors.

Studies reporting on poor outcome, and thereby not differentiating between sequelae or mortality, also reported coma, seizures, shock, a low WBC count both peripheral as well as in CSF and a low CSF glucose level and a high CSF protein level to be important risk factors. Yet they also identified young age (indicated as younger than two years old) and prolonged seizure duration (>12 hours after admission) as important prognostic factors.

When considering all moderate/high quality studies combined, the factors of history of symptoms longer than 48 hours, male gender, fever and absence of petechiae were also found more than once. Although these factors have not been found in more than one study of moderate/high quality for a specific outcome category, they may be important prognostic factors for sequelae or mortality in general.

The 17 identified risk factors were also found in several studies of low quality (see last column of Table 4).

Discussion

We identified 31 studies in the literature on prognostic factors predicting sequelae or death due to BM in children 0-18 years of age. The included studies have presented a large number of potentially important prognostic factors. Only those factors reported in more than one moderate/high quality study were considered as showing some evidence of being important. These factors included several clinical parameters: coma/impaired consciousness, seizures, shock, peripheral circulatory failure, severe respiratory distress, (prolonged) fever and prolonged duration of seizures, which are all signs of severity during the acute phase of the disease. In addition, the presented factors also included results from diagnostic tests which are performed during admission of the patient in the hospital: low peripheral WBC and low WBC count in CSF, low CSF glucose level and high CSF protein level. These factors are indicators of an acute severe CNS infection and thus are also parameters of severity of the disease.

The presence of these clinical and diagnostic factors in our study demonstrates that severe illness at admission contributes to BM-related mortality and long-term sequelae. In addition, young age was also considered an important prognostic factor. This might be explained by the immature immune status resulting in more severe infections (especially in neonates and children younger than six months) and the developing (and thus more vulnerable) brain of young children. Although it is thought that young children have a higher capability of neurogenesis than older children and adults which leads to better structural repair of brain tissue, and it is known they have a higher plasticity of the brain that allows intact parts to take over functions of damaged areas, early disruption of the developing brain may leads to more functional damage [4043]. Further, sequelae of meningitis like epilepsy, cerebral palsy and hearing problems can independently cause developmental problems in the young child.

Another prognostic factor which we also demonstrated to be related to severity was the causative pathogen of BM. S. pneumoniae seemed to be an important prognostic factor, suggesting a more pathogenic potency of this species in comparison to other bacteria. This has also been found in other studies presenting association or prognostic models in children or adults [3, 10, 44]. We also found the absence of petechiae to be a prognostic factor. Since petechiae are strongly related with the causative pathogen (occurring mostly in Neisseria meningitidis infections, and much less in S. pneumoniae meningitis), it supports the finding that S. pneumoniae is responsible for a non favorable outcome. In studies of high and moderate quality that reported the absence of petechiae as a risk factor, S. pneumoniae was also a prognostic factor of importance. Finally, male gender was found as an important prognostic factor, for which we do not have an explanation. All of these factors might be important to assess in children with BM when trying to identify those at the highest risk for the development of sequelae.

The main concern about the interpretation of the prognostic factors is the fact that due to limited quality of the included studies and heterogeneity of the data it is impossible to perform a meta-analysis and to construct an overall prediction model.

Limitations

The search strategy was restricted to full report articles published in English, in journals available in the used electronic databases. This might have led to language or publication bias by missing relevant studies.

The quality of studies was assessed using the QUIPS instrument, designed for prognosis studies addressing all common sources of bias. The QUIPS, however, lacks discriminative power. We defined a scoring algorithm for better discrimination of study quality. This scoring algorithm and cutoff points used to qualify the quality of the studies are quite arbitrary. However, all identified prognostic factors found in the included studies are presented in Table 3, allowing readers to draw their own conclusions.

We encountered some problems in interpreting the results of the studies. Only significant prognostic factors of the original studies were presented in our review. However, lack of statistical significance may be due to lack of power. Furthermore, many studies performed only univariate analysis and the presented factors might not have been found significant if multivariate analysis had been performed.

In our overview of prognostic factors we only stratified per type of outcome. We did not compare other subgroups, thereby ignoring the heterogeneity in all other study characteristics (study design, method of analysis, follow-up duration, population, age at infection, pathogen and country of study). We refrained from this since strata would include too few studies of moderate/high quality and too many prognostic factors to discriminate between the groups and draw reliable conclusions.

Finally, due to the limited quality of most studies, and the heterogeneous nature of study characteristics and results, the factors found must only be used with caution.

Conclusions

Several plausible and important prognostic factors for the prediction of sequelae or mortality after BM in childhood were proposed. Because of the limited quality of most studies and the heterogeneous nature of study characteristics and results, findings must be interpreted critically and the prognostic factors found may be used only with caution. This demonstrates that more high quality prognostic studies on factors related to sequelae or death after BM in childhood are clearly needed.

Appendix 1

The 10 most common causative pathogens of BM according to the Netherlands Reference Laboratory for Bacterial Meningitis [38]:
  • Streptococcus pneumoniae

  • Neisseria meningitidis

  • Haemophilus influenzae type B (HiB)

  • Listeria monocytogenes

  • Escherichia coli

  • Streptococcus agalactiae (Group B Streptococcus, GBS)

  • Streptococcus pyogenes

  • Staphylococcus aureus

  • Coagulase-negative Staphylococcus (CoNS)

  • Cryptococcus neoformans

Appendix 2: used search strategies for Medline and Embase

Medline

#1 search terms on "Bacterial meningitis"

"Meningitis, Bacterial"[Mh] OR "Meningitis, Bacterial/complications"[Mh] OR "Meningitis, Bacterial/diagnosis"[Mh] OR "Meningitis, Bacterial/epidemiology"[Mh] OR "Meningitis, Bacterial/physiopathology"[Mh] OR "Meningitis, Bacterial/psychology"[Mh] OR "Meningitis, Meningococcal"[Mh] OR "Meningitis, Meningococcal/complications"[Mh] OR "Meningitis, Meningococcal/diagnosis"[Mh] OR "Meningitis, Meningococcal/mortality"[Mh] OR "Meningitis, Pneumococcal"[Mh] OR "Meningitis, Pneumococcal/complications"[Mh] OR "Meningitis, Pneumococcal/diagnosis"[Mh] OR "Meningitis, Pneumococcal/mortality"[Mh] OR "Meningitis, Escherichia coli"[Mh] OR "Meningitis, Escherichia coli/complications"[Mh] OR "Meningitis, Escherichia coli/diagnosis"[Mh] OR "Meningitis, Escherichia coli/mortality"[Mh] OR "Meningitis, Haemophilus"[Mh] OR "Meningitis, Haemophilus/complications"[Mh] OR "Meningitis, Haemophilus/diagnosis"[Mh] OR "Meningitis, Haemophilus/mortality"[Mh] OR "Meningitis, Listeria"[Mh] OR "Meningitis, Listeria/complications"[Mh] OR "Meningitis, Listeria/diagnosis"[Mh] OR "Meningitis, Listeria/mortality"[Mh] OR meningitis[tw] AND (bacterial[tw] OR meningococcal[tw] OR pneumococcal[tw] OR Neisseria[tw] OR meningitides[tw] OR Streptococcus[tw] OR pneumoniae[tw] OR Haemophilus[tw] OR Hib[tw] OR influenzae[tw] OR Listeria[tw] OR monocytogenes[tw] OR Escherichia[tw] OR coli[tw] OR agalactiae[tw] OR pyogenes[tw] OR Staphylococcus[tw] OR aureus[tw] OR Cryptococcus[tw] OR neoformans[tw])

#2 search terms on "prognosis"

Morbidity[Mh:noexp] OR mortality[Mh:noexp] OR "cause of death"[Mh] OR survival rate [Mh] OR prognos*[tw] OR predict*[tw] OR course*[tw] OR longitudinal[tw] OR follow-up[tw] OR followup[tw] OR follow up[tw] OR cohort*[tw] OR survival[tw] OR cohort studies[mh] OR follow-up studies[mh]

#3 search terms exclusions

("addresses"[Pt] OR "biography"[Pt] OR "case reports"[Pt] OR "comment"[Pt] OR "directory"[Pt] OR "editorial"[Pt] OR "festschrift"[Pt] OR "interview"[Pt] OR "lectures"[Pt] OR "legal cases"[Pt] OR "legislation"[Pt] OR "letter"[Pt] OR "news"[Pt] OR "newspaper article"[Pt] OR "patient education handout"[Pt] OR "popular works"[Pt] OR "congresses"[Pt] OR "consensus development conference"[Pt] OR "consensus development conference, nih"[Pt] OR "practice guideline"[Pt]) NOT ("animals"[Mh Terms] NOT "humans"[Mh Terms])

Final search on Bacterial meningitis and prognosis with exclusions

#1 AND #2 NOT #3

Embase

#1 search terms on "Bacterial meningitis"

((('bacterial meningitis'/exp OR 'bacterial meningitis') OR ('epidemic meningitis'/exp OR 'epidemic meningitis')) OR ('meningitis'/de OR 'meningitis') AND (bacterial OR meningococcal OR pneumococcal OR ('neisseria'/de OR 'neisseria') OR meningitides OR ('streptococcus'/de OR 'streptococcus') OR pneumoniae OR ('haemophilus'/de OR 'haemophilus') OR hib OR influenzae OR ('listeria'/de OR 'listeria') OR monocytogenes OR ('escherichia'/de OR 'escherichia') OR coli OR agalactiae OR pyogenes OR ('staphylococcus'/de OR 'staphylococcus') OR aureus OR ('cryptococcus'/de OR 'cryptococcus') OR neoformans)). include text word

#2 search terms on "prognosis"

((('morbidity'/de OR 'morbidity') OR ('mortality'/de OR 'mortality') OR ('cause of death'/exp OR 'cause of death') OR ('survival rate'/exp OR 'survival rate') OR ('cohort analysis'/exp OR 'cohort analysis') OR ('follow up'/exp OR 'follow up')) OR prognos* OR predict* OR course* OR cohort* OR longitudinal OR ('follow up'/de OR 'follow up') OR ('followup'/de OR 'followup') OR ('survival'/de OR 'survival')). include text word

#3 search terms exclusions

(('literature'/exp OR 'literature'/de) OR ('case report'/exp OR 'case report'/de) OR ('directory'/exp OR 'directory'/de) OR ('editorial'/exp OR 'editorial'/de) OR ('interview'/exp OR 'interview'/de) OR ('medicolegal aspect'/exp OR 'medicolegal aspect'/de) OR ('reading'/exp OR 'reading'/de) OR ('publication'/exp OR 'publication'/de) OR ('patient education'/exp OR 'patient education'/de) OR ('organization'/exp OR 'organization'/de) OR ('consensus development'/exp OR 'consensus development'/de) OR ('practice guideline'/exp OR 'practice guideline'/de)) NOT (('animal'/exp OR 'animal'/de) NOT ('human'/exp OR 'human'/de))

Final search Bacterial meningitis and prognosis with exclusions

#1 AND #2 NOT #3

Declarations

Acknowledgements

The authors thank Ricky Levitan for her help with the English language. There was no funding.

Authors’ Affiliations

(1)
Department of Pediatrics and Infectious Diseases, VU University Medical Center
(2)
Emma Children's Hospital - Academic Medical Center, University of Amsterdam, Department of Neonatology
(3)
Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center

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  45. Pre-publication history

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