Pneumonia in childhood bacterial meningitis-Experience from three continents.

INTRODUCTION: Although concomitant pneumonia is sometimes diagnosed in childhood bacterial meningitis, its role in the illness course and prognosis is not known. We examined these associations using prospectively collected data from Finland, Latin America and Angola. METHODS: This was a secondary descriptive analysis of prospectively collected data (clinical and laboratory findings at admission, during hospitalisation and outcome) from five clinical bacterial meningitis trials. We included children aged 2 months to 15 years from sites with confirmed bacterial meningitis and potential concomitant pneumonia (diagnosed clinically with or without a chest radiograph). RESULTS: Pneumonia was not observed in the 341 children included in Finland. Pneumonia was observed in 8% (51/606) of children in Latin America and in 46% (377/819) in Angola (p < 0.0001). In multivariate analyses, predisposing factors for pneumonia in Latin America were age <1 year, seizures and severe anaemia; the corresponding factors for Angola were preadmission duration of illness >3 days and non-meningococcal meningitis. Concomitant pneumonia increased the severity of the disease and disabling sequelae. CONCLUSION: Bacterial meningitis with pneumonia is a major, previously undescribed entity of severe bacterial meningitis, especially in Angola.

Seizures, focal neurological signs, and pneumococcal aetiology associate with impaired consciousness in childhood bacterial meningitis.

AIM: A low Glasgow Coma Scale Score (GCS) on admission is a known predictor of poor outcome from childhood bacterial meningitis. In turn, the factors associated with the admission GCS are less known. Our aim was to identify them, both for clinical alerts of reserved prognosis and to find potential targets for intervention. METHODS: This study is a secondary analysis of data collected prospectively in Angola and in Latin America between 1996 and 2007. Children with bacterial meningitis were examined on hospital admission and their GCS was assessed using the age-adjusted scale. Associations between on-admission GCS and host clinical factors were examined. RESULTS: A total of 1376 patients with confirmed bacterial meningitis were included in the analysis (609 from Latin America and 767 from Angola). The median GCS was 13 for all patients (12 in Angola and 13 in Latin America). In the multivariate analysis, in the areas combined, seizures, focal neurological signs, and pneumococcal aetiology associated with GCS <13, as did treatment delay in Latin America. CONCLUSION: Besides pneumococcal aetiology, we identified characteristics, easily registrable on admission, which are associated with a low GCS in childhood bacterial meningitis. Of these, expanding pneumococcal vaccinations and treatment delays could be modified.

Unusual Gram-negative bacteria cause more severe bacterial meningitis than the three classical agents in children.

AIM: To compare the characteristics, mortality and sequelae at hospital discharge of childhood bacterial meningitis (BM) caused by the three "classical" agents Neisseria meningitidis, Haemophilus influenzae or Streptococcus pneumoniae versus BM due to other aetiology in Finland, Latin America and Angola. METHODS: This observational study is a secondary analysis of data from five prospective treatment trials on non-neonatal BM in Finland, Latin America and Angola in 1984-2017. RESULTS: Of the 1568 cases, 1459 (93%) were caused by the classics, 80 (5%) by other Gram-negative and 29 (2%) by other Gram-positive bacteria. Nonclassical Gram-negative disease was encountered especially in Angola (p < 0.0001). Overall, children in the nonclassical group presented later for treatment and were more often underweight and anaemic (p < 0.001). In multivariate analysis, even if the area was strongest predictor of poor outcome, nonclassical Gram-negative BM increased the odds for death twofold and the odds for death or severe sequelae 2.5-fold. CONCLUSION: BM of a nonclassical aetiology is a particularly severe disease affecting especially Angolan children poorly armoured to fight infections. Since vaccinations are diminishing the role of classical agents, that of nonclassical agents is growing.

Extended Continuous ß-Lactam Infusion With Oral Acetaminophen in Childhood Bacterial Meningitis: A Randomized, Double-blind Clinical Trial.

BACKGROUND: In our previous study in Luanda, Angola, initial continuous ß-lactam infusion for 24 hours combined with oral acetaminophen for 48 hours showed promising results as a new treatment for childhood bacterial meningitis. We investigated whether extending this treatment regimen to 4 days would improve the outcomes further. METHODS: We conducted a randomized, double-blind, parallel-group study at the same hospital in Luanda. Children aged 2 months to 15 years presenting to hospital with symptoms and signs of bacterial meningitis were randomized to receive, for the first 4 days, a continuous infusion of cefotaxime (250 mg/kg/day) with simultaneous oral acetaminophen (first dose 30 mg/kg, then 20 mg/kg every 6 hours), or cefotaxime conventionally as boluses (62.5 mg/kg, 4 times per day) with placebo orally. All children received also glycerol orally. The primary outcome was mortality by day 7. RESULTS: In all, 375 patients were included in the study between 22 January 2012 and 21 January 2017. As 2 children succumbed before treatment initiation, 187 vs 186 participants remained in the intervention and control groups, respectively. On day 7, 61 of 187 (32.6%) children in the intervention group vs 64 of 186 (34.4%) in the control group had died (risk ratio, 0.95 [95% confidence interval {CI}, .71-1.26]; absolute risk difference, 1.8% [95% CI, -7.8 to 11.4]). At discharge from hospital, the corresponding numbers were 71 of 187 (38.0%) and 75 of 186 (40.3%), respectively. CONCLUSIONS: Prolonged continuous ß-lactam infusion combined with oral acetaminophen did not improve the gloomy outcomes of childhood bacterial meningitis in Angola. CLINICAL TRIALS REGISTRATION: NCT01540838.

The Potential Role of Matrix Metalloproteinases 8 and 9 and Myeloperoxidase in Predicting Outcomes of Bacterial Meningitis of Childhood.

BACKGROUND: Matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) contribute to the inflammatory cascade in the cerebrospinal fluid (CSF) during bacterial meningitis. We determined levels of MPO, MMP-8, MMP-9, and tissue inhibitor of metalloproteinase- (TIMP-) 1 in the CSF of children with bacterial meningitis and investigated how these inflammatory mediators relate to each other and to the disease outcomes. METHODS: Clinical data and the diagnostic CSF samples from 245 children (median age eight months) with bacterial meningitis were obtained from a clinical trial in Latin America in 1996-2003. MMP-9 levels in the CSF were assessed by zymography, while MMP-8, MPO, and TIMP-1 concentrations were determined with immunofluorometric and enzyme-linked immunosorbent assays. RESULTS: MPO correlated positively with MMP-8 (rho 0.496, P < 0.001) and MMP-9 (rho 0.153, P = 0.02) but negatively with TIMP-1 (rho -0.361, P < 0.001). MMP-8 emerged as the best predictor of disease outcomes: a CSF MMP-8 concentration above the median increased the odds of death 4.9-fold (95% confidence interval 1.8-12.9). CONCLUSIONS: CSF MMP-8 presented as an attractive prognostic marker in children with bacterial meningitis.

Vitamin D was not associated with survival or cerebrospinal fluid cathelicidin levels in children with bacterial meningitis.

AIM: Vitamin D deficiency impairs the immunological system and has been associated with worse outcomes of infectious diseases, but its role in bacterial meningitis remains unknown. We investigated whether serum 25-hydroxyvitamin D concentrations related to disease outcomes and to cerebrospinal fluid (CSF) cathelicidin concentrations in childhood bacterial meningitis. METHODS: All consecutively enrolled patients in a clinical trial on childhood bacterial meningitis in Latin America in 1996-2003 were considered, and 142 children, with a median age of seven months who had a confirmed bacterial aetiology and frozen serum available for further analyses, were included in this study. Serum 25-hydroxyvitamin D concentrations were determined with a chemiluminescence immunoassay analyser, while CSF cathelicidin was measured by enzyme-linked immunosorbent assay. RESULTS: The median serum 25-hydroxyvitamin D concentration was 96 (range 19-251) nmol/L. No relationship was found with patient survival, but children with any neurological sequelae had lower serum 25-hydroxyvitamin D levels than children without sequelae. Serum 25-hydroxyvitamin D was unrelated to cathelicidin concentrations in CSF. CONCLUSION: Although serum 25-hydroxyvitamin D in children with bacterial meningitis was not associated with survival or CSF cathelicidin concentrations, its relationship with more detailed disease outcomes warrants further study.

A psychometric appraisal of the dundee ready education environment measure in a medical school in Chile.

Background: The Dundee Ready Education Environment Measure (DREEM) is used in the curricular development of future health professionals worldwide, but often without first locally testing its psychometric qualities, for example, construct validity and internal consistency. These characteristics are modified by different environments, but must be locally appropriate to obtain unequivocal and reliable conclusions about the strong and weak areas of a curriculum. Here, we report the results of the psychometric testing of DREEM results in our institution in Chile. Methods: All 1st-5th-year undergraduate medical students were asked to respond the DREEM questionnaire. The construct validity of the results was assessed by an exploratory factor analysis (EFA), and their internal consistency was assessed by Cronbach's α. The Institutional Review Board approved the study, and each student signed an informed consent. Results: A total of 304 (88%) eligible students, aged 22 ± 2 years, 46% of females, answered the questionnaire. The EFA determined four instead of the original DREEM's five subareas with clearly different item contents. The inner consistencies of the locally defined subareas of teaching, learning, teachers and organizational aspects, and self-perception surpassed the originals with Cronbach's α values of 0.79, 0.78, 0.77, and 0.82, respectively. Discussion: The optimal psychometric structure to accurately interpret our DREEM results differed from both the original and previous similar studies, including one from Chile. There are several potential explanations for these differences, but most importantly, they underline the need to first define the psychometric characteristics of the test results, to obtain accurate conclusions about the strengths and the weaknesses of a curriculum.

Swiftly Decreasing Cerebrospinal Fluid Cathelicidin Concentration Predicts Improved Outcome in Childhood Bacterial Meningitis.

We investigated cerebrospinal fluid (CSF) cathelicidin concentrations in childhood bacterial meningitis on admission and during antimicrobial treatment. CSF cathelicidin concentrations on admission correlated with CSF white cell counts and protein levels but not with bacterial etiology. A greater decrease in the concentration in response to treatment was associated with a better outcome. Since the CSF cathelicidin concentration reflects the degree of central nervous system (CNS) inflammation, it may be used as a novel biomarker in childhood bacterial meningitis. An early decrease during treatment likely signals more rapid mitigation of the disease process and thus a better outcome.

Changes in MMP-9 and TIMP-1 Concentrations in Cerebrospinal Fluid after 1 Week of Treatment of Childhood Bacterial Meningitis.

We explored the changes of the initially highly upgraded cerebrospinal fluid matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of MMP 1 (TIMP-1) response during recovery of childhood bacterial meningitis and their association with outcome. The sizes of these changes varied substantially, but a steeper decrease in the MMP-9 and an increase of the TIMP-1 concentrations augured a better outcome.

Vaccine-induced waning of Haemophilus influenzae empyema and meningitis, Angola.

In Angola during 2003-2012, we detected Haemophilus influenzae in 18% of 2,634 and 26% of 2,996 bacteriologically positive pleural or cerebrospinal fluid samples, respectively, from children. After vaccination launch in 2006, H. influenzae empyema declined by 83% and meningitis by 86%. Severe H. influenzae pneumonia and meningitis are preventable by vaccination.

Clinical Picture and Risk Factors for Poor Outcome in Streptococcus pneumoniae Meningitis of Childhood on Three Continents.

BACKGROUND: Streptococcus pneumoniae meningitis (SpM) remains a major health burden worldwide, particularly in low- and middle-income countries. Identifying the patients at highest risk for mortality and disabling sequelae may reveal potentially avoidable predisposing factors and identify patients most in need of intensive care. We searched for factors that do not require laboratory facilities. METHODS: This study was a secondary analysis of prospectively collected data from 5 clinical trials of childhood bacterial meningitis on 3 continents between 1984 and 2017. SpM cases were analyzed by study site and predictors for poor outcome (death or severe sequelae) were identified from the whole series, Latin America and Angola. RESULTS: Among a total of 1575 children (age range: 2 months to 15 years), 505 cases were due to pneumococci. Compared to other etiologies, SpM doubled the death rate (33% vs. 17%) and tripled poor outcome (15% vs. 6%). In SpM, Glasgow Coma Score <13 [odds ratio (OR): 4.73] and previous antibiotics in Angola (OR: 1.70) were independent predictors for death. Predictors for poor outcome were age <1 year (OR: 2.41) and Glasgow Coma Score <13 (OR: 6.39) in the whole series, seizures in Latin America (OR: 3.98) and previous antibiotics in Angola (OR: 1.91). Angolan children had a 17-fold increased risk for poor outcome when compared with Finnish children ( P = 0.011). CONCLUSIONS: Our study proved the severity of SpM when compared with other etiologies. The outcome was especially poor in Angola. Most patients at risk for poor outcome are easily identified by clinical factors on admission.

The Effect of Blood Transfusion on the Survival of Children with Both Severe Anemia and Bacterial Meningitis.

In areas with suboptimal resources, blood transfusion may not be feasible even when mandatory for severely anemic children with a life-threatening disease. We evaluated how much not having received a transfusion affected the survival in 171 children with an admission blood hemoglobin level of < 6 g/dL and bacterial meningitis in Luanda, Angola. Of these children, 75% (128 of 171) had received a blood transfusion during hospitalization, but 25% (43 of 171) had not. Within the first week, 33% of patients (40 of 121) with transfusion and 50% (25 of 50) without a transfusion died (P = 0.04). Early transfusion (days 1-2 of hospitalization) prolonged the time of survival from a median of 132 hours [interquartile range (IQR), 15-168] to 168 hours (IQR, 69-168; P = 0.004), and had odds of 0.49 (95% CI, 0.25-0.97; P = 0.040) for death compared with no transfusion. The effect of transfusion/no transfusion at any time during hospitalization on mortality within 30 days, and prolongation of the time of survival were similar to early transfusion but showed even clearer benefits. Our results emphasize the value of timely transfusion in facilities that care for severely anemic children with severe infections to maximize their chances of survival.

Clinical blindness in conjunction with childhood bacterial meningitis.

Although rarely reported, bilateral loss of vision is a severe complication of childhood bacterial meningitis. We assessed its frequency in five prospective treatment trials performed in Europe, Latin America, and Angola in 1984-2017. Course of illness, follow-up findings, and child's sight were recorded. Sight was examined at discharge, and conditions permitting, also at 1-3 months post-hospitalization and in Angola on hospital day 7. Experienced pediatricians diagnosed clinical blindness if the child did not make eye contact, did not blink or move the eyes, or remained unresponsive to bright light or movement of large objects before their eyes. Of 1515 patients, 351, 654, and 510 were from Finland, Latin America, and Angola, respectively. At discharge, blindness was observed in 0 (0%), 8 (1.2%), and 51 (10%) children, respectively. In Angola, 64 children appeared to be blind on day 7; 16 of these children died. Blindness found at discharge in Angola was not invariably irreversible; approximately 40% had restored the sight at follow-up visit. Clinical blindness rarely occurred in isolation and was usually associated with young age and poor general condition at hospital arrival. Various other serious sequelae were common among the survivors with clinical blindness.

High Concentration of Protein Oxidation Biomarker O-Tyr/Phe Predicts Better Outcome in Childhood Bacterial Meningitis.

Neuronal damage in bacterial meningitis (BM) partly stems from the host´s inflammatory response and induced oxidative stress (OS). We studied the association of cerebrospinal fluid (CSF) biomarkers indicating oxidative damage to proteins with course of illness and outcome in childhood BM in Angola. Ortho-tyrosine/phenylalanine (o-Tyr/Phe), 3-chlorotyrosine/para-tyrosine (3Cl-Tyr/p-Tyr), and 3-nitrotyrosine/para-tyrosine (3NO2-Tyr/p-Tyr) concentration ratios were measured in 79 BM admission CSF samples, employing liquid chromatography coupled to tandem mass spectrometry. Besides death, disease outcomes were registered on Day 7 of treatment and one month after discharge (control visit). The outcome was graded according to the modified Glasgow Outcome Scale (GOS), which considers neurological and audiological sequelae. Children with a o-Tyr/Phe ratio below the median were more likely to present focal convulsions and secondary fever during recovery and suboptimal outcome (GOS < 5) on Day 7 and at control visit (odds ratio (OR) 2.85; 95% CI 1.14-7.14 and OR 5.23; 95% CI 1.66-16.52, respectively). Their most common sequela was ataxia on Day 7 and at control visit (OR 8.55; 95% CI 2.27-32.22 and OR 5.83; 95% CI 1.12-30.4, respectively). The association of a higher admission CSF o-Tyr/Phe ratio with a better course and outcome for pediatric BM points to a beneficial effect of OS.

Picornaviruses in cerebrospinal fluid of children with meningitis in Luanda, Angola.

Human enteroviruses are the most common cause of viral meningitis. Viral-bacterial interaction may affect the clinical course and outcome of bacterial meningitis. In Africa, viruses might be responsible for 14-25% of all meningitis cases. However, only few studies from Africa have reported detection of viruses in the cerebrospinal fluid (CSF) or mixed viral-bacterial infections of the central nervous system (CNS). The aim of the present study was to investigate the presence of picornaviruses in the CSF of children suffering from meningitis in Luanda, Angola. The study included 142 consecutive children enrolled in a prospective study of bacterial meningitis in Luanda between 2005 and 2006, from whom a CSF sample was available. CSF samples were obtained at hospital admission, stored in a deep-freeze, and transported to Finland for testing by real-time PCR for picornaviruses. Enteroviruses were detected in 4 (3%) of 142 children with presumed bacterial meningitis. A 5-month-old girl with rhinovirus and Haemophilus influenzae meningitis recovered uneventfully. An 8-year-old girl with human enterovirus and pneumococcal meningitis developed no sequelae. A 2-month-old girl with human enterovirus and malaria recovered quickly. A 7-month-old girl with human enterovirus was treated for presumed tuberculous meningitis and survived with severe sequelae. Mixed infections of the CNS with picornaviruses and bacteria are rare. Detection of an enterovirus does not affect the clinical picture and outcome of bacterial meningitis.

Prognostic accuracy of five simple scales in childhood bacterial meningitis.

BACKGROUND: In childhood acute bacterial meningitis, the level of consciousness, measured with the Glasgow coma scale (GCS) or the Blantyre coma scale (BCS), is the most important predictor of outcome. The Herson-Todd scale (HTS) was developed for Haemophilus influenzae meningitis. Our objective was to identify prognostic factors, to form a simple scale, and to compare the predictive accuracy of these scales. METHODS: Seven hundred and twenty-three children with bacterial meningitis in Luanda were scored by GCS, BCS, and HTS. The simple Luanda scale (SLS), based on our entire database, comprised domestic electricity, days of illness, convulsions, consciousness, and dyspnoea at presentation. The Bayesian Luanda scale (BLS) added blood glucose concentration. The accuracy of the 5 scales was determined for 491 children without an underlying condition, against the outcomes of death, severe neurological sequelae or death, or a poor outcome (severe neurological sequelae, death, or deafness), at hospital discharge. RESULTS: The highest accuracy was achieved with the BLS, whose area under the curve (AUC) for death was 0.83, for severe neurological sequelae or death was 0.84, and for poor outcome was 0.82. Overall, the AUCs for SLS were ≥0.79, for GCS were ≥0.76, for BCS were ≥0.74, and for HTS were ≥0.68. CONCLUSIONS: Adding laboratory parameters to a simple scoring system, such as the SLS, improves the prognostic accuracy only little in bacterial meningitis.

Importance of underweight in childhood bacterial meningitis in Finland, Latin America and Angola.

Our objective was to explore the importance of underweight on the course of childhood bacterial meningitis (BM) at different study sites, because prior studies showed discrepant results. Using directly comparable, prospective data from three continents, weight-for-age z-scores (WAZ) were determined by WHO Anthro programs in children with BM in Finland (N = 318), LatAm (N = 580), and Angola (N = 780) and compared with data describing the admission, course, and outcome of BM. WAZ < -1 indicates underweight; either mild (< -1 to -2), moderate (< -2 to -3), or severe (< -3). The mean WAZ (SD) was 0.17 (1.17), -0.42 (1.53), and -1.36 (1.44), and the prevalence of moderate-severe underweight 2.8%, 12.6%, and 31.3%, in Finland, LatAm, and Angola, respectively. In univariate analysis, LatAm and Angola showed an association between lower WAZ and poorer condition on admission, slower recovery, and more deaths. In Finland, infrequent underweight limited meaningful analysis. In multivariate analysis of different variables for increasing the odds of death, severe underweight had lower odds compared to disease severity in Angola, but highest in LatAm. Thus, the apparent discrepancy in underweights´ importance for increasing deaths varied from primary to more secondary according to locally more prominent risks.

Bacterial Meningitis in Children With Sickle Cell Disease in Angola.

Sickle cell disease (SCD) was found in 10% of children with bacterial meningitis (BM) in Luanda, 5-fold more than in the general population. BM children with SCD versus BM children without SCD had higher inflammatory markers, more often had pneumococcal meningitis (71% vs. 39%), and either died (39% vs. 22%) or had a longer hospital stay (15 vs. 11 days).

Prevalence and significance of anaemia in childhood bacterial meningitis: a secondary analysis of prospectively collected data from clinical trials in Finland, Latin America and Angola.

OBJECTIVES: To describe the prevalence and severity of anaemia and to examine its associations with outcome in children with bacterial meningitis (BM). DESIGN: Secondary analysis of descriptive data from five randomised BM treatment trials. SETTING: Hospitals in Finland, Latin America and Angola. PARTICIPANTS: Consecutive children from 2 months to 15 years of age admitted with BM and who had haemoglobin (Hb) measured on admission. OUTCOME MEASURES: Prevalence and degree of anaemia using the WHO criteria, and their associations with recovery with sequelae or death. RESULTS: The median Hb was 11.8 g/dL in Finland (N=341), 9.2 g/dL in Latin America (N=597) and 7.6 g/dL in Angola (N=1085). Of the children, 79% had anaemia, which was severe in 29%, moderate in 58% and mild in 13% of cases. Besides study area, having anaemia was independently associated with age <1 year, treatment delay >3 days, weight-for-age z-score <-3 and other than meningococcal aetiology. Irrespective of the study area, anaemia correlated with the markers of disease severity. In children with severe to moderate anaemia (vs mild or no anaemia), the risk ratio for death was 3.38 and for death or severe sequelae was 3.07. CONCLUSION: Anaemia, mostly moderate, was common in children with BM, especially in Angola, in underweight children, among those with treatment delay, and in pneumococcal meningitis. Poor outcome was associated with anaemia in all three continents. TRIAL REGISTRATION NUMBER: The registration numbers of Angolan trials were ISRCTN62824827 and NCT01540838.

Otorhinolaryngological findings and hearing in HIV-positive and HIV-negative children in a developing country.

The otorhinolaryngological (ORL) manifestations of Human Immunodeficiency virus (HIV) are common, but remain poorly characterized among children of Sub-Saharan Africa, where 90% of new pediatric infections occur. Our objective was to compare ORL findings and hearing in HIV-positive and -negative children of Luanda, Angola, using a comparative study of 78 outpatients from the HIV polyclinic and of 78 age- and sex-matched controls in a pediatric hospital with interview, general and ORL examination, brainstem auditory evoked potentials, and at age >5 years pure tone open-air audiometry. ORL pathology emerged in 92% of HIV-positive and 78% (p = 0.02) of control children. HIV-associated ORL findings comprised dental caries (56 vs. 32%; p = 0.0009), cervical lymphadenopathy >1 cm (45 vs. 10%; p < 0.0001), facial skin lesions (32 vs. 5.1%; p < 0.0001), chronic suppurative otitis media (26 vs. 3.8%; p = 0.0002), dry tympanic membrane perforations (9 vs. 1%; p = 0.03), tonsils of Mallampati score 0-1 (87 vs. 64%; p = 0.0009), and bilateral hearing loss of >25 dB (13 vs. 1%; p = 0.009). Other HIV-associated characteristics included ear pain (44 vs. 27%; p = 0.006), earlier otorrhea episodes (34 vs. 17%; p = 0.004), tuberculosis (29 vs. 2.6%; p < 0.0001), and pneumonia (22 vs. 2.6%; p = 0.0003). ORL pathology appeared usual in both HIV-positive and -negative children. However, the overall high frequency and severity of the findings among the HIV-positive children require regular inclusion of the ORL area in these children's clinical evaluation.