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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., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

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., Competing Interests: T.P. received research grant from Pediatric Research Foundation, Helsinki, Finland. All other authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2024 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

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., (© 2023. Springer Nature Limited.)

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 (3NO 2 -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.

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.

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)., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

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., (© 2022. The Author(s).)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The diagnosis of bacterial meningitis (BM) is problematic in young infants, as clinical features may be nonspecific or even absent. Cerebrospinal fluid (CSF) analysis usually confirms the diagnosis, but the CSF parameters can be normal also in culture-proven BM. Our objective was to identify the clinical and CSF indices, that quickly and without laboratory likely lead to the diagnosis of confirmed of probable BM in young infants in Angola., Methods: We conducted a prospective, observational, single-site study from February 2016 to October 2017 in the Pediatric Hospital of Luanda. All assessed infants showed symptoms and signs compatible of BM or neonatal sepsis and were <90 days of age., Results: Of the 1088 infants, 212 (19%) showed bacteria in CSF, while 88 (8%) had probable BM. Independent clinical indicators of BM were not-clear CSF, seizures, weight <2500 g and illness >7 days. In infants with BM, CSF leukocytes were >10 × 106/L in 46%, CSF glucose <25 mg/dL in 43% and CSF protein >120 mg/dL in 58%. All measured parameters were in normal range in 25% of patients. In 515 infants with normal CSF parameters, bacteria were found in 74 (14%). In these infants, illness >7 days, weight <2500 g and malnutrition increased the probability of BM., Conclusions: Our study confirms and underlines the problems in diagnosing BM in young infants. While the CSF parameters were normal in 25% of infants, the easily recognizable unclear appearance of CSF was the single strongest predictor of BM., Competing Interests: T.P. and S.U. report grants from the Paediatric Research Foundation, and T.P. from the Päivikki and Sakari Sohlberg Foundation, Helsinki, Finland. M.H.K. was employee of Sanofi Pasteur during the implementation of the study. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Our objective was to quantify the differences in the outcomes from childhood bacterial meningitis (BM) and to describe the factors associated with them in different parts of the world. This study is a secondary analysis of prospectively collected data from five clinical BM trials conducted in Finland, Latin America (LatAm), and Angola between 1984 and 2017. As all data were collected uniformly, direct comparison of the series was possible. Associations between patient characteristics and death or dismal outcome-the triad of death, severe neurological sequelae, or deafness-were explored. In all, data on 2123 children with BM were analyzed. Etiology was confirmed in 95%, 83%, and 64%, in Finland, LatAm and Angola, respectively. The leading agents were Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. Dismal outcome was the end result for 54%, 31%, and 5% of children in Angola, LatAm, and Finland, respectively. Although underweight, anemia, and tardy arrival worsened prognoses in Angola and LatAm, it was the presenting condition that was central in terms of outcome. In multivariate analysis, the factors independently associated with dismal outcome were the study site (Angola vs. Finland, OR 11.91, 95% CI 5.54-25.63, p < 0.0001 or LatAm vs. Finland, OR 9.46, 95% CI 4.35-20.61, p < 0.0001), Glasgow Coma Score < 13 (OR 4.58, 95% CI 3.31-6.32, p < 0.0001), seizures (OR 1.96, 95% CI 1.43-2.69), age < 1 year (OR 1.55, 95% CI 1.13-2.14, p = 0.007), and pneumococcal etiology (OR 1.49, 95% CI 1.08-2.06, p = 0.015). Greatly dissimilar outcomes from BM reflected the findings on admission on all three continents. Optimizing growth, preventing anemia, and prompt treatment may improve outcomes in resource poor areas., (© 2021. The Author(s).)

Background: Survivors of bacterial meningitis (BM) often suffer from impaired quality of life that stems from disabling sequelae. The authors aimed to estimate health-related quality of life (HRQOL) and the influence of neurologic and audiologic sequelae among pediatric BM survivors., Methods: Survivors of 2 BM treatment trials at Luanda Children's Hospital, Angola were evaluated for severity of disability via the modified Glasgow Outcome Scale, which considers neurologic and audiologic sequelae. Children who received vaccinations at the hospital during the time of the study (1-2, 2017) and survivors' siblings served as controls. The Pediatric Quality of Life Inventory tool (PedsQL) enabled identifying HRQOL disparities between the cases and controls., Results: In all, 68 BM survivors (median time since BM: 28 months) and 35 controls participated. Survivors scored significantly lower than controls per PedsQL parent-proxy reports, indicating lower HRQOL (physical health: 82.5 vs. 100, P = 0.001; psychosocial health: 80 vs. 90, P = 0.005; and total score: 82.61 vs. 93, P = 0.004), while no difference prevailed between cases and controls in PedsQL child self-reporting. In all Glasgow Outcome Scale classes, cases differed significantly from controls in PedsQL parent-proxy reporting terms, with total scores of 84.21 (mild/no disability), 43.54 (moderate disability) and 55.56 (severe disability), while the controls scored 91.3 (P = 0.04, P = 0.02 and P < 0.001, respectively)., Conclusions: Irrespective of possible disability, BM survivors' HRQOL is impaired, according to parents' perceptions. There is a need to facilitate follow-ups for all BM survivors, to enable timely rehabilitation when needed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In our previous study in Luanda, Angola, initial continuous β-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 β-lactam infusion combined with oral acetaminophen did not improve the gloomy outcomes of childhood bacterial meningitis in Angola., Clinical Trials Registration: NCT01540838., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Yearly, about two million infants die during the first 28 days of life. Most of these deaths occur in sub-Saharan Africa and a third of those are caused by severe infections. The early identification of infants at risk of death is important when trying to prevent poor outcomes., Objective: The aim of this study was to identify risk factors for death among young infants with possible serious bacterial infection (pSBI) at hospital admission., Methods: This prospective, observational, single-site, descriptive study forms part of a larger study on bacterial meningitis in infants <90 days of age admitted to the Pediatric Hospital of Luanda, the capital of Angola, from February 1, 2016 to October 23, 2017. Infants with pSBI, a known outcome, and a final diagnosis were included., Results: Of 574 young infants with pSBI, 115 (20%) died in hospital. An altered level of consciousness, absence of spontaneous movements, dyspnea, CSF that is not clear, low CSF glucose, high CSF protein, heart rate over the median, and seizures were identified as risk factors for death in the univariate analysis. In the multivariate analysis, only heart rate over the median and seizures were independent predictors of death., Conclusions: Easily recognizable clinical signs - tachycardia and seizures - may guide clinicians to identify infants at high risk of death due to severe bacterial infections in sub-Saharan Africa., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) of TLR4 and TLR9 are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPs TLR4 rs4986790 (896A > G) and TLR9 rs187084 (-1486T > C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes in TLR4 was significantly higher in patients with Haemophilus influenzae meningitis than controls (odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2-5.4; p = 0.021), whereas the frequency of variant genotypes in TLR9 was significantly lower in patients with H. influenzae meningitis than controls (OR, 0.4; 95% CI, 0.2-0.9; p = 0.036). No such differences were found with other causative pathogens, such as Streptococcus pneumoniae and Neisseria meningitidis . At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variant TLR4 genotypes had a higher risk of ataxia (OR, 12.91; 95% CI, 1.52-109.80; p = 0.019) and other neurological sequelae (OR, 11.85; 95% CI, 1.07-131.49; p = 0.044) than those with the wild-type TLR4 genotype. Our study suggests an association between H. influenzae meningitis and genetic variation between TLR4 and TLR9 in Angolan children.