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Survivors of childhood bacterial meningitis (BM) often develop hearing impairment (HI). In low- and middle-income countries (LMICs), BM continues to be a significant cause of hearing disability. We assessed hearing among BM survivors using auditory steady-state responses (ASSR), providing frequency-specific estimated audiograms, and examined whether ASSR would provide a greater understanding of BM-induced HI. Survivors from two prospective BM trials (ISRCTN62824827; NCT01540838) from Luanda Children’s Hospital were examined in a follow-up visit with a median duration of 26 months after BM. The hearing of 50 BM survivors and 19 control children was evaluated using ASSR and auditory brainstem response (ABR) after interview and neurological and otorhinolaryngological examinations. The median age of survivors was 80 (IQR 86) months. We diagnosed HI (better ear hearing ≥ 26 dB) in 9/50 (18%) children. Five of the fifty survivors (10%) and 14/100 ears (14%) had profound HI (>80 dB). Severe-to-profound HI affected all frequencies steadily, affecting only the ears of BM survivors (18/100 vs. 0/38, p = 0.003). When looking only at the severely or profoundly affected ears, young age, low Glascow coma score, pneumococcal aetiology, and ataxia were associated with a worse hearing outcome.

This study examined whether gene polymorphisms for toll-like receptor 10 (TLR10) associated with the susceptibility to and outcomes of bacterial meningitis (BM) in Angolan children. The study cohort consisted of 190 BM patients and the determination of ten single-nucleotide polymorphisms (SNPs) by Sanger sequencing. Patients with BM caused by Streptococcus pneumoniae who carried the following variants of TLR10 SNPs exhibited an increased risk of coexisting pneumonia: rs10004195 (T A) (p = 0.025), rs10856837 (G A) (p = 0.018) or rs11096956 (G T) (p = 0.010). Yet, TLR10 SNPs rs11466652 (A G), rs10856837 (G A) and rs11096956 (G T) influenced the protein levels in the cerebrospinal fluid (CSF). Moreover, compared with the wild type, patients with pneumococcal meningitis carrying a variant genotype of TLR10 SNP rs11466648 (A G) exhibited an increased risk of developing blindness (p = 0.025), whereas patients with TLR10 SNP rs10004195 (T A) exhibited a lower risk of convulsions at admission (p = 0.039) and a lower risk of altered consciousness (p = 0.029). This study suggests a relationship exists between coexisting pneumonia, protein levels in CSF, blindness, convulsions and an altered consciousness with genetic variations of TLR10 in BM in Angolan children.

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.

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.

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 &gt, G) and TLR9 rs187084 (&minus, 1486T &gt, 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&ndash, 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&ndash, 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&ndash, 109.80, p = 0.019) and other neurological sequelae (OR, 11.85, 95% CI, 1.07&ndash, 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.

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.

Background Bacterial meningitis (BM) is a significant cause of mortality in children; with deaths from BM in children aged \

INTRODUCTION Ataxia, deemed usually a minor sequela, follows childhood bacterial meningitis (BM) in up to 18% of cases. Although mostly transient and benign, it can predict permanent hearing loss and vestibular dysfunction. We explored the clinical meaning of ataxia by following its course in a large number of BM patients and examining its relation with hearing loss. METHODS The presence, degree (no, mild, moderate and severe) and course (transient, prolonged and late) of ataxia in BM were registered prospectively by predefined criteria. These data were compared with several patient, disease, and outcome variables including hearing loss (none, moderate, severe and profound) on day 7 of treatment and at a follow-up visit 1 month after discharge. RESULTS Ataxia was present in 243 of 361 (67%) patients on day 7, being slight in 21%, moderate in 38% and severe in 41%. Its course was transient in 41%, prolonged in 24% and late in 5%, whereas 30% of the patients did not present ataxia at any time. Ataxia associated most significantly not only with several measures of BM severity and suboptimal outcome (P < 0.0001), but also specifically, albeit not consistently, with hearing loss (P = 0.001). The degree of ataxia correlated with the extent of hearing loss (rho, 0.37; P < 0.0001). CONCLUSIONS Ataxia is more frequent and lasts longer after BM than learned from previous studies. The presence and intensity of ataxia associate with hearing loss and its magnitude.

BACKGROUND Hearing loss from childhood bacterial meningitis is believed to develop early and have little tendency for recovery. We performed serial hearing evaluations in a large number of children with bacterial meningitis in Luanda, Angola to clarify if, and how often, the result changed. METHODS Children with confirmed bacterial meningitis and hearing evaluations on admission, day 7 of treatment and the follow-up visit formed the study group. Hearing was tested by auditory brainstem response audiometry using stimuli of 40 dB, 60 dB and 80 dB. Threshold changes are described between the composite levels of 40/60 dB and 80/>80 dB. RESULTS In all, 235 ears were tested. While the ≤ 60 dB and ≥ 80 dB levels were maintained through all 3 examinations in 54% and 5% of ears, respectively, changes occurred in 41%. Deterioration from the ≤ 60 dB level to ≥ 80 dB was found in 10% of the ears transiently and in 7% permanently. Improvement from the ≥ 80 dB level to ≤ 60 dB occurred in 22% of the ears. Half of the ears with ≥ 80 dB impairment at the follow-up visit arrived with this finding; the others lost hearing later. Maintaining the ≤ 60 dB level throughout was associated with milder disease (P = 0.003), fewer convulsions (P < 0.0001) and older age (P = 0.009). CONCLUSIONS Almost half of the ears showed threshold changes after admission during recovery from bacterial meningitis, most frequently improvement of initially severely impaired hearing, but some normal ears or with moderate impairment became severely impaired.

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.

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.

Background In Sub-Saharan Africa, both malaria (M), and bacterial meningitis (BM) cause fever and central nervous system (CNS) disturbance. We studied their prevalence, characteristics, outcome, and risk factors for poor outcome to better understand the clinical impact of suspected CNS infection in children. Methods We conducted a prospective study in the Children’s Hospital (HPDB) in the capital of Angola which attends 300 new patients daily. Spinal tap (ST) was performed for children presenting with altered consciousness, convulsions, prostration, or meningism. The analysis included children aged 3 month to 15 years with confirmed discharge diagnosis in 2016–2017. Results Of 941 children, the diagnosis was M in 56% (525), BM in 12% (116), epilepsy/convulsions in 9% (88), and other infections in 6% (60). Of all children, 16% (150/941) died, 6% (45/733) had severe, 14% (93/655) any neurological sequelae, and 27% (243/897) either died or had neurological sequelae. In children with M, the corresponding figures were 7% (35/525), 1.5% (7/476), 4% (19/443), and 11% (54/514). In children with BM, the figures were 41% (47/116), 15% (8/54), 33% (11/33), and 55% (58/105), respectively. Comparing with M, children with BM were younger (median age (IQR) 28 (61) vs. 60 (68) months, P < 0.0001), had an underlying illness (23/97 vs. 19/374, P < 0.0001), like sickle-cell disease (18/96 vs. 9/372, P < 0.0001), longer duration of illness (4 (4) vs. 3 (3) days, P < 0.0001, dyspnea (70/119 vs. 210/463, P = 0.009), were dehydrated (36/113 vs. 67/441, P < 0.0001), or malnourished (38/115 vs. 75/447, P = 0.0001). Multivariate analysis revealed as independent risk factors for death or neurological sequelae age 3 days (2.48, 1.68–3.64, P < 0.0001), malnutrition (1.92, 1.20–3.05, P = 0.006), and dehydration (1.92, 1.16–3.14, P = 0.01). When BM vs. M was included in the analysis, BM appeared as the most important risk factor (OR 8.06, 4.44–14.65, P < 0.0001) and age lost its significance. Conclusion In suspected CNS infection, M was the final diagnosis of most children. However, BM caused more deaths and neurological sequelae. Amendable factors, such as delay in treatment, dehydration, and malnutrition, appeared as risk factors for poor outcome. Disclosures T. Pelkonen, sanofi pasteur: Investigator, Sanofi Paster funded this study. Paediatric Research Foundation, Helsinki, Finland: Grant Investigator, Grant recipient. Päivikki and Sakari Sohlberg Foundation, Helsinki, Finland: Grant Investigator, Grant recipient

Objective Childhood bacterial meningitis (BM) damages hearing, but the potential of different agents to cause impairment in developing countries is poorly understood. We compared the extent of hearing impairment in BM caused by Haemophilus influenzae type b (Hib), Streptococcus pneumoniae or Neisseria meningitidis among children aged 2 months to 13 years in Luanda, Angola. Methods Hearing of 685 ears of 351 (78%) survivors among 723 enrolled patients was tested by brainstem-evoked response audiometry on day 7 of hospitalization. The causative agent was sought by cerebrospinal fluid culture, PCR or the latex-agglutination test. Results Altogether, 45 (12%) of the survivors were deaf (threshold >80 dB), and 20 (6%) had a threshold of 80 dB. The incidence of any kind of hearing loss, with ≥60 dB, was 34% with Hib, 30% with S. pneumoniae , 19% with N. meningitidis and 33% with other bacteria. Examining all ears combined and using the ≥60 dB threshold, the agents showed dissimilar harm ( P = 0.005), Hib being the most frequent and N. meningitidis the most infrequent cause. Compared to other agents, S. pneumoniae more often caused deafness ( P = 0.025) and hearing impairment at ≥60 dB ( P = 0.017) in infants, whereas this level of hearing loss in older survivors was most commonly caused by Hib ( P = 0.031). Conclusions BM among children in Angola is often followed by hearing impairment, but the risk depends on the agent. S. pneumoniae is a major problem among infants, whereas Hib is mainly a risk beyond 12 months. N. meningitidis impairs hearing less frequently.

Hearing was evaluated in 244 ears of 124 children in Angola by auditory brainstem response audiometry 3 months after bacterial meningitis. Of all ears, 81% recovered without impairment. Of all children, 74% recovered without impairment, 5% had unilateral and 11% bilateral impairment. Seizures before or during hospital stay and disease severity were the best predictors of ≥ 80 dB impairment.

Background Survivors of childhood bacterial meningitis (BM) from low-income countries are at increased risk of sequelae. How BM survivors’ daily life is affected in the developing world, is not known. We aimed to investigate the quality of life among pediatric survivors of BM in Luanda, Angola assessing both physical and psychosocial health-related quality of life (HRQOL). Methods Survivors from two BM treatment trials (ISRCTN62824827; NCT01540838) from Luanda Children’s Hospital were called to follow-up visits in January 2017 with a median duration of 26 months after BM. We administered Pediatric Quality of Life InventoryTM (PedsQLTM) 4.0 Generic Core Scales and Infant Scales, designed to measure HRQOL in children, to patients and/or parents. The generic core scales were administered to 64 and 32 families, and the infant scores to 8 and 3 care-givers of patients and controls, respectively. We used age-appropriate versions of the scales. We calculated the total, physical and psychosocial HRQOL domains. To determine internal consistency, Cronbach’s alpha coefficients were calculated for generic score scales. Results In all, 73 survivors of BM and 36 control children participated. 18 (51%) of controls were siblings of survivors; others visited the hospital for vaccinations. The median age of children was 6 years (81 months, IQR 85 months). Survivors of BM scored significantly lower on the PedsQLTM 4.0 generic core and infant scales than control children according to parent proxy reports indicating lower HRQOL (total score 81.04 vs. 91.30, P = 0.001; physical health 87.50 vs. 100.00, P = 0.0002; psychosocial health 79.06 vs. 90.00, P = 0.001). Child self-report scores were also lower within BM survivors who were able to answer; however, the difference was not statistically significant. In total sample of survivors, the Cronbach’s alphas reached sufficient reliability of 0.70 in all three domains calculated (total score, α=0.79; physical health α= 0.77; psychosocial health α= 0.89 for child self-reports and α=0.91, α=0.91, and α=0.84 for parent proxy-reports, respectively). Conclusion The survivors of pediatric BM endure a clearly suboptimal quality of life compared with siblings and other control children. HRQOL can be measured reliably among BM patients in developing country setting. Disclosures All authors: No reported disclosures.

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.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.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.Adding laboratory parameters to a simple scoring system, such as the SLS, improves the prognostic accuracy only little in bacterial meningitis.

Summary Background New antimicrobials or adjunctive treatments have not substantially reduced mortality from acute childhood bacterial meningitis. Paracetamol seems to have beneficial effects in bacteraemic adults and some experts recommend initial slow β-lactam infusion. We investigated whether these treatments had benefits in children with bacterial meningitis. Methods We did a prospective, double-blind, single-centre study with a two-by-two factorial design in Luanda, Angola. 723 participants aged 2 months to 13 years were randomly assigned two 12 h intravenous infusions, without loading doses, of 125 mg/kg bodyweight cefotaxime (total dose 250 mg/kg) given over 24 h, or 250 mg/kg bodyweight cefotaxime given as four boluses, one every 6 h over 24 h. Patients also received oral paracetamol at an initial dose of 30 mg/kg then 20 mg/kg every 6 h for 48 h or placebo. Two primary endpoints, death or severe neurological sequelae and deafness, were analysed by intention to treat. The study was registered as ISRCTN62824827. Findings 183 patients were assigned cefotaxime infusion plus paracetamol and 180 patients to each of the other three treatment groups. Causative agents were identified in 63% of cases and were mostly Haemophilus influenzae type b, Streptococcus pneumoniae , or Neisseria meningitidis . Death or severe neurological sequelae were seen in 340 (47%) of 723 children and deafness in 45 (12%) of 374 tested, both distributed similarly across treatment groups. In a predefined subgroup analysis of death or any sequelae, by causative agent, a benefit was seen in favour of infusion over bolus in children with pneumococcal meningitis (infusion plus placebo, odds ratio 0·18, 95% CI 0·03–0·90, p=0·04). A similar effect was seen for children receiving cefotaxime infusion plus paracetamol, but the difference was not significant (OR 0·22, 95% CI 0·04–1·09, p=0·06). A post-hoc analysis suggested that cefotaxime infusion plus paracetamol lowered mortality at least during the first 3 days, irrespective of cause. Interpretation Although no tested regimen improved the final outcomes of these very ill children, studies of longer courses of β-lactam infusion plus paracetamol seem warranted. Funding The Paivikki and Sakari Sohlberg, the Sigrid Juselius, and the Paediatric Research Foundations, and the daily newspaper Helsingin Sanomat .