Tuula Pelkonen

Slow initial β-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial

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 Päivikki and Sakari Sohlberg, the Sigrid Jusélius, and the Paediatric Research Foundations, and the daily newspaper Helsingin Sanomat.

Risk Factors for Death and Severe Neurological Sequelae in Childhood Bacterial Meningitis in Sub-Saharan Africa

We report a morality rate of 33% among 403 children with bacterial meningitis in Angola. A fatal outcome was associated with impaired consciousness, severe dyspnea, and seizures, and severe neurological sequelae (found in 25% of our patients) was associated with delayed presentation to the hospital, impaired consciousness, and seizures. Being underweight was of secondary importance. Treatment with ceftriaxone, rather than with penicillin plus chloramphenicol, did not improve outcome.

Acute childhood bacterial meningitis in Luanda, Angola

Incidence, morbidity and mortality of bacterial meningitis in developing countries are manifold greater than those in the industrialized world. We reviewed retrospectively children with meningitis treated in the paediatric hospital of Luanda in 2004. Among the 555 children, median age 11.0 months, the leading agents were Haemophilus influenzae type b (Hib), pneumococcus, and meningococcus in 60%, 24%, and 10%, respectively. The median length of illness before admission was 7 d. 65% had convulsed. Altered level of consciousness was observed in 61% and blood haemoglobin lower than 8 g/dl in 36% of cases. Case fatality was 35% and, of survivors, 24% were left with severe neurological sequelae. Blood transfusion appeared beneficial since fatality of children with and without transfusion was 23% versus 39% (p=0.003). While awaiting large-scale vaccinations, tools to improve the prognosis of meningitis in Angola comprise generating better awareness to reduce the delay, better fluid treatment and monitoring and active use of blood transfusions.

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. J. Med. Virol. 84: 1080–1083, 2012.

Chronic suppurative otitis media in children of Luanda, Angola.

Aim:  Evaluation of clinical characteristics, bacteriology and hearing in paediatric patients with and without chronic suppurative otitis media (CSOM) in Luanda, Angola.

Predictive Value of Cerebrospinal Fluid Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Concentrations in Childhood Bacterial Meningitis

Background: Increased concentrations of matrix metalloproteinases (MMP) in cerebrospinal fluid are part of the host response in bacterial meningitis (BM). We investigated whether the concentrations of MMP-9 and the tissue inhibitor of metalloproteinase (TIMP)-1 predict the outcome in childhood BM. Methods: Cerebrospinal fluid MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were quantified by an enzyme-linked immunosorbent assay from 264 and 335 patients, respectively; 43 children without BM served as controls. The results were compared with previously known independent predictors of death and sequelae. Results: Higher MMP-9 and TIMP-1 values distinguished the controls from the BM patients (P < 0.0001). A MMP-9 concentration >940 ng/mL proved an independent predictor of death [adjusted odds ratio: 4.03; 95% confidence interval (CI): 2.09−7.77; P < 0.0001]. If the patient additionally presented with a Glasgow Coma Score below 9, the odds increased to 13.21 (95% CI: 5.44−32.08; P < 0.0001). TIMP-1 levels correlated with the severity of sequelae (&rgr;: 0.30; P < 0.0001), but not with death. Its concentration above 390 ng/mL increased the likelihood of sequelae 3.43-fold (95% CI: 1·73−6·79; P = 0.0004), and up to 31.18-fold (95% CI: 4.05−239.8; P = 0.0009) if the patient also presented a Glasgow Coma Score < 12. Conclusions: Elevated cerebrospinal fluid MMP-9 and TIMP-1 values predict 2 important outcomes in childhood BM. Combined with a clinical evaluation, quantification of these indices augments the chances to identify the patients in greatest need of better treatment modalities.

Prognostic accuracy of five simple scales in childhood bacterial meningitis.

Abstract 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.AbstractBackground: 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...

Factors Affecting Time to Death From Start of Treatment Among Children Succumbing to Bacterial Meningitis

Background: Many risks of death in childhood bacterial meningitis are well-identified, but factors influencing survival time have received less attention. Better understanding of this issue could help explain why adjuvant medications have performed unevenly in different trials. Methods: In a post hoc analysis of prospectively collected data from a large bacterial meningitis treatment trial in Luanda, Angola, we compared time to death after initiation of antimicrobial treatment among 206 children with etiology and other patient characteristics. The risks of dying very quickly (0–4 hours), quickly (4–8 hours) or after longer periods were analyzed by logistic regression. Results: Median time to death was 18.5 hours, half the time in Streptococcus pneumoniae (11.8 hours) compared with Haemophilus influenzae (26.8 hours) meningitis. Of all deaths caused by pneumococcal or H.influenzae meningitis, 42% versus 16%, respectively, occurred within the first 8 hours. In addition, patients who succumbed within 8 hours, unlike those dying later, had a short disease history, shock, hypoglycemia and poor cerebrospinal fluid white cell response. Conclusions: Time to death in Angola is so short that hardly anything, except perhaps modern intensive care, is likely to improve outcome in a patient with meningitis, especially the pneumococcal disease.

Hearing impairment after childhood bacterial meningitis dependent on etiology in Luanda, Angola

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 loss in Angolan children with sickle‐cell disease

Hearing loss and pneumococcal infections occur in children with sickle‐cell disease (SCD). We assessed the prevalence of hearing loss and otological findings, especially otitis media, among children with SCD in Luanda, Angola.