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).

Hearing impairment in Angolan children with acute bacterial meningitis with and without otitis media.

AIM: Bacterial meningitis (BM) is a common cause of hearing loss in childhood. Our aim was to investigate bacterial aetiology, hearing impairment and outcome in childhood BM with vs. without otitis media (OM) in Angola. METHODS: Hearing was tested by auditory brainstem response in 391 (76%) children with confirmed BM. The bacteria identified from the ear discharge were compared to those from cerebrospinal fluid (CSF). The hearing findings were compared among children with vs. without OM on days 1 and 7 of hospitalization, and at follow-ups of 1, 3 and 6 month(s). RESULTS: No correlation was found in bacteriology between the ear discharge and CSF. On day 7 in hospital, hearing impairment (>40 dB) was common, regardless of whether concomitant OM or not (in 27% vs. 30%, respectively). Any hearing deficit on day 7 was associated with a higher risk of complicated or fatal clinical course (OR 2.76, CI95% 1.43-5.29, p = 0.002). CONCLUSION: No significant difference prevailed in hearing thresholds between children with or without OM in hospital on day 7 or at later follow-ups. Any hearing impairment during hospital stay associated with a higher risk for complicated clinical course or death.

Otitis Media-associated Bacterial Meningitis in Children in a Low-income Country.

BACKGROUND: Otitis media (OM) is a common childhood infection that may result in bacterial meningitis (BM). However, OM-associated BM remains poorly characterized. We aimed to study the occurrence, clinical presentation and outcome of this type of childhood BM in Luanda, Angola. METHODS: Five hundred twelve children from our previous clinical BM trial, with the ear meticulously examined, were analyzed whether they had or not OM, and according to their age, ≤12 month old and >12 month old. Prospectively collected clinical data, laboratory test results and outcome for these groups were assessed. RESULTS: Sixty-two children (12%) had OM-associated BM, of whom 39 had otorrhea. Ear discharge was more common in older children (median age 45 months old vs. 12 months old; P < 0.001). Children with OM often showed an additional infectious focus (n = 20, 32% vs. n = 82, 18%; P = 0.016), were dehydrated (n = 16, 26% vs. n = 66, 15%; P = 0.04), and showed higher odds of complicated clinical course or death (odds ratios 2.27, 95% CI: 1.004-5.15, P = 0.049) compared with children without OM. The >12-month-old children with OM often arrived in poor clinical condition with coma and/or ptosis. Otorrhea was associated with HIV positivity. Infants with otorrhea frequently lived under poor socioeconomic conditions. CONCLUSIONS: Children with OM-associated BM were prone to many problems, such as being especially ill at presentation, undergoing a difficult clinical course and showing a higher risk of complicated or fatal outcome. HIV infection and malnutrition were common in children with otorrhea, which was also associated with low socioeconomic status.

Etiology of Childhood Otorrhea in Luanda, Angola, and a Review of Otitis Media in African Children.

BACKGROUND: In resource-poor settings, otorrhea causes a significant burden of disease in children. Etiologic studies and structured data on otorrhea and chronic otitis media among African children remain scarce. METHODS: Here, we reviewed 678 bacteriologically analyzed otorrhea samples from Luanda Children's Hospital from children ≤15 years of age between 2008 and 2015. We then compared these with data from other studies among African children through a literature review of 20 articles published over 2 decades. RESULTS: Overall, 32 different bacteria were identified among 542 isolates from 654 children in Luanda. Gram-negative bacteria constituted the majority of all isolates (85%), whereby Pseudomonas spp. was the most common (n = 158; 29%), followed by Proteus spp. (n = 134; 25%). Among Staphylococcus aureus (n = 54; 10%), 69% of tested isolates were Methicillin-resistant S. aureus, and among Enterobacteriaceae, 14% were expanded-spectrum ß-lactamase isolates. Resistance to quinolones was rare. Furthermore, in a review of the literature, we found a high occurrence of otorrhea and chronic suppurative otitis media in children as well as possible gaps in existing knowledge. CONCLUSIONS: In Angola, Gram-negative rods emerged as common causative agents of otorrhea in children followed by S. aureus. The magnitude of chronic otorrhea in Africa represents a cause for public health concern.

Prognostic Value and Changes of Auditory Brain Stem Response in Children With Bacterial Meningitis in Luanda, Angola.

OBJECTIVE: To assess the role of single and repeated auditory brain stem response (ABR) in predicting mortality and severe neurological injury among children having bacterial meningitis (BM) in Luanda, Angola. METHODS: The morphology of ABR traces of 221 children (aged 2 months to 12 years) from admission day was analyzed and compared with age-matched normative data. Absence and delay of traces were compared with mortality and mortality or severe neurological injury in subgroup analyses. Outcome was also evaluated with repeated ABR of 166 children based on presence or absence of responses at 80 dB nHL (normal hearing level) stimulation level. RESULTS: Individually, the absence of typical ABR waveform did not signify poor outcome. At the group level, latencies and interpeak latencies (IPLs) were significantly prolonged among patients with BM in comparison with controls, and the prolongation correlated with higher mortality or severe neurological sequelae. CONCLUSIONS: We confirmed the effect of BM on neural conduction time in auditory pathway. However, ABR in similar settings seems not useful for individual prognostication, although at the group level, delayed latencies, IPLs, or both associated with poorer outcome.

Predicting Outcome of Childhood Bacterial Meningitis With a Single Measurement of C-Reactive Protein.

INTRODUCTION: C-reactive protein (CRP), a marker of inflammation, shows high serum levels in invasive bacterial infections. We investigated the potential of a single CRP measurement at different phases of acute childhood bacterial meningitis to predict outcomes. METHODS: Using whole-blood finger-prick samples with no centrifugation, CRP was measured quantitatively on arrival and on day 3 or 4 in children participating in 2 prospective, randomized, double-blind treatment studies conducted in Latin America or Angola. The results were compared with patient outcomes. RESULTS: Although initial CRP values from 669 children gave useful prognostic information, the 3rd or 4th day measurements taken from 275 children associated significantly with seizures, slow recovery and low scores on the Glasgow Outcome Scale, with odds ratios for CRP values above the median (62 mg/L) ranging from 2 to 6, 2 to 5, and 3 to 5 (Latin America-Angola), respectively. Hearing impairment, although not full deafness, was 3 to 7 times more likely if CRP was above the median soon after hospitalization. CONCLUSIONS: Especially in resource-poor settings, clinicians have few simple-enough tools to identify the child with meningitis who requires maximum attention. CRP is a worthy addition.

A Cost-Effectiveness Analysis of a Pilot Neonatal Screening Program for Sickle Cell Anemia in the Republic of Angola.

OBJECTIVE: To assess the cost-effectiveness of a pilot newborn screening (NBS) and treatment program for sickle cell anemia (SCA) in Luanda, Angola. STUDY DESIGN: In July 2011, a pilot NBS and treatment program was implemented in Luanda, Angola. Infants identified with SCA were enrolled in a specialized SCA clinic in which they received preventive care and sickle cell education. In this analysis, the World Health Organization (WHO) and generalized cost-effectiveness analysis methods were used to estimate gross intervention costs of the NBS and treatment program. To determine healthy life-years (HLYs) gained by screening and treatment, we assumed NBS reduced mortality to that of the Angolan population during the first 5 years based upon WHO and Global Burden of Diseases Study 2010 estimates, but provided no significant survival benefit for children who survive through age 5 years. A secondary sensitivity analysis with more conservative estimates of mortality benefits also was performed. The costs of downstream medical costs, including acute care, were not included. RESULTS: Based upon the costs of screening 36,453 infants and treating the 236 infants with SCA followed after NBS in the pilot project, NBS and treatment program is projected to result in the gain of 452-1105 HLYs, depending upon the discounting rate and survival assumptions used. The corresponding estimated cost per HLY gained is $1380-$3565, less than the gross domestic product per capita in Angola. CONCLUSIONS: These data demonstrate that NBS and treatment for SCA appear to be highly cost-effective across all scenarios for Angola by the WHO criteria.

C-reactive protein in children with malaria in Luanda, Angola: a prospective study.

BACKGROUND: C-reactive protein (CRP) is an acute phase reactant of which little is known in malaria, especially in central Africa. METHODS: In this prospective study CRP was measured in children with suspected malaria. RESULTS: Of 346 children, 234 had positive and 112 negative malaria microscopy. Their median CRP was 140 mg/L (IQR 88) vs 69 mg/L (IQR 129; p<0.001) respectively. CRP was positively correlated with parasitemia (p<0.001), and length of hospital stay (p=0.01), and negatively with thrombocyte count (p=0.01), and hemoglobin level (p=0.01). CONCLUSION: C-reactive protein increases in malaria and correlates with parasitemia and some manifestations of complicated disease.

Ataxia and Its Association with Hearing Impairment in Childhood Bacterial Meningitis.

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.

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.

Impact of a training course on the quality of malaria diagnosis by microscopy in Angola.

BACKGROUND: In Angola, malaria is an endemic disease having a major impact on the economy. The WHO recommends testing for all suspected malaria cases, to avoid the presumptive treatment of this disease. In malaria endemic regions laboratory technicians must be very comfortable with microscopy, the golden standard for malaria diagnosis, to avoid the incorrect diagnosis. The improper use of medication promotes drug resistance and undesirable side effects. The present study aims to assess the impact of a three-day refresher course on the knowledge of technicians, quality of blood smears preparation and accuracy of microscopy malaria diagnosis, using qPCR as reference method. METHODS: This study was implemented in laboratories from three hospitals in different provinces of Angola: Bengo, Benguela and Luanda. In each laboratory samples were collected before and after the training course (slide with thin and thick blood smears, a dried blood spot and a form). The impact of the intervention was evaluated through a written test, the quality of slide preparation and the performance of microscopy. RESULTS: It was found a significant increase on the written test median score, from 52.5% to 65.0%. A total of 973 slides were analysed to evaluate the quality of thick and thin blood smears. Considering all laboratories there was a significant increase in quality of thick and thin blood smears. To determine the performance of microscopy using qPCR as the reference method we used 1,028 samples. Benguela presented the highest values for specificity, 92.9% and 98.8% pre and post-course, respectively and for sensitivity the best pre-course was Benguela (75.9%) and post-course Luanda (75.0%). However, no significant increase in sensitivity and specificity after the training course was registered in any laboratory analysed. DISCUSSION: The findings of this study support the need of continuous refresher training for microscopists and other laboratory staff. The laboratories should have a quality control programme to supervise the diagnosis and also to assess the periodicity of new training. However, other variables needed to be considered to have a correct malaria diagnosis, such as adequate equipment and reagents for staining and visualization, good working conditions, motivated and qualified personnel.

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.

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.

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 (ρ: 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.

Human rhino- and enteroviruses in children with respiratory symptoms in Luanda, Angola.

OBJECTIVES: The role of human rhinoviruses (HRV) and human enteroviruses (HEV) in common colds, as well as their seasonality, remains largely unknown in tropical environments. The study aimed to define the frequency and clinical features of HRV and HEV in children with respiratory symptoms in tropical Africa during autumn and winter. METHODS: Clinical data and PCR assays of nasopharyngeal swabs (NPS) were collected from 67 (66%) children with and 35 (34%) children without chronic illnesses who were attending different outpatient clinics at a paediatric tertiary-care hospital in Luanda, Angola. RESULTS: Thirty-six (35%) children had HIV infection, and 27 (26%) were malnourished. Thirty-seven (36%) out of 102 NPS specimens were virus-positive: 34 (33%) for HRV and 10 (10%) for HEV. Seven (7%) had co-infection. The highest HRV-positivity rate (47%) occurred in July (P = 0·02), a mid-winter month with high relative humidity but no precipitation. Virus positivity was associated with younger age (median 36 vs 52 months, P = 0·02) but not with specific symptoms or findings. CONCLUSIONS: HRVs play a major role in young children's respiratory infections in urban tropical Angola during autumn and winter. A better understanding is required of the seasonality and clinical outcomes of these viruses in children living in resource-poor tropical countries.

A prospective newborn screening and treatment program for sickle cell anemia in Luanda, Angola.

Over 300,000 infants are born annually with sickle cell anemia (SCA) in sub-Saharan Africa, and >50% die young from infection or anemia, usually without diagnosis of SCA. Early identification by newborn screening (NBS), followed by simple interventions dramatically reduced the mortality of SCA in the United States, but this strategy is not yet established in Africa. We designed and implemented a proof-of-principle NBS and treatment program for SCA in Angola, with focus on capacity building and local ownership. Dried bloodspots from newborns were collected from five birthing centers. Hemoglobin identification was performed using isoelectric focusing; samples with abnormal hemoglobin patterns were analyzed by capillary electrophoresis. Infants with abnormal FS or FSC patterns were enrolled in a newborn clinic to initiate penicillin prophylaxis and receive education, pneumococcal immunization, and insecticide-treated bed nets. A total of 36,453 infants were screened with 77.31% FA, 21.03% FAS, 1.51% FS, and 0.019% FSC. A majority (54.3%) of affected infants were successfully contacted and brought to clinical care. Compliance in the newborn clinic was excellent (96.6%). Calculated first-year mortality rate for babies with SCA compares favorably to the national infant mortality rate (6.8 vs. 9.8%). The SCA burden is extremely high in Angola, but NBS is feasible. Capacity building and training provide local healthcare workers with skills needed for a functional screening program and clinic. Contact and retrieval of all affected SCA infants remains a challenge, but families are compliant with clinic appointments and treatment. Early mortality data suggest screening and early preventive care saves lives.

Hearing loss in Angolan children with sickle-cell disease.

BACKGROUND: 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. METHODS: We performed otorhinolaryngological examination, tympanometry and, at ages over 5 years, pure-tone audiometry, in 61 outpatients of the SCD clinic and 61 healthy controls in the Paediatric Hospital of Luanda. RESULTS: Bilateral hearing loss exceeding 25 dB occurred in nine (36%; median age 7.8 years) SCD children versus three (11%; P = 0.047) control children. The hearing loss in the SCD group was predominantly mild (26-40 dB), involved low- and speech-range frequencies, and was sex independent. Acute otitis media occurred in two (3%) children with SCD versus four (6%; P = 0.68) control children, chronic otitis in zero versus two (3%; P = 0.50), and middle-ear effusion in one versus one (2%; P > 0.99). We found no significant differences in the otological profiles of the study groups. CONCLUSIONS: In sub-Saharan Africa, hearing screening of SCD children is a must at preschool age. The actual prevalence of otitis media and its role in the cause of hearing loss in children with SCD remain subjects for further research.

Molecular epidemiology of group B streptococcal meningitis in children beyond the neonatal period from Angola.

Streptococcus agalactiae is a major pathogen of neonates and immunocompromised adults. Prior studies have demonstrated that, beyond the neonatal period, S. agalactiae rarely causes invasive infections in children. However, during 2004-2005, S. agalactiae was the causative agent of 60 meningitis episodes in children aged 3 months to 12 years from Angola. To identify and study the specific causative genetic lineages of S. agalactiae childhood meningitis, which lack characterization to date, we conducted an extensive molecular analysis of the recovered isolates (n = 21). This constitutes what we believe to be the first molecular study of the population structure of invasive S. agalactiae isolates from Africa. A low genetic diversity was observed among the isolates, where the majority belonged to clonal complex (CC) 17 presenting the capsular subtype III-2 (86 % of cases) and marked by the intron group II GBSi1, which has previously been observed to be associated with neonatal hosts. The predominance of single-locus variants of sequence type (ST) 17 suggested the local diversification of this hypervirulent clone, which displayed novel alleles of the fbsB and sip virulence genes. The absence of the scpB-lmb region in two S. agalactiae isolates with the Ia/ST23 genotype is more typical of cattle than human isolates. Globally, these data provide novel information about the enhanced invasiveness of the CC17 genetic lineage in older children and suggest the local diversification of this clone, which may be related to the future emergence of a novel epidemic clone in Angola.

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. METHODS: Interview, clinical examination, ear-discharge culture, open air pure-tone audiometry and brainstem auditory-evoked potentials of 23 outpatients with CSOM and 23 controls in a paediatric hospital. RESULTS: Of the CSOM vs. control children, 35% vs. 26% had running water, 70% vs. 70% electricity, 64% vs. 0% HIV (p<0.0001) and 36% vs. 0% tuberculosis in history (p=0.002). Ten (43%) children had bilateral CSOM. The major ear-discharge pathogens were Proteus spp. (44%) and Pseudomonas (22%). Hearing impairment of >25 dB was present in 52% of CSOM-affected ears and bilateral hearing loss in 7 (30%) CSOM children vs. zero control child (p=0.009). Only one hearing-impaired child's family had previously detected the handicap. CONCLUSION: CSOM occurred in children with high co-morbidity. Persistent otorrhoea was usually caused by Proteus spp. or Pseudomonas, and often suggestive of either HIV or hearing impairment. In the developing countries, prompt diagnosis and treatment of CSOM would enhance the children's linguistic and academic development.

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.