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Abstract: Introduction: Acute bacterial meningitis (ABM) is one of the most severe diseases in Sub-Saharan Africa. Although data for the continent is very limited, more than one million cases are estimated per year, with mortality and life-long sequelae occurring in 50% of these cases. Methods: As part of the clinical management of children admitted to the Manhiça District Hospital, information on cases of ABM was recorded. We analysed data from June 1998 to November 2003. Results: During the study period, 475 cerebrospinal-fluid (CSF) samples were collected from 20,173 children <15 years of age admitted to hospital. Culture results confirmed 71 (15%) cases of ABM. The most prevalent bacterial aetiologies were Streptotoccus pneumoniae (pneumococcus, n =31), Haemophilus influenzae (n =13) and Neisseria meningitis (n =8). Other important bacteria were Streptococcus sp. (n =7), Salmonella sp. (n =4) and Staphylococcus aureus (n =3). Crude incidence rates of ABM and pneumococcal meningitis were 20/100,000 and 10/100,000 children-year-at-risk, respectively. Incidences were more than three times higher in the <1 year age group. Overall case fatality rate was 36%, and was highest for H. influenzae and pneumococcal meningitis (55% and 45%, respectively, p =0.044). Pneumococcal susceptibility was 81% for oxacillin and 93% for chloramphenicol. For H. influenzae isolates, susceptibility was 54% for ampicillin and 62% for chloramphenicol. Conclusions: S. pneumoniae and H. influenzae are the main aetiologies responsible for the high burden of morbidity and mortality associated with ABM in rural Mozambique. These findings are important to evaluate treatment guidelines and potential impact of control measures. [Copyright &y& Elsevier]

Antibiotic resistance in Africa is increasing but insufficiently recognized as a public health problem. However, there are scarce data for antimicrobial resistance trends among bloodstream isolates in sub-Saharan Africa. Antimicrobial drug resistance trends among bacteria isolated from blood of children < 15 years of age admitted to the Manhiça District Hospital in Mozambique during May 2001-April 2006 were monitored by disk diffusion. We documented a linear trend of increasing resistance throughout the study period to chloramphenicol among isolates of Non-typhi Salmonella (P < 0.001), Escherichia coli (P = 0.002), Staphylococcus aureus (P < 0.001), and Haemophilus influenzae (P < 0.001). Increasing resistance to ampicillin was also observed for H. influenzae isolates (P < 0.001). We report trends of increasing resistance among the most frequent etiologies of bacteremia to the most commonly used antibiotics for empirical therapy in this community. Quinolones and third-generation cephalosporines may be needed in the short term to manage community-acquired infections.

Objective: To describe the epidemiology and clinical presentation of invasive non-typhoidal Salmonella (NTS) in Mozambique., Methodology: We analysed the epidemiology, clinical presentation and serotype distribution of invasive NTS among Mozambican children admitted to the Manhiça District Hospital between May 2001 and April 2006., Results: A total of 401 NTS cases were analysed; the median age was 16 months [interquartile range (IQR): 10-24]. Fever, cough and increased respiratory rate were the most common symptoms reported, while diarrhoea was present in only 29%. In the univariate analysis, invasive NTS was associated with age, fever, diarrhoea, increased respiratory rate, splenomegaly, hepatomegaly, severe malnutrition, and severe anaemia. Young age, severe malnutrition, diarrhoea and pneumonia were independent risk factors of death. S. typhimurium (66%), and S. enteritidis (25%) were the most frequent serotypes, with incidence rates of 240.4 and 108.6 per 100,000 child years among infants for S. typhimurium and S. enteritidis, respectively; and no significant differences were found regarding their clinical presentation. Resistance to ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole was high for both S. typhimurium and S. enteritidis., Conclusions: Clinical presentation of invasive NTS was non-specific and similar to that of other infections, with some factors being associated with NTS. Antibiotic resistance was very common to currently recommended and available antibiotics for suspected sepsis.

Objective: To measure the disease burden and epidemiological characteristics of invasive Haemophilus influenzae in rural Mozambican children., Methods: As part of the clinical management of children admitted to Manhiça District Hospital, blood and cerebrospinal fluid samples were collected between May 2001 and April 2005 for children aged <5 years. The level of antibiotic resistance of the isolates was analysed., Results: During the surveillance period, there were 106 episodes of invasive H. influenzae disease. The estimated minimum incidence rate of invasive disease among children <5 years of age was 125/100,000 per child-year-at-risk. Fifty-six (59/106) per cent of cases were infants aged 3 to <12 months. Confirmed meningitis explained 16% of the episodes (n = 17) but was probably underestimated, as meningitis surveillance was not well implemented in the setting during the study. The case-fatality-rate was 21%, being highest among children with meningitis (odds ratio = 4.38, P = 0.011). Resistance to the antibiotics most commonly used in Mozambique was high--chloramphenicol 39%, ampicillin 35% and cotrimoxazol 74%-- and had increased over the years (P < 0.001 for chloramphenicol)., Conclusion: Invasive H. influenzae disease is of considerable public health importance in Mozambique; implementing H. influenzae type b vaccination in sub-Saharan Africa has the potential to increase child survival.

RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on the Plasmodium falciparum circumsporozoite surface antigen and is currently the most advanced malaria vaccine candidate in development. A proof of concept phase IIb trial of the RTS,S/AS02A in Mozambican children aged 1-4 years determined a vaccine efficacy against risk of clinical malaria of 35.3% (95% CI 21.6-46.6; p<0.0001) and against severe malaria of 48.6% (95% CI 12.3-71.0; p=0.02). We evaluated the safety of the RTS,S/AS02A vaccine. 2022 children that received at least one vaccine dose of RTS,S/AS02A or control vaccines were included in the intention to treat safety analysis. Vaccine safety was evaluated using active and passive follow-up. Participants were observed for at least 1h after each dose. Trained field workers visited children at home daily for the next 3 days to record solicited and unsolicited local and general symptoms. Investigators followed-up participants with severe adverse events until month 21. Overall, we recorded 1712 unsolicited adverse events after vaccination, 53% in the intervention and 47% in the control group. Most unsolicited adverse events reported with RTS,S/AS02A were self-limited, and participants recovered without sequelae. Local reactogenicity increased with the number of doses. The proportion of children experiencing serious adverse events was lower in the RTS,S/AS02A recipients compared to the control group (Engerix-Btrade mark or Prevnartrade mark and Hiberixtrade mark). Overall, these results indicate that the RTS,S/AS02A vaccine has a good safety profile and well tolerated when given in three doses to semi-immune children living in malaria-endemic areas.

Rectal swabs were collected from 1354 children <5 years of age with diarrhea attending Manhiça District Hospital and from 227 healthy community controls. Shigellosis incidence was high among children aged 12-47 months (488.4/10(5) child-years at risk). Fever and dysentery were prominent clinical findings. Shigella was more frequently isolated from cases than controls (6.7% versus 0.4%, P = 0.004), and from dysentery than nondysenteric diarrhea (24.1% versus 3.5%, P < 0.001). Shigella flexneri 2a, S. sonnei, and S. flexneri 6, were the most prevalent serotypes.

Objectives: To describe the antimicrobial susceptibility profile of isolated Vibrio cholerae O1 serotype Ogawa recovered from patients admitted to the cholera facility in the Manhiça District Hospital (MDH), Mozambique., Methods: Rectal swabs were collected from patients with complaints symptomatic of cholera admitted to the MDH cholera facility. Samples were processed for V. cholerae isolation at the Centro de Investigação em Saúde da Manhiça (CISM) and identified by biochemical reaction. Serotypes were determined by slide-agglutination antisera. Susceptibilities were determined by disc diffusion., Results: Seventy-seven isolates were examined for their resistance profile. High incidences of antimicrobial resistance were found for chloramphenicol (57.9%), co-trimoxazole (96.6%) and tetracycline (97.3%). Quinolone resistance remained low (4.2%)., Conclusions: Although V. cholerae infections in Africa do not usually require antimicrobial treatment, strains in rural Mozambique show high incidences of resistance to readily available drugs. When appropriate, quinolones or third-generation cephalosporins can be used as treatment options.

Introduction: The reference intervals of haematological and biochemical indices currently used in Africa are derived from data collected from populations living in industrialized countries. Few studies have been performed in Africa questioning the validity of these values when applied to local African populations., Objective: To provide reference intervals of haematological [haemoglobin (Hb), white blood cells (WBC), haematocrit (Htc) and platelets] and biochemical indices (ALT, creatinine and bilirubin) for children aged 1-4 from a rural area of southern Mozambique., Methods: Reference intervals were developed using the 2.5 and 97.5 centiles. Partition tests were performed to evaluate age and gender differences. Quantile regression models were estimated for those variables in which age partition was recommended. Deviances from linearity in the estimated models were evaluated using fractional polynomials of first or second degree. Agreement to classify normality, using the estimated reference intervals or values in use in a western paediatric hospital, was made using the kappa statistic., Results: Reference intervals for Hb, WBC, Htc, platelets, ALT and creatinine show significant differences by age. Gender differences were observed for creatinine values, while for bilirubin there were no significant differences for age or gender. Estimated Hb and Htc reference intervals in African children were lower than the accepted western ones, while ALT values were higher in the former. Agreement between normal classification, using the estimated intervals or the western values, was from slight to fair., Conclusions: Reference intervals of haematological and biochemical indices based on results from western individuals of the same age are not in agreement with the estimated values for African children. These observed values should not be used as a rule to define normality, but are the ones usually found in this population where anaemia, malaria and high mortality rates are also common.

Objectives: To estimate the incidence and epidemiological characteristics of invasive pneumococcal disease (IPD) in children<5 years of age living in a rural area of southern Mozambique., Methods: As part of the clinical management of children admitted to Manhiça District Hospital, prospective surveillance for invasive bacterial disease was conducted from June 2001 to May 2003. The level of antibiotic resistance of the isolates was also analysed., Results: Pneumococcus was the most commonly isolated bacterium, accounting for 212 episodes. The estimated crude incidence rate of IPD in the study area among children<5 years of age was 416/100,000 per child-year at risk. The youngest age group (<3 months) had the highest incidence (779/100,000). Cases were detected during both rainy and dry seasons. The most common clinical diagnosis was pneumonia, made in 146/212 (69%) of the episodes of IPD. The overall case fatality rate was 10%, being highest among children with pneumococcal meningitis (5/9=56%). Pneumococcal isolates were highly susceptible to penicillin (86% susceptible and 14% with intermediate resistance) and chloramphenicol (98% susceptible). In contrast, up to 37% of the isolates tested were non-susceptible to cotrimoxazole., Conclusions: Incidence rates of IPD and associated mortality shown in this study highlight the need for pneumococcal vaccines in rural Africa, which must be effective in infants and young children.

Introduction: Anaemia is the most frequent haematological disorder in childhood. The notion that defines naemia does not change throughout life, although parameters used for its evaluation show significant variations during childhood. Haematocrit (Hct) (%) is usually defined as three times the value of haemoglobin (Hgb) (g/dl), while the clinical definition of anaemia is related to either an abnormal Hct or Hgb value., Objective: To evaluate the agreement between Hgb and Hct values in the definition of anaemia, the relationship between these two parameters and their age-dependence., Methods: The Hct and Hgb paired values from children aged 2-18 months from Ifakara (Tanzania) and children aged 1-4 years from Manhiça (Mozambique) were analysed. Haematological determinations of the Manhiça samples were done using a KX-21N cell counter (Kobe, Japan) and Ifakara samples were analysed in a semiautomatic cell counter (Sysmex F800 microcell counter, TOA Medical Electronics, Kobe, Japan). The kappa-statistic was used to calculate the agreement between anaemia definitions in each group. Crude and multivariate relationship between Hct and Hgb levels were analysed by linear regression model estimation. The age-dependence of the crude ratio (Hct/Hgb) was analysed using linear regression models and fractional polynomials., Results: The prevalences of mild and moderate anaemia as defined by Hgb levels in the Manhiça group were 61% and 6%, respectively, and 41% and 2% by Hct. In the Ifakara group these were 74% and 10%, respectively, by Hgb and 42% and 3% by Hct, respectively. Agreement between mild and moderate anaemia definitions made up from Hgb or from Hct levels were from fair to moderate. Hct levels decreased with age for high Hgb levels, whereas they increased for low Hgb levels. The classification of cases is improved when higher age-related cut-off values for Hct are used. The crude relationship between Hct and Hgb levels was significantly different from 3, and this was modified by age. The evaluation of the age-dependence ratio (Hct/Hgb) showed a non-linear relationship with an asymptotic trend to 3., Conclusions: Measurement of haematocrit count is easy and can be performed in most rural health care centres. However, the corresponding Hgb levels cannot be derived with an acceptable accuracy using the value 3 as a conversion factor. Furthermore, the commonly assumed 'equivalent' cut-off points for anaemia definitions need to be re-evaluated.

Background: RTS,S/AS02A is a pre-erythrocytic stage malaria vaccine that provides partial protection against infection in malaria-naive adult volunteers and hyperimmune adults. A previous report showed that this vaccine reduced risk of clinical malaria, delayed time to new infection, and reduced episodes of severe malaria over 6 months in African children. An important remaining issue is the durability of protection against clinical disease in these children., Methods: We did a randomised, controlled, phase IIb trial of RTS,S/AS02A given at 0, 1, and 2 months in 2022 Mozambican children aged 1-4 years. We previously determined vaccine efficacy (VE) against clinical malaria in a double-blind phase that included study months 2.5-8.5 (VE(2.5-8.5)). We now report VE in a single-blind phase up to month 21 (VE(8.5-21)). The primary endpoint was time to first or only clinical episode of Plasmodium falciparum malaria (axillary temperature 37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) detected through a passive case detection system. We also determined VE for other case definitions and for episodes of severe malaria. This study is registered with the ClinicalTrials.gov identifier NCT00197041., Findings: During the single-blind phase, VE(8.5-21) was 28.9% (95% CI 8.4-44.8; p=0.008). At month 21, prevalence of P falciparum infection was 29% lower in the RTS,S/AS02A group than in the control (p=0.017). Considering the entire study period, VE(2.5-21) was 35.3% (95% CI 21.6-46.6; p<0.0001) and VE(2.5-21) for severe malaria was 48.6% (95% CI 12.3-71.0; p=0.02)., Interpretation: These results show that RTS,S/AS02A confers partial protection in African children aged 1-4 years living in rural endemic areas against a range of clinical disease caused by P falciparum for at least 18 months, and confirm the potential of malaria vaccines to become credible control tools for public-health use.