The epidemiology of febrile illness in sub-Saharan Africa: implications for diagnosis and management.

BACKGROUND: Fever is among the most common symptoms of people living in Africa, and clinicians are challenged by the similar clinical features of a wide spectrum of potential aetiologies. AIM: To summarize recent studies of fever aetiology in sub-Saharan Africa focusing on causes other than malaria. SOURCES: A narrative literature review by searching the MEDLINE database, and recent conference abstracts. CONTENT: Studies of multiple potential causes of fever are scarce, and for many participants the infecting organism remains unidentified, or multiple co-infecting microorganisms are identified, and establishing causation is challenging. Among ambulatory patients, self-limiting arboviral infections and viral upper respiratory infections are common, occurring in up to 60% of children attending health centres. Among hospitalized patients there is a high prevalence of potentially fatal infections requiring specific treatment. Bacterial bloodstream infection and bacterial zoonoses are major causes of fever. In recent years, the prevalence of antimicrobial resistance among bacterial isolates has increased, notably with spread of extended spectrum ß-lactamase-producing Enterobacteriaceae and fluoroquinolone-resistant Salmonella enterica. Among those with human immunodeficiency virus (HIV) infection, Mycobacterium tuberculosis bacteraemia has been confirmed in up to 34.8% of patients with sepsis, and fungal infections such as cryptococcosis and histoplasmosis remain important. IMPLICATIONS: Understanding the local epidemiology of fever aetiology, and the use of diagnostics including malaria and HIV rapid-diagnostic tests, guides healthcare workers in the management of patients with fever. Current challenges for clinicians include assessing which ambulatory patients require antibacterial drugs, and identifying hospitalized patients infected with organisms that are not susceptible to empiric antibacterial regimens.

Serotype-specific pneumococcal disease may be influenced by mannose-binding lectin deficiency.

Previous studies of the association between the mannose-binding lectin pathway deficiencies and invasive pneumococcal disease are inconclusive. Invasiveness of Streptococcus pneumoniae is dependent on serotype. We aimed to determine the association between invasive pneumococcal disease and MBL2 and MASP2 genetic variants, regarding serotype distribution. A hospital-based case-control study was conducted in children admitted to hospital in rural Mozambique in June 2002-November 2003. The study included children admitted to hospital with invasive pneumococcal disease, in whom S. pneumoniae was isolated from blood and subsequently serotyped. Sequence-based typing analysis of amplicons covering the polymorphic regions of MASP2 (exon 3) and MBL2 (promoter and exon 1) was performed. An overall high frequency of MBL2 genotypes associated with low serum levels of MBL (43%) was found. Carriers of MBL-deficient genotypes were associated with invasive pneumococcal disease produced by low-invasive serotypes (OR 5.55, 95% CI 1.4-21.9; p = 0.01). Our data suggest that susceptibility to pneumococcal disease among MBL-deficient patients may be influenced by serotype invasiveness. Type-specific capsular serotype of S. pneumoniae would need to be taken into account in further genetic association studies of invasive pneumococcal disease.

Genetic and structural analysis of MBL2 and MASP2 polymorphisms in south-eastern African children.

The mannose-binding lectin (MBL) pathway of complement system is activated when carbohydrate-bound MBL forms complexes with different serine proteases (MASP-1, MASP-2 and MASP-3), among which MASP-2 has a predominant functional role. Polymorphisms impairing the quantity and/or the functional activity of proteins encoded by the MBL2 and MASP2 genes have been reported in all human populations showing different allelic frequency and distribution. This likely reflects the existence of environmental influences on MBL2 and MASP2 genetic evolution. Herewith, we conducted a study in a children population from Mozambique to analyse the genetic diversity of sequences corresponding to the promoter and collagen-like region (exon 1) of MBL2 and to the CUB-1 and epidermal growth factor domain (exon 3) of MASP2, which are critical regions for the formation of functional MBL/MASP-2 complexes. Our results show a high prevalence of MBL-intermediate/low genotypes (43.5%); the description of new alleles and a high level of sequence polymorphism at both MBL2 and MASP2, with no statistical evidence for positive or balancing selection. Furthermore, Biacore analyses performed to explore the functional relevance of the MASP2 variants found [T73M (2.9%), R84Q (12.7%) and P111L (25.4%)] were compared with those of two previously reported variants (R103C and D105G). None of the analysed MASP2 variants, with the exception of D105G, interfered with interactions with either MBL or ficolins (H and L).

Surveillance of acute bacterial meningitis among children admitted to a district hospital in rural Mozambique.

BACKGROUND: Acute bacterial meningitis (ABM) remains an important cause of mortality among African children. Epidemiologic data with regard to ABM infection are necessary for prioritizing public health interventions. METHODS: We strengthened hospital-based surveillance of ABM among children admitted to Manhiça District Hospital (Maputo, Mozambique). Cerebrospinal fluid (CSF) samples were collected from children admitted to the hospital who met clinical criteria of ABM. Laboratory determinations were performed. Clinical information and outcome of cases were recorded. RESULTS: During the first 12 months of surveillance, which began in January 2006, CSF samples were collected from 642 children <15 years of age with suspected meningitis (18% of all pediatric patients admitted to the hospital during that time). ABM was confirmed in 43 (7%) of the 642 cases. Haemophilus influenzae type b (Hib) (14 cases), pneumococcus (9 cases), and meningococcus (7 cases) represented approximately 70% of confirmed cases. Four of the 9 pneumococci were serotypes covered by the 7-valent pneumococcal conjugate vaccine. The case fatality rate among patients with ABM was 24% (8 of 33 with known outcome); an additional 8 patients left the hospital before discharge. The incidence of ABM was 85 per 100,000 population, which peaked at 2-12 months of age at 1078 cases per 100,000 population. All 9 pneumococci isolates were susceptible to chloramphenicol, and 8 were susceptible to penicillin (the additional 1 had intermediate resistance). For the 10 Hib isolates tested, only 1 was susceptible to chloramphenicol, and 5 were susceptible to ampicillin. CONCLUSION: These data reinforce the importance of ABM as a cause of hospital admission and death in rural sub-Saharan Africa. Most observed ABM cases could have been prevented by current pneumococcal and Hib conjugate vaccines.

Mother-to-child transmission of HIV-1: association with malaria prevention, anaemia and placental malaria.

OBJECTIVES: Malaria infection may impact on mother-to-child transmission (MTCT) of HIV-1. Prevention of malaria in pregnancy could thus potentially affect MTCT of HIV. We studied the impact of intermittent preventive treatment during pregnancy (IPTp) on HIV-1 MTCT in southern Mozambique. METHODS: A total of 207 HIV-positive Mozambican pregnant women were enrolled in the study as part of a randomized placebo-controlled trial of two-dose sulfadoxine-pyrimethamine (SP) IPTp in women receiving single-dose nevirapine to prevent MTCT of HIV. HIV RNA viral load, maternal anaemia and peripheral and placental malaria were assessed at delivery. Infant HIV status was determined by DNA polymerase chain reaction (PCR) at 1 month of age. RESULTS: There were 19 transmissions of HIV in 153 mother-infant pairs. IPTp with SP did not have a significant impact on MTCT (11.8% in the SP group vs. 13.2% in the placebo group; P=0.784) or on maternal HIV RNA viral load [16 312 (interquartile range {IQR} 4076-69 296) HIV-1 RNA copies/mL in the SP group vs. 18 274 (IQR 5471-74 104) copies/mL in the placebo group; P=0.715]. In multivariate analysis, maternal HIV RNA viral load [adjusted odds ratio (AOR) 19.9; 95% confidence interval (CI) 2.3-172; P=0.006] and anaemia (haematocrit <33%; AOR 7.5; 95% CI 1.7-32.4; P=0.007) were independent risk factors for MTCT. Placental malaria was associated with a decrease in MTCT (AOR 0.23; 95% CI 0.06-0.89; P=0.034). CONCLUSIONS: IPTp with SP was not associated with a significant impact on MTCT of HIV. Maternal anaemia was an independent risk factor for MTCT.

Acute bacterial meningitis among children, in Manhiça, a rural area in Southern Mozambique.

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.

Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

BACKGROUND: The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. OBJECTIVE: We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. METHOD: Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). RESULTS: The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.

Invasive pneumococcal disease in children<5 years of age in rural Mozambique.

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.