HTLV-1 and HIV-2 infection are associated with increased mortality in a rural West African community

Background

Survival of people with HIV-2 and HTLV-1 infection is better than that of HIV-1 infected people, but long-term follow-up data are rare. We compared mortality rates of HIV-1, HIV-2, and HTLV-1 infected subjects with those of retrovirus-uninfected people in a rural community in Guinea-Bissau.

Methods

In 1990, 1997 and 2007, adult residents (aged ≥15 years) were interviewed, a blood sample was drawn and retroviral status was determined. An annual census was used to ascertain the vital status of all subjects. Cox regression analysis was used to estimate mortality hazard ratios (HR), comparing retrovirus-infected versus uninfected people.

Results

A total of 5376 subjects were included; 197 with HIV-1, 424 with HIV-2 and 325 with HTLV-1 infection. The median follow-up time was 10.9 years (range 0.0–20.3). The crude mortality rates were 9.6 per 100 person-years of observation (95% confidence interval 7.1-12.9) for HIV-1, 4.1 (3.4–5.0) for HIV-2, 3.6 (2.9–4.6) for HTLV-1, and 1.6 (1.5–1.8) for retrovirus-negative subjects. The HR comparing the mortality rate of infected to that of uninfected subjects varied significantly with age. The adjusted HR for HIV-1 infection varied from 4.0 in the oldest age group (≥60 years) to 12.7 in the youngest (15–29 years). The HR for HIV-2 infection varied from 1.2 (oldest) to 9.1 (youngest), and for HTLV-1 infection from 1.2 (oldest) to 3.8 (youngest).

Conclusions

HTLV-1 infection is associated with significantly increased mortality. The mortality rate of HIV-2 infection, although lower than that of HIV-1 infection, is also increased, especially among young people.     

Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina

We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 3′ UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61–0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58–1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61–1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it.     

Reduced in-hospital mortality after improved management of children under 5 years admitted to hospital with malaria: randomised trial

Objective To test whether strict implementation of a standardised protocol for the management of malaria and provision of a financial incentive for health workers reduced mortality.Design Randomised controlled intervention trial.Setting Paediatric ward at the national hospital in Guinea-Bissau. All children admitted to hospital with severe malaria received free drug kits.Participants 951 children aged 3 months to 5 years admitted to hospital with a diagnosis of malaria randomised to normal or intervention wards.Interventions Before the start of the study, all personnel were trained in the use of the standardised guidelines for the management of malaria, including strict follow-up procedures. Nurses and doctors were randomised to work on intervention or control wards. Personnel in the intervention ward received a small financial incentive ($50 (£25; €35)/month for nurses and $160 for doctors) and their compliance with standard case management was closely monitored.Main outcome measures In-hospital mortality and cumulative mortality within 4 weeks of hospital admission.Results In-hospital mortality was 5% for the intervention group and 10% in the control group (risk ratio 0.48, 95% confidence interval 0.29 to 0.79). The effect may have been stronger in patients with positive malaria slides (0.36, 0.16 to 0.80). Cumulative mortality 4 weeks after discharge was also lower in the intervention group (0.61, 0.40 to 0.95).Conclusions Supervising healthcare workers to adhere to a standardised treatment protocol was associated with greatly reduced in-hospital mortality. Financial incentives may be important for the dedication and compliance of staff members.Trial registration Clinical Trials {"type":"clinical-trial","attrs":{"text":"NCT00465777","term_id":"NCT00465777"}}NCT00465777.     

Utility of the Plasma Level of suPAR in Monitoring Risk of Mortality during TB Treatment

Objective

To investigate whether changes in the plasma level of soluble urokinase plasminogen activator receptor (suPAR) can be used to monitor tuberculosis (TB) treatment efficacy.

Design

This prospective cohort study included 278 patients diagnosed with active pulmonary TB and followed throughout the 8-month treatment period.

Results

Mortality during treatment was higher in the highest inclusion quartile of suPAR (23%) compared to the lowest three quartiles (7%), the risk ratio being 3.1 (95% CI 1.65–6.07). No association between early smear conversion and subsequent mortality or inclusion suPAR was observed. After 1 and 2 months of treatment, an increase in suPAR compared to at diagnosis was associated with a Mortality Rate Ratio (MRR) of 4.5 (95%CI: 1.45–14.1) and 2.1 (95%CI 0.62–6.82), respectively, for the remaining treatment period.

Conclusions

The present study confirmed that elevated suPAR level at time of initiation of TB treatment is associated with increased risk of mortality. Furthermore, increased suPAR levels after one month of treatment was associated with increased risk of mortality during the remaining 7-month treatment period.     

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

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Prolonged breast feeding,diarrhoeal disease,and survival of children in Guinea-Bissau.

OBJECTIVE--To analyse the impact of breast feeding on diarrhoeal disease and survival in children above 1 year of age in Guinea-Bissau, west Africa. DESIGN--A community study of an open cohort followed up weekly by interviews over 15 months. Data on feeding practices, anthropometry, and survival were recorded for three years. SETTING--301 randomly selected houses in a semiurban area in the capital, Bissau. SUBJECTS--849 children aged less than 3 years. MAIN OUTCOME MEASURES--Incidence and duration of diarrhoea, weight for age, and death of a child. RESULTS--The incidence of diarrhoea was higher in weaned children than in partially breast fed children, both in 1 year olds (relative risk 1.41; 95% confidence interval 1.23 to 1.62) and in 2 year olds (1.67; 1.29 to 2.15). The mean duration of an episode of diarrhoea was 5.3 days in breast fed children compared with 6.3 days in weaned children (P = 0.001). Independent of the age of weaning, a similar increase was found in an analysis comparing, for each child, the rate and duration of diarrhoea one month before and one month after weaning. Children with low weight for age were breast fed longer than the better nourished children (P = 0.02). Children aged 12-35 months who were not breast fed had a 3.5 times higher mortality (1.4 to 8.3) than breast fed children. CONCLUSIONS--The beneficial effects of breast feeding are not restricted to infancy. Though children who are partially breast fed after infancy may have a lower state of nutrition than the weaned ones, the benefit in terms of lower morbidity may be more important for child survival in places with a high morbidity from diarrhoea and with high mortality.     

A Randomized Trial of an Early Measles Vaccine at 4? Months of Age in Guinea-Bissau: Sex-Differential Immunological Effects

Background

After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females.

Objective

We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality.

Methods

Within a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A.

Results

Overall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction.

Conclusions

In this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects.

Trial Registration

clinicaltrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT 00168545","term_id":"NCT00168545"}}NCT 00168545     

Molecular epidemiology of endemic human T-lymphotropic virus type 1 in a rural community in Guinea-Bissau

Background

Human T-Lymphotropic Virus Type 1 (HTLV-1) infection causes lethal adult T-cell leukemia (ATL) and severely debilitating HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in up to 5% of infected adults. HTLV-1 is endemic in parts of Africa and the highest prevalence in West Africa (5%) has been reported in Caio, a rural area in the North-West of Guinea-Bissau. It is not known which HTLV-1 variants are present in this community. Sequence data can provide insights in the molecular epidemiology and help to understand the origin and spread of HTLV-1.

Objective

To gain insight into the molecular diversity of HTLV-1 in West Africa.

Methods

HTLV-1 infected individuals were identified in community surveys between 1990–2007. The complete Long Terminal Repeat (LTR) and p24 coding region of HTLV-1 was sequenced from infected subjects. Socio-demographic data were obtained from community census and from interviews performed by fieldworkers. Phylogenetic analyses were performed to characterize the relationship between the Caio HTLV-1 and HTLV-1 from other parts of the world.

Results

LTR and p24 sequences were obtained from 72 individuals (36 LTR, 24 p24 only and 12 both). Consistent with the low evolutionary change of HTLV-1, many of the sequences from unrelated individuals showed 100% nucleotide identity. Most (45 of 46) of the LTR sequences clustered with the Cosmopolitan HTLV-1 subtype 1a, subgroup D (1aD). LTR and p24 sequences from two subjects were divergent and formed a significant cluster with HTLV-1 subtype 1g, and with the most divergent African Simian T-cell Lymphotropic Virus, Tan90.

Conclusions

The Cosmopolitan HTLV-1 1aD predominates in this rural West African community. However, HTLV-1 subtype 1g is also present. This subtype has not been described before in West Africa and may be more widespread than previously thought. These data are in line with the hypothesis that multiple monkey-to-man zoonotic events are contributing to HTLV-1 diversity.     

CD209 genetic polymorphism and tuberculosis disease

Background

Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded by CD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP)-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans. The present study investigates the role of the CD209 -336A/G variant in susceptibility to tuberculosis in a large sample of individuals from sub-Saharan Africa.

Methods and Findings

A total of 2,176 individuals enrolled in tuberculosis case-control studies from four sub-Saharan Africa countries were genotyped for the CD209 -336A/G SNP (rs4804803). Significant overall protection against pulmonary tuberculosis was observed with the -336G allele when the study groups were combined (n = 914 controls vs. 1262 cases, Mantel-Haenszel 2x2 χ² = 7.47, P = 0.006, odds ratio = 0.86, 95%CI 0.77–0.96). In addition, the patients with -336GG were associated with a decreased risk of cavitory tuberculosis, a severe form of tuberculosis disease (n = 557, Pearson''s 2×2 χ² = 17.34, P = 0.00003, odds ratio = 0.42, 95%CI 0.27–0.65). This direction of association is opposite to a previously observed result in a smaller study of susceptibility to tuberculosis in a South African Coloured population, but entirely in keeping with the previously observed protective effect of the -336G allele.

Conclusion

This study finds that the CD209 -336G variant allele is associated with significant protection against tuberculosis in individuals from sub-Saharan Africa and, furthermore, cases with -336GG were significantly less likely to develop tuberculosis-induced lung cavitation. Previous in vitro work demonstrated that the promoter variant -336G allele causes down-regulation of CD209 mRNA expression. Our present work suggests that decreased levels of the DC-SIGN receptor may therefore be protective against both clinical tuberculosis in general and cavitory tuberculosis disease in particular. This is consistent with evidence that Mycobacteria can utilize DC-SIGN binding to suppress the protective pro-inflammatory immune response.