Effect of HIV on the Frequency and Number of Mycobacterium tuberculosis-Specific CD4+ T Cells in Blood and Airways During Latent M. tuberculosis Infection.

Human immunodeficiency virus type 1 (HIV) infection substantially increases the risk of developing tuberculosis. There is extensive depletion of Mycobacterium tuberculosis-specific CD4+ T cells in blood during early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4+ T-cell destruction, we investigated M. tuberculosis-specific responses in bronchoalveolar lavage (BAL) from persons with latent M. tuberculosis infection and untreated HIV coinfection with preserved CD4+ T-cell counts. M. tuberculosis-specific CD4+ T-cell cytokine (interferon γ, tumor necrosis factor α, and interleukin 2) responses were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected persons as compared to uninfected persons (P = .048), whereas blood responses were 2-fold lower (P = .006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M. tuberculosis-specific CD4+ T cells in BAL being similar. Our study highlights the important insights gained from studying M. tuberculosis immunity at the site of disease during HIV infection.

Artemisinin combination therapy mass drug administration in a setting of low malaria endemicity: programmatic coverage and adherence during an observational study in Zanzibar.

BACKGROUND: Mass drug administration (MDA) appears to be effective in reducing the risk of malaria parasitaemia. This study reports on programmatic coverage and compliance of MDA using artemisinin-based combination therapy (ACT) in four shehias (smallest administration unit) that had been identified as hotspots through Zanzibar's malaria case notification surveillance system. METHODS: Mass drug administration was done in four shehias selected on the basis of: being an established malaria hot spot; having had mass screening and treatment (MSaT) 2-6 weeks previously; and exceeding the epidemic alert threshold of 5 cases within a week even after MSaT. Communities were sensitized and MDA was conducted using a house-to-house approach. All household members, except pregnant women and children aged less than 2 months, were provided with ACT medicine. Two weeks after the MDA campaign, a survey was undertaken to investigate completion of ACT doses. RESULTS: A total of 8816 [97.1% of eligible; 95% confidence interval (CI) 96.8-97.5] people received ACT. During post MDA surveys, 2009 people were interviewed: 90.2% reported having completed MDA doses; 1.9% started treatment but did not complete dosage; 4.7% did not take treatment; 2.0% were absent during MDA and 1.2% were ineligible (i.e. infants <2 months and pregnant women). Main reasons for failure to complete treatment were experience of side-effects and forgetting to take subsequent doses. Failure to take treatment was mainly due to fear of side-effects, reluctance due to lack of malaria symptoms and caregivers forgetting to give medication to children. CONCLUSION: Mass drug administration for malaria was well accepted by communities at high risk of malaria in Zanzibar, with high participation and completion rates. Further work to investigate the potential of MDA in accelerating Zanzibar's efforts towards malaria elimination should be pursued.

Dysregulation of the Immune Environment in the Airways During HIV Infection.

HIV-1 increases susceptibility to pulmonary infection and disease, suggesting pathogenesis in the lung. However, the lung immune environment during HIV infection remains poorly characterized. This study examined T cell activation and the cytokine milieu in paired bronchoalveolar lavage (BAL) and blood from 36 HIV-uninfected and 32 HIV-infected participants. Concentrations of 27 cytokines were measured by Luminex, and T cells were phenotyped by flow cytometry. Blood and BAL had distinct cytokine profiles (p=0.001). In plasma, concentrations of inflammatory cytokines like IFN-γ (p=0.004) and TNF-α (p=0.004) were elevated during HIV infection, as expected. Conversely, BAL cytokine concentrations were similar in HIV-infected and uninfected individuals, despite high BAL viral loads (VL; median 48,000 copies/ml epithelial lining fluid). HIV-infected individuals had greater numbers of T cells in BAL compared to uninfected individuals (p=0.007); and BAL VL positively associated with CD4+ and CD8+ T cell numbers (p=0.006 and p=0.0002, respectively) and CXCL10 concentrations (p=0.02). BAL T cells were highly activated in HIV-infected individuals, with nearly 2-3 fold greater frequencies of CD4+CD38+ (1.8-fold; p=0.007), CD4+CD38+HLA-DR+ (1.9-fold; p=0.0006), CD8+CD38+ (2.8-fold; p=0.0006), CD8+HLA-DR+ (2-fold; p=0.022) and CD8+CD38+HLA-DR+ (3.6-fold; p<0.0001) cells compared to HIV-uninfected individuals. Overall, this study demonstrates a clear disruption of the pulmonary immune environment during HIV infection, with readily detectable virus and activated T lymphocytes, which may be driven to accumulate by local chemokines.

Dietary Intake of Flavonoids and Ventilatory Function in European Adults: A GA²LEN Study.

BACKGROUND: Flavonoids exert anti-inflammatory properties and modulate oxidative stress in vitro, suggesting a protective effect on lung function, but epidemiological studies examining this association are scarce. METHODS: A stratified random sample was drawn from the GA²LEN screening survey, in which 55,000 adults aged 15 to 75 answered a questionnaire on respiratory symptoms. Post-bronchodilator spirometry was obtained from 2850 subjects. Forced vital capacity (FVC), the ratio between the forced exhaled volume in 1 second (FEV1) and FVC (FEV1/FVC), FVC below lower limit of normal (FVC < LLN), and FEV1/FVC < LLN were calculated. Intake of the six main subclasses of flavonoids was estimated using the GA²LEN Food Frequency Questionnaire. Adjusted associations between outcomes and each subclass of flavonoids were examined with multivariate regressions. Simes' procedure was used to test for multiple comparisons. RESULTS: A total of 2599 subjects had valid lung function and dietary data. A lower prevalence of FVC < LLN (airway restriction) was observed in those with higher total flavonoid (adjusted odds ratio (aOR), higher vs. lowest quintile intake 0.58; 95% Confidence Interval (CI) 0.36, 0.94), and pro-anthocyanidin intakes (aOR 0.47; 95% CI 0.27, 0.81). A higher FEV1/FVC was associated with higher intakes of total flavonoids and pro-anthocyanidins (adjusted correlation coefficient (a ß-coeff 0.33; 0.10, 0.57 and a ß-coeff 0.44; 95% CI 0.19, 0.69, respectively). After Simes' procedure, the statistical significance of each of these associations was attenuated but remained below 0.05, with the exception of total flavonoids and airway restriction. CONCLUSIONS: This population-based study in European adults provides cross-sectional evidence of a positive association of total flavonoid intake and pro-anthocyanidins and ventilatory function, and a negative association with spirometric restriction in European adults.

Taking local ownership: government and household contribution to indoor residual spraying in Zanzibar and mainland Tanzania.

BACKGROUND: While donor funding is instrumental in initiation and implementation of malaria control efforts, national government contributions are key to local ownership and sustainability. This study explored in-kind contributions of local government and households towards the cost of indoor residual spraying (IRS) interventions in Tanzania. METHODS: Data were collected through interviews with local government officials and technical teams in the IRS project. Household contribution was based on provision of water for IRS. Government contributions included government-provided warehouse and office space, vehicles, and staff labour. In-kind contributions were aggregated at the district, regional and national level. Calculations were based on proportion of total costs of IRS from 2010 to 2012. RESULTS: The mainland government provided larger amounts of in-kind contribution in absolute value (mean of US$454 200) compared to Zanzibar (US$89 163). On average, in-kind contribution was 5.5% of total costs in Zanzibar and 2.9% in mainland. The proportion of government in-kind contribution was higher in Zanzibar versus the mainland (86% vs 50%) while household contribution was higher in mainland compared to Zanzibar (50% vs 14%). CONCLUSION: Government involvement, particularly through budgetary allocations and increased in-kind contribution, needs to be encouraged for malaria control efforts to be locally owned, managed and sustained.

School Distribution as Keep-Up Strategy to Maintain Universal Coverage of Long-Lasting Insecticidal Nets: Implementation and Results of a Program in Southern Tanzania.

Tanzania successfully scaled up coverage of long-lasting insecticidal nets (LLINs) through mass campaigns. To sustain these gains, a school-based approach was piloted in the country's Southern Zone starting in 2013, called the School Net Program 1 (SNP1). We report on the design, implementation, monitoring, and outputs of the second round (SNP2) undertaken in 2014. SNP2 was conducted in all schools in Lindi, Mtwara, and Ruvuma regions, targeting students in primary (Standards 1, 3, 5, and 7) and secondary (Forms 2 and 4) schools and all teachers. In Lindi region, 2 additional classes (Standards 2 and 4) were targeted. LLIN distribution data were managed using an Android software application called SchoolNet. SNP2 included 2,337 schools, 473,700 students, and 25,269 teachers. A total of 5,070 people were trained in LLIN distribution (487 trainers and 4,583 distributors), and 4,392 (434 ward and 3,958 village) community change agents undertook sensitization and mobilization. A total of 507,775 LLINs were distributed to schools, with 464,510 (97.9% of those registered) students and 24,206 (95.8% of those registered) school teachers receiving LLINs. LLIN ownership and use is expected to have increased, potentially further reducing the burden of malaria in the Southern Zone of Tanzania.

The impact of different sprayable surfaces on the effectiveness of indoor residual spraying using a micro encapsulated formulation of lambda-cyhalothrin against Anopheles gambiae s.s.

BACKGROUND: The type of sprayable surface impacts on residual efficacy of insecticide used in indoor residual spraying (IRS). However, there is limited data on common types of wall surfaces sprayed in Zanzibar and mainland Tanzania where IRS began in 2006 and 2007 respectively. The study investigated residual efficacy of micro-encapsulated lambda-cyhalothrin sprayed on common surfaces of human dwellings and domestic animal shelters in Zanzibar and mainland Tanzania. METHODS: An experimental hut was constructed with different types of materials simulating common sprayable surfaces in Zanzibar and mainland Tanzania. Surfaces included cement plastered wall, mud-daub, white-wash, wood, palm-thatch, galvanized iron-sheets, burnt-bricks, limestone and oil-paint. The World Health Organization (WHO) procedure for IRS was used to spray lambda-cyhalothrin on surfaces at the dose of 20-25 mg/m(2). Residual efficacy of insecticide was monitored through cone bioassay using laboratory-reared mosquitoes; Kisumu strain (R-70) of Anopheles gambiae ss. Cone bioassay was done every fortnight for a period of 152 days. The WHO Pesticide Evaluation Scheme (WHOPES) threshold (80% mortality) was used as cut-off point for acceptable residual efficacy. RESULTS: A total of 5,800 mosquitoes were subjected to contact cone bioassay to test residual efficacy of lambda-cyhalothrin. There was a statistically significant variation in residual efficacy between the different types of wall surfaces (r = 0.24; p < 0.001). Residual efficacy decreased with increasing pH of the substrate (r = -0.5; p < 0.001). Based on WHOPES standards, shorter residual efficacy (42-56 days) was found in wall substrates made of cement, limestone, mud-daub, oil paint and white wash. Burnt bricks retained the residual efficacy up to 134 days while galvanized iron sheets, palm thatch and wood retained the recommended residual efficacy beyond 152 days. CONCLUSION: The study revealed a wide variation in residual efficacy of micro encapsulated formulation of lambda-cyhalothrin across the different types of wall surfaces studied. In areas where malaria transmission is bimodal and wall surfaces with short residual efficacy comprise > 20% of sprayable structures, two rounds of IRS using lambda-cyhalothrin should be considered. Further studies are required to investigate the impact of sprayable surfaces on residual efficacy of other insecticides commonly used for IRS in Zanzibar and mainland Tanzania.

Efficacy, persistence and vector susceptibility to pirimiphos-methyl (Actellic 300CS) insecticide for indoor residual spraying in Zanzibar.

BACKGROUND: Indoor residual spraying (IRS) of households with insecticide is a principal malaria vector control intervention in Zanzibar. In 2006, IRS using the pyrethroid lambda-cyhalothrine was introduced in Zanzibar. Following detection of pyrethroid resistance in 2010, an insecticide resistance management plan was proposed, and IRS using bendiocarb was started in 2011. In 2014, bendiocarb was replaced by pirimiphos methyl. This study investigated the residual efficacy of pirimiphos methyl (Actellic 300CS) sprayed on common surfaces of human dwellings in Zanzibar. METHODS: The residual activity of Actellic 300CS was determined over 9 months through bioassay tests that measured the mortality of female Anopheles mosquitoes, exposed to sprayed surfaces under a WHO cone. The wall surfaces included; mud wall, oil or water painted walls, lime washed wall, un-plastered cement block wall and stone blocks. Insecticide susceptibility testing was done to investigate the resistance status of local malaria vectors against Actellic 300CS using WHO protocols; Anopheline species were identified using PCR methods. RESULTS: Baseline tests conducted one-day post-IRS revealed 100% mortality on all sprayed surfaces. The residual efficacy of Actellic 300CS was maintained on all sprayed surfaces up to 8 months post-IRS. However, the bioassay test conducted 9 months post-IRS showed the 24 h mortality rate to be ≤80% for lime wash, mud wall, water paint and stone block surfaces. Only oil paint surface retained the recommended residual efficacy beyond 9 months post-IRS, with mortality maintained at ≥97 %. Results of susceptibility tests showed that malaria vectors in Zanzibar were fully (100%) susceptible to Actellic 300CS. The predominant mosquito vector species was An. arabiensis (76.0%) in Pemba and An. gambiae (83.5%) in Unguja. CONCLUSION: The microencapsulated formulation of pirimiphos methyl (Actellic 300CS) is a highly effective and appropriate insecticide for IRS use in Zanzibar as it showed a relatively prolonged residual activity compared to other products used for the same purpose. The insecticide extends the residual effect of IRS thereby making it possible to effectively protect communities with a single annual spray round reducing overall costs. The insecticide proved to be a useful alternative in insecticide resistance management plans.

Use of insecticide quantification kits to investigate the quality of spraying and decay rate of bendiocarb on different wall surfaces in Kagera region, Tanzania.

BACKGROUND: Bendiocarb was introduced for the first time for Indoor Residual Spraying (IRS) in Tanzania in 2012 as part of the interim national insecticide resistance management plan. This move followed reports of increasingly alarming levels of pyrethroid resistance across the country. This study used the insecticide quantification kit (IQK) to investigate the intra-operational IRS coverage and quality of spraying, and decay rate of bendiocarb on different wall surfaces in Kagera region. METHODS: To assess intra-operational IRS coverage and quality of spraying, 104 houses were randomly selected out of 161,414 sprayed houses. A total of 509 samples (218 in Muleba and 291 in Karagwe) were obtained by scraping the insecticide samples from wall surfaces. To investigate decay rate, 66 houses (36 in Muleba and 30 in Karagwe) were selected and samples were collected monthly for a period of five months. Laboratory testing of insecticide concentration was done using IQK(TM) [Innovative Vector Control Consortium]. RESULTS: Of the 509 samples, 89.5% met the World Health Organization (WHO) recommended concentration (between 100-400 mg/m(2)) for IRS target dosage. The proportion of samples meeting WHO standards varied between Karagwe (84.3%) and Muleba (96.3%) (p < 0.001). Assessment of quality of spraying at house level revealed that Muleba (84.8%) had a significantly higher proportion of households that met the expected target dosage (100-400 mg/m(2)) compared to Karagwe (68.9%) (p < 0.001). The quality of spraying varied across different wall substrates in both districts. Evaluation of bendiocarb decay showed that the proportion of houses with recommended concentration declined from 96.9%, 93.5% and 76.2% at months one, two, and three post IRS, respectively (p-trend = 0.03). The rate of decay increased in the fourth and fifth month post spraying with only 55.9% and 26.3% houses meeting the WHO recommendations, respectively. CONCLUSION: IQK is an important tool for assessing IRS coverage and quality of spraying. The study found adequate coverage of IRS; however, residual life of bendiocarb was observed to be three months. Results suggest that in order to maintain the recommended concentrations with bendiocarb, a second spray cycle should be carried out after three months.