Research Article: Measures of Malaria Burden after Long-Lasting Insecticidal Net Distribution and Indoor Residual Spraying at Three Sites in Uganda: A Prospective Observational Study

Date Published: November 8, 2016

Publisher: Public Library of Science

Author(s): Agaba Katureebe, Kate Zinszer, Emmanuel Arinaitwe, John Rek, Elijah Kakande, Katia Charland, Ruth Kigozi, Maxwell Kilama, Joaniter Nankabirwa, Adoke Yeka, Henry Mawejje, Arthur Mpimbaza, Henry Katamba, Martin J. Donnelly, Philip J. Rosenthal, Chris Drakeley, Steve W. Lindsay, Sarah G. Staedke, David L. Smith, Bryan Greenhouse, Moses R. Kamya, Grant Dorsey, Paul Garner

Abstract: BackgroundLong-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) are the primary vector control interventions used to prevent malaria in Africa. Although both interventions are effective in some settings, high-quality evidence is rarely available to evaluate their effectiveness following deployment by a national malaria control program. In Uganda, we measured changes in key malaria indicators following universal LLIN distribution in three sites, with the addition of IRS at one of these sites.Methods and FindingsComprehensive malaria surveillance was conducted from October 1, 2011, to March 31, 2016, in three sub-counties with relatively low (Walukuba), moderate (Kihihi), and high transmission (Nagongera). Between 2013 and 2014, universal LLIN distribution campaigns were conducted in all sites, and in December 2014, IRS with the carbamate bendiocarb was initiated in Nagongera. High-quality surveillance evaluated malaria metrics and mosquito exposure before and after interventions through (a) enhanced health-facility-based surveillance to estimate malaria test positivity rate (TPR), expressed as the number testing positive for malaria/number tested for malaria (number of children tested for malaria: Walukuba = 42,833, Kihihi = 28,790, and Nagongera = 38,690); (b) cohort studies to estimate the incidence of malaria, expressed as the number of episodes per person-year [PPY] at risk (number of children observed: Walukuba = 340, Kihihi = 380, and Nagongera = 361); and (c) entomology surveys to estimate household-level human biting rate (HBR), expressed as the number of female Anopheles mosquitoes collected per house-night of collection (number of households observed: Walukuba = 117, Kihihi = 107, and Nagongera = 107). The LLIN distribution campaign substantially increased LLIN coverage levels at the three sites to between 65.0% and 95.5% of households with at least one LLIN. In Walukuba, over the 28-mo post-intervention period, universal LLIN distribution was associated with no change in the incidence of malaria (0.39 episodes PPY pre-intervention versus 0.20 post-intervention; adjusted rate ratio [aRR] = 1.02, 95% CI 0.36–2.91, p = 0.97) and non-significant reductions in the TPR (26.5% pre-intervention versus 26.2% post-intervention; aRR = 0.70, 95% CI 0.46–1.06, p = 0.09) and HBR (1.07 mosquitoes per house-night pre-intervention versus 0.71 post-intervention; aRR = 0.41, 95% CI 0.14–1.18, p = 0.10). In Kihihi, over the 21-mo post-intervention period, universal LLIN distribution was associated with a reduction in the incidence of malaria (1.77 pre-intervention versus 1.89 post-intervention; aRR = 0.65, 95% CI 0.43–0.98, p = 0.04) but no significant change in the TPR (49.3% pre-intervention versus 45.9% post-intervention; aRR = 0.83, 95% 0.58–1.18, p = 0.30) or HBR (4.06 pre-intervention versus 2.44 post-intervention; aRR = 0.71, 95% CI 0.30–1.64, p = 0.40). In Nagongera, over the 12-mo post-intervention period, universal LLIN distribution was associated with a reduction in the TPR (45.3% pre-intervention versus 36.5% post-intervention; aRR = 0.82, 95% CI 0.76–0.88, p < 0.001) but no significant change in the incidence of malaria (2.82 pre-intervention versus 3.28 post-intervention; aRR = 1.10, 95% 0.76–1.59, p = 0.60) or HBR (41.04 pre-intervention versus 20.15 post-intervention; aRR = 0.87, 95% CI 0.31–2.47, p = 0.80). The addition of three rounds of IRS at ~6-mo intervals in Nagongera was followed by clear decreases in all outcomes: incidence of malaria (3.25 pre-intervention versus 0.63 post-intervention; aRR = 0.13, 95% CI 0.07–0.27, p < 0.001), TPR (37.8% pre-intervention versus 15.0% post-intervention; aRR = 0.54, 95% CI 0.49–0.60, p < 0.001), and HBR (18.71 pre-intervention versus 3.23 post-intervention; aRR = 0.29, 95% CI 0.17–0.50, p < 0.001). High levels of pyrethroid resistance were documented at all three study sites. Limitations of the study included the observational study design, the lack of contemporaneous control groups, and that the interventions were implemented under programmatic conditions.ConclusionsUniversal distribution of LLINs at three sites with varying transmission intensity was associated with modest declines in the burden of malaria for some indicators, but the addition of IRS at the highest transmission site was associated with a marked decline in the burden of malaria for all indicators. In highly endemic areas of Africa with widespread pyrethroid resistance, IRS using alternative insecticide formulations may be needed to achieve substantial gains in malaria control.

Partial Text: Over the last fifteen years, funding for malaria control activities has increased dramatically across Africa, leading to the scale-up of proven interventions including distribution of long-lasting insecticidal nets (LLINs), indoor residual spraying of insecticide (IRS), and treatment of malaria cases with artemisinin-based combination therapy (ACT) [1]. Substantial declines in measures of malaria burden have been attributed to the expansion of these interventions at various scales, from the sub-national level to the entire continent [2–4]. Despite these advances, the burden of malaria remains high, with an estimated 215 million cases and 438,000 deaths worldwide in 2015, of which 88% of cases and 90% of deaths were in Africa [1].

Health-facility-based surveillance involved a total of 110,313 outpatient visits among children 0.5 to 10 y of age from all three sites combined over the 4.5-y observation period (Table 1). The proportion of visits for which malaria was suspected ranged from 54.9% to 82.4% across the three sites. Over 98% of patients with suspected malaria underwent laboratory testing at all three sites, and the TPR ranged from 26.4% in Walukuba to 48.4% in Kihihi. For the cohort studies, a total of 1,081 children were observed over 3,258 person-years. A total of 5,213 episodes of malaria were diagnosed, with an incidence ranging from 0.29 episodes PPY in Walukuba to 2.41 episodes PPY in Nagongera. Only 12 episodes of malaria (0.2% of total) met criteria for severe malaria (5 severe anemia, 4 multiple convulsions, 2 cerebral malaria, and 1 respiratory distress). There were no deaths due to malaria. Two children with negative blood smears died of diarrheal illnesses. Monthly entomology surveys were conducted in 331 households involving 15,206 nights of collection. A total of 155,613 female Anopheles mosquitoes were collected, demonstrating daily HBRs ranging from 0.88 in Walukuba to 26.12 in Nagongera and sporozoite rates ranging from 0.84% in Walukuba to 1.84% in Nagongera. Estimates of the annual entomological inoculation rate were 2.71, 20.90, and 175.54 infectious bites PPY in Walukuba, Kihihi, and Nagongera, respectively (Table 1). The primary vector species in Walukuba was A. arabiensis, followed by A. gambiae s.s. and A. funestus. In Kihihi almost all mosquitoes were A. gambiae s.s., and in Nagongera the primary vector was A. gambiae s.s., followed by A. arabiensis and A. funestus (Table 1). Insecticide susceptibility testing was performed using WHO bioassays for available vector species from the study sites in 2014. Testing of A. gambiae s.s. in Kihihi and Nagongera revealed moderate to high resistance to DDT and pyrethroids (deltamethrin and permethrin), lower resistance to bendiocarb, and full susceptibility to organophosphates (fenitrothion and malathion). Testing of A. arabiensis in Walukuba and Nagongera revealed low resistance to DDT (Walukuba only), high resistance to pyrethroids, and full susceptibility to bendiocarb and organophosphates (Fig 2).

We utilized a comprehensive malaria surveillance system in three sites in Uganda with varied malaria epidemiology to measure changes in malaria metrics and mosquito exposure before and after malaria control interventions were delivered under operational conditions at the population level. The primary intervention was a national universal LLIN distribution campaign, with the goal of providing one LLIN for every two persons. The distribution campaign substantially increased LLIN coverage levels, but did not reach the universal coverage target. LLIN distribution was associated with modest reductions in malaria TPRs at all three sites, but the reduction reached statistical significance only in the highest transmission intensity site (Nagongera). There was a reduction in the incidence of malaria only in the medium transmission site (Kihihi) and reductions in the HBR that did not reach statistical significance at any of the sites. In contrast, in the highest transmission site (Nagongera), delivery of three rounds of IRS with the carbamate bendiocarb was associated with marked declines in all three malaria metrics. Notably, we documented high-level pyrethroid resistance among A. gambiae s.s. and A. arabiensis vectors across our study sites, which may have contributed to the limited changes seen following the distribution of LLINs. Our results suggest that IRS with non-pyrethroid insecticides is currently the most effective intervention available for reducing the burden of malaria in Uganda in areas where maximum bednet coverage is not obtained despite attempts at universal distribution.



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