A cluster randomized trial of delivery of intermittent preventive treatment of malaria in pregnancy at the community level in Malawi.

BACKGROUND: Malaria in pregnancy doubles the risk of low birthweight; up to 11% of all neonatal deaths in sub-Saharan Africa are associated with malaria in pregnancy. To prevent these and other adverse health consequences, the World Health Organization recommends administering intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for all pregnant women at each antenatal care (ANC) visit, starting as early as possible in the second trimester. The target is for countries to administer a minimum of three doses (IPTp3+) to at least 85% of pregnant women. METHODS: A cluster randomized, controlled trial was conducted to assess the effect of delivery of IPTp by community health workers on the coverage of IPTp3 + and ANC visits in Malawi. Community delivery of IPTp was implemented within two districts in Malawi over a 21-month period, from November 2018 to July 2020. In control sites, IPTp was delivered at health facilities. Representative samples of women who delivered in the prior 12 months were surveyed at baseline (n = 370, December 2017) and endline (n = 687, August 2020). A difference in differences analysis was conducted to assess the change in coverage of IPTp and ANC over time, accounting for clustering at the health facility level. RESULTS: Overall IPTp coverage increased over the study period. At baseline, women received a mean of 2.3 IPTp doses (range 0-5 doses) across both arms, and at endline, women received a mean of 2.8 doses (range 0-9 doses). Despite overall increases, the change in IPTp3 + coverage was not significantly different between intervention and control groups (6.9%, 95% CI: -5.9%, 19.6%). ANC4 + coverage increased significantly in the intervention group compared with the control group, with a difference-in-differences of 25.3% points (95% CI: 1.3%, 49.3%). CONCLUSIONS: In order to reduce the burden of malaria in pregnancy, new strategies are needed to improve uptake of effective interventions such as IPTp. While community health workers' delivery of IPTp did not increase uptake in this study, they may be effective in other settings or circumstances. Further research can help identify the health systems characteristics that are conducive to community delivery of IPTp and the operational requirements for effective implementation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03376217. Registered December 6, 2017, https://clinicaltrials.gov/ct2/show/NCT03376217 .

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study.

BACKGROUND: Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. METHODS AND FINDINGS: Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. CONCLUSIONS: This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.

Household costs among patients hospitalized with malaria: evidence from a national survey in Malawi, 2012.

BACKGROUND: With 71% of Malawians living on < $1.90 a day, high household costs associated with severe malaria are likely a major economic burden for low income families and may constitute an important barrier to care seeking. Nevertheless, few efforts have been made to examine these costs. This paper describes household costs associated with seeking and receiving inpatient care for malaria in health facilities in Malawi. METHODS: A cross-sectional survey was conducted in a representative nationwide sample of 36 health facilities providing inpatient treatment for malaria from June-August, 2012. Patients admitted at least 12 h before study team visits who had been prescribed an antimalarial after admission were eligible to provide cost information for their malaria episode, including care seeking at previous health facilities. An ingredients-based approach was used to estimate direct costs. Indirect costs were estimated using a human capital approach. Key drivers of total household costs for illness episodes resulting in malaria admission were assessed by fitting a generalized linear model, accounting for clustering at the health facility level. RESULTS: Out of 100 patients who met the eligibility criteria, 80 (80%) provided cost information for their entire illness episode to date and were included: 39% of patients were under 5 years old and 75% had sought care for the malaria episode at other facilities prior to coming to the current facility. Total household costs averaged $17.48 per patient; direct and indirect household costs averaged $7.59 and $9.90, respectively. Facility management type, household distance from the health facility, patient age, high household wealth, and duration of hospital stay were all significant drivers of overall costs. CONCLUSIONS: Although malaria treatment is supposed to be free in public health facilities, households in Malawi still incur high direct and indirect costs for malaria illness episodes that result in hospital admission. Finding ways to minimize the economic burden of inpatient malaria care is crucial to protect households from potentially catastrophic health expenditures.

Scheduled Intermittent Screening with Rapid Diagnostic Tests and Treatment with Dihydroartemisinin-Piperaquine versus Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy in Malawi: An Open-Label Randomized Controlled Trial.

BACKGROUND: In Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP. METHODS AND FINDINGS: This was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat. Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI -3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90-1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92-1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71-1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference = 7.85%, [95% CI 3.07%-12.63%]; all women: RR = 1.19 [95% CI 1.07-1.33], p = 0.007; paucigravidae: RR = 1.16 [95% CI 1.04-1.31], p = 0.011; multigravidae: RR = 1.29 [95% CI 1.02-1.63], p = 0.037). Fetal loss was more common with ISTp-DP (2.6% versus 1.3%; RR = 2.06 [95% CI 1.01-4.21], p = 0.046) and highest among non-DP-recipients (3.1%) in the ISTp-DP arm. Limitations included the open-label design. CONCLUSIONS: Scheduled screening for malaria parasites with the current generation of RDTs three to four times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in this area with high malaria transmission and high SP resistance and was associated with higher fetal loss and more malaria at delivery. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930.

Scale-up of integrated malaria vector control: lessons from Malawi.

PROBLEM: Indoor residual spraying and long-lasting insecticidal nets (LLINs) are key tools for malaria vector control. Malawi has struggled to scale up indoor residual spraying and to improve LLIN coverage and usage. APPROACH: In 2002, the Malawian National Malaria Control Programme developed guidelines for insecticide treated net distribution to reach the strategic target of at least 60% coverage of households with an LLIN. By 2005, the target coverage was 80% of households and the Global Fund financed the scale-up. The US President's Malaria Initiative funded the indoor residual spraying intervention. LOCAL SETTING: Malawi's entire population is considered to be at risk of malaria. Poor vector control, insecticide resistance in malaria vectors and insufficient technical and financial support have exacerbated the malaria burden. RELEVANT CHANGES: Between 2002 and 2012, 18 248 206 LLINs had been distributed. The coverage of at least one LLIN per household increased from 27% (3689/13 664) to 58% (1974/3404). Indoor residual spraying coverage increased from 28 227 to 653 592 structures between 2007 and 2011. However, vector resistance prompted a switch from pyrethroids to organophosphates for indoor residual spraying, which increased the cost and operations needed to be cut back from seven to one district. Malaria cases increased from 2 853 315 in 2002 to 6 748 535 in 2010, and thereafter dropped to 4 922 596 in 2012. LESSONS LEARNT: A single intervention-based approach for vector control may have suboptimal impact. Well-coordinated integrated vector management may offer greater benefits. A resistance management plan is essential for effective and sustainable vector control.

In vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine for uncomplicated Plasmodium falciparum malaria in Malawi, 2014.

BACKGROUND: Malaria causes significant morbidity in Malawi, with an estimated 5 million cases in 2014. Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first- and second-line treatments for uncomplicated malaria, respectively, but emerging resistance threatens their efficacy. In order to understand whether AL and ASAQ remain efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Malawi, a therapeutic efficacy trial was conducted. METHODS: During March-July 2014, febrile children aged 6-59 months with microscopy-confirmed uncomplicated P. falciparum malaria (1000-200,000 parasites/µL) were enrolled in a 28-day randomized in vivo efficacy trial at three sites: one each in northern (Karonga), central (Nkhotakota) and southern (Machinga) Malawi. The study was powered to estimate site-specific efficacy for AL and overall efficacy for ASAQ, with 3:1 randomization to AL or ASAQ. Blood was collected for malaria microscopy and molecular testing on days 0-3, 7, 14, 21, and 28. Recrudescence and reinfection were differentiated using polymerase chain reaction (PCR) genotyping of merozoite surface protein. The primary outcome was the PCR-corrected day 28 Kaplan-Meier cumulative success rate. RESULTS: A total of 452 children were enrolled; 303/338 (89 %) and 98/114 (86 %) reached a study endpoint in AL and ASAQ arms, respectively. All treatment failures occurred after day 3. The day 28 uncorrected cumulative success rate was 97.1 % (95 % confidence interval [CI]: 93.9-100 %) for ASAQ and 76.8 % (95 % CI 72.1-81.5 %) for AL, with 82.5 % (95 % CI 75.4-89.7 %), 69 % (95 % CI 59.9-78.1 %), and 78.2 % (95 % CI 70.2-86.3 %) success in the northern, central, and southern regions, respectively. The day 28 PCR-corrected cumulative success rate was 99 % (95 % CI 97.2-100 %) in the ASAQ arm and 99.3 % (95 % CI 98.3-100 %) in the AL arm, with 98-100 % efficacy in each site. CONCLUSIONS: As evidenced by the day 28 PCR-corrected cumulative success rates, both AL and ASAQ remain efficacious treatments for uncomplicated malaria in Malawi. The lower uncorrected efficacy in the AL arm compared to ASAQ may be explained by the shorter half-life of lumefantrine (3-6 days) compared to amodiaquine (9-18 days). The high reinfection rate suggests that there is a continued need to scale-up effective malaria prevention interventions.

Adherence to national guidelines for the diagnosis and management of severe malaria: a nationwide, cross-sectional survey in Malawi, 2012.

BACKGROUND: Severe malaria has a case fatality rate of 10-20 %; however, few studies have addressed the quality of severe malaria case management. This study evaluated the diagnostic and treatment practices of malaria patients admitted to inpatient health facilities (HF) in Malawi. METHODS: In July-August 2012, a nationwide, cross-sectional survey of severe malaria management was conducted in 36 HFs selected with equal probability from all eligible public sector HFs in Malawi. Patient records from all admissions during October 2011 and April 2012 (low and high season, respectively) were screened for an admission diagnosis of malaria or prescription of any anti-malarial. Eligible records were stratified by age (< 5 or ≥ 5 years). A maximum of eight records was randomly selected within each age and month stratum. Severe malaria was defined by admission diagnosis or documentation of at least one sign or symptom of severe malaria. Treatment with intravenous (IV) quinine or artesunate was considered correct. Patients without documentation of severe malaria were analysed as uncomplicated malaria patients; treatment with an artemisinin-based combination therapy (ACT) or oral quinine based on malaria test results was considered correct. All analyses accounted for HF level clustering and sampling weights. RESULTS: The analysis included 906 records from 35 HFs. Among these, 42 % (95 % confidence interval [CI] 35-49) had a severe malaria admission diagnosis and 50 % (95 % CI 44-57) had at least one severe malaria sign or symptom documented. Severe malaria patients defined by admission diagnosis (93, 95 % CI 86-99) were more likely to be treated correctly compared to patients defined by a severe sign (82, 95 % CI 75-89) (p < 0.0001). Among uncomplicated malaria patients, 26 % (95 % CI 18-35) were correctly treated and 53 % (95 % CI 42-64) were adequately treated with IV quinine alone or in combination with an ACT or oral quinine. CONCLUSIONS: A majority of patients diagnosed with severe malaria received the recommended IV therapy in accordance with national treatment guidelines. However, the inconsistencies between diagnosis of severe malaria and documentation of severe signs and symptoms highlight the need to improve healthcare worker recognition and documentation of severe signs and symptoms.

Increasing insecticide resistance in Anopheles funestus and Anopheles arabiensis in Malawi, 2011-2015.

BACKGROUND: Susceptibility of principal Anopheles malaria vectors to common insecticides was monitored over a 5-year period across Malawi to inform and guide the national malaria control programme. METHODS: Adult blood-fed Anopheles spp. and larvae were collected from multiple sites in sixteen districts across the country between 2011 and 2015. First generation (F1) progeny aged 2-5 days old were tested for susceptibility, using standard WHO procedures, against pyrethroids (permethrin and deltamethrin), carbamates (bendiocarb and propoxur), organophosphates (malathion and pirimiphos-methyl) and an organochlorine (DDT). RESULTS: Mortality of Anopheles funestus to deltamethrin, permethrin, bendiocarb and propoxur declined significantly over the 5-year (2011-2015) monitoring period. There was wide variation in susceptibility to DDT but it was not associated with time. In contrast, An. funestus exhibited 100% mortality to the organophosphates (malathion and pirimiphos-methyl) at all sites tested. There was reduced mortality of Anopheles arabiensis to deltamethrin over time though this was not statistically significant. However, mortality of An. arabiensis exposed to permethrin declined significantly over time. Anopheles arabiensis exposed to DDT were more likely to be killed if there was high ITN coverage in the mosquito collection area the previous year. There were no other associations between mosquito mortality in a bioassay and ITN coverage or IRS implementation. Mortality of An. funestus from four sites exposed to deltamethrin alone ranged from 2 to 31% and from 41 to 94% when pre-exposed to the synergist piperonyl butoxide followed by deltamethrin. For permethrin alone, mortality ranged from 2 to 13% while mortality ranged from 63 to 100% when pre-exposed to PBO. CONCLUSION: Pyrethroid resistance was detected in An. funestus and An. arabiensis populations across Malawi and has worsened over the last 5 years. New insecticides and control strategies are urgently needed to reduce the burden of malaria in Malawi.

The A581G Mutation in the Gene Encoding Plasmodium falciparum Dihydropteroate Synthetase Reduces the Effectiveness of Sulfadoxine-Pyrimethamine Preventive Therapy in Malawian Pregnant Women.

BACKGROUND: The A581 G: mutation in the gene encoding Plasmodium falciparum dihydropteroate synthase (dhps), in combination with the quintuple mutant involving mutations in both dhps and the gene encoding dihydrofolate reductase (dhfr), the so-called sextuple mutant, has been associated with increased placental inflammation and decreased infant birth weight among women receiving intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) during pregnancy. METHODS: Between 2009 and 2011, delivering women without human immunodeficiency virus infection were enrolled in an observational study of IPTp-SP effectiveness in Malawi. Parasites were detected by polymerase chain reaction (PCR); positive samples were sequenced to genotype the dhfr and dhps loci. The presence of K540 E: in dhps was used as a marker for the quintuple mutant. RESULTS: Samples from 1809 women were analyzed by PCR; 220 (12%) were positive for P. falciparum. A total of 202 specimens were genotyped at codon 581 of dhps; 17 (8.4%) harbored the sextuple mutant. The sextuple mutant was associated with higher risks of patent infection in peripheral blood (adjusted prevalence ratio [aPR], 2.76; 95% confidence interval [CI], 1.82-4.18) and placental blood (aPR 3.28; 95% CI, 1.88-5.78) and higher parasite densities. Recent SP use was not associated with increased parasite densities or placental pathology overall and among women with parasites carrying dhps A581 G: . CONCLUSIONS: IPTp-SP failed to inhibit parasite growth but did not exacerbate pathology among women infected with sextuple-mutant parasites. New interventions to prevent malaria during pregnancy are needed urgently.

The use of intermittent preventive treatment in pregnancy and insecticide-treated bed nets for malaria prevention by women of child-bearing age in eight districts in Malawi.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated bed nets (ITNs) can reduce the morbidity and mortality associated with malaria in pregnancy. Although the coverage for both IPTp and ITN use have been described in Malawi, the analysis of factors associated with IPTp receipt and ITN use is lacking. This analysis was conducted to assess IPTp and ITN use and predictors of use by women of child-bearing age (WOCBA). METHODS: A two-stage cluster-sample cross-sectional survey was conducted April 16-30, 2009 in eight districts across Malawi. Information on receipt of two or more doses of IPTp, ITN ownership, and ITN use the night before the survey was collected. Multivariate logistic regression was used to assess predictors of IPTp and ITN use. RESULTS: Data were collected from 7407 households containing 6985 WOCBA and 3213 recently pregnant women (women who reported a completed pregnancy in the 2 years before the survey). Most recently pregnant women (96 %) had at least one antenatal care (ANC) clinic visit; 91 % reported receiving at least one dose of IPTp, and 72 % reported receiving two or more doses of IPTp. Women in Phalombe, Rumphi, and Lilongwe were more likely to receive two doses of IPTp than those in Blantyre [adjusted odds ratio (aOR) 2.5 (95 % CI 1.5-4.5), 2.5 (95 % CI 1.5-4.3), and 2.0 (95 % CI 1.2-3.1), respectively]. Educated women were more likely to have received IPTp compared to women with no education [aOR 1.6 (95 % CI 1.0-2.6) for those who completed primary school, aOR1.9 (95 % CI 1.1-3.3) for some secondary school, and aOR 4.1 (95 % CI 1.9-8.7) for completed secondary school or above], and women in the poorest socioeconomic status quintile were less likely to receive IPTp than those in the least poor quintile [aOR 0.68 (95 % CI 0.48-0.97)]. In all, 53 % of WOCBA used an ITN the previous night. Women in Nkhotkhota and Phalombe were less likely to have slept under an ITN the previous night compared to those in Blantyre [aOR 0.52 (95 % CI 0.39-0.69) and aOR 0.67 (95 % CI 0.47-0.95), respectively]. In addition, age [aOR 0.61 (95 % CI 0.45-0.83) for women 15-19 years old], and either being currently pregnant [aOR 1.5 (95 % CI 1.2-2.0)] or having been pregnant in the previous 2 years [aOR 2.4, (95 % CI 2.1-2.8)] were associated with ITN use. CONCLUSION: In Malawi in 2009, IPTp and ITN use in WOCBA fell short of national and international goals. Adoption of new guidelines encouraging administration of IPTp at every scheduled ANC visit might increase IPTp use. Increasing health promotion activities to encourage earlier attendance at ANC clinics and create demand for IPTp and ITNs might improve overall IPTp and ITN use.

Monitoring the efficacy of artemether-lumefantrine for the treatment of uncomplicated malaria in Malawian children.

BACKGROUND: The resistance of malaria parasites to sulphadoxine-pyrimethamine (SP) in 2007 led to the Malawi Ministry of Health changing to artemether-lumefantrine (AL) as first-line for uncomplicated malaria treatment. This study determined the efficacy and safety of AL for the treatment of uncomplicated Plasmodium falciparum malaria among six to 59 months old Malawian children. METHODS: This was a prospective study of children six to 59 months old treated with AL after presenting with uncomplicated malaria in the six health facilities in Malawi. The children were followed up on days 1, 2, 3, 7, 14, 21 and 28 days post-treatment and assessed for clinical and parasitological responses. The Kaplan Meier survival estimate was used to measure the efficacy of AL by calculating the cumulative risk of failure at day 28. RESULTS: A total of 322 children were recruited into the study across the six sites. The overall intention-to-treat (ITT) polymerase chain reaction (PCR)-corrected cure rate was 93.4%. Per protocol overall PCR-corrected cure rates for the study sites were; Karonga 98.0%, Kawale 97.4%, Machinga 90.2%, Mangochi 95.4% and Rumphi 91.3%. Nkhotakota study site had the lowest cure rate of 78.0%. CONCLUSIONS: There is evidence of good efficacy of AL in Malawi notwithstanding geographical contrasts and this supports the continued use of AL as the first-line treatment for uncomplicated malaria. However there may be need to further investigate the comparatively low efficacy rate found in Nkhotakota district in order to identify possible determinants of treatment failure.

Preventing malaria transmission by indoor residual spraying in Malawi: grappling with the challenge of uncertain sustainability.

BACKGROUND: In the past decade, there has been rapid scale-up of insecticide-based malaria vector control in the context of integrated vector management (IVM) according to World Health Organization recommendations. Endemic countries have deployed indoor residual spraying (IRS) and long-lasting insecticidal nets as hallmark vector control interventions. This paper discusses the successes and continued challenges and the way forward for the IRS programme in Malawi. CASE DESCRIPTION: The National Malaria Control Programme in Malawi, with its efforts to implement an integrated approach to malaria vector control, was the 'case' for this study. Information sources included all available data and accessible archived documentary records on IRS in Malawi. A methodical assessment of published and unpublished documents was conducted via a literature search of online electronic databases. DISCUSSION: Malawi has implemented IRS as the main malaria transmission-reducing intervention. However, pyrethroid and carbamate resistance in malaria vectors has been detected extensively across the country and has adversely affected the IRS programme. Additionally, IRS activities have been characterized by substantial inherent logistical and technical challenges culminating into missed targets. As a consequence, programmatic IRS operations have been scaled down from seven districts in 2010 to only one district in 2014. The future of the IRS programme in Malawi is uncertain due to limited funding, high cost of alternative insecticides and technical resource challenges being experienced in the country. CONCLUSIONS: The availability of a long-lasting formulation of the organophosphate pirimiphos-methyl makes the re-introduction of IRS a possibility and may be a useful approach for the management of pyrethroid resistance. Implementing the IVM strategy, advocating for sustainable domestic funding, including developing an insecticide resistance monitoring and management plan and vector surveillance guidelines will be pivotal in steering entomologic monitoring and future vector control activities in Malawi.

Design, implementation and evaluation of a training programme for school teachers in the use of malaria rapid diagnostic tests as part of a basic first aid kit in southern Malawi.

BACKGROUND: With increasing levels of enrolment, primary schools present a pragmatic opportunity to improve the access of school children to timely diagnosis and treatment of malaria, increasingly recognised as a major health problem within this age group. The expanded use of malaria rapid diagnostic tests (RDTs) and artemisinin combination therapy (ACT) by community health workers (CHWs) has raised the prospect of whether teachers can provide similar services for school children. We describe and evaluate the training of primary school teachers to use a first aid kit containing malaria RDTs and ACT for the diagnosis and treament of uncomplicated malaria in school children in southern Malawi. METHODS: We outline the development of the intervention as: (1) conception and design, (2) pilot training, (3) final training, and (4) 7-month follow up. The training materials were piloted at a four-day workshop in July 2013 following their design at national stakeholders meetings. The evaluation of the pilot training and materials were assessed in relation to increased knowledge and skill sets using checklist evaluations and questionnaires, the results of which informed the design of a final seven-day training programme held in December 2013. A follow up of trained teachers was carried out in July 2014 following 7 months of routine implementation. A total of 15 teachers were evaluated at four stages: pilot training, two weeks following pilot, final training and seven months following final training. RESULTS: A total of 15 and 92 teachers were trained at the pilot and final training respectively. An average of 93 % of the total steps required to use RDTs were completed correctly at the final training, declining to 87 % after 7 months. All teachers were observed correctly undertaking safe blood collection and handling, accurate RDT interpretation, and correct dispensing of ACT. The most commonly observed errors were a failure to wait 20 minutes before reading the test result, and adding an incorrect volume of buffer to the test cassette. CONCLUSION: Following training, teachers are able to competently use RDTs and ACTs test and treat children at school for uncomplicated malaria safely and accurately. Teachers demonstrate a comparable level of RDT use relative to non-health professional users of RDTs, and sustain this competency over a period of seven months during routine implementation.

Patient-, health worker-, and health facility-level determinants of correct malaria case management at publicly funded health facilities in Malawi: results from a nationally representative health facility survey.

BACKGROUND: Prompt and effective case management is needed to reduce malaria morbidity and mortality. However, malaria diagnosis and treatment is a multistep process that remains problematic in many settings, resulting in missed opportunities for effective treatment as well as overtreatment of patients without malaria. METHODS: Prior to the widespread roll-out of malaria rapid diagnostic tests (RDTs) in late 2011, a national, cross-sectional, complex-sample, health facility survey was conducted in Malawi to assess patient-, health worker-, and health facility-level factors associated with malaria case management quality using multivariate Poisson regression models. RESULTS: Among the 2,019 patients surveyed, 34% had confirmed malaria defined as presence of fever and parasitaemia on a reference blood smear. Sixty-seven per cent of patients with confirmed malaria were correctly prescribed the first-line anti-malarial, with most cases of incorrect treatment due to missed diagnosis; 31% of patients without confirmed malaria were overtreated with an anti-malarial. More than one-quarter of patients were not assessed for fever or history of fever by health workers. The most important determinants of correct malaria case management were patient-level clinical symptoms, such as spontaneous complaint of fever to health workers, which increased both correct treatment and overtreatment by 72 and 210%, respectively (p<0.0001). Complaint of cough was associated with a 27% decreased likelihood of correct malaria treatment (p=0.001). Lower-level cadres of health workers were more likely to prescribe anti-malarials for patients, increasing the likelihood of both correct treatment and overtreatment, but no other health worker or health facility-level factors were significantly associated with case management quality. CONCLUSIONS: Introduction of RDTs holds potential to improve malaria case management in Malawi, but health workers must systematically assess all patients for fever, and then test and treat accordingly, otherwise, malaria control programmes might miss an opportunity to dramatically improve malaria case management, despite better diagnostic tools.

Effectiveness of intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy on maternal and birth outcomes in Machinga district, Malawi.

BACKGROUND: Malaria during pregnancy is associated with low birth weight and increased perinatal mortality, especially among primigravidae. Despite increasing prevalence of malarial parasite resistance to sulfadoxine-pyrimethamine (SP), SP continues to be recommended for intermittent preventive treatment in pregnancy (IPTp). METHODS: Women without human immunodeficiency virus infection were enrolled upon delivery. Data on the number of SP doses received during pregnancy were recorded. The primary outcome was placental infection demonstrated by histologic analysis. Secondary outcomes included malaria parasitemia (in peripheral, placental, cord blood specimens) at delivery and composite birth outcome (small for gestational age, preterm delivery, or low birth weight). RESULTS.: Of 703 women enrolled, 22% received <2 SP doses. Receipt of ≥ 2 SP doses had no impact on histologically confirmed placental infection. IPTp-SP was associated with a dose-dependent protective effect on composite birth outcome in primigravidae, with an adjusted prevalence ratio of 0.50 (95% confidence interval [CI], .30-.82), 0.30 (95% CI, .19-.48), and 0.18 (95% CI, .05-.61) for 1, 2, and ≥ 3 doses, respectively, compared with 0 doses. CONCLUSIONS: IPTp-SP did not reduce the frequency of placental infection but was associated with improved birth outcomes. Few women received no SP, so the true effect of IPTp-SP may be underestimated. Malawian pregnant women should continue to receive IPTp-SP, but alternative strategies and antimalarials for preventing malaria during pregnancy should be investigated.

Adherence to treatment with artemether-lumefantrine for uncomplicated malaria in rural Malawi.

BACKGROUND: In 2007, Malawi replaced the first-line medication for uncomplicated malaria, sulfadoxine-pyrimethamine-a single-dose regimen-with artemether-lumefantrine (AL)-a 6-dose, 3-day regimen. Because of concerns about the complex dosing schedule, we assessed patient adherence to AL 2 years after routine implementation. METHODS: Adults and children with uncomplicated malaria were recruited at 3 health centers. We conducted both pill counts and in-home interviews on medication consumption 72 hours after patients received AL. Complete adherence was defined as correctly taking all 6 AL doses, as assessed by pill count and dose recall. We used logistic regression to identify factors associated with complete adherence. RESULTS: Of 386 patients, 65% were completely adherent. Patients were significantly more likely to be completely adherent if they received their first dose of AL as directly observed therapy at the health center (odds ratio [OR], 2.4; P < .01), received instructions using the medication package as a visual aid (OR, 2.5; P = .02), and preferred AL over other antimalarials (OR, 2.7; P < .001). In contrast, children <5 years of age were significantly less likely to be adherent (OR, 0.5; P = .05). CONCLUSIONS: Adherence to AL treatment for uncomplicated malaria was moderate, and children, who are the most likely to die of malaria, were less adherent than adults. Efforts to improve adherence should be focused on this vulnerable group. Interventions including the introduction of child-friendly antimalarial formulations, direct observation of the first dose, use of the AL package as a visual aid for instructions, and enhancing patient preference for AL could potentially increase AL adherence and overall effectiveness.

Feasibility and acceptability of ACT for the community case management of malaria in urban settings in five African sites.

BACKGROUND: The community case management of malaria (CCMm) is now an established route for distribution of artemisinin-based combination therapy (ACT) in rural areas, but the feasibility and acceptability of the approach through community medicine distributors (CMD) in urban areas has not been explored. It is estimated that in 15 years time 50% of the African population will live in urban areas and transmission of the malaria parasite occurs in these densely populated areas. METHODS: Pre- and post-implementation studies were conducted in five African cities: Ghana, Burkina Faso, Ethiopia and Malawi. CMDs were trained to educate caregivers, diagnose and treat malaria cases in < 5-year olds with ACT. Household surveys, focus group discussions and in-depth interviews were used to evaluate impact. RESULTS: Qualitative findings: In all sites, interviews revealed that caregivers' knowledge of malaria signs and symptoms improved after the intervention. Preference for CMDs as preferred providers for malaria increased in all sites.Quantitative findings: 9001 children with an episode of fever were treated by 199 CMDs in the five study sites. Results from the CHWs registers show that of these, 6974 were treated with an ACT and 6933 (99%) were prescribed the correct dose for their age. Fifty-four percent of the 3,025 children for which information about the promptness of treatment was available were treated within 24 hours from the onset of symptoms.From the household survey 3700 children were identified who had an episode of fever during the preceding two weeks. 1480 (40%) of them sought treatment from a CMD and 1213 of them (82%) had received an ACT. Of these, 1123 (92.6%) were administered the ACT for the correct number of doses and days; 773 of the 1118 (69.1%) children for which information about the promptness of treatment was available were treated within 24 hours from onset of symptoms, and 768 (68.7%) were treated promptly and correctly. CONCLUSIONS: The concept of CCMm in an urban environment was positive, and caregivers were generally satisfied with the services. Quality of services delivered by CMDs and adherence by caregivers are similar to those seen in rural CCMm settings. The proportion of cases seen by CMDs, however, tended to be lower than was generally seen in rural CCMm. Urban CCMm is feasible, but it struggles against other sources of established healthcare providers. Innovation is required by everyone to make it viable.

Comparative field performance and adherence to test results of four malaria rapid diagnostic tests among febrile patients more than five years of age in Blantyre, Malawi.

BACKGROUND: Malaria rapid diagnostics tests (RDTs) can increase availability of laboratory-based diagnosis and improve the overall management of febrile patients in malaria endemic areas. In preparation to scale-up RDTs in health facilities in Malawi, an evaluation of four RDTs to help guide national-level decision-making was conducted. METHODS: A cross sectional study of four histidine rich-protein-type-2- (HRP2) based RDTs at four health centres in Blantyre, Malawi, was undertaken to evaluate the sensitivity and specificity of RDTs, assess prescriber adherence to RDT test results and explore operational issues regarding RDT implementation. Three RDTs were evaluated in only one health centre each and one RDT was evaluated in two health centres. Light microscopy in a reference laboratory was used as the gold standard. RESULTS: A total of 2,576 patients were included in the analysis. All of the RDTs tested had relatively high sensitivity for detecting any parasitaemia [Bioline SD (97%), First response malaria (92%), Paracheck (91%), ICT diagnostics (90%)], but low specificity [Bioline SD (39%), First response malaria (42%), Paracheck (68%), ICT diagnostics (54%)]. Specificity was significantly lower in patients who self-treated with an anti-malarial in the previous two weeks (odds ratio (OR) 0.5; p-value < 0.001), patients 5-15 years old versus patients > 15 years old (OR 0.4, p-value < 0.001) and when the RDT was performed by a community health worker versus a laboratory technician (OR 0.4; p-value < 0.001). Health workers correctly prescribed anti-malarials for patients with positive RDT results, but ignored negative RDT results with 58% of patients with a negative RDT result treated with an anti-malarial. CONCLUSIONS: The results of this evaluation, combined with other published data and global recommendations, have been used to select RDTs for national scale-up. In addition, the study identified some key issues that need to be further delineated: the low field specificity of RDTs, variable RDT performance by different cadres of health workers and the need for a robust quality assurance system. Close monitoring of RDT scale-up will be needed to ensure that RDTs truly improve malaria case management.

Comparison of anaemia and parasitaemia as indicators of malaria control in household and EPI-health facility surveys in Malawi.

BACKGROUND: The World Health Organization has recommended that anaemia be used as an additional indicator to monitor malaria burden at the community level as malaria interventions are nationally scaled up. To date, there are no published evaluations of this recommendation. METHODS: To evaluate this recommendation, a comparison of anaemia and parasitaemia among 6-30 month old children was made during two repeated cross-sectional household (HH) and health facility (HF) surveys in six districts across Malawi at baseline (2005) and in a follow-up survey (2008) after a scale up of malaria control interventions. RESULTS: HH net ownership did not increase between the years (50.5% vs. 49.8%), but insecticide treated net (ITN) ownership increased modestly from 41.5% (95% CI: 37.2%-45.8%) in 2005 to 45.3% (95% CI: 42.6%-48.0%) in 2008. ITN use by children 6-30 months old, who were living in HH with at least one net, increased from 73.6% (95% CI:68.2%-79.1%) to 80.0% (95% CI:75.9%-84.1%) over the three-year period. This modest increase in ITN use was associated with a decrease in moderate to severe anaemia (Hb <8 g/dl) from 18.4% (95% CI:14.9%-21.8%) in 2005 to 15.4% (13.2%-17.7%) in 2008, while parasitaemia, measured as positive-slide microscopy, decreased from 18.9% (95% CI:14.7%-23.2%) to 16.9% (95% CI:13.8%-20.0%), a relative reduction of 16% and 11%, respectively. In HF surveys, anaemia prevalence decreased from 18.3% (95% CI: 14.9%-21.7%) to 15.4% (95% CI: 12.7%-18.2%), while parasitaemia decreased from 30.6% (95% CI: 25.7%-35.5%) to 13.2% (95% CI: 10.6%-15.8%), a relative reduction of 15% and 57%, respectively. CONCLUSION: Increasing access to effective malaria prevention was associated with a reduced burden of malaria in young Malawian children. Anaemia measured at the HF level at time of routine vaccination may be a good surrogate indicator for its measurement at the HH level in evaluating national malaria control programmes.

Prevalence and Clinical Management of Non-malarial Febrile Illnesses among Outpatients in the Era of Universal Malaria Testing in Malawi.

Increasing access to rapid diagnostic tests for malaria (mRDTs) has raised awareness of the challenges healthcare workers face in managing non-malarial febrile illnesses (NMFIs). We examined NMFI prevalence, clinical diagnoses, and prescribing practices in outpatient clinics across different malaria transmission settings in Malawi. Standardized facility-based malaria surveillance was conducted at three facilities one of every 4 weeks over 2 years. Information on demographics, presenting symptoms, temperature, clinical diagnosis, and treatment were collected from outpatients presenting with malaria-like symptoms. Of the 25,486 patients with fever, 69% had NMFI. Non-malarial febrile illness prevalence was lower in 5- to 15-year-old patients (55%) than in children < 5 years (72%) and adults > 15 years of age (77%). The most common clinical diagnoses among febrile patients with negative mRDTs in all age-groups and settings were respiratory infections (46%), sepsis (29%), gastroenteritis (13%), musculoskeletal pain (9%), and malaria (5%). Antibiotic prescribing was high in all age-groups and settings. Trimethoprim-sulfamethoxazole (40%) and amoxicillin (29%) were the most commonly prescribed antibiotics and were used for nearly all clinical diagnoses. In these settings with minimal access to diagnostic tools, patients with fever and a negative mRDT received a limited number of clinical diagnoses. Many were likely to be inaccurate and were associated with the inappropriate use of the limited range of available antibiotics. Prescription and diagnostic practices for NMFIs in the facilities require research and policy input. Resource-limited malaria-endemic countries urgently need more point-of-care diagnostic tools and evidence-based diagnosis and treatment algorithms to provide effective and cost-efficient care.