EFFICACY OF REHABILITATION METHODS ON CITRUS CANKER DISEASE IN NORTHERN UGANDA

Citrus ( Citrus sinensis ) is an important crop in Uganda, where it is produced for both domestic consumption and regional markets. Unfortunately it is increasingly devastated by canker disease. Several measures are often recommended for citrus canker management worldwide; the major ones being orchard inspection, quarantines, protective copper sprays and the on-site burning of infected trees. The adoption rate for these options in Northern Uganda has not been possible and as a result, the disease has reached epiphytotic level. Cultural practices and phytosanitary measures, consisting of removal of inoculum sources, timely application of protective chemical sprays and field sanitation could restore citrus orchards in areas affected by citrus canker. This study was carried out to determine the most effective method of eliminating inoculum sources and appropriate chemical sprays after inoculum suppression, to prevent re-infection. On-station trials were carried out in three fields (orchards), with 90-100% of trees infected at the beginning of the experiment. Treatments evaluated were: (i) bark horning during the dry season, (ii) bark horning during the wet season, and (iii) protective copper sprays. Each orchard was divided into three portions and each portion consisted of a minimum of 10 trees. For each orchard, one portion received bark horning treatment during the wet season (November) and the other portion during the dry season (December). The third portion was treated with 0.2% copper oxychloride. Inspection and removal of twigs emerging with symptoms two months after bark horning treatment, application of protective copper and insecticide sprays two, three and four months after bark horning were administered as a follow up treatments to bark horning. The effect of treatments on citrus canker incidence was significant (P<0.05). The incidence of re-infection was highest in plots that were bark horned during the wet season (23.4%), and lowest in plots bark horned during the dry season (3.3%). Complete bark horning of infected orchards at the beginning of dry season, followed by at least 6 months of regular orchard inspection; removal of re-infected branches and judicious application of chemical sprays (copper oxychloride fungicide and pyrinex insecticide) was the best option for managing citrus canker disease. Use of cultural practice and phytosanitary measures is, hence, recommended.Le citronnier ( Citrus sinensis ) est une culture importante en Ouganda, o\uf9 il est produit pour la consommation domestique et pour des march\ue9s r\ue9gionaux. Malheureusement, il est de plus en plus d\ue9vast\ue9 par la maladie du chancre. Plusieurs mesures sont souvent recommand\ue9es pour le contr\uf4le du chancre du citronnier dans le monde, entre autre les plus importantes sont l\u2019inspection des vergers, la mise en quarantaine, pulv\ue9risation protective du cuivre et l\u2019incin\ue9ration des arbres infect\ue9s. L\u2019adoption de ces pratiques au nord de l\u2019Ouganda n\u2019a pas \ue9t\ue9 possible, et en cons\ue9quence, la maladie a atteint un niveau \ue9piphytotique. Ces pratiques culturales et mesures phytosanitaires consistant \ue0 l\u2019enl\ue8vement des sources d\u2019inoculum, application opportune des produits chimiques de pulv\ue9risation et la sanitation du champ pourraient restaurer les vergers de citronniers dans les milieux affect\ue9s par le chancre du citronnier. Cette \ue9tude \ue9tait conduite pour d\ue9terminer la m\ue9thode la plus efficace pour l\u2019enl\ue8vement des sources d\u2019inoculum et les produits chimiques appropri\ue9s de pulv\ue9risation apr\ue8s l\u2019enl\ue8vement de l\u2019inoculum, afin de s\u2019assurer que les vergers ne seront plus r\ue9infect\ue9s. Des essais en station \ue9taient utilis\ue9s pour \ue9valuer les syst\ue8mes de gestion int\ue9gr\ue9e du chancre du citronnier. Ces essais \ue9taient conduits dans vergers, avec 90-100% d\u2019arbres infectes au d\ue9but de l\u2019exp\ue9rimentation. Les traitements incluaient: (i) bark horning pendant la saison s\ue8che, (ii) bark horning pendant la saison humide, et (iii) pulv\ue9risation protective du cuivre. Chaque verger \ue9tait subdivis\ue9 en trois parties et chaque partie contenait un minimum de dix arbres. Chaque partie de chaque verger avait re\ue7u un traitement de bark horning pendant la saison humide (Novembre) et l\u2019autre portion durant la saison s\ue8che (D\ue9cembre). La troisi\ue8me partie \ue9tait trait\ue9e avec 0.2% de l\u2019oxychlorure de cuivre. L\u2019inspection et l\u2019enl\ue8vement des brindilles poussant avec sympt\uf4mes deux mois apr\ue8s le traitement du bark horning, application protective du cuivre et la deuxi\ue8me pulv\ue9risation d\u2019insecticide, trois et quatre mois apr\ue8s l\u2019administration du bark horning comme traitements de suivi du bark horning. L\u2019effet de traitements sur le chancre du citronnier \ue9tait significatif (P<0.05). L\u2019incidence de la r\ue9infection \ue9tait la plus \ue9lev\ue9e dans les parcelles trait\ue9es avec le bark horn pendant la saison humide (23.4%), et moins \ue9lev\ue9e dans celles trait\ue9es avec le bark horn pendant la saison s\ue8che (3.3%). Un traitement complet au bark horn des vergers infect\ue9s au d\ue9but de la saison humide, suivi d\u2019au moins six mois d\u2019inspection r\ue9guli\ue8re de verger, l\u2019enl\ue8vement des branches r\ue9infect\ue9es et une application judicieuse des pulv\ue9risation chimiques (fongicide du chlorure de cuivre et insecticide pyrinex) \ue9tait la meilleur option pour la gestion du chancre du citronnier. L\u2019utilisation de la pratique culturale et les mesures phytosanitaires, et ainsi recommand\ue9e

The Impact of an Intervention to Improve Malaria Care in Public Health Centers on Health Indicators of Children in Tororo, Uganda (PRIME): A Cluster-Randomized Trial.

Optimizing quality of care for malaria and other febrile illnesses is a complex challenge of major public health importance. To evaluate the impact of an intervention aiming to improve malaria case management on the health of community children, a cluster-randomized trial was conducted from 2010-2013 in Tororo, Uganda, where malaria transmission is high. Twenty public health centers were included; 10 were randomized in a 1:1 ratio to intervention or control. Households within 2 km of health centers provided the sampling frame for the evaluation. The PRIME intervention included training in fever case management using malaria rapid diagnostic tests (mRDTs), patient-centered services, and health center management; plus provision of mRDTs and artemether-lumefantrine. Cross-sectional community surveys were conducted at baseline and endline (N = 8,766), and a cohort of children was followed for approximately 18 months (N = 992). The primary outcome was prevalence of anemia (hemoglobin < 11.0 g/dL) in children under 5 years of age in the final community survey. The intervention was delivered successfully; however, no differences in prevalence of anemia or parasitemia were observed between the study arms in the final community survey or the cohort. In the final survey, prevalence of anemia in children under 5 years of age was 62.5% in the intervention versus 63.1% in control (adjusted risk ratio = 1.01; 95% confidence interval = 0.91-1.13; P = 0.82). The PRIME intervention, focusing on training and commodities, did not produce the expected health benefits in community children in Tororo. This challenges common assumptions that improving quality of care and access to malaria diagnostics will yield health gains

The impact of an intervention to introduce malaria rapid diagnostic tests on fever case management in a high transmission setting in Uganda: A mixed-methods cluster-randomized trial (PRIME).

Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda. A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT. There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 95\% CI: 0.56, 1.17 p = 0.24). Most children (76.0\%) tested positive by reference mRDT, but many were not prescribed AL (22.5\% intervention versus 25.9\% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3\% invention vs 42.4\% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure. The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management

Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

BACKGROUND: New antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. CASE DESCRIPTION: Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. DISCUSSION AND EVALUATION: Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. CONCLUSION: Although the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy

Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>Artesunate-amodiaquine (AS&AQ) is a widely used artemisinin combination therapy (ACT) for falciparum malaria. A comprehensive appreciation of its effects on haematology <it>vs </it>other anti-malarials is needed in view of potential safety liabilities.</p> <p>Methods</p> <p>Individual-patient data analysis conducted on a database from seven randomized controlled trials conducted in sub-Saharan African comparing AS&AQ to reference treatments in uncomplicated falciparum malaria patients of all ages. Haematologic values (white cells total and neutrophil counts, haemoglobin/haematocrit, platelets) were analysed as both continuous and categorical variables for their occurrence, (severity grade 1-4) and changes during follow-up. Risks and trends were calculated using multivariate logistic random effect models.</p> <p>Results</p> <p>4,502 patients (72% < 5 years old), from 13 sites in nine countries with 28-day follow-up were treated with AS&AQ (45%) or a comparator (other forms of ACT accounted for 27%, other combination 12%, mono-therapies 16%). Pre-treatment leucopaenia (3%) and neutropaenia (6%) were infrequent; anaemia was common (39%). The treatment-emergent adverse events incidence (TEAE = condition not present or less severe pre-treatment) was 11% for neutropaenia, 6% for thrombocytopaenia with AS&AQ and not different from treatment groups; anaemia was higher with AS&AQ (20%) or other forms of ACT (22%) than in non-artemisinin groups (4%, <it>p </it>= 0.001). Multivariate analysis showed that the risk of anaemia, thrombocytopaenia, and leucopaenia decreased with follow-up time, while neutropaenia increased; the risk of anaemia and thrombocytopaenia increased with higher baseline parasitaemia and parasitological reappearance. White cells total count was not a good surrogate for neutropaenia. No systematic significant difference between treatments was detected. Older patients were at lower risks.</p> <p>Conclusion</p> <p>The effects of AS&AQ on haematologic parameters were not different from those of other anti-malarial treatments used in sub-Saharan Africa. This analysis provides the basis for a broader evaluation of haematology following anti-malarial treatment. Continuing monitoring of haematologic safety on larger databases is required.</p

Impact of COVID-19 on routine malaria indicators in rural Uganda: an interrupted time series analysis.

BACKGROUND: In March 2020, the government of Uganda implemented a strict lockdown policy in response to the COVID-19 pandemic. Interrupted time series analysis (ITSA) was performed to assess whether major changes in outpatient attendance, malaria burden, and case management occurred after the onset of the COVID-19 epidemic in rural Uganda. METHODS: Individual level data from all outpatient visits collected from April 2017 to March 2021 at 17 facilities were analysed. Outcomes included total outpatient visits, malaria cases, non-malarial visits, proportion of patients with suspected malaria, proportion of patients tested using rapid diagnostic tests (RDTs), and proportion of malaria cases prescribed artemether-lumefantrine (AL). Poisson regression with generalized estimating equations and fractional regression was used to model count and proportion outcomes, respectively. Pre-COVID trends (April 2017-March 2020) were used to predict the'expected' trend in the absence of COVID-19 introduction. Effects of COVID-19 were estimated over two six-month COVID-19 time periods (April 2020-September 2020 and October 2020-March 2021) by dividing observed values by expected values, and expressed as ratios. RESULTS: A total of 1,442,737 outpatient visits were recorded. Malaria was suspected in 55.3% of visits and 98.8% of these had a malaria diagnostic test performed. ITSA showed no differences between observed and expected total outpatient visits, malaria cases, non-malarial visits, or proportion of visits with suspected malaria after COVID-19 onset. However, in the second six months of the COVID-19 time period, there was a smaller mean proportion of patients tested with RDTs compared to expected (relative prevalence ratio (RPR) = 0.87, CI (0.78-0.97)) and a smaller mean proportion of malaria cases prescribed AL (RPR = 0.94, CI (0.90-0.99)). CONCLUSIONS: In the first year after the COVID-19 pandemic arrived in Uganda, there were no major effects on malaria disease burden and indicators of case management at these 17 rural health facilities, except for a modest decrease in the proportion of RDTs used for malaria diagnosis and the mean proportion of malaria cases prescribed AL in the second half of the COVID-19 pandemic year. Continued surveillance will be essential to monitor for changes in trends in malaria indicators so that Uganda can quickly and flexibly respond to challenges imposed by COVID-19

An Economic Evaluation of Home Management of Malaria in Uganda: An Interactive Markov Model

BACKGROUND: Home management of malaria (HMM), promoting presumptive treatment of febrile children in the community, is advocated to improve prompt appropriate treatment of malaria in Africa. The cost-effectiveness of HMM is likely to vary widely in different settings and with the antimalarial drugs used. However, no data on the cost-effectiveness of HMM programmes are available. METHODS/PRINCIPAL FINDINGS: A Markov model was constructed to estimate the cost-effectiveness of HMM as compared to conventional care for febrile illnesses in children without HMM. The model was populated with data from Uganda, but is designed to be interactive, allowing the user to adjust certain parameters, including the antimalarials distributed. The model calculates the cost per disability adjusted life year averted and presents the incremental cost-effectiveness ratio compared to a threshold value. Model output is stratified by level of malaria transmission and the probability that a child would receive appropriate care from a health facility, to indicate the circumstances in which HMM is likely to be cost-effective. The model output suggests that the cost-effectiveness of HMM varies with malaria transmission, the probability of appropriate care, and the drug distributed. Where transmission is high and the probability of appropriate care is limited, HMM is likely to be cost-effective from a provider perspective. Even with the most effective antimalarials, HMM remains an attractive intervention only in areas of high malaria transmission and in medium transmission areas with a lower probability of appropriate care. HMM is generally not cost-effective in low transmission areas, regardless of which antimalarial is distributed. Considering the analysis from the societal perspective decreases the attractiveness of HMM. CONCLUSION: Syndromic HMM for children with fever may be a useful strategy for higher transmission settings with limited health care and diagnosis, but is not appropriate for all settings. HMM may need to be tailored to specific settings, accounting for local malaria transmission intensity and availability of health services

Efficacy, Safety, and Tolerability of Three Regimens for Prevention of Malaria: A Randomized, Placebo-Controlled Trial in Ugandan Schoolchildren

BACKGROUND: Intermittent preventive treatment (IPT) is a promising malaria control strategy; however, the optimal regimen remains unclear. We conducted a randomized, single-blinded, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of a single course of sulfadoxine-pyrimethamine (SP), amodiaquine + SP (AQ+SP) or dihydroartemisinin-piperaquine (DP) among schoolchildren to inform IPT. METHODS: Asymptomatic girls aged 8 to 12 years and boys aged 8 to 14 years enrolled in two primary schools in Tororo, Uganda were randomized to receive one of the study regimens or placebo, regardless of presence of parasitemia at enrollment, and followed for 42 days. The primary outcome was risk of parasitemia at 42 days. Survival analysis was used to assess differences between regimens. RESULTS: Of 780 enrolled participants, 769 (98.6%) completed follow-up and were assigned a treatment outcome. The risk of parasitemia at 42 days varied significantly between DP (11.7% [95% confidence interval (CI): 7.9, 17.1]), AQ+SP (44.3% [37.6, 51.5]), and SP (79.7% [95% CI: 73.6, 85.2], p<0.001). The risk of parasitemia in SP-treated children was no different than in those receiving placebo (84.6% [95% CI: 79.1, 89.3], p = 0.22). No serious adverse events occurred, but AQ+SP was associated with increased risk of vomiting compared to placebo (13.0% [95% CI: 9.1, 18.5] vs. 4.7% [95% CI: 2.5, 8.8], respectively, p = 0.003). CONCLUSIONS: DP was the most efficacious and well-tolerated regimen tested, although AQ+SP appears to be a suitable alternative for IPT in schoolchildren. Use of SP for IPT may not be appropriate in areas with high-level SP resistance in Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT00852371

Safety profile of Coartem®: the evidence base

This article reviews the comprehensive data on the safety and tolerability from over 6,300 patients who have taken artemether/lumefantrine (Coartem®) as part of Novartis-sponsored or independently-sponsored clinical trials. The majority of the reported adverse events seen in these studies are mild or moderate in severity and tend to affect the gastrointestinal or nervous systems. These adverse events, which are common in both adults and children, are also typical of symptoms of malaria or concomitant infections present in these patients. The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. This finding is especially relevant for children from regions with high malaria transmission rates who often receive many courses of anti-malarial medications during their lifetime. Data are also available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations. In addition, post-marketing experience, based on the delivery of 250 million treatments as of July 2009, has not identified any new safety concerns for artemether/lumefantrine apart from hypersensitivity and allergies, known class effects of artemisinin derivatives