Baseline prevalence of molecular marker of sulfadoxine/pyrimethamine resistance in Ebonyi and Osun states, Nigeria: amplicon deep sequencing of dhps-540.

BACKGROUND: Chemoprevention plays an important role in malaria control strategy. Perennial malaria chemoprevention (PMC) using sulfadoxine/pyrimethamine (SP) is a WHO-approved strategy to combat malaria in young children and may lead to drug pressure. Introducing SP-PMC may therefore be compromised due to the emergence of Plasmodium falciparum resistant to SP, particularly mutation at K540E of the dihydropteroate synthase (dhps) gene. Molecular surveillance of resistance markers can support assessment of antimalarial efficacy and effectiveness. High prevalence of 540E is associated with reduced effectiveness of SP, and areas with more than 50% prevalence are considered unsuitable for intermittent preventative treatment in pregnancy (IPTp) implementation. Assessing 540E prevalence is an important undertaking before implementation of SP-PMC. METHODS: We conducted a rapid surveillance of dhps-540E to assess the suitability of SP as PMC in field studies from Ebonyi and Osun states in Nigeria. We used an in-house developed amplicon deep-sequencing method targeting part of the dhps gene. RESULTS: Our data reveal that 18.56% of individuals evaluated carried the 540E mutation mixed with the WT K540. Mutant variant 540E alone was not found, and 80% of isolates harboured only WT (K540). Clonal analysis of the sequencing data shows a very low proportion of 540E circulating in both states. CONCLUSIONS: Our data show that both states are suitable for SP-PMC implementation and, based on this finding, SP-PMC was implemented in Osun in 2022. Continuous monitoring of 540E will be required to ensure the chemoprevention effectiveness of SP in Nigeria.

Perennial malaria chemoprevention with and without malaria vaccination to reduce malaria burden in young children: a modelling analysis.

BACKGROUND: A recent WHO recommendation for perennial malaria chemoprevention (PMC) encourages countries to adapt dose timing and number to local conditions. However, knowledge gaps on the epidemiological impact of PMC and possible combination with the malaria vaccine RTS,S hinder informed policy decisions in countries where malaria burden in young children remains high. METHODS: The EMOD malaria model was used to predict the impact of PMC with and without RTS,S on clinical and severe malaria cases in children under the age of two years (U2). PMC and RTS,S effect sizes were fit to trial data. PMC was simulated with three to seven doses (PMC-3-7) before the age of eighteen months and RTS,S with three doses, shown to be effective at nine months. Simulations were run for transmission intensities of one to 128 infectious bites per person per year, corresponding to incidences of < 1 to 5500 cases per 1000 population U2. Intervention coverage was either set to 80% or based on 2018 household survey data for Southern Nigeria as a sample use case. The protective efficacy (PE) for clinical and severe cases in children U2 was calculated in comparison to no PMC and no RTS,S. RESULTS: The projected impact of PMC or RTS,S was greater at moderate to high transmission than at low or very high transmission. Across the simulated transmission levels, PE estimates of PMC-3 at 80% coverage ranged from 5.7 to 8.8% for clinical, and from 6.1 to 13.6% for severe malaria (PE of RTS,S 10-32% and 24.6-27.5% for clinical and severe malaria, respectively. In children U2, PMC with seven doses nearly averted as many cases as RTS,S, while the combination of both was more impactful than either intervention alone. When operational coverage, as seen in Southern Nigeria, increased to a hypothetical target of 80%, cases were reduced beyond the relative increase in coverage. CONCLUSIONS: PMC can substantially reduce clinical and severe cases in the first two years of life in areas with high malaria burden and perennial transmission. A better understanding of the malaria risk profile by age in early childhood and on feasible coverage by age, is needed for selecting an appropriate PMC schedule in a given setting.

The private sector market for malaria rapid diagnostic tests in Nigeria: results of the 2018 market survey.

BACKGROUND: To avoid misuse of anti-malarials, correct diagnosis of fever prior to drug prescription is essential. Presumptive treatment in the private healthcare sector is a concern in Nigeria, where availability of affordable artemisinin-based combination therapy (ACT) is high following the implementation of subsidy schemes from 2010 to 2017. Similar subsidies have not, however, been implemented for malaria rapid diagnostic tests (RDTs). A market survey in 2018 predominantly designed to assess the ACT market in the private sector also collected data related to RDTs, results of which are presented herein. METHODS: A 2018 market survey consisted of (i) an outlet survey targeting private pharmacies and Proprietary and Patent Medicine Vendors (PPMVs) across different regions of Nigeria to assess supply-side market factors related to availability of RDTs (defined as having stock available for purchase at the time of the survey) and (ii) a household survey to determine demand-side factors related to knowledge of RDTs, healthcare-seeking practices and affordability. RESULTS: Availability of RDTs at the time of the survey was low in both outlet types and significantly lower in PPMVs (22.1%, 95% CI) among pharmacies versus (13.6%, 95% CI) among PPMVs (p < 0.01). Reasons for not restocking RDTs included low demand and no supply. The majority of households diagnose malaria based on experience, while one-third would visit a PPMV or pharmacy. Half of households had heard of RDTs (48.4%) and 38.6% thought they were affordable. CONCLUSIONS: Low availability of RDTs among PPMVs and pharmacies may be attributed to lack of demand, supply-side issues and cost. Increasing household knowledge of RDTs may aid increasing demand, while subsidized RDTs may address supply and price issues. Addressing the deficit in RDT provision is important for targeting of ACT medicines.

The impact of the private sector co-payment mechanism (PSCM) on the private market for ACT in Nigeria: results of the 2018 cross-sectional outlet and household market surveys.

BACKGROUND: The private sector plays a large role in malaria treatment provision in Nigeria. To improve access to, and affordability of, quality-assured artemisinin-based combination therapy (QA-ACT) within this sector, the Affordable Medicines Facility-Malaria began operations in 2010 and transitioned to a private sector co-payment mechanism (PSCM) until 2017. To assess the impact of the scheme on the ACT market, cross-sectional household and outlet surveys were conducted in 2018 to coincide with the final stockages of ACT medicines procured under the PSCM. METHODS: An outlet survey was conducted targeting private pharmacies and Proprietary and Patent Medicine Vendors (PPMVs) across different regions of Nigeria to assess supply-side market factors related to availability and cost of anti-malarials, including artemisinin-based combinations subsidised under the PSCM (called green leaf ACT on account of their green leaf logo) and those not subsidised (non-green leaf ACT). A concurrent household survey was conducted to determine demand-side factors related to treatment-seeking practices, ACT brand preference and purchase decision. Data were compared with previous ACTWatch surveys to consider change over time. RESULTS: Availability of artemisinin-based combinations increased significantly over the PSCM period and was almost universal by the time of the 2018 market survey. This increase was seen particularly among PPMVs. While the cost of green leaf ACT remained relatively stable over time, the cost of non-green leaf ACT reduced significantly so that by 2018 they had equivalent affordability. Unsubsidised brands were also available in different formulations and dosages, with double-strength artemisinin-based combination reported as the most frequently purchased dosage type, and child artemisinin-based combinations popular in suspension and dispersible forms (forms not subsidised by the PSCM). CONCLUSIONS: The PSCM had a clear impact on increasing not only the reach of subsidized QA brands, but also of non-subsidised brands. Increased market competition led to innovation from unsubsidised brands and large reductions in costs to make them competitive with subsidised brands. Concerns are drawn from the large market share that non-QA brands have managed to gain as well as the continued market share of oral artemisinin monotherapies. Continued monitoring of the market is recommended, along with improved local capacity for QA-certification and monitoring.

Determinants of malaria testing at health facilities: the case of Uganda.

BACKGROUND: The World Health Organization (WHO) recommends prompt malaria diagnosis with either microscopy or malaria rapid diagnostic tests (RDTs) and treatment with an effective anti-malarial, as key interventions to control malaria. However, in sub-Saharan Africa, malaria diagnosis is still often influenced by clinical symptoms, with patients and care providers often interpreting all fevers as malaria. The Ministry of Health in Uganda defines suspected malaria cases as those with a fever. A target of conducting testing for at least 75% of those suspected to have malaria was established by the National Malaria Reduction Strategic Plan 2014-2020. METHODS: This study investigated factors that affect malaria testing at health facilities in Uganda using data collected in March/April 2017 in a cross-sectional survey of health facilities from the 52 districts that are supported by the US President's Malaria Initiative (PMI). The study assessed health facility capacity to provide quality malaria care and treatment. Data were collected from all 1085 public and private health facilities in the 52 districts. Factors assessed included supportive supervision, availability of malaria management guidelines, laboratory infrastructure, and training health workers in the use of malaria rapid diagnostic test (RDT). Survey data were matched with routinely collected health facility malaria data obtained from the district health information system Version-2 (DHIS2). Associations between testing at least 75% of suspect malaria cases with several factors were examined using multivariate logistic regression. RESULTS: Key malaria commodities were widely available; 92% and 85% of the health facilities reported availability of RDTs and artemether-lumefantrine, respectively. Overall, 933 (86%) of the facilities tested over 75% of patients suspected to have malaria. Predictors of meeting the testing target were: supervision in the last 6 months (OR: 1.72, 95% CI 1.04-2.85) and a health facility having at least one health worker trained in the use of RDTs (OR: 1.62, 95% CI 1.04-2.55). CONCLUSION: The study findings underscore the need for malaria control programmes to provide regular supportive supervision to health facilities and train health workers in the use of RDTs.

Eliminating Plasmodium falciparum malaria: results from tailoring active case detection approaches to remote populations in forested border areas in north-eastern Cambodia.

BACKGROUND: Remaining Plasmodium falciparum cases in Cambodia are concentrated in forested border areas and in remote populations who are hard to reach through passive case detection. A key approach to reach these populations is active case detection by mobile malaria workers (MMWs). However, this is operationally challenging because of changing movement patterns of the target population moving into less accessible areas. From January 2018 to December 2020, a tailored package of active case detection approaches was implemented in forested border areas of three provinces in north-eastern Cambodia to reach remote populations and support the elimination of falciparum malaria. METHODS: Key elements of this project were to tailor approaches to local populations, use responsive monitoring systems, maintain operational flexibility, build strong relationships with local communities, and implement close supervision practices. MMWs were recruited from local communities. Proactive case detection approaches included mobile malaria posts positioned at frequented locations around and within forests, and locally informed outreach activities targeting more remote locations. Reactive case detection was conducted among co-travellers of confirmed cases. Testing for malaria was conducted independent of fever symptoms. Routine monitoring of programmatic data informed tactical adaptations, while supervision exercises ensured service quality. RESULTS: Despite operational challenges, service delivery sites were able to maintain consistently high testing rates throughout the implementation period, with each of 45 sites testing a monthly average of 64 (SD 6) people in 2020. In 2020, project MMWs detected only 32 P. falciparum cases. Over the project period, the P. falciparum/P. vivax ratio steadily inversed. Including data from neighbouring health centres and village malaria workers, 45% (80,988/180,732) of all people tested and 39% (1280/3243) of P. falciparum cases detected in the area can be attributed to project MMWs. Remaining challenges of the last elimination phase include maintaining intensified elimination efforts, addressing the issue of detecting low parasitaemia cases and shifting focus to P. vivax malaria. CONCLUSIONS: Reaching remote populations through active case detection should remain a key strategy to eliminate P. falciparum malaria. This case study presented a successful approach combining tailored proactive and reactive strategies that could be transferred to similar settings in other areas of the Greater Mekong Subregion.

A feasibility study to assess non-clinical community health workers' capacity to use simplified protocols and tools to treat severe acute malnutrition in Niger state Nigeria.

BACKGROUND: Severe acute malnutrition (SAM) is a major determinant of childhood mortality and morbidity. Although integrated community case management (iCCM) of childhood illnesses is a strategy for increasing access to life-saving treatment, malnutrition is not properly addressed in the guidelines. This study aimed to determine whether non-clinical Community Health Workers (called Community-Oriented Resource Persons, CORPs) implementing iCCM could use simplified tools to treat uncomplicated SAM. METHODS: The study used a sequential multi-method design and was conducted between July 2017 and May 2018. Sixty CORPs already providing iCCM services were trained and deployed in their communities with the target of enrolling 290 SAM cases. Competency of CORPs to treat and the treatment outcomes of enrolled children were documented. SAM cases with MUAC of 9 cm to < 11.5 cm without medical complications were treated for up to 12 weeks. Full recovery was at MUAC≥12.5 cm for two consecutive weeks. Supervision and quantitative data capturing were done weekly while qualitative data were collected after the intervention. RESULTS: CORPs scored 93.1% on first assessment and increment of 0.11 (95% CI, 0.05-0.18) points per additional supervision conducted. The cure rate from SAM to full recovery, excluding referrals from the denominator in line with the standard for reporting SAM recovery rates, was 73.5% and the median length of treatment was 7 weeks. SAM cases enrolled at 9 cm to < 10.25 cm MUAC had 31% less likelihood of recovery compared to those enrolled at 10.25 cm to < 11.5 cm. CORPs were not burdened by the integration of SAM into iCCM and felt motivated by children's recovery. Operational challenges like bad terrains for supervision, supply chain management and referrals were reported by supervisors, while Government funding was identified as key for sustainability. CONCLUSION: The study demonstrated that with training and supportive supervision, CORPs in Nigeria can treat SAM among under-fives, and refer complicated cases using simplified protocols as part of an iCCM programme. This approach seemed acceptable to all stakeholders, however, the effect of the extra workload of integrating SAM into iCCM on the quality of care provided by the CORPs should be assessed further.

An assessment of the knowledge, practices and resources during the delivery of malaria health care services among private health care practitioners: a cross section study in the Mid-Western Region of Uganda.

BACKGROUND: Approximately 50 % of the population in Uganda seeks health care from private facilities but there is limited data on the quality of care for malaria in these facilities. This study aimed to document the knowledge, practices and resources during the delivery of malaria care services, among private health practitioners in the Mid-Western region of Uganda, an area of moderate malaria transmission. METHODS: This was a cross sectional study in which purposive sampling was used to select fifteen private-for-profit facilities from each district. An interviewer-administered questionnaire that contained both quantitative and open-ended questions was used. Information was collected on availability of treatment aides, knowledge on malaria, malaria case management, laboratory practices, malaria drugs stock and data management. We determined the proportion of health workers that adequately provided malaria case management according to national standards. RESULTS: Of the 135 health facilities staff interviewed, 61.48 % (52.91-69.40) had access to malaria treatment protocols while 48.89 % (40.19-57.63) received malaria training. The majority of facilities, 98.52 % (94.75-99.82) had malaria diagnostic services and the most commonly available anti-malarial drug was artemether-lumefantrine, 85.19 % (78-91), followed by Quinine, 74.81 % (67-82) and intravenous artesunate, 72.59 % (64-80). Only 14.07 % (8.69-21.10) responded adequately to the acceptable cascade of malaria case management practice. Specifically, 33.33 % (25.46-41.96) responded correctly to management of a patient with a fever, 40.00 % (31.67-48.79) responded correctly to the first line treatment for uncomplicated malaria, whereas 85.19 % (78.05-90.71) responded correctly to severe malaria treatment. Only 28.83 % submitted monthly reports, where malaria data was recorded, to the national database. CONCLUSIONS: This study revealed sub-optimal malaria case management knowledge and practices at private health facilities with approximately 14 % of health care workers demonstrating correct malaria case management cascade practices. To strengthen the quality of malaria case management, it is recommended that the NMCD distributes current guidelines and tools, coupled with training; continuous mentorship and supportive supervision; provision of adequate stock of essential anti-malarials and RDTs; reinforcing communication and behavior change; and increasing support for data management at private health facilities.

Health systems readiness and quality of inpatient malaria case-management in Kano State, Nigeria.

BACKGROUND: Nigeria was among the first African countries to adopt and implement change of treatment policy for severe malaria from quinine to artesunate. Seven years after the policy change health systems readiness and quality of inpatient malaria case-management practices were evaluated in Kano State of Nigeria. METHODS: A cross-sectional survey was undertaken in May 2019 at all public hospitals. Data collection comprised hospital assessments, interviews with inpatient health workers and data extraction from medical files for all suspected malaria patients admitted to the paediatric and medical wards in April 2019. Descriptive analyses included 22 hospitals, 154 health workers and 1,807 suspected malaria admissions analysed from malaria test and treat case-management perspective. RESULTS: 73% of hospitals provided malaria microscopy, 27% had rapid diagnostic tests and 23% were unable to perform any parasitological malaria diagnosis. Artemisinin-based combination therapy (ACT) was available at 96% of hospitals, artemether vials at 68% while injectable quinine and artesunate were equally stocked at 59% of hospitals. 32%, 21% and 15% of health workers had been exposed to relevant trainings, guidelines and supervision respectively. 47% of suspected malaria patients were tested while repeat testing was rare (7%). 60% of confirmed severe malaria patients were prescribed artesunate. Only 4% of admitted non-severe test positive cases were treated with ACT, while 76% of test negative patients were prescribed an anti-malarial. Artemether was the most common anti-malarial treatment for non-severe test positive (55%), test negative (43%) and patients not tested for malaria (45%). In all categories of the patients, except for confirmed severe cases, artemether was more commonly prescribed for adults compared to children. 44% of artesunate-treated patients were prescribed ACT follow-on treatment. Overall compliance with test and treat policy for malaria was 13%. CONCLUSIONS: Translation of new treatment policy for severe malaria into inpatient practice is compromised by lack of malaria diagnostics, stock-outs of artesunate and suboptimal health workers' practices. Establishment of the effective supply chain and on-going supportive interventions for health workers accompanied with regular monitoring of the systems readiness and clinical practices are urgently needed.

What drives the consistent use of long-lasting insecticidal nets over time? A multi-method qualitative study in mid-western Uganda.

BACKGROUND: The distribution of long-lasting insecticidal nets (LLINs) through universal coverage campaigns is a widely adopted approach for the prevention of malaria at scale. While post-distribution surveys play a valuable role in determining cross-sectional levels of LLIN retention and use, as well as frequently cited reasons for non-use, few studies have explored the consistency of LLIN use over time, within the expected lifespan of the net, and the factors which may drive this. METHODS: In this qualitative study, 74 in-depth interviews were conducted with (male) household heads and (female) caregivers of children in LLIN recipient households, as well as community health workers, in Buliisa, Hoima and Kiboga districts in Uganda, 25-29 months following a LLIN mass campaign distribution. A triangulation approach to data analysis was taken, incorporating thematic analysis, most significant change and positive deviance. RESULTS: The factors found to be most influential in encouraging long-term LLIN use were positive experience of net use prior to the distribution, and appreciation or awareness of a range of benefits arising from their use, including protection from malaria as well as importantly, other health, lifestyle, social and economic benefits. Social support from within the community was also identified as an important factor in determining continued use of LLINs. Net use appeared to be more consistent amongst settled urban and rural communities, compared with fishing, pastoralist, refugee and immigrant communities. CONCLUSIONS: A multitude of interplaying factors encouraged consistent LLIN use in this setting. Whilst the protection of malaria remains a powerful motivator, social and behaviour change (SBC) strategies should also capitalize on the non-malaria benefits of net use that provide a long-term rationale for consistent use. Where supplies are available, SBC campaigns should promote replacement options, emphasizing ongoing net care and replacement as a household responsibility, thus reducing dependence on free distributions. The triangulation approach to qualitative data analysis enabled increased confidence in the validity of findings and an enhanced contextual understanding of the factors promoting consistent net use in mid-western Uganda. The approach should be considered when designing future studies to explore factors driving net retention and use trends.

Why do health workers give anti-malarials to patients with negative rapid test results? A qualitative study at rural health facilities in western Uganda.

BACKGROUND: The large-scale introduction of malaria rapid diagnostic tests (RDTs) promises to improve management of fever patients and the rational use of valuable anti-malarials. However, evidence on the impact of RDT introduction on the overprescription of anti-malarials has been mixed. This study explored determinants of provider decision-making to prescribe anti-malarials following a negative RDT result. METHODS: A qualitative study was conducted in a rural district in mid-western Uganda in 2011, ten months after RDT introduction. Prescriptions for all patients with negative RDT results were first audited from outpatient registers for a two month period at all facilities using RDTs (n = 30). Facilities were then ranked according to overall prescribing performance, defined as the proportion of patients with a negative RDT result prescribed any anti-malarial. Positive and negative deviant facilities were sampled for qualitative investigation; positive deviants (n = 5) were defined ex post facto as <0.75% and negative deviants (n = 7) as >5%. All prescribing clinicians were targeted for qualitative observation and in-depth interview; 55 fever cases were observed and 22 providers interviewed. Thematic analysis followed the 'framework' approach. RESULTS: 8344 RDT-negative patients were recorded at the 30 facilities (prescription audit); 339 (4.06%) were prescribed an anti-malarial. Of the 55 observed patients, 38 tested negative; one of these was prescribed an anti-malarial. Treatment decision-making was influenced by providers' clinical beliefs, capacity constraints, and perception of patient demands. Although providers generally trusted the accuracy of RDTs, anti-malarial prescription was driven by perceptions of treatment failure or undetectable malaria in patients who had already taken artemisinin-based combination therapy prior to facility arrival. Patient assessment and other diagnostic practices were minimal and providers demonstrated limited ability to identify alternative causes of fever. Provider perceptions of patient expectations sometimes appeared to influence treatment decisions. CONCLUSIONS: The study found high provider adherence to RDT results, but that providers believed in certain clinical exceptions and felt they lacked alternative options. Guidance on how the RDT works and testing following partial treatment, better methods for assisting providers in diagnostic decision-making, and a context-appropriate provider behaviour change intervention package are needed.

Mortality after fluid bolus in African children with severe infection.

BACKGROUND: The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established. METHODS: We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. RESULTS: The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. CONCLUSIONS: Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.).

Mobile health (mHealth) approaches and lessons for increased performance and retention of community health workers in low- and middle-income countries: a review.

BACKGROUND: Mobile health (mHealth) describes the use of portable electronic devices with software applications to provide health services and manage patient information. With approximately 5 billion mobile phone users globally, opportunities for mobile technologies to play a formal role in health services, particularly in low- and middle-income countries, are increasingly being recognized. mHealth can also support the performance of health care workers by the dissemination of clinical updates, learning materials, and reminders, particularly in underserved rural locations in low- and middle-income countries where community health workers deliver integrated community case management to children sick with diarrhea, pneumonia, and malaria. OBJECTIVE: Our aim was to conduct a thematic review of how mHealth projects have approached the intersection of cellular technology and public health in low- and middle-income countries and identify the promising practices and experiences learned, as well as novel and innovative approaches of how mHealth can support community health workers. METHODS: In this review, 6 themes of mHealth initiatives were examined using information from peer-reviewed journals, websites, and key reports. Primary mHealth technologies reviewed included mobile phones, personal digital assistants (PDAs) and smartphones, patient monitoring devices, and mobile telemedicine devices. We examined how these tools could be used for education and awareness, data access, and for strengthening health information systems. We also considered how mHealth may support patient monitoring, clinical decision making, and tracking of drugs and supplies. Lessons from mHealth trials and studies were summarized, focusing on low- and middle-income countries and community health workers. RESULTS: The review revealed that there are very few formal outcome evaluations of mHealth in low-income countries. Although there is vast documentation of project process evaluations, there are few studies demonstrating an impact on clinical outcomes. There is also a lack of mHealth applications and services operating at scale in low- and middle-income countries. The most commonly documented use of mHealth was 1-way text-message and phone reminders to encourage follow-up appointments, healthy behaviors, and data gathering. Innovative mHealth applications for community health workers include the use of mobile phones as job aides, clinical decision support tools, and for data submission and instant feedback on performance. CONCLUSIONS: With partnerships forming between governments, technologists, non-governmental organizations, academia, and industry, there is great potential to improve health services delivery by using mHealth in low- and middle-income countries. As with many other health improvement projects, a key challenge is moving mHealth approaches from pilot projects to national scalable programs while properly engaging health workers and communities in the process. By harnessing the increasing presence of mobile phones among diverse populations, there is promising evidence to suggest that mHealth can be used to deliver increased and enhanced health care services to individuals and communities, while helping to strengthen health systems.

Access, acceptability and utilization of community health workers using diagnostics for case management of fever in Ugandan children: a cross-sectional study.

BACKGROUND: Use of diagnostics in integrated community case management (iCCM) of fever is recognized as an important step in improving rational use of drugs and quality of care for febrile under-five children. This study assessed household access, acceptability and utilization of community health workers (CHWs) trained and provided with malaria rapid diagnostic tests (RDTs) and respiratory rate timers (RRTs) to practice iCCM. METHODS: A total of 423 households with under-five children were enrolled into the study in Iganga district, Uganda. Households were selected from seven villages in Namungalwe sub-county using probability proportionate to size sampling. A semi-structured questionnaire was administered to caregivers in selected households. Data were entered into Epidata statistical software, and analysed using SPSS Statistics 17.0, and STATA version 10. RESULTS: Most (86%, 365/423) households resided within a kilometre of a CHW's home, compared to 26% (111/423) residing within 1 km of a health facility (p < 0.001). The median walking time by caregivers to a CHW was 10 minutes (IQR 5-20). The first option for care for febrile children in the month preceding the survey was CHWs (40%, 242/601), followed by drug shops (33%, 196/601).Fifty-seven percent (243/423) of caregivers took their febrile children to a CHW at least once in the three month period preceding the survey. Households located 1-3 km from a health facility were 72% (AOR 1.72; 95% CI 1.11-2.68) more likely to utilize CHW services compared to households within 1 km of a health facility. Households located 1-3 km from a CHW were 81% (AOR 0.19; 95% CI 0.10-0.36) less likely to utilize CHW services compared to those households residing within 1 km of a CHW.A majority (79%, 336/423) of respondents thought CHWs services were better with RDTs, and 89% (375/423) approved CHWs' continued use of RDTs. Eighty-six percent (209/243) of respondents who visited a CHW thought RRTs were useful. CONCLUSION: ICCM with diagnostics is acceptable, increases access, and is the first choice for caregivers of febrile children. More than half of caregivers of febrile children utilized CHW services over a three-month period. However, one-third of caregivers used drug shops in spite of the presence of CHWs.

Programme level implementation of malaria rapid diagnostic tests (RDTs) use: outcomes and cost of training health workers at lower level health care facilities in Uganda.

BACKGROUND: The training of health workers in the use of malaria rapid diagnostic tests (RDTs) is an important component of a wider strategy to improve parasite-based malaria diagnosis at lower level health care facilities (LLHFs) where microscopy is not readily available for all patients with suspected malaria. This study describes the process and cost of training to attain competence of lower level health workers to perform malaria RDTs in a public health system setting in eastern Uganda. METHODS: Health workers from 21 health facilities in Uganda were given a one-day central training on the use of RDTs in malaria case management, including practical skills on how to perform read and interpret the test results. Successful trainees subsequently integrated the use of RDTs into their routine care for febrile patients at their LLHFs and transferred their acquired skills to colleagues (cascade training model). A cross-sectional evaluation of the health workers' competence in performing RDTs was conducted six weeks following the training, incorporating observation, in-depth interviews with health workers and the review of health facility records relating to tests offered and antimalarial drug (AMD) prescriptions pre and post training. The direct costs relating to the training processes were also documented. RESULTS: Overall, 135 health workers were trained including 63 (47%) nursing assistants, a group of care providers without formal medical training. All trainees passed the post-training concordance test with ≥ 80% except 12 that required re-training. Six weeks after the one-day training, 51/64 (80%) of the health workers accurately performed the critical steps in performing the RDT. The performance was similar among the 10 (16%) participants who were peer-trained by their trained colleagues. Only 9 (14%) did not draw the appropriate amount of blood using pipette. The average cost of the one-day training was US$ 101 (range $92-$112), with the main cost drivers being trainee travel and per-diems. Health workers offered RDTs to 76% of febrile patients and AMD prescriptions reduced by 37% six weeks post-training. CONCLUSION: One-day training on the use of RDTs successfully provided adequate skill and competency among health workers to perform RDTs in fever case management at LLHF in a Uganda setting. The cost averaged at US$101 per health worker trained, with the main cost drivers being trainee travel and per diems. Given the good peer training noted in this study, there is need to explore the cost-effectiveness of a cascade training model for large scale implementation of RDTs.

Current malaria infection, previous malaria exposure, and clinical profiles and outcomes of COVID-19 in a setting of high malaria transmission: an exploratory cohort study in Uganda.

BACKGROUND: The potential effects of SARS-CoV-2 and Plasmodium falciparum co-infection on host susceptibility and pathogenesis remain unknown. We aimed to establish the prevalence of malaria and describe the clinical characteristics of SARS-CoV-2 and P falciparum co-infection in a high-burden malaria setting. METHODS: This was an exploratory prospective, cohort study of patients with COVID-19 who were admitted to hospital in Uganda. Patients of all ages with a PCR-confirmed diagnosis of SARS-CoV-2 infection who had provided informed consent or assent were consecutively enrolled from treatment centres in eight hospitals across the country and followed up until discharge or death. Clinical assessments and blood sampling were done at admission for all patients. Malaria diagnosis in all patients was done by rapid diagnostic tests, microscopy, and molecular methods. Previous P falciparum exposure was determined with serological responses to a panel of P falciparum antigens assessed using a multiplex bead assay. Additional evaluations included complete blood count, markers of inflammation, and serum biochemistries. The main outcome was overall prevalence of malaria infection and malaria prevalence by age (including age categories of 0-20 years, 21-40 years, 41-60 years, and >60 years). The frequency of symptoms was compared between patients with COVID-19 with P falciparum infection versus those without P falciparum infection. The frequency of comorbidities and COVID-19 clinical severity and outcomes was compared between patients with low previous exposure to P falciparum versus those with high previous exposure to P falciparum. The effect of previous exposure to P falciparum on COVID-19 clinical severity and outcomes was also assessed among patients with and those without comorbidities. FINDINGS: Of 600 people with PCR-confirmed SARS-CoV-2 infection enrolled from April 15, to Oct 30, 2020, 597 (>99%) had complete information and were included in our analyses. The majority (502 [84%] of 597) were male individuals with a median age of 36 years (IQR 28-47). Overall prevalence of P falciparum infection was 12% (95% CI 9·4-14·6; 70 of 597 participants), with highest prevalence in the age groups of 0-20 years (22%, 8·7-44·8; five of 23 patients) and older than 60 years (20%, 10·2-34·1; nine of 46 patients). Confusion (four [6%] of 70 patients vs eight [2%] of 527 patients; p=0·040) and vomiting (four [6%] of 70 patients vs five [1%] of 527 patients; p=0·014] were more frequent among patients with P falciparum infection than those without. Patients with low versus those with high previous P falciparum exposure had a increased frequency of severe or critical COVID-19 clinical presentation (16 [30%] of 53 patients vs three [5%] of 56 patients; p=0·0010) and a higher burden of comorbidities, including diabetes (12 [23%] of 53 patients vs two [4%] of 56 patients; p=0·0010) and heart disease (seven [13%] of 53 patients vs zero [0%] of 56 patients; p=0·0030). Among patients with no comorbidities, those with low previous P falciparum exposure still had a higher proportion of cases of severe or critical COVID-19 than did those with high P falciparum exposure (six [18%] of 33 patients vs one [2%] of 49 patients; p=0·015). Multivariate analysis showed higher odds of unfavourable outcomes in patients who were older than 60 years (adjusted OR 8·7, 95% CI 1·0-75·5; p=0·049). INTERPRETATION: Although patients with COVID-19 with P falciparum co-infection had a higher frequency of confusion and vomiting, co-infection did not seem deleterious. The association between low previous malaria exposure and severe or critical COVID-19 and other adverse outcomes will require further study. These preliminary descriptive observations highlight the importance of understanding the potential clinical and therapeutic implications of overlapping co-infections. FUNDING: Malaria Consortium (USA).

Limited ability of Plasmodium falciparum pfcrt, pfmdr1, and pfnhe1 polymorphisms to predict quinine in vitro sensitivity or clinical effectiveness in Uganda.

Quinine is a standard drug for treating severe malaria in Africa, and it is also increasingly used to treat uncomplicated disease. However, failures of quinine therapy are common, and it is unknown if failures in Africa are due to drug resistance. Recent studies have identified associations between in vitro quinine sensitivity and polymorphisms in genes encoding putative transporters, including well-described polymorphisms in pfcrt and pfmdr1 and varied numbers of DNNND or DDNHNDNHNND repeats in microsatellite 4760 (ms4760) of the predicted sodium-hydrogen exchanger, pfnhe1. To better characterize mediators of quinine response, we assessed associations between genetic polymorphisms, in vitro quinine sensitivity, and quinine treatment responses in Kampala, Uganda. Among 172 fresh clinical isolates tested in vitro, decreasing sensitivity to quinine was associated with accumulation of pfmdr1 mutations at codons 86, 184, and 1246. Nearly all parasites had pfcrt 76T, preventing analysis of associations with this mutation. pfnhe1 ms4760 was highly polymorphic. Parasites with 2 copies of either ms4760 repeat showed modest decreases in quinine sensitivity compared to those with 1 or ≥3 repeats, but the differences were not statistically significant. None of the above polymorphisms predicted treatment failure among 66 subjects treated with quinine for uncomplicated malaria. Our data suggest that quinine sensitivity is a complex trait and that known polymorphisms in pfcrt, pfmdr1, and pfnhe1, while associated with quinine sensitivity, are not robust markers for quinine resistance.

Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria.

Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.

Placental Plasmodium falciparum malaria infection: operational accuracy of HRP2 rapid diagnostic tests in a malaria endemic setting.

BACKGROUND: Malaria has a negative effect on the outcome of pregnancy. Pregnant women are at high risk of severe malaria and severe haemolytic anaemia, which contribute 60-70% of foetal and perinatal losses. Peripheral blood smear microscopy under-estimates sequestered placental infections, therefore malaria rapid diagnostic tests (RDTs) detecting histidine rich protein-2 antigen (HRP-2) in peripheral blood are a potential alternative. METHODS: HRP-2 RDTs accuracy in detecting malaria in pregnancy (MIP >28 weeks gestation) and placental Plasmodium falciparum malaria (after childbirth) were conducted using Giemsa microscopy and placental histopathology respectively as the reference standard. The study was conducted in Mbale Hospital, using the midwives to perform and interpret the RDT results. Discordant results samples were spot checked using PCR techniques. RESULTS: Among 433 febrile women tested, RDTs had a sensitivity of 96.8% (95% CI 92-98.8), specificity of 73.5% (95% CI 67.8-78.6), a positive predictive value (PPV) of 68.0% (95% CI 61.4-73.9), and negative predictive value (NPV) of 97.5% (95% CI 94.0-99.0) in detecting peripheral P. falciparum malaria during pregnancy. At delivery, in non-symptomatic women, RDTs had a 80.9% sensitivity (95% CI 57.4-93.7) and a 87.5% specificity (95%CI 80.9-92.1), PPV of 47.2% (95% CI 30.7-64.2) and NPV of 97.1% (95% CI 92.2-99.1) in detecting placental P. falciparum infections among 173 samples. At delivery, 41% of peripheral infections were detected by microscopy without concurrent placental infection. The combination of RDTs and microscopy improved the sensitivity to 90.5% and the specificity to 98.4% for detecting placental malaria infection (McNemar's X(2)> 3.84). RDTs were not superior to microscopy in detecting placental infection (McNemar's X(2)< 3.84). Presence of malaria in pregnancy and active placental malaria infection were 38% and 12% respectively. Placental infections were associated with poor pregnancy outcome [pre-term, still birth and low birth weight] (aOR = 37.9) and late pregnancy malaria infection (aOR = 20.9). Mosquito net use (aOR 2.1) and increasing parity (aOR 2.7) were associated with lower risk for malaria in pregnancy. CONCLUSION: Use of HRP-2 RDTs to detect malaria in pregnancy in symptomatic women was accurate when performed by midwives. A combination of RDTs and microscopy provided the best means of detecting placental malaria. RDTs were not superior to microscopy in detecting placental infection. With a high sensitivity and specificity, RDTs could be a useful tool for assessing malaria in pregnancy, with further (cost-) effectiveness studies.

The impact of malaria coinfection on Ebola virus disease outcomes: A systematic review and meta-analysis.

INTRODUCTION: Viral outbreaks present a particular challenge in countries in Africa where there is already a high incidence of other infectious diseases, including malaria which can alter immune responses to secondary infection. Ebola virus disease (EVD) is one such problem; understanding how Plasmodium spp. and Ebolavirus (EBOV) interact is important for future outbreaks. METHODS: We conducted a systematic review in PubMed and Web of Science to find peer-reviewed papers with primary data literature to determine 1) prevalence of EBOV/Plasmodium spp. coinfection, 2) effect of EBOV/Plasmodium spp. coinfection on EVD pathology and the immune response, 3) impact of EBOV/Plasmodium spp. coinfection on the outcome of EVD-related mortality. Random effects meta-analyses were conducted with the R package meta to produce overall proportion and effect estimates as well as measure between-study heterogeneity. RESULTS: From 322 peer-reviewed papers, 17 were included in the qualitative review and nine were included in a meta-analysis. Prevalence of coinfection was between 19% and 72%. One study reported significantly lower coagulatory response biomarkers in coinfected cases but no difference in inflammatory markers. Case fatality rates were similar between EBOV(+)/Pl(+) and EBOV(+)/Pl(-) cases (62.8%, 95% CI 49.3-74.6 and 56.7%, 95% CI 53.2-60.1, respectively), and there was no significant difference in risk of mortality (RR 1.09, 95% CI 0.90-1.31) although heterogeneity between studies was high. One in vivo mouse model laboratory study found no difference in mortality by infection status, but another found prior acute Plasmodium yoeli infection was protective against morbidity and mortality via the IFN-γ signalling pathway. CONCLUSION: The literature was inconclusive; studies varied widely and there was little attempt to adjust for confounding variables. Laboratory studies may present the best option to answer how pathogens interact within the body but improvement in data collection and analysis and in diagnostic methods would aid patient studies in the future.