Viewpoint: Antimicrobial Resistance Diagnostics Use Accelerator: Qualitative Research on Adherence to Prescriptions.

In this Viewpoint, the authors explore the determinants of patients' prescription adherence behaviors as part of FIND's Advancing Access to Diagnostic Innovation essential for Universal Health Coverage and AMR Prevention (ADIP) trials (ClinicalTrials.gov identifier: NCT04081051). Research findings from Burkina Faso, Ghana, and Uganda show that basic knowledge and understanding of prescription instructions are essential for adherence and can be improved through better communication. However, there are a range of other factors that influence adherence, some of which can be influenced through tailored communication messages from healthcare workers. These messages may contribute to changes in adherence behavior but may require other reinforcing interventions to be effective. Finally, there are some drivers of nonadherence centered around costs and time pressure that require other forms of intervention.

What Influences Patients' Adherence to Healthcare Worker Prescription in Primary Healthcare Facilities in Burkina Faso? A Qualitative Account of Barriers and Facilitators.

BACKGROUND: This study explores the factors influencing patients and caregivers' adherence to prescription of healthcare workers (HCWs). METHODS: The study was conducted in Temnaore and Pella, in the Nanoro health district in Burkina Faso. HCWs and community members were purposively recruited from 4 communities seeking care at the selected primary healthcare facilities for the clinical trial to attend in-depth interviews and focus group discussions on the factors influencing adherence to prescription. The Behaviour Change Wheel incorporating the Capability, Opportunity, and Motivation Behaviour approach was used. RESULTS: Factors influencing the ability of patients to obtain the prescribed medicine include the availability of medicines and money and the perception of consequences for not getting the medicine. Regarding compliance with the intake of medicines, communication was considered a key factor whose effectiveness depends on the performance of HCWs and on the attention of patients. It is followed by other factors such as adequate management of patients, social influences, the patient's beliefs regarding treatment, and memory. CONCLUSIONS: This research highlights factors influencing adherence to HCWs' prescription from the perspective of the community members and HCWs and therefore provides contextual enablers and barriers, which allows for the development of an intervention to support the clinical trial.

A Randomized Trial to Assess the Impact of a Package of Diagnostic Tools and Diagnostic Algorithm on Antibiotic Prescriptions for the Management of Febrile Illnesses Among Children and Adolescents in Primary Health Facilities in Burkina Faso.

BACKGROUND: Low- and middle-income countries face significant challenges in differentiating bacterial from viral causes of febrile illnesses, leading to inappropriate use of antibiotics. This trial aimed to evaluate the impact of an intervention package comprising diagnostic tests, a diagnostic algorithm, and a training-and-communication package on antibiotic prescriptions and clinical outcomes. METHODS: Patients aged 6 months to 18 years with fever or history of fever within the past 7 days with no focus, or a suspected respiratory tract infection, arriving at 2 health facilities were randomized to either the intervention package or standard practice. The primary outcomes were the proportions of patients who recovered at day 7 (D7) and patients prescribed antibiotics at day 0. RESULTS: Of 1718 patients randomized, 1681 (97.8%; intervention: 844; control: 837) completed follow-up: 99.5% recovered at D7 in the intervention arm versus 100% in standard practice (P = .135). Antibiotics were prescribed to 40.6% of patients in the intervention group versus 57.5% in the control arm (risk ratio: 29.3%; 95% CI: 21.8-36.0%; risk difference [RD]: -16.8%; 95% CI: -21.7% to -12.0%; P < .001), which translates to 1 additional antibiotic prescription saved every 6 (95% CI: 5-8) consultations. This reduction was significant regardless of test results for malaria, but was greater in patients without malaria (RD: -46.0%; -54.7% to -37.4%; P < .001), those with a respiratory diagnosis (RD: -38.2%; -43.8% to -32.6%; P < .001), and in children 6-59 months old (RD: -20.4%; -26.0% to -14.9%; P < .001). Except for the period July-September, the reduction was consistent across the other quarters (P < .001). CONCLUSIONS: The implementation of the package can reduce inappropriate antibiotic prescription without compromising clinical outcomes. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov; NCT04081051.

Healthcare seeking outside healthcare facilities and antibiotic dispensing patterns in rural Burkina Faso: A mixed methods study.

OBJECTIVE: Optimising antibiotic use is important to limit increasing antibiotic resistance. In rural Burkina Faso, over-the-counter dispensing of antibiotics in community pharmacies and non-licensed medicine retail outlets facilitates self-medication. We investigated its extent, reasons and dispensing patterns. METHODS: In an exploratory mixed-method design conducted between October 2020 and December 2021, this study first explored illness perceptions, the range of healthcare providers in communities, antibiotics knowledge and reasons for seeking healthcare outside healthcare facilities. Second, frequencies of illness and healthcare utilisation in the last 3 months were quantitatively measured. RESULTS: Participants distinguished between natural and magico-religious illnesses, according to origins. For illnesses considered to be 'natural', healthcare was mainly sought at healthcare facilities, private pharmacies and informal drug outlets. For illnesses considered as magico-religious, traditional healers were mainly visited. Antibiotics were perceived in the community as medicines similar to painkillers. Healthcare-seeking outside healthcare facilities was reported by 660/1973 (33.5%) participants reporting symptoms, including 315 (47.7%) to informal vendors. Healthcare seeking outside facilities was less common for 0-4-year-olds (58/534, 10.9% vs. 379/850, 44.1% for ≥5-year-olds) and decreased with improving socio-economic status (108/237, 45.6% in the lowest quintile; 96/418, 23.0% in the highest). Reported reasons included financial limitation, and also proximity to informal drug vendors, long waiting times at healthcare facilities, and health professionals' non-empathetic attitudes towards their patients. CONCLUSION: This study highlights the need to facilitate and promote access to healthcare facilities through universal health insurance and patient-centred care including reducing patients' waiting time. Furthermore, community-level antibiotic stewardship programmes should include community pharmacies and informal vendors.

Could combined rapid diagnostic testing for malaria and c-reactive protein be helpful for the diagnosis and management of febrile illnesses in children under-5 years of age in rural Burkina Faso?

BACKGROUND: Febrile illnesses are among the most important reasons for medical consultation in sub-Saharan Africa and are frequently treated with antimicrobials due to the unavailability of appropriate diagnostic tools. This practice leads to antimicrobial resistance, with increasing mortality and morbidity as result. One of the few accessible diagnostic tools available in low resource settings is malaria rapid diagnostic tests (mRDTs) which contributed to reducing the over-prescription of anti-malarials, but cannot guide antibiotic prescriptions. To circumvent this problem, we explored whether combined testing with mRDT and c-reactive protein (CRP) could improve the diagnosis of febrile illnesses and subsequent prescription of antibiotics. METHODS: Clinical specimens (blood, stool and urine) collected from 396 febrile children (axillary temperature of ≥ 37.5 °C) were analyzed with rapid diagnostic tests (malaria and CRP) and microbiology culture to establish the possible cause of fever. Actual antimicrobial prescriptions given to the children were compared with those that could be given based on combined CRP-malaria testing. RESULTS: In total, 68.7% (272/396) of malaria cases were diagnosed by mRDT-Pf-HRP-2. CRP test was positive in 84.3% (334/396) of the children, but bacterial infections were confirmed in 12.4% (49/396) of them. A possible cause of fever could not be established in 20.5% (81/396) of cases. Based on the diagnostic practice in place, 265 of the children with a positive mRDT-Pf-HRP-2 received anti-malarial treatment. Furthermore, 89.5% (111/124) of negative mRDT results received antibiotic treatment and 37.1% (46/124) received antimalarial treatment. Of these 124 cases, 80 had positive CRP tests and 44 negative CRP tests. If the results of CRP testing are considered, 44 CRP/mRDT negative children would not get antibiotic treatment, resulting in a 35.5% reduction in antibiotic prescriptions. However, 2 cases with a bacterial infection would be denied appropriate treatment. CONCLUSION: Combining mRDT-PfHRP2 with CRP testing is particularly useful in children for whom both tests are negative as it results in a reduction of antibiotics prescriptions. However, there is a risk to miss potential severe bacterial infections and a close follow-up of these cases is strongly recommended.

Diagnostic Performance of Plasmodium falciparum Histidine-Rich Protein-2 Antigen-Specific Rapid Diagnostic Test in Children at the Peripheral Health Care Level in Nanoro (Burkina Faso).

(1) Background: Malaria control has strongly benefited from the implementation of rapid diagnostic tests (RDTs). The malaria RDTs used in Burkina Faso, as per the recommendation of the National Malaria Control Program, are based on the detection of histidine-rich protein-2 (PfHRP2) specific to Plasmodium falciparum, which is the principal plasmodial species causing malaria in Burkina Faso. However, there is increasing concern about the diagnostic performance of these RDTs in field situations, and so constant monitoring of their accuracy is warranted. (2) Methods: A prospective study was performed in the health district of Nanoro, where 391 febrile children under 5 years with an axillary temperature ≥37.5 °C presenting at participating health facilities were subjected to testing for malaria. The HRP2-based RDT and expert microscopy were used to determine the diagnostic performance of the former. Retrospectively, the correctness of the antimalaria prescriptions was reviewed. (3) Results: Taking expert malaria microscopy as the gold standard, the sensitivity of the employed RDT was 98.5% and the specificity 40.5%, with a moderate agreement between the RDT testing and microscopy. In total, 21.7% of cases received an inappropriate antimalarial treatment based on a retrospective assessment with expert microscopy results. (4) Conclusion: Malaria remains one of the principal causes of febrile illness in Burkina Faso. Testing with HRP2-based RDTs is inaccurate, in particular, due to the low specificity, which results in an over-prescription of antimalarials, with emerging antimalarial drug resistance as an important risk and many children not being treated for potential other causes of fever.

Phase 3 evaluation of an innovative simple molecular test for the diagnosis of malaria in different endemic and health settings in sub-Saharan Africa (DIAGMAL).

BACKGROUND: Rapid Diagnostic Tests (RDTs) have become the cornerstone for the management of malaria in many endemic settings, but their use is constrained for several reasons: (i) persistent malaria antigen (histidine-rich protein 2; HRP2) leading to false positive test results; (ii) hrp2 deletions leading to false negative PfHRP2 results; and (iii) limited sensitivity with a detection threshold of around 100 parasites/µl blood (pLDH- and HRP2-based) leading to false negative tests. Microscopy is still the gold standard for malaria diagnosis, and allows for species determination and quantitation, but requires trained microscopists, maintained microscopes and has detection limit issues. Consequently, there is a pressing need to develop and evaluate more sensitive and accurate diagnostic tests. To address this need we have developed a direct on blood mini PCR-NALFIA test that combines the benefits of molecular biology with low infrastructural requirements and extensive training. METHODS: This is a Phase 3 diagnostic evaluation in 5 African countries. Study sites (Sudan, Ethiopia, Burkina, Kenya and Namibia) were selected to ensure wide geographical coverage of Africa and to address various malaria epidemiological contexts ranging from high transmission to near elimination settings with different clinical scenarios and diagnostic challenges. Study participants will be enrolled at the study health facilities after obtaining written informed consent. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practices in place at the selected sites and to quantitative PCR as the reference test. DISCUSSION: This phase 3 study is designed to validate the clinical performance and feasibility of implementing a new diagnostic tool for the detection of malaria in real clinical settings. If successful, the proposed technology will improve the diagnosis of malaria. Enrolment started in November 2022 (Kenya) with assessment of long term outcome to be completed by 2023 at all recruitment sites. TRIAL REGISTRATION: Pan African Clinical Trial Registry (www.pactr.org) PACTR202202766889963 on 01/02/2022 and ISCRTN (www.isrctn.com/) ISRCTN13334317 on 22/02/2022.

Development and evaluation of an electronic algorithm using a combination of a two-step malaria RDT and other rapid diagnostic tools for the management of febrile illness in children under 5 attending outpatient facilities in Burkina Faso.

BACKGROUND: In Sub-Saharan Africa (SSA), febrile illnesses remain a major public health problem in children. However, the persistence of hrp2 antigen and the low sensitivity of pLDH RDT negatively affect antimalarials and antibiotics prescription practices. These limitations lead to poor management of febrile diseases and antimicrobial resistance (AMR). To improve the diagnosis of these febrile diseases and subsequent prescription of antimicrobials, it is hypothesized that the implementation of an algorithm including a two-step malaria RDT PfHRP2/pLDH supported by point-of-care (PoC) tests for bacterial infections could significantly improve the management of febrile diseases and thereby tackling AMR. METHODS: To assess the value of the proposed algorithm, an open-label randomized controlled trial with three arms, enrolling febrile children from 6 to 59 months is proposed. In the control arm, febrile children will be managed according to the Integrated Management of Childhood Illnesses (IMCI), which is part of the standard of care in Burkina Faso. Treatment will be done according to national guidelines. In the RDT decisional algorithm (RDT-DA) arm (intervention), the clinical examination based on IMIC will be supported by a two-step malaria RDT and bacterial infections RDTs. Prescription will be left to the discretion of the healthcare workers based on clinical examination and PoC test results. In the e-algorithm arm (intervention), artificial intelligence integrating multiple layers of clinical information such as clinical examination, signs/symptoms and medical history, and biological information such as biomarkers (CRP and WBC) and pathogen-specific PoC tests, and oximetry will be developed. The e-algorithm will serve to guide the diagnostic and management of febrile infections in children. In the 3 arms, the case report forms will be digitalized. A final follow-up visit (day 7) will be scheduled for all participants. Patients will be asked to come back to the health facilities before the scheduled visit if the symptoms persist or in case of health condition worsening. DISCUSSION: If successful, this study could contribute to improve the management of febrile diseases and reduce inappropriate use of antimicrobials. TRIAL REGISTRATION: The trial is registered at ClinicalTrial.gov, NCT05285657. Enrolment started on 4 March 2022 with long-term outcome being assessed completely by 2023.

Phase 3 Evaluation of an Innovative Simple Molecular Test for the Diagnosis of Malaria and Follow-Up of Treatment Efficacy in Pregnant Women in Sub-Saharan Africa (Preg-Diagmal).

The malaria parasite Plasmodium falciparum (Pf) can sequester in the placenta resulting in low density of peripheral parasitemia and consequently in false negative malaria diagnosis (by microscopy) in pregnant women. Moreover, the use of rapid diagnostic tests (RDTs) in diagnostic strategies, including those for the detection of a malaria infection during pregnancy, is constrained by either persistent malaria antigen (histidine-rich protein 2; HRP2) after successful treatment, leading to false positive test results, or by false negative results as previously mentioned due to parasite sequestration (which is further exacerbated due to the low limited of detection [LoD] of conventional RDTs) or to HRP2 deletion. Recently, a direct blood polymerase chain reaction combined with a nucleic acid lateral flow immunoassay (dbPCR-NALFIA) has been developed, which circumvents these challenges and has demonstrated its diagnostic potential in phase 1 and 2 studies. The PREG-DIAGMAL trial presented in this manuscript will assess the diagnostic performance of dbPCR-NALFIA for the diagnostic of malaria in pregnant women and its potential to monitor treatment efficacy in these subjects. The work is ancillary embedded in an ongoing EDCTP funded trial, the PyraPreg project (PACTR202011812241529) in which the safety and efficacy of a newly registered Artemisinin-Based Combination (Pyronaridine-Artesunate) is being evaluated in pregnant women. This is a Phase 3 diagnostic evaluation conducted in 2 African countries: Democratic Republic of the Congo (DRC) and Burkina Faso. Pregnant women fulfilling the inclusion criteria of the PyraPreg study will be also invited to participate in the PREG-DIAGMAL study. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practice in place at the selected settings (microscopy and/or RDT) and to quantitative PCR as the reference test. This phase 3 diagnostic study is designed towards the evaluation of the performance of a new diagnostic tool for the screening of malaria and the monitoring of treatment in pregnant women under real conditions life. If successful, the dbPCR-NALFIA could be a valuable tool to add to the diagnostic arsenal for malaria, in particular during pregnancy. Trial registration: Pan African Clinical Trial Registry database (PACTR202203780981413). Registered on 17 March 2022.

Antibiotic susceptibility profile of bacterial isolates from febrile children under 5 years of age in Nanoro, Burkina Faso.

OBJECTIVES: Antibiotics efficacy is severely threatened due to emerging resistance worldwide, but there is a paucity of antibiotics efficacy data for the West African region in general. Therefore, this study aimed to determine the antibiotic susceptibility profile of bacterial isolated from febrile children under 5 years of age in Nanoro (Burkina Faso). METHODS: Blood, stool and urine samples were collected from 1099 febrile children attending peripheral health facilities and the referral hospital in Nanoro Health district. Bacterial isolates from these samples were assessed for their susceptibility against commonly used antibiotics by Kirby-Bauer method. RESULTS: In total, 141 bacterial isolates were recovered from 127 febrile children of which 65 from blood, 65 from stool and 11 from urine. Salmonella isolates were most frequently isolated and found to be highly resistant to ampicillin (70%; 56/80) and trimethoprim-sulphamethoxazole (65%; 52/80). Escherichia coli isolates showed a high resistance rate to trimethoprim-sulphamethoxazole (100%), ampicillin (100%), ciprofloxacin (71.4%; 10/14), amoxicillin-clavulanate (64.3%; 9/14), ceftriaxone (64.3%; 9/14) and gentamycin (50%; 7/14). Moreover, half of the E. coli isolates produced ß-lactamase suggesting multi-drug resistance against ß-lactam as well as non-ß-lactam antibiotics. Multi-drug resistance was observed in 54.6% (59/108) of the isolates, mainly Gram-negative bacteria. CONCLUSIONS: This study showed high resistance rates to common antibiotics used to treat bacterial infections in Nanoro. The work prompts the need to expand antibiotic resistance surveillance studies in Burkina Faso.

Antibiotic Susceptibility of Staphylococcus aureus and Streptococcus pneumoniae Isolates from the Nasopharynx of Febrile Children under 5 Years in Nanoro, Burkina Faso.

(1) Background: nasopharynx colonization by resistant Staphylococcus aureus and Streptococcus pneumoniae can lead to serious diseases. Emerging resistance to antibiotics commonly used to treat infections due to these pathogens poses a serious threat to the health system. The present study aimed to determine the antibiotic susceptibility of S. aureus and S. pneumoniae isolates from the febrile children's nasopharynx under 5 years in Nanoro (Burkina Faso). (2) Methods: bacterial isolates were identified from nasopharyngeal swabs prospectively collected from 629 febrile children. Antibiotic susceptibility of S. aureus and S. pneumoniae isolates was assessed by Kirby-Bauer method and results were interpreted according to the Clinical and Laboratory Standard Institute guidelines. (3) Results: bacterial colonization was confirmed in 154 (24.5%) of children of whom 96.1% carried S. aureus, 3.2% had S. pneumoniae, and 0.6% carried both bacteria. S. aureus isolates showed alarming resistance to penicillin (96.0%) and S. pneumoniae was highly resistant to tetracycline (100%) and trimethoprim-sulfamethoxazole (83.3%), and moderately resistant to penicillin (50.0%). Furthermore, 4.0% of S. aureus identified were methicillin resistant. (4) Conclusion: this study showed concerning resistance rates to antibiotics to treat suspected bacterial respiratory tract infections. The work highlights the necessity to implement continuous antibiotic resistance surveillance.

Impact of a package of diagnostic tools, clinical algorithm, and training and communication on outpatient acute fever case management in low- and middle-income countries: protocol for a randomized controlled trial.

BACKGROUND: The management of acute febrile illnesses places a heavy burden on clinical services in many low- and middle-income countries (LMICs). Bacterial and viral aetiologies of acute fevers are often clinically indistinguishable and, in the absence of diagnostic tests, the 'just-in-case' use of antibiotics by many health workers has become common practice, which has an impact on drug-resistant infections. Our study aims to answer the following question: in patients with undifferentiated febrile illness presenting to outpatient clinics/peripheral health centres in LMICs, can we demonstrate an improvement in clinical outcomes and reduce unnecessary antibiotic prescription over current practice by using a combination of simple, accurate diagnostic tests, clinical algorithms, and training and communication (intervention package)? METHODS: We designed a randomized, controlled clinical trial to evaluate the impact of our intervention package on clinical outcomes and antibiotic prescription rates in acute febrile illnesses. Available, point-of-care, pathogen-specific and non-pathogen specific (host markers), rapid diagnostic tests (RDTs) included in the intervention package were selected based on pre-defined criteria. Nine clinical study sites in six countries (Burkina Faso, Ghana, India, Myanmar, Nepal and Uganda), which represent heterogeneous outpatient care settings, were selected. We considered the expected seasonal variations in the incidence of acute febrile illnesses across all the sites by ensuring a recruitment period of 12 months. A master protocol was developed and adapted for country-specific ethical submissions. Diagnostic algorithms and choice of RDTs acknowledged current data on aetiologies of acute febrile illnesses in each country. We included a qualitative evaluation of drivers and/or deterrents of uptake of new diagnostics and antibiotic use for acute febrile illnesses. Sample size estimations were based on historical site data of antibiotic prescription practices for malarial and non-malarial acute fevers. Overall, 9 semi-independent studies will enrol a minimum of 21,876 patients and an aggregate data meta-analysis will be conducted on completion. DISCUSSION: This study is expected to generate vital evidence needed to inform policy decisions on the role of rapid diagnostic tests in the clinical management of acute febrile illnesses, with a view to controlling the rise of antimicrobial resistance in LMICs. TRIAL REGISTRATION: Clinicaltrials.gov NCT04081051 . Registered on 6 September 2019. Protocol version 1.4 dated 20 December 2019.

Algorithms for sequential interpretation of a malaria rapid diagnostic test detecting two different targets of Plasmodium species to improve diagnostic accuracy in a rural setting (Nanoro, Burkina Faso).

BACKGROUND: Malaria rapid diagnostic tests (RDT) have limitations due to the persistence of histidine-rich protein 2 (HRP2) antigen after treatment and low sensitivity of Plasmodium lactate dehydrogenase (pLDH) based RDTs. To improve the diagnosis of malaria in febrile children, two diagnostic algorithms, based on sequential interpretation of a malaria rapid diagnostic test detecting two different targets of Plasmodium species and followed by expert microscopy, were evaluated. METHODS: Two diagnostic algorithms were evaluated using 407 blood samples collected between April and October 2016 from febrile children and the diagnostic accuracy of both algorithms was determined. Algorithm 1: The result of line T1-HRP2 were read first; if negative, malaria infection was considered to be absent. If positive, confirmation was done with the line T2-pLDH. If T2-pLDH test was negative, the malaria diagnosis was considered as "inconclusive" and microscopy was performed; Algorithm 2: The result of line T2-pLDH were read first; if positive, malaria infection was considered to be present. If negative, confirmation was done with the line T1-HRP2. If T1-HRP2 was positive the malaria diagnosis was considered as "inconclusive" and microscopy was performed. In absence of malaria microscopy, a malaria infection was ruled out in children with an inconclusive diagnostic test result when previous antimalarial treatment was reported. RESULTS: For single interpretation, the sensitivity of PfHRP2 was 98.4% and the specificity was 74.2%, and for the pLDH test the sensitivity was 89.3% and the specificity was 98.8%. Malaria was accurately diagnosed using both algorithms in 84.5% children. The algorithms with the two-line malaria RDT classified the test results into two groups: conclusive and inconclusive results. The diagnostic accuracy for conclusive results was 98.3% using diagnostic algorithm 1 and 98.6% using algorithm 2. The sensitivity and specificity for the conclusive results were 98.2% and 98.4% for algorithm 1, and 98.6% and 98.4% for algorithm 2, respectively. There were 63 (15.5%) children who had an "inconclusive" result for whom expert microscopy was needed. In children with inconclusive results (PfHRP2+/pLDH- only) previous antimalarial treatment was reported in 16 children with malaria negative microscopy (16/40; 40%) and 1 child with malaria positive microscopy (1/23; 4.3%). CONCLUSION: The strategy of sequential interpretation of two-line malaria RDT can improve the diagnosis of malaria. However, some cases will still require confirmative testing with microscopy or additional investigations on previous antimalarial treatment.

The effect of malaria rapid diagnostic tests results on antimicrobial prescription practices of health care workers in Burkina Faso.

BACKGROUND: Malaria rapid diagnostic tests (RDT) are widely used in endemic areas in order to comply with the recommendation that malaria treatment should only be given after the clinical diagnosis has been confirmed by RDT or microscopy. However, the overestimation of malaria infection with the use of PfHRP2 based RDT, makes the management of febrile illnesses more challenging. This study aimed to assess the effect of the use of malaria RDT on antimicrobial prescription practices. METHODS: A prospective study was conducted among febrile children under-5 years of age attending four health facilities and the referral hospital in the Nanoro Health District (Burkina Faso). To assess the effect of malaria RDT testing on the prescriptions of antimicrobials in febrile children, the initial diagnosis and antimicrobial prescriptions following a malaria RDT testing were recorded. The necessity of these prescriptions was subsequently checked by assessing the actual cause of fever by expert malaria microscopy and a microbiology analysis of blood, urine, stool and nasopharynx swabs that were collected from febrile cases to determine the actual cause of the fever episode. RESULTS: Malaria was diagnosed by nurses, who are the primary health care providers, with a malaria RDT in 72.7% (798/1098) of febrile children, but only 53.7% (589/1097) cases could be confirmed by expert microscopy. Health care workers were likely to prescribe antimalarials to malaria positive RDT compared to malaria negative RDT (RR = 7.74, p = 0.00001). Malaria negative RDT result had a significant influence on the antibiotic prescriptions (RR = 3.57, p = 0.0001). The risk of prescribing antimicrobials was higher in health facility level compared to referral hospital. By cross-checking of laboratory findings to antimicrobial prescriptions, an important part of children with positive bacterial infection have received antibiotic prescriptions although the majority without any infection have also received antibiotics. CONCLUSION: Despite the good attitude of health care workers to adhere to diagnostic test results, antimalarials and antibiotics remain inappropriate prescribed to febrile children. The low specificity of malaria RDT used could be an important cause of these practices.

Can clinical signs or symptoms combined with basic hematology data be used to predict the presence of bacterial infections in febrile children under - 5 years?

BACKGROUND: Infectious diseases in children living in resource-limited settings are often presumptively managed on the basis of clinical signs and symptoms. Malaria is an exception. However, the interpretation of clinical signs and symptoms in relation to bacterial infections is often challenging, which may lead to an over prescription of antibiotics when a malaria infection is excluded. The present study aims to determine the association between clinical signs and symptoms and basic hematology data, with laboratory confirmed bacterial infections. METHODS: A health survey was done by study nurses to collect clinical signs/symptoms in febrile (axillary temperature ≥ 37.5 °C) children under - 5 years of age. In addition, blood, stool and urine specimen were systematically collected from each child to perform bacterial culture and full blood cell counts. To determine the association between a bacterial infection with clinical signs/symptoms, and if possible supported by basic hematology data (hemoglobin and leucocyte rates), a univariate analysis was done. This was followed by a multivariate analysis only on those variables with a p-value p < 0.1 in the univariate analysis. Only a p-value of < 0.05 was considered as significant for multivariate analysis. RESULTS: In total, 1099 febrile children were included. Bacteria were isolated from clinical specimens (blood-, stool- and urine- culture) of 127 (11.6%) febrile children. Multivariate logistical regression analysis revealed that a general bacterial infection (irrespective of the site of infection) was significantly associated with the following clinical signs/symptoms: diarrhea (p = 0.003), edema (p = 0.010) and convulsion (p = 0.021). Bacterial bloodstream infection was significantly associated with fever> 39.5 °C (p = 0.002), diarrhea (p = 0.019) and edema (p = 0.017). There was no association found between bacterial infections and basic haematological findings. If diarrhea and edema were absent, a good negative predictive value (100%) of a bacterial bloodstream infection was found, but the positive predictive value was low (33.3%) and the confidence interval was very large (2.5-100; 7.5-70.1). CONCLUSION: Our study demonstrates that clinical signs and symptoms, combined with basic hematology data only, cannot predict bacterial infections in febrile children under - 5 years of age. The development of practical and easy deployable diagnostic tools to diagnose bacterial infections remains a priority.

Implementation of a malaria rapid diagnostic test in a rural setting of Nanoro, Burkina Faso: from expectation to reality.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) are nowadays widely used in malaria endemic countries as an alternative to microscopy for the diagnosis of malaria. However, quality control of test performance and execution in the field are important in order to ensure proper use and adequate diagnosis of malaria. The current study compared the performance of a histidine-rich protein 2-based RDT used at peripheral health facilities level in real life conditions with that performed at central reference laboratory level with strict adherence to manufacturer instructions. METHODS: Febrile children attending rural health clinics were tested for malaria with a RDT provided by the Ministry of Health of Burkina Faso as recommended by the National Malaria Control Programme. In addition, a blood sample was collected in an EDTA tube from all study cases for retesting with the same brand of RDT following the manufacturer's instructions with expert malaria microscopy as gold standard at the central reference laboratory. Fisher exact test was used to compare the proportions by estimating the p-value (p ≤ 0.05) as statistically significant. RESULTS: In total, 407 febrile children were included in the study and malaria was diagnosed in 59.9% (244/407) of the cases with expert malaria microscopy. The sensitivity of malaria RDT testing performed at health facilities was 97.5% and comparable to that achieved at the laboratory (98.8%). The number of malaria false negatives was not statistically significant between the two groups (p = 0.5209). However, the malaria RDT testing performed at health facilities had a specificity issue (52.8%) and was much lower compared to RDT testing performed at laboratory (74.2%). The number of malaria false positives was statistically significantly different between the two groups (p = 0.0005). CONCLUSION: Malaria RDT testing performed at the participating rural health facilities resulted in more malaria false positives compared to those performed at central laboratory. Several factors, including storage and transportation conditions but also training of health workers, are most likely to influence test performance. Therefore, it is very important to have appropriate quality control and training programmes in place to ensure correct performance of RDT testing.

Treatable causes of fever among children under five years in a seasonal malaria transmission area in Burkina Faso.

BACKGROUND: Fever remains a major public health problem. In Burkina Faso, more than half of febrile children are considered not to be infected by malaria. This study prospectively assessed probable (treatable) causes of fever in Burkinabe children. METHODS: A prospective study was conducted among febrile children (≥37.5 °C) under 5 years of age presenting at four health facilities and one referral hospital in rural Burkina Faso. From each participant, blood was collected for malaria microscopy and culture, urine for dipstick testing and culturing if tested positive for leucocytes and nitrite, stool for rotavirus/adenovirus testing, culture and parasitology, and a nasopharyngeal swab for culture. RESULTS: In total 684 febrile children were included in the study. Plasmodium falciparum malaria was found in 49.7% (340/684) of the participants and non-malaria infections in 49.1% (336/684) of children. The non-nalaria infections included gastro-intestinal infections (37.0%), common bacterial pathogens of nasopharynx (24.3%), bacterial bloodstream infections (6.0%) and urinary tract infections (1.8%). Nearly 45% (154/340) of the malaria infected children were co-infected with non-nalaria infections, but only 3.2% (11/340) of these co-infections could be considered as a possible alternative cause of fever. In contrast, in the malaria microscopy negative children 18.0% (62/344) of the infections could be the probable cause of the fever. Pathogens were not isolated from 23.7% (162/684) of the febrile cases. CONCLUSIONS: Malaria remains the most common pathogen found in febrile children in Burkina Faso. However, a relative high number of febrile children had non-malaria infections. The correct diagnosis of these non-malaria fevers is a major concern, and there is an urgent need to develop more point-of-care diagnostic tests and capacities to identify and treat the causes of these fevers.

Accuracy of a Plasmodium falciparum specific histidine-rich protein 2 rapid diagnostic test in the context of the presence of non-malaria fevers, prior anti-malarial use and seasonal malaria transmission.

BACKGROUND: It remains challenging to distinguish malaria from other fever causing infections, as a positive rapid diagnostic test does not always signify a true active malaria infection. This study was designed to determine the influence of other causes of fever, prior anti-malarial treatment, and a possible seasonality of the performance of a PfHRP2 RDT for the diagnosis of malaria in children under-5 years of age living in a malaria endemic area. METHODS: A prospective etiology study was conducted in 2015 among febrile children under 5 years of age in Burkina Faso. In order to assess the influence of other febrile illnesses, prior treatment and seasonality on the performance of a PfHRP2 RDT in diagnosing malaria, the RDT results were compared with the gold standard (expert microscopic diagnosis of Plasmodium falciparum) and test results were analysed by assuming that prior anti-malarial use and bacterial/viral infection status would have been known prior to testing. To assess bacterial and viral infection status blood, urine and stool samples were analysed. RESULTS: In total 683 blood samples were analysed with microscopy and RDT-PfHRP2. Plasmodium falciparum malaria was diagnosed in 49.8% (340/683) by microscopy compared to 69.5% (475/683) by RDT-PfHRP2. The RDT-PfHRP2 reported 29.7% (141/475) false positive results and 1.8% (6/340) false negative cases. The RDT-PfHRP2 had a high sensitivity (98.2%) and negative predictive value (97.1%), but a low specificity (58.9%) and positive predictive value (70.3%). Almost 50% of the alternative cause of fever were diagnosed by laboratory testing in the RDT false positive malaria group. CONCLUSIONS: The use of a malaria RDT-PfHRP2 in a malaria endemic area may cause misdiagnosis of the actual cause of fever due to false positive test results. The development of a practical diagnostic tool to screen for other causes of fever in malaria endemic areas is required to save lives.