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Effective and sustainable strategies are needed to address the burden of preventable deaths among children under-five in resource-constrained settings. The Tools for Integrated Management of Childhood Illness (TIMCI) project aims to support healthcare providers to identify and manage severe illness, whilst promoting resource stewardship, by introducing pulse oximetry and clinical decision support algorithms (CDSAs) to primary care facilities in India, Kenya, Senegal and Tanzania. Health impact is assessed through: a pragmatic parallel group, superiority cluster randomised controlled trial (RCT), with primary care facilities randomly allocated (1:1) in India to pulse oximetry or control, and (1:1:1) in Tanzania to pulse oximetry plus CDSA, pulse oximetry, or control; and through a quasi-experimental pre-post study in Kenya and Senegal. Devices are implemented with guidance and training, mentorship, and community engagement. Sociodemographic and clinical data are collected from caregivers and records of enrolled sick children aged 0–59 months at study facilities, with phone follow-up on Day 7 (and Day 28 in the RCT). The primary outcomes assessed for the RCT are severe complications (mortality and secondary hospitalisations) by Day 7 and primary hospitalisations (within 24 hours and with referral); and, for the pre-post study, referrals and antibiotic. Secondary outcomes on other aspects of health status, hypoxaemia, referral, follow-up and antimicrobial prescription are also evaluated. In all countries, embedded mixed-method studies further evaluate the effects of the intervention on care and care processes, implementation, cost and cost-effectiveness. Pilot and baseline studies started mid-2021, RCT and post-intervention mid-2022, with anticipated completion mid-2023 and first results late-2023. Study approval has been granted by all relevant institutional review boards, national and WHO ethical review committees. Findings will be shared with communities, healthcare providers, Ministries of Health and other local, national and international stakeholders to facilitate evidence-based decision-making on scale-up. Study registration: NCT04910750 and NCT05065320

In many regions of sub-Saharan Africa, both HIV and helminth infections are prevalent. HIV-1 (human immunodeficiency virus type 1) and helminth infections can both compromise immune responses in humans. To determine whether the presence of helminth infection or the treatment of helminth infection alters unstimulated vaccine responses among HIV-1 infected individuals, we conducted two nested serologic studies. Blood samples were collected for HIV disease monitoring and vaccine-specific serologic assays, while stool was evaluated by direct microscopy methods. We compared antibody responses to measles and tetanus vaccines in helminth-infected (Ascaris, Trichuris, hookworm and/or Schistosoma mansoni) and uninfected adults 18 years and older (n = 100). We also compared measles and tetanus antibody responses in Ascaris only-infected adults receiving 400 mg albendazole daily for 3 days (n = 16) vs. placebo (n = 19) in a separate study. In both cohorts, over 70% of participants had measles and tetanus responses above the protective threshold. Prevalence of measles responses were similar between helminth-infected and uninfected individuals (82%, 95% CI: 71–93% vs 72%, 95% CI: 59–85%), as well as log10 tetanus antibody levels (−0.133 IU/mL vs −0.190 IU/mL, p > 0.05), and did not differ by helminth species. In the Ascaris-infected cohort, changes in measles responses and tetanus responses did not differ between those who received anthelminthic vs. placebo (p > 0.05 for both). In these studies, neither helminth infection, nor deworming, appeared to affect previously administered vaccine responsiveness in HIV-1 infected, ART naïve, adults in Kenya.

Lipoarabinomannan (LAM) is a promising target biomarker for diagnosing subclinical and clinical tuberculosis (TB). Urine LAM (uLAM) testing using rapid diagnostic tests (RDTs) has been approved for people living with HIV (PLWH), however there is limited data regarding uLAM levels in HIV-negative (HIV-ve) adults with clinical TB. We conducted a clinical study of adults presenting with clinical TB-related symptoms at the National Lung Hospital in Hanoi, Vietnam. The uLAM concentrations were measured using electrochemiluminescent (ECL) immunoassays and compared to a microbiological reference standard (MRS) using GeneXpert Ultra and TB culture testing. Estimated uLAM concentrations above plate specific calculated limit of detection (LOD) were considered uLAM positive. Additional microbiological testing was conducted for possible extrapulmonary TB (EPTB). Among 745 participants enrolled, 335 (44.9%) participants with presumptive pulmonary TB (PTB) and 6 (11.3%) participants with presumptive EPTB had confirmed TB disease. Overall, the S/A antibody pair had a sensitivity of 39% (95% Confidence Interval [CI] 0.33, 0.44) and a specificity of 97% (95% CI 0.96, 0.99) compared to the MRS. The F/A antibody pair had a sensitivity of 41% (95% CI 0.35, 0.47) and a specificity of 79% (95% CI 0.75, 0.84). S/A provided greater discriminatory ability compared to F/A for both individuals with presumptive PTB (AUROC: 0.74 vs 0.63, p

BackgroundSoil-transmitted helminths (STHs) are parasitic nematodes that inhabit the human intestine. They affect more than 1.5 billion people worldwide, causing physical and cognitive impairment in children. The global strategy to control STH infection includes periodic mass drug administration (MDA) based on the results of diagnostic testing among populations at risk, but the current microscopy method for detecting infection has diminished sensitivity as the intensity of infection decreases. Thus, improved diagnostic tools are needed to support decision-making for STH control programs.MethodologyWe developed a nucleic acid amplification test based on recombinase polymerase amplification (RPA) technology to detect STH in stool. We designed primers and probes for each of the four STH species, optimized the assay, and then verified its performance using clinical stool samples.Principal findingsEach RPA assay was as sensitive as a real-time polymerase chain reaction (PCR) assay in detecting copies of cloned target DNA sequences. The RPA assay amplified the target in DNA extracted from human stool samples that were positive for STH based on the Kato-Katz method, with no cross-reactivity of the non-target genomic DNA. When tested with clinical stool samples from patients with infections of light, moderate, and heavy intensity, the RPA assays demonstrated performance comparable to that of real-time PCR, with better results than Kato-Katz. This new rapid, sensitive and field-deployable method for detecting STH infections can help STH control programs achieve their goals.ConclusionsSemi-quantitation of target by RPA assay is possible and is comparable to real-time PCR. With proper instrumentation, RPA assays can provide robust, semi-quantification of STH DNA targets as an alternative field-deployable indicator to counts of helminth eggs for assessing infection intensity.

Soil-transmitted helminths (STHs) affect more than 1.5 billion people. The global strategy to control STH infections requires periodic mass drug administration (MDA) based on prevalence among populations at risk determined by diagnostic testing. Widely used copromicroscopy methods to detect infection, however, have low sensitivity as the prevalence and intensity of STH infections decline with repeated MDA. More sensitive diagnostic tools are needed to inform program decision-making. Using an integrated product development process, PATH conducted qualitative and quantitative formative research to inform the design and development of a more sensitive test for STH infections. The research, grounded in a conceptual framework for ensuring access to health products, involved stakeholder analysis, key opinion leader interviews, observational site visits of ongoing STH surveillance programs, and market research including market sizing, costing and willingness-to-pay analyses. Stakeholder analysis identified key groups and proposed strategic engagement of stakeholders during product development. Interviews highlighted features, motivations and concerns that are important for guiding design and implementation of new STH diagnostics. Process mapping outlined current STH surveillance workflows in Kenya and the Philippines. Market sizing in 2016 was estimated around half a million tests for lower STH burden countries, and 1-2 million tests for higher STH burden countries. The cost of commodities per patient for a molecular STH diagnostic may be around $10, 3-4 times higher than copromicroscopy methods, though savings may be possible in time and staffing requirements. The market is highly price sensitive as even at $5 per test, only 27% of respondents thought the test would be used by surveillance programs. A largely subsidized STH control strategy and a semi-functional Kato-Katz test may have created few incentives for manufacturers to innovate in STH diagnostics. Diverse partnerships, as well as balancing needs and expectations for new STH diagnostics are necessary to ensure access to needed products.

As effective onchocerciasis control efforts in Africa transition to elimination efforts, different diagnostic tools are required to support country programs. Senegal, with its long standing, successful control program, is transitioning to using the SD BIOLINE Onchocerciasis IgG4 (Ov16) rapid test over traditional skin snip microscopy. The aim of this study is to demonstrate the feasibility of integrating the Ov16 rapid test into onchocerciasis surveillance activities in Senegal, based on the following attributes of acceptability, usability, and cost. A cross-sectional study was conducted in 13 villages in southeastern Senegal in May 2016. Individuals 5 years and older were invited to participate in a demographic questionnaire, an Ov16 rapid test, a skin snip biopsy, and an acceptability interview. Rapid test technicians were interviewed and a costing analysis was conducted. Of 1,173 participants, 1,169 (99.7%) agreed to the rapid test while 383 (32.7%) agreed to skin snip microscopy. The sero-positivity rate of the rapid test among those tested was 2.6% with zero positives 10 years and younger. None of the 383 skin snips were positive for Ov microfilaria. Community members appreciated that the rapid test was performed quickly, was not painful, and provided reliable results. The total costs for this surveillance activity was $22,272.83, with a cost per test conducted at $3.14 for rapid test, $7.58 for skin snip microscopy, and $13.43 for shared costs. If no participants had refused skin snip microscopy, the total cost per method with shared costs would have been around $16 per person tested. In this area with low onchocerciasis sero-positivity, there was high acceptability and perceived value of the rapid test by community members and technicians. This study provides evidence of the feasibility of implementing the Ov16 rapid test in Senegal and may be informative to other country programs transitioning to Ov16 serologic tools.

Global efforts to address schistosomiasis and soil-transmitted helminthiases (STH) include deworming programs for school-aged children that are made possible by large-scale drug donations. Decisions on these mass drug administration (MDA) programs currently rely on microscopic examination of clinical specimens to determine the presence of parasite eggs. However, microscopy-based methods are not sensitive to the low-intensity infections that characterize populations that have undergone MDA. Thus, there has been increasing recognition within the schistosomiasis and STH communities of the need for improved diagnostic tools to support late-stage control program decisions, such as when to stop or reduce MDA. Failure to adequately address the need for new diagnostics could jeopardize achievement of the 2020 London Declaration goals. In this report, we assess diagnostic needs and landscape potential solutions and determine appropriate strategies to improve diagnostic testing to support control and elimination programs. Based upon literature reviews and previous input from experts in the schistosomiasis and STH communities, we prioritized two diagnostic use cases for further exploration: to inform MDA-stopping decisions and post-MDA surveillance. To this end, PATH has refined target product profiles (TPPs) for schistosomiasis and STH diagnostics that are applicable to these use cases. We evaluated the limitations of current diagnostic methods with regards to these use cases and identified candidate biomarkers and diagnostics with potential application as new tools. Based on this analysis, there is a need to develop antigen-detecting rapid diagnostic tests (RDTs) with simplified, field-deployable sample preparation for schistosomiasis. Additionally, there is a need for diagnostic tests that are more sensitive than the current methods for STH, which may include either a field-deployable molecular test or a simple, low-cost, rapid antigen-detecting test.

Novel typhoid diagnostics currently under development have the potential to improve clinical care, surveillance, and the disease burden estimates that support vaccine introduction. Blood culture is most often used as the reference method to evaluate the accuracy of new typhoid tests; however, it is recognized to be an imperfect gold standard. If no single gold standard test exists, use of a composite reference standard (CRS) can improve estimation of diagnostic accuracy. Numerous studies have used a CRS to evaluate new typhoid diagnostics; however, there is no consensus on an appropriate CRS. In order to evaluate existing tests for use as a reference test or inclusion in a CRS, we performed a systematic review of the typhoid literature to include all index/reference test combinations observed. We described the landscape of comparisons performed, showed results of a meta-analysis on the accuracy of the more common combinations, and evaluated sources of variability based on study quality. This wide-ranging meta-analysis suggests that no single test has sufficiently good performance but some existing diagnostics may be useful as part of a CRS. Additionally, based on findings from the meta-analysis and a constructed numerical example demonstrating the use of CRS, we proposed necessary criteria and potential components of a typhoid CRS to guide future recommendations. Agreement and adoption by all investigators of a standardized CRS is requisite, and would improve comparison of new diagnostics across independent studies, leading to the identification of a better reference test and improved confidence in prevalence estimates.

Objective Screening for diabetes in low-resource countries is a growing challenge, necessitating tests that are resource and context appropriate. The aim of this study was to determine the diagnostic accuracy of a self-administered urine glucose test strip compared with alternative diabetes screening tools in a low-resource setting of Cambodia. Design Prospective cross-sectional study. Setting Members of the Borey Santepheap Community in Cambodia (Phnom Penh Municipality, District Dangkao, Commune Chom Chao). Participants All households on randomly selected streets were invited to participate, and adults at least 18 years of age living in the study area were eligible for inclusion. Outcomes The accuracy of self-administered urine glucose test strip positivity, Hemoglobin A1c (HbA1c)>6.5% and capillary fasting blood glucose (cFBG) measurement =126 mg/dL were assessed against a composite reference standard of cFBGmeasurement =200 mg/dL or venous blood glucose 2 hours after oral glucose tolerance test (OGTT) =200 mg/dL. Results Of the 1289 participants, 234 (18%) had diabetes based on either cFBG measurement (74, 32%) or the OGTT (160, 68%). The urine glucose test strip was 14% sensitive and 99% specific and failed to identify 201 individuals with diabetes while falsely identifying 7 without diabetes. Those missed by the urine glucose test strip had lower venous fasting blood glucose, lower venous blood glucose 2 hours after OGTT and lower HbA1c compared with those correctly diagnosed. Conclusions Low cost, easy to use diabetes tools are essential for low-resource communities with minimal infrastructure. While the urine glucose test strip may identify persons with diabetes that might otherwise go undiagnosed in these settings, its poor sensitivity cannot be ignored. The massive burden of diabetes in low-resource settings demands improvements in test technologies. [ABSTRACT FROM AUTHOR]

Diagnostics are critical tools that guide clinical decision-making for patient care and support disease surveillance. Despite its importance, developers and manufacturers often note that access to specimen panels and essential reagents is one of the key challenges in developing quality diagnostics, particularly in low-resource settings. A recent example, as the COVID-19 pandemic unfolded there was a need for clinical samples across the globe to support the rapid development of diagnostics. To address these challenges and gaps, PATH, a global nonprofit, along with its partners collaborated to create a COVID-19 biorepository to improve access to biological samples. Since then, the need for data resources to advance universal rapid diagnostic test (RDT) readers and noninvasive clinical measurement tools for screening children have also been identified and initiated. From biospecimens to data files, there are more similarities than differences in creating open-access repositories. And to ensure equitable technologies are developed, diverse sample panels and datasets are critical in the development process. Here we share one experience in creating open-access repositories as a case study to describe the steps taken, the key factors required to establish a biorepository, the ethical and legal frameworks that guided the initiative and the lessons learned. As diagnostic tools are evolving, more forms of data are critical to de-risk and accelerate early research and development (R&D) for products serving low resource settings. Creating physical and virtual repositories of freely available, well characterized, and high quality clinical and electronic data resources defray development costs to improve equitable access and test affordability.