Low Endemic Settings Research Articles

Patients exposed to vancomycin-resistant enterococci during in-hospital outbreaks in a low endemic setting: a proposal for risk-based screening

BackgroundThe optimal extent of screening of contact patients (CoPat) after exposure to patients infected or colonized with vancomycin-resistant enterococci (VRE) remains controversial.MethodsWe retrospectively developed a new risk stratification for screening patients exposed to VRE, based on data from three outbreaks—two with Enterococcus faecium vanB and one with Enterococcus faecium vanA involving 1096 CoPat—in a low endemic setting. We classified them into four risk groups: three on environmental exposure, one by healthcare exposure: high (sharing the same room/bathroom with a VRE-colonized patient), medium (hospitalization in the same room after a VRE-colonized patient’s discharge until terminal disinfection including ultraviolet C (UVc)-disinfection), low (hospitalized in the same room within three weeks before the VRE-colonized patient), and “staff” (screening of patients having the same medical care team).ResultsVRE-transmission occurred in 7.9% in the high-risk group compared to 0.6% and 0% in the medium and low risk groups. There was a significant trend to higher rates of transmission by risk level of exposure (p < 0.001). In the “staff” group, VRE transmission rate was 2.3%.ConclusionBased on this stratification, we recommend to focus screening of exposed CoPat on the high-risk and “staff” group, saving resources and costs, but larger studies will allow to further improve the yield of VRE screening in the outbreak setting.

Two-stage lot quality assurance sampling framework for monitoring and evaluation of neglected tropical diseases, allowing for imperfect diagnostics and spatial heterogeneity.

BackgroundMonitoring and evaluation (M&E) is a key component of large-scale neglected tropical diseases (NTD) control programs. Diagnostic tests deployed in these M&E surveys are often imperfect, and it remains unclear how this affects the population-based program decision-making.MethodologyWe developed a 2-stage lot quality assurance sampling (LQAS) framework for decision-making that allows for both imperfect diagnostics and spatial heterogeneity of infections. We applied the framework to M&E of soil-transmitted helminth control programs as a case study. For this, we explored the impact of the diagnostic performance (sensitivity and specificity), spatial heterogeneity (intra-cluster correlation), and survey design on program decision-making around the prevalence decisions thresholds recommended by WHO (2%, 10%, 20% and 50%) and the associated total survey costs.Principal findingsThe survey design currently recommended by WHO (5 clusters and 50 subjects per cluster) may lead to incorrect program decisions around the 2% and 10% prevalence thresholds, even when perfect diagnostic tests are deployed. To reduce the risk of incorrect decisions around the 2% prevalence threshold, including more clusters (≥10) and deploying highly specific diagnostic methods (≥98%) are the most-cost saving strategies when spatial heterogeneity is moderate-to-high (intra-cluster correlation >0.017). The higher cost and lower throughput of improved diagnostic tests are compensated by lower required sample sizes, though only when the cost per test is <6.50 US$ and sample throughput is ≥3 per hour.Conclusion/SignificanceOur framework provides a means to assess and update M&E guidelines and guide product development choices for NTD. Using soil-transmitted helminths as a case study, we show that current M&E guidelines may severely fall short, particularly in low-endemic and post-control settings. Furthermore, specificity rather than sensitivity is a critical parameter to consider. When the geographical distribution of an NTD within a district is highly heterogeneous, sampling more clusters (≥10) may be required.

Polymerase Chain Reaction-Based Malaria Diagnosis Can Be Increasingly Adopted during Current Phase of Malaria Elimination in India.

Despite commendable progress in control of malaria in India and other countries, there are hidden reservoirs of parasites in human hosts that continually feed malaria transmission. Submicroscopic infections are a significant proportion in low-endemic settings like India, and these infections possess transmission potential. Hence, these reservoirs of infection add to the existing roadblocks for malaria elimination. It is crucial that this submerged burden of malaria is detected and treated to curtail further transmission. The currently used diagnostic tools, including the so-called "gold standard" microscopy, are incapable of detecting these submicroscopic infections and thus are suboptimal. It is an opportune time to usher in more sensitive molecular tools like polymerase chain reaction (PCR) for routine diagnosis at all levels of healthcare as an additional diagnostic tool in routine settings. PCR assays have been developed into user-friendly formats for field diagnostics and are near-point-of-collection. Because of the COVID-19 pandemic in India, these are being used rampantly across the country. The facilities created for COVID-19 diagnosis can easily be co-opted and harnessed for malaria diagnosis to augment surveillance by the inclusion of molecular techniques like PCR in the routine national malaria control program.

Motivation to test, treat, and report malaria cases: a quantitative assessment among private sector providers in the Greater Mekong Subregion

BackgroundAccurately testing, treating, and tracking all malaria cases is critical to achieving elimination. Ensuring health providers are able and motivated to test, treat, and report cases is a necessary component of elimination programmes, and particularly challenging in low endemic settings where providers may not encounter a large volume of cases. This study aimed to understand provider motivations to test, treat, and report malaria cases to better optimize programme design, adjust incentive schemes, and ultimately improve reporting rates while growing the evidence base around private providers in the Greater Mekong Subregion (GMS).MethodsWith funding from the Bill & Melinda Gates Foundation, this study aimed to identify and validate distinctive subtypes of motivation among private sector providers enrolled in the Greater Mekong Subregion Elimination of Malaria through Surveillance (GEMS) programme, implemented by Population Services International. Quantitative questionnaires were administered electronically in person by trained enumerators to various provider groups in Myanmar, Lao PDR, and Vietnam. A three-stage confirmatory factor analysis was then conducted in STATA.ResultsFollowing this analysis, a two-factor solution that describes motivation in this population of providers was identified, and providers were scored on the two dimensions of motivation. The correlation between the two rotated factors was 0.3889, and the Kaiser–Meyer–Olkin (KMO) measure of sampling adequacy was 0.93, indicating an excellent level of suitability. These providers, who are often assumed to only be financially motivated, engaged in malaria elimination activities because of both internal and external motivational factors that are independent of remuneration or financial gain. For all three countries’ data, significant covariances between the two latent variables for internal and external motivation were found. The models were found to be of adequate to good fit for the data across all three countries. It was determined that private sector providers, who were previously believed to be primarily financially motivated, were also motivated by personal factors. Motivation was also associated with key outcomes of importance to malaria elimination, such as reporting and stocking of tests and treatments.ConclusionMaintaining or increasing provider motivation to test and treat is essential in the fight to eliminate malaria from the GMS, as it helps to ensure that providers continue to pursue this goal, even in a low incidence environment where cases may be rare and in which providers face financial pressure to focus on areas of health service provision. Establishing mechanisms to better motivate providers through intrinsic factors is likely to have a substantive impact on the sustainability of malaria case management activities.

Diagnosis of Visceral Leishmaniasis in an Elimination Setting: A Validation Study of the Diagnostic Algorithm in India.

Visceral leishmaniasis (VL) is on the verge of elimination on the Indian subcontinent. Nonetheless, the currently low VL-incidence setting brings along new challenges, one of which is the validity of the diagnostic algorithm, based on a combination of suggestive clinical symptoms in combination with a positive rK39 Rapid Diagnostic Test (RDT). With this study, we aimed to assess the positive predictive value of the diagnostic algorithm in the current low-endemic setting in India by re-assessing newly diagnosed VL patients with a qPCR analysis on venous blood as the reference test. In addition, we evaluated the specificity of the rK39 RDT by testing non-VL cases with the rK39 RDT. Participants were recruited in Bihar and Uttar Pradesh, India. VL patients diagnosed based on the diagnostic algorithm were recruited through six primary health care centers (PHCs); non-VL cases were identified through a door-to-door survey in currently endemic, previously endemic, and non-endemic clusters, and tested with rK39 RDT, as well as—if positive—with qPCR on peripheral blood. We found that 95% (70/74; 95% CI 87–99%) of incident VL cases diagnosed at the PHC level using the current diagnostic algorithm were confirmed by qPCR. Among 15,422 non-VL cases, 39 were rK39 RDT positive, reflecting a specificity of the test of 99.7% (95% CI 99.7–99.8%). The current diagnostic algorithm combining suggestive clinical features with a positive rK39 RDT still seems valid in the current low-endemic setting in India.

The Early Warning and Response System (EWARS-TDR) for dengue outbreaks: can it also be applied to chikungunya and Zika outbreak warning?

BackgroundIn the Americas, endemic countries for Aedes-borne diseases such as dengue, chikungunya, and Zika face great challenges particularly since the recent outbreaks of CHIKV and ZIKV, all transmitted by the same insect vectors Aedes aegypti and Ae. albopictus. The Special Program for Research and Training in Tropical Diseases (TDR-WHO) has developed together with partners an Early Warning and Response System (EWARS) for dengue outbreaks based on a variety of alarm signals with a high sensitivity and positive predictive value (PPV). The question is if this tool can also be used for the prediction of Zika and chikungunya outbreaks.MethodologyWe conducted in nine districts of Mexico and one large city in Colombia a retrospective analysis of epidemiological data (for the outbreak definition) and of climate and entomological data (as potential alarm indicators) produced by the national surveillance systems for dengue, chikungunya and Zika outbreak prediction covering the following outbreak years: for dengue 2012–2016, for Zika 2015–2017, for chikungunya 2014–2016. This period was divided into a “run in period” (to establish the “historical” pattern of the disease) and an “analysis period” (to identify sensitivity and PPV of outbreak prediction).ResultsIn Mexico, the sensitivity of alarm signals for correctly predicting an outbreak was 100% for dengue, and 97% for Zika (chikungunya data could not be obtained in Mexico); the PPV was 83% for dengue and 100% for Zika. The time period between alarm and start of the outbreak (i.e. the time available for early response activities) was for Zika 4–5 weeks. In Colombia the sensitivity of the outbreak prediction was 92% for dengue, 93% for chikungunya and 100% for Zika; the PPV was 68% for dengue, 92% for chikungunya and 54% for Zika; the prediction distance was for dengue 3–5 weeks, for chikungunya 10–13 weeks and for Zika 6–10 weeks.ConclusionEWARS demonstrated promising capability of timely disease outbreak prediction with an operational design likely to improve the coordination among stakeholders. However, the prediction validity varied substantially across different types of diseases and appeared less optimal in low endemic settings.

Dysglycaemia among tuberculosis patients without known diabetes in a low-endemic setting.

With a high prevalence of dysglycaemia (29.1%) among tuberculosis patients without previously known diabetes, this study highlights the importance of comanagement of tuberculosis and diabetes, even in a low-endemic setting https://bit.ly/3Gj0gmN

Potential of the CRISPR-Cas system for improved parasite diagnosis: CRISPR-Cas mediated diagnosis in parasitic infections: CRISPR-Cas mediated diagnosis in parasitic infections.

CRISPR-Cas technology accelerates development of fast, accurate, and portable diagnostic tools, typified by recent applications in COVID-19 diagnosis. Parasitic helminths cause devastating diseases afflicting 1.5 billion people globally, representing a significant public health and economic burden, especially in developing countries. Currently available diagnostic tests for worm infection are neither sufficiently sensitive nor field-friendly for use in low-endemic or resource-poor settings, leading to underestimation of true prevalence rates. Mass drug administration programs are unsustainable long-term, and diagnostic tools - required to be rapid, specific, sensitive, cost-effective, and user-friendly without specialized equipment and expertise - are urgently needed for rapid mapping of helminthic diseases and monitoring control programs. We describe the key features of the CRISPR-Cas12/13 system and emphasise its potential for the development of effective tools for the diagnosis of parasitic and other neglected tropical diseases (NTDs), a key recommendation of the NTDs 2021-2030 roadmap released by the World Health Organization.

Strengthening Tuberculosis Services for Children and Adolescents in Low Endemic Settings.

In low tuberculosis-burden countries, children and adolescents with the highest incidence of tuberculosis (TB) infection or disease are usually those who have immigrated from high-burden countries. It is, therefore, essential that low-burden countries provide healthcare services to immigrant and refugee families, to assure that their children can receive proper testing, evaluation, and treatment for TB. Active case-finding through contact tracing is a critical element of TB prevention in children and in finding TB disease at an early, easily treated stage. Passive case-finding by evaluating an ill child is often delayed, as other, more common infections and conditions are suspected initially. While high-quality laboratory services to detect Mycobacterium tuberculosis are generally available, they are often underutilized in the diagnosis of childhood TB, further delaying diagnosis in some cases. Performing research on TB disease is difficult because of the low number of cases that are spread over many locales, but critical research on the evaluation and treatment of TB infection has been an important legacy of low-burden countries. The continued education of medical providers and the involvement of educational, professional, and non-governmental organizations is a key element of maintaining awareness of the presence of TB. This article provides the perspective from North America and Western Europe but is relevant to many low-endemic settings. TB in children and adolescents will persist in low-burden countries as long as it persists throughout the rest of the world, and these wealthy countries must increase their financial commitment to end TB everywhere.

Clinical and epidemiological trends in childhood leprosy: A 20-year retrospective analysis from a tertiary care hospital in Jammu, North India.

Background Slightly more than half the total number of childhood leprosy cases worldwide are from India. Aim To analyze the clinical and epidemiological trends of childhood leprosy over 20 years in a tertiary care hospital. Methods We retrieved the medical records of all children less than 15 years of age registered in the leprosy clinic between April 1998 and March 2018. We tabulated and analyzed data pertaining to demographic details along with clinical findings such as cutaneous lesions, nerves involved, sensory loss, deformities, reactions, smear status, histopathology and treatment. Results Out of total 1548 leprosy cases registered during the study period, 55 (3.55%) cases of childhood leprosy were diagnosed. Thirty five (63.6%) children were in the age group of 11-15 years and 83.7% were migrants from other states. Thirteen (23.6%) children reported contact with a diagnosed case of leprosy, mainly in close contacts. Fifty three (96.4%) children presented with cutaneous lesions while 2 (3.6%) had pure neural involvement. Borderline tuberculoid leprosy was the most common clinical presentation in 27 (49.1%) followed by borderline lepromatous leprosy in 11 (18%). Thickened peripheral nerve trunks were detected in 42 (76.4%), most commonly the ulnar nerve. Reactional episodes occurred in 12 (21.8%) cases (Type 1 reaction, 10 (18.2%); Type 2 reaction, 2 (3.6%)). Grade 2 disability was detected in 4 (7.3%). Multidrug therapy was started in all patients, multibacillary (MB) regimen in 42 (76.3%) patients and paucibacillary (PB) regimen in 13 (23.7%). Twenty five (45.4%) children defaulted from the treatment. On comparing the data of 2008-18 with that of the previous decade (1998-2007), there was a higher proportion of migrant cases as compared to local cases (3:1-11:1) and MB cases as compared to PB cases (2:1-6:1). The proportion of treatment defaulters declined from 60% to 36%. Limitations Relapse rate could not be calculated due to inadequate follow-up period. As it is a hospital-based retrospective study with no active surveys, these findings may not reflect trends in the community. Conclusion Childhood leprosy continues to be a significant problem. There is a clear need to strengthen early detection, treatment and regular follow-up of these cases in both high and low endemic settings.

Household and individual level risk factors associated with declining malaria incidence in Meghalaya, India: implications for malaria elimination in low-endemic settings

BackgroundA detailed analysis of household and individual level Plasmodium infection patterns in two low-endemic districts of Meghalaya was undertaken to better understand the epidemiology of malaria in northeast India.MethodsSocio-demographic and behavioural information from residents (aged 1–69 years) of households were collected through pre-tested, questionnaire conducted in 2018 and 2019. Blood samples collected from participants were tested for Plasmodium falciparum and/or Plasmodium vivax infection using rapid diagnostic test, microscopy and PCR. Plasma samples from a subset of participants were analysed for antibodies against thirteen P. falciparum and four P. vivax antigens. Associations between household and individual level risk factors, and Plasmodium infections were evaluated using multilevel logistic regression models.ResultsA total of 2753 individuals from 827 households were enrolled in 2018, and 834 individuals from 222 households were enrolled in 2019. Of them, 33 (1.2%) were positive by PCR for P. falciparum in 2018 and none were positive for P. vivax. In 2019, no PCR-positive individuals were detected. All, but one, infections were asymptomatic; all 33 infections were sub-microscopic. Reported history of malaria in the past 12 months (OR = 8.84) and history of travel in the past 14 days (OR = 10.06) were significantly associated with Plasmodium infection. A significant trend of increased seropositivity with age was noted for all 17 antigens. Although adults (≥ 18 years) consistently had the highest seropositivity rates, a sizeable proportion of under-five children were also found to be seropositive. Almost all individuals (99.4%) reported sleeping under an insecticide-treated bed-net, and household indoor residual spray coverage in the 12 months preceding the survey was low (23%). Most participants correctly identified common signs and symptoms of malaria, i.e., fever (96.4%), headache (71.2%), chills (83.2%) and body-ache (61.8%). Almost all participants (94.3%) used government-provided services for treatment of malaria.ConclusionThis study explored the epidemiology of malaria in two communities in Meghalaya, India, in the context of declining transmission. The presence of widespread asymptomatic infections and seropositivity among under-five children suggest that low-level Plasmodium transmission persists in this region. Implications of the study findings for malaria elimination efforts in low-transmission settings are discussed.

Malaria awareness of adults in high, moderate and low transmission settings: A cross-sectional study in rural East Nusa Tenggara Province, Indonesia.

The 2009 Indonesian roadmap to malaria elimination indicated that the nation had been progressing towards achieving malaria elimination by 2030. Currently, most of the districts in the western part of Indonesia have eliminated malaria; however, none of the districts in the East Nusa Tenggara Province (ENTP) have met these set targets. This study aimed to investigate the status of malaria awareness of rural adults in the ENTP. A community-based cross-sectional study was conducted between October and December 2019 in high, moderate, and low malaria-endemic settings (MESs) in the ENTP. After obtaining informed consent, data were collected using an interviewer-administered structure questionnaire among 1503 participants recruited by a multi-stage cluster sampling method. A malaria awareness index was developed based on ten questions. A binary logistic regression method was applied to investigate the significance of any association between malaria awareness and the different MESs. The participation rate of the study was 99.5%. Of this number, 51.4% were female and 45.5% had completed primary education. The malaria awareness index was significantly low (48.8%, 95% confidence interval [CI]: 45.2-52.4). Malaria awareness of rural adults residing in low endemic settings was two times higher than for those living in high endemic settings (adjusted odds ratio [AOR]: 2.41, 95% CI: 1.81-3.21) and the basic malaria knowledge of participants living in low malaria-endemic settings was almost four times higher than that in high endemic settings (AOR: 3.75, 95% CI: 2.75-5.11). Of the total participants, 81.3% (95% CI: 79.1-83.5) were aware that malaria could be prevented and 75.1% (95% CI: 72.6-77.6) knew at least one prevention measure. Overall, the awareness of fever as the main symptom of malaria, mosquito bites as the transmission mode of malaria, and seeking treatment within 24 hours of suffering from malaria was poor at 37.9% (95% CI: 33.9-41.9), 59.1% (95% CI: 55.9-62.3), and 46.0% (95% CI: 42.3-49.7), respectively. The poor level of awareness was significantly different amongst the three MESs, with the lowest levels of awareness in the high endemic setting. Malaria awareness of rural adults needs to be improved to address Indonesia's national roadmap for malaria elimination. Results indicated that public health programs at a local government level should incorporate the malaria awareness index in their key strategic intervention to address malaria awareness.

Preventing leprosy with retrospective active case finding combined with single-dose rifampicin for contacts in a low endemic setting: results of the Leprosy Post-Exposure Prophylaxis program in Cambodia

Post-exposure prophylaxis (PEP) with single-dose rifampicin (SDR) reduces the risk of developing leprosy among contacts of leprosy patients. Most evidence for the feasibility of the intervention is from highly endemic settings while low-endemic areas present unique challenges including reduced awareness of the disease among the population and in the health system, and the only sporadic occurrence of cases which together make defining any type of routine process challenging.We complemented the retrospective active case finding (RACF) approach with SDR administration to eligible contacts, and piloted the intervention across 31 operational districts in Cambodia. The aim was to demonstrate the feasibility of improving early case detection and administering SDR in a low endemic setting. The intervention focused on leprosy patients diagnosed since 2011 and was implemented between October 2016 – September 2019. The “drives” approach was employed to trace contacts: a trained team systematically contacted all eligible cases in a district, traced and screened contacts, and administered SDR.A total of 555 index patients were traced by the drive team, and 10,410 contacts in their household and 5 immediate neighbor houses listed. Among these contacts, 72.0% could be screened while most others were absent on the screening day. A total of 33 new leprosy cases were diagnosed and 6189 contacts received SDR (82.6% of the screened contacts). Sixty-one contacts refused SDR administration.We conclude that integrating PEP with SDR in RACF campaigns is feasible, and that this approach is appropriate in low resource and low endemic settings. Over time, evidence on whether or not the approach reduced leprosy transmission in Cambodia, may become clear.

The Impact of Borderline Quantiferon-TB Gold Plus Results for Latent Tuberculosis Screening under Routine Conditions in a Low-Endemicity Setting

Quantiferon-TB Gold Plus (QFT-Plus) is an interferon gamma release assay used to diagnose latent tuberculosis (LTB). A borderline range (0.20 to 0.99 IU/ml) around the cutoff (0.35 IU/ml) has been suggested for the earlier QFT version. Our aims were to evaluate the borderline range for QFT-Plus and the contribution of the new TB2 antigen tube. QFT-Plus results were collected from clinical laboratories in Sweden and linked to incident active TB within 3 to 24 months using the national TB registry. Among QFT-Plus results from 58,539 patients, 83% were negative (<0.20 IU/ml), 2.4% were borderline negative (0.20 to 0.34 IU/ml), 3.4% were borderline positive (0.35 to 0.99 IU/ml), 9.6% were positive (≥1.0 IU/ml), and 1.6% were indeterminate. Follow-up tests after initial borderline results were negative (<0.20 IU/ml) in 38.3%, without any cases of incident active TB within 2 years. Applying the 0.35-IU/ml cutoff, 1.5% of TB1 and TB2 results were discrepant, of which 52% were within the borderline range. A TB2 result of ≥0.35 IU/ml with a TB1 result of <0.20 IU/ml was found in 0.4% (231/58,539) of all included baseline QFT-Plus test results, including 1.8% (1/55) of incident TB cases. A borderline range for QFT-Plus is clinically useful as more than one-third of those with borderline results are convincingly negative upon retesting, without developing incident active TB. The TB2 tube contribution to LTB diagnosis appears limited.

Molecular epidemiology of dengue in a setting of low reported endemicity: Kupang, East Nusa Tenggara province, Indonesia.

Most regions in Indonesia experience annual dengue epidemics. However, the province of East Nusa Tenggara has consistently reported low incidence. We conducted a dengue molecular epidemiology study in Kupang, the capital of the province. Dengue patients were recruited from May 2016 to September 2017. Dengue virus (DENV) screening was performed using NS1 and immunoglobulin G (IgG)/IgM detection. Serotype was determined using reverse transcription polymerase chain reaction and the envelope genes were sequenced to infer the genetic identity and phylogeny. From 119 patients, dengue was confirmed in 62 (52%). Compared with official data, underreporting of dengue incidence was observed. The majority (36%) of patients were children <10y of age. Most patients (80%) experienced mild fever. All serotypes were detected, with DENV-3 as the predominant (57%). Kupang DENV-1 isolate was classified as genotype IV, an old and endemic strain, DENV-2 as cosmopolitan, DENV-3 as genotype I and DENV-4 as genotype II. Most isolates showed relatively low evolutionary rates and are closely related with strains from Bali and Timor Leste. The low dengue incidence was most likely caused by sustained local circulation of endemic viruses. This study provides information on the epidemiology of dengue in a low-endemicity setting that should help future mitigation and disease management.

Similar Ferroportin Q248H polymorphism prevalence in patients with Plasmodium falciparum malaria and control subjects in the low-endemic setting of Botswana

IntroductionRecent evidence suggests that ferroportin (FPN) Q248H may confer a survival advantage against malaria by reducing erythrocytic intracellular iron in Africans. We investigated if FPN Q248H mutation, that is prevalent in Batswana, is a factor in limiting the susceptibility to Plasmodium falciparum malaria. Methods264 archived dried blood spot samples (183 P. falciparum malaria cases and 81 controls, matched for geographical region and season for equal exposure) were genotyped. Human and P. falciparum DNA was extracted using Chelex-100 resin and P. falciparum molecular confirmation performed. Ferroportin Q248H mutation was identified by restriction fragment length polymorphism. The prevalence of the FPN Q248H mutation and allele frequency and the accompanying 95% confidence interval were calculated. A qPCR method was employed to estimate P. falciparum parasitaemia. Association between FPN and malaria susceptibility was tested using Pearson Chi-square test and Mood's median test was used to compare P. falciparum parasitaemias according to FPN Q248H mutation. ResultsAll samples were successfully genotyped. The FPN Q248H allele frequency was 0.08 (95% CI: 0.05–0.11) in cases and 0.08 (95% CI: 0.02–0.14) in controls, consistent with Hardy-Weinberg equilibrium. The prevalence of FPN Q248H phenotype was comparable in patients with P. falciparum malaria and in un-infected individuals, 16.4% (95% CI: 11.0–21.8) vs 14.8% (95% CI: 7.1–22.5), P = 0.746. In addition, no association of presence of FPN Q248H with reduced parasitaemia was recorded, P = 0.837. ConclusionIn this small study, FPN Q248H polymorphism prevalence was comparable between patients with P. falciparum malaria and control subjects in the low-endemic setting of Botswana.

Immunomics-guided discovery of serum and urine antibodies for diagnosing urogenital schistosomiasis: a biomarker identification study

SummaryBackgroundSensitive diagnostics are needed for effective management and surveillance of schistosomiasis so that current transmission interruption goals set by WHO can be achieved. We aimed to screen the Schistosoma haematobium secretome to find antibody biomarkers of schistosome infection, validate their diagnostic performance in samples from endemic populations, and evaluate their utility as point of care immunochromatographic tests (POC-ICTs) to diagnose urogenital schistosomiasis in the field.MethodsWe did a biomarker identification study, in which we constructed a proteome array containing 992 validated and predicted proteins from S haematobium and screened it with serum and urine antibodies from endemic populations in Gabon, Tanzania, and Zimbabwe. Arrayed antigens that were IgG-reactive and a select group of antigens from the worm extracellular vesicle proteome, predicted to be diagnostically informative, were then evaluated by ELISA using the same samples used to probe arrays, and samples from individuals residing in a low-endemicity setting (ie, Pemba and Unguja islands, Zanzibar, Tanzania). The two most sensitive and specific antigens were incorporated into POC-ICTs to assess their ability to diagnose S haematobium infection from serum in a field-deployable format.FindingsFrom array probing, in individuals who were infected, 208 antigens were the targets of significantly elevated IgG responses in serum and 45 antigens were the targets of significantly elevated IgG responses in urine. Of the five proteins that were validated by ELISA, Sh-TSP-2 (area under the curve [AUC]serum=0·98 [95% CI 0·95–1·00]; AUCurine=0·96 [0·93–0·99]), and MS3_01370 (AUCserum=0·93 [0·89–0·97]; AUCurine=0·81 [0·72–0·89]) displayed the highest overall diagnostic performance in each biofluid and exceeded that of S haematobium-soluble egg antigen in urine (AUC=0·79 [0·69–0·90]). When incorporated into separate POC-ICTs, Sh-TSP-2 showed absolute specificity and a sensitivity of 75% and MS3_01370 showed absolute specificity and a sensitivity of 89%.InterpretationWe identified numerous biomarkers of urogenital schistosomiasis that could form the basis of novel antibody diagnostics for this disease. Two of these antigens, Sh-TSP-2 and MS3_01370, could be used as sensitive, specific, and field-deployable diagnostics to support schistosomiasis control and elimination initiatives, with particular focus on post-elimination surveillance.FundingAustralian Trade and Investment Commission and Merck Global Health Institute.

Identification of the asymptomatic Plasmodium falciparum and Plasmodium vivax gametocyte reservoir under different transmission intensities.

BackgroundUnderstanding epidemiological variables affecting gametocyte carriage and density is essential to design interventions that most effectively reduce malaria human-to-mosquito transmission.Methodology/Principal findingsPlasmodium falciparum and P. vivax parasites and gametocytes were quantified by qPCR and RT-qPCR assays using the same methodologies in 5 cross-sectional surveys involving 16,493 individuals in Brazil, Thailand, Papua New Guinea, and Solomon Islands. The proportion of infections with detectable gametocytes per survey ranged from 44–94% for P. falciparum and from 23–72% for P. vivax. Blood-stage parasite density was the most important predictor of the probability to detect gametocytes. In moderate transmission settings (prevalence by qPCR>5%), parasite density decreased with age and the majority of gametocyte carriers were children. In low transmission settings (prevalence<5%), >65% of gametocyte carriers were adults. Per survey, 37–100% of all individuals positive for gametocytes by RT-qPCR were positive by light microscopy for asexual stages or gametocytes (overall: P. falciparum 178/348, P. vivax 235/398).Conclusions/SignificanceInterventions to reduce human-to-mosquito malaria transmission in moderate-high endemicity settings will have the greatest impact when children are targeted. In contrast, all age groups need to be included in control activities in low endemicity settings to achieve elimination. Detection of infections by light microscopy is a valuable tool to identify asymptomatic blood stage infections that likely contribute most to ongoing transmission at the time of sampling.

Accuracy of Two Circulating Antigen Tests for the Diagnosis and Surveillance of Schistosoma mansoni Infection in Low-Endemicity Settings of Côte d'Ivoire.

ABSTRACT.In low-endemicity settings, current tools for the diagnosis and surveillance of schistosomiasis are often inaccurate in detecting true infection. We assessed the accuracy of an up-converting phosphor lateral flow circulating anodic antigen (UCP-LF CAA) test and a point-of-care circulating cathodic antigen (POC-CCA) urine cassette test for the diagnosis of Schistosoma mansoni. Our study was conducted in eight schools of western Côte d’Ivoire. Fifty children, aged 9–12 years, were enrolled per school. From each child, a single urine specimen and two stool specimens were collected over consecutive days for diagnostic work-up. Urine samples were subjected to UCP-LF CAA and POC-CCA tests. From each stool sample, triplicate Kato-Katz thick smears were examined. Overall, 378 children had complete data records. The prevalence of S. mansoni, as assessed by six Kato-Katz thick smears, was 4.0%. The UCP-LF CAA and POC-CCA tests revealed S. mansoni prevalence of 25.4% and 30.7%, respectively, when considering trace results as positive, and prevalence of 23.3% and 10.9% when considering trace results as negative. In the latter case, based on a composite “gold” standard, the sensitivity of UCP-LF CAA (80.7%) was considerably higher than that of POC-CCA (37.6%) and six Kato-Katz thick smears (13.8%). The negative predictive value of UCP-LF CAA, POC-CCA, and six Kato-Katz thick smears was 92.8%, 79.8%, and 74.1%, respectively. Our results confirm that UCP-LF CAA is more accurate than Kato-Katz and POC-CCA for the diagnosis of S. mansoni in low-endemicity settings.

Low-level Plasmodium vivax exposure, maternal antibodies, and anemia in early childhood: Population-based birth cohort study in Amazonian Brazil.

Malaria causes significant morbidity and mortality in children under 5 years of age in sub-Saharan Africa and the Asia-Pacific region. Neonates and young infants remain relatively protected from clinical disease and the transplacental transfer of maternal antibodies is hypothesized as one of the protective factors. The adverse health effects of Plasmodium vivax malaria in early childhood-traditionally viewed as a benign infection-remain largely neglected in relatively low-endemicity settings across the Amazon. Overall, 1,539 children participating in a birth cohort study in the main transmission hotspot of Amazonian Brazil had a questionnaire administered, and blood sampled at the two-year follow-up visit. Only 7.1% of them experienced malaria confirmed by microscopy during their first 2 years of life- 89.1% of the infections were caused by P. vivax. Young infants appear to be little exposed to, or largely protected from infection, but children >12 months of age become as vulnerable to vivax malaria as their mothers. Few (1.4%) children experienced ≥4 infections during the 2-year follow-up, accounting for 43.4% of the overall malaria burden among study participants. Antenatal malaria diagnosed by microscopy during pregnancy or by PCR at delivery emerged as a significant correlate of subsequent risk of P. vivax infection in the offspring (incidence rate ratio, 2.58; P = 0.002), after adjusting for local transmission intensity. Anti-P. vivax antibodies measured at delivery do not protect mothers from subsequent malaria; whether maternal antibodies transferred to the fetus reduce early malaria risk in children remains undetermined. Finally, recent and repeated vivax malaria episodes in early childhood are associated with increased risk of anemia at the age of 2 years in this relatively low-endemicity setting. Antenatal infection increases the risk of vivax malaria in the offspring and repeated childhood P. vivax infections are associated with anemia at the age of 2 years.