Endemic Settings Research Articles

Effectiveness of two doses of Euvichol-plus oral cholera vaccine in response to the 2017/2018 outbreak: a matched case–control study in Lusaka, Zambia

IntroductionZambia experienced a major cholera outbreak in 2017–2018, with more than 5905 cases reported countrywide, predominantly from the peri-urban slums of Lusaka city. The WHO recommends the use of oral...

Monkey Pox Pathogenesis, Diagnosis, Treatment: A Comprehensive Review

Human monkeypox is a zoonotic Orthopoxvirus with a presentation similar to smallpox. Clinical differentiation of the disease from smallpox and varicella is difficult. Laboratory diagnostics are principal components to identification and surveillance of disease, and new tests are needed for a more precise and rapid diagnosis. The majority of human infections occur in Central Africa, where surveillance in rural areas with poor infrastructure is difficult but can be accomplished with evidence-guided tools and educational materials to inform public health workers of important principles. As the fear of the coronavirus disease 2019 (COVID-19) pandemic subsides, countries around the globe are now dealing with a fear of the epidemic surrounding the prevalence of monkeypox cases in various regions. Previously endemic to regions of Africa, the majority of monkeypox cases associated with the 2022 outbreak are being noted in countries around Europe and in the western hemisphere. While contact-tracing projects are being conducted by various organizations, it is unknown how this outbreak began. Monkeypox virus is one of the many zoonotic viruses that belong to the Orthopoxvirus genus of the Poxviridae family. Monkeypox cases received global attention during the 1970s, after the global eradication of smallpox. The smallpox vaccine provided cross-immunity to the monkeypox virus. Upon the cessation of smallpox vaccine administration, monkeypox cases became more prevalent. It was not until the 2003 US outbreak that monkeypox truly gained global attention. Despite the virus being named monkeypox, monkeys are not the origin of the virus. Several rodents and small mammals have been attributed as the source of the virus; however, it is unknown what the true origin of monkeypox is. The name monkeypox is due to the viral infection being first witnessed in macaque monkeys. Though human-to-human transmission of monkeypox is very rare, it is commonly attributed to respiratory droplets or direct contact with mucocutaneous lesions of an infected individual. Currently, there is no treatment allocated for infected individuals, however, supportive treatments can be administered to provide symptom relief to individuals; Medications such as tecovirimat may be administered in very severe cases. These treatments are subjective, as there are no exact guidelines for symptom relief. Contemporary epidemiological studies are needed now that populations do not receive routine smallpox vaccination. New therapeutics and vaccines offer hope for the treatment and prevention of monkeypox; however, more research must be done before they are ready to be deployed in an endemic setting. There is a need for more research in the epidemiology, ecology, and biology of the virus in endemic areas to better understand and prevent human infections.

Development and validation of a resazurin assay for in vitro susceptibility testing of Actinomadura madurae: a common causative agent of actinomycetoma.

Actinomycetoma is a chronic granulomatous disease affecting skin, subcutaneous tissue, fascia, muscle and bones. With increasing resistance against commonly used treatment regimens, susceptibility testing is urgently needed. We developed an in vitro susceptibility assay for Actinomadura madurae, one of the common causative agents of actinomycetoma, employing resazurin for endpoint reading. Using this assay, reproducible MICs were determined for the most commonly used antibacterial agents for actinomycetoma treatment. The tested antibacterial agents included trimethoprim/sulfamethoxazole, amikacin, streptomycin, amoxicillin, ceftriaxone, gentamicin, ciprofloxacin, doxycycline, imipenem, linezolid, penicillin G and rifampicin. Following the clinical breakpoints as stated by CLSI, 100% of the tested strains were susceptible to trimethoprim/sulfamethoxazole (MIC 0.03/0.59-1/19 mg/L), amikacin (MIC 0.0078-0.25 mg/L), doxycycline (MIC <0.25-1 mg/L) and linezolid (MIC <0.25-2 mg/L), 90% to ciprofloxacin (MIC <0.25-2 mg/L), 80% to ceftriaxone (MIC <0.5 to >64 mg/L) and imipenem (MIC <0.25-32 mg/L) and only 20% to amoxicillin (MIC <0.5 to >64 mg/L) and rifampicin (MIC 0.5 to >32 mg/L). Determinations of MICs by visual readings of colour changes versus spectrophotometric readings were comparable. This convenient visual reading has the advantage of feasible implementation in endemic settings.

Driving down malaria transmission with engineered gene drives.

The last century has witnessed the introduction, establishment and expansion of mosquito-borne diseases into diverse new geographic ranges. Malaria is transmitted by female Anopheles mosquitoes. Despite making great strides over the past few decades in reducing the burden of malaria, transmission is now on the rise again, in part owing to the emergence of mosquito resistance to insecticides, antimalarial drug resistance and, more recently, the challenges of the COVID-19 pandemic, which resulted in the reduced implementation efficiency of various control programs. The utility of genetically engineered gene drive mosquitoes as tools to decrease the burden of malaria by controlling the disease-transmitting mosquitoes is being evaluated. To date, there has been remarkable progress in the development of CRISPR/Cas9-based homing endonuclease designs in malaria mosquitoes due to successful proof-of-principle and multigenerational experiments. In this review, we examine the lessons learnt from the development of current CRISPR/Cas9-based homing endonuclease gene drives, providing a framework for the development of gene drive systems for the targeted control of wild malaria-transmitting mosquito populations that overcome challenges such as with evolving drive-resistance. We also discuss the additional substantial works required to progress the development of gene drive systems from scientific discovery to further study and subsequent field application in endemic settings.

Epileptic spasms: A South African overview of aetiologies, interventions, and outcomes.

To better understand the aetiologies of epileptic spasms in infants, as well as the safety and efficacy of high dose corticosteroids in tuberculosis and human immunodeficiency virus (HIV) endemic resource-limited settings. This was a retrospective analysis of infants with epileptic spasms managed at the tertiary referral centres in the Western Cape, South Africa. Of 175 children with epileptic spasms, the median age at onset was 6 months (interquartile range 4-8 months). Structural aetiologies were most common (115 out of 175 [66%]), with two-thirds related to perinatal insults. A lead time to treatment (LTTT) of less than 1 month was more likely in the epileptic encephalopathy/developmental and epileptic encephalopathy (DEE) group: 58 out of 92 (63%), compared to 28 out of 76 (37%) of those with developmental encephalopathy (p=0.001). Failure to recognize preceding developmental delay was common. Ninety-nine children (57%) received first line hormonal therapy such as adrenocorticotropic hormone. A total of 111 out of 172 children (65%) from the developmental encephalopathy and epileptic encephalopathy/DEE groups had clinical and/or electroencephalogram resolution of spasms within 14 days. In our population, children in whom an aetiology could not be identified were statistically more likely to have moderate to profound developmental delay at 1 year of age: 33 out of 44 (p=0.001). Based on reported incidence of epileptic spasms, 23 to 58 cases per annum would be expected but a far smaller proportion presented to our centres. Whilst this is the largest cohort of infants with epileptic spasms from sub-Saharan Africa, the study size is less than expected; this may reflect misdiagnosis and failure of referral pathways. Despite a reported shorter LTTT, infants with DEE had worse developmental outcomes compared to international studies. Hormonal therapy was safe and effective in our setting, despite exposure to high levels of tuberculosis and HIV. The number of unreferred cases of epileptic spasms in South Africa remains high. Caregivers and health care workers in primary care facilities often fail to recognize developmental delay. The burden of disease from hypoxic-ischaemic encephalopathy remains high in our resource-limited setting. Hormonal treatment (e.g. adrenocorticotropic hormone) was safe and effective despite the high prevalence of human immunodeficiency virus and tuberculosis.

Q fever screening among pregnant women with pre-term delivery in northern Israel: An observational study.

The relationship between Q fever, caused by Coxiella burnetii, and obstetrical complications is debatable. Since Q fever is endemic in Israel, we aimed to assess its seroprevalence and clinical characteristics in pre-term deliveries. Between 1 August 2017 and 31 December 2019, we conducted serological screening for C.burnetii in pregnant women who presented to Rambam Health Care Campus with pre-term delivery (before 37 weeks of gestation). Anti-C.burnetii antibodies were tested first by enzyme-linked immunosorbent assay for the detection of phase I-IgG, phase II-IgG and phase II-IgM. Positive results were confirmed by indirect immunofluorescence with titre determination. Seropositivity was classified into past, acute and chronic infection. Demographic and clinical data of mothers and neonates were collected and compared between seropositive and seronegative women. Out of 386 pregnant women screened for anti-C.burnetii antibodies, 16 (4.1%) were seropositive, of whom three were diagnosed with past, 12 with acute and one with chronic infection. A higher percentage of seropositive women were immunosuppressed, 2/16 (12.5%) compared with 7/370 (1.9%) in seronegative women, (p= .05). Neonates with small for gestational age were born to 2/16 (12.5%) seropositive women compared with 29/370 (7.8%) to seronegative women, (p= .35). The seroprevalence of Q fever among pregnant women with pre-term birth reached 4% in northern Israel. This high rate in an endemic setting encourages investigating the role of routine screening for Q fever during pregnancy. Special attention should be given to pregnant immunosuppressed women at risk for exposure to Q fever.

Evaluating and mitigating the potential indirect effect of COVID-19 on control programmes for seven neglected tropical diseases: a modelling study

BackgroundIn line with movement restrictions and physical distancing essential for the control of the COVID-19 pandemic, WHO recommended postponement of all neglected tropical disease (NTD) control activities that involve community-based surveys, active case finding, and mass drug administration in April, 2020. Following revised guidance later in 2020, and after interruptions to NTD programmes of varying lengths, NTD programmes gradually restarted in the context of an ongoing pandemic. However, ongoing challenges and service gaps have been reported. This study aimed to evaluate the potential effect of the programmatic interruptions and strategies to mitigate this effect.MethodsFor seven NTDs, namely soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis, trachoma, visceral leishmaniasis, and human African trypanosomiasis, we used mathematical transmission models to simulate the effect of programme interruptions on the dynamics of each of these diseases in different endemic settings. We also explored the potential benefit of implementing mitigation strategies, primarily in terms of minimising the delays to control targets.FindingsWe show that the effect of the COVID-19-induced interruption in terms of delay to achieving elimination goals might in some cases be much longer than the duration of the interruption. For schistosomiasis, onchocerciasis, trachoma, and visceral leishmaniasis, a mean delay of 2–3 years for a 1-year interruption is predicted in areas of highest prevalence. We also show that these delays can largely be mitigated by measures such as additional mass drug administration or enhanced case-finding.InterpretationThe COVID-19 pandemic has brought infectious disease control to the forefront of global consciousness. It is essential that the NTDs, so long neglected in terms of research and financial support, are not overlooked, and remain a priority in health service planning and funding.FundingBill & Melinda Gates Foundation, Medical Research Council, and the UK Foreign, Commonwealth & Development Office.

Epidemiology of tick-borne pathogens of cattle and tick control practices in coastal Kenya

Tick-borne diseases (TBD) are a major constraint to livestock health and productivity in sub-Saharan Africa. Nonetheless, there are relatively few robust epidemiologic studies documenting TBD and its management in different endemic settings in Kenya. Therefore, a cross-sectional study using multi-stage cluster sampling was undertaken to characterize the epidemiology of TBD and management factors among zebu cattle reared under an extensive system in coastal Kenya. Blood samples from 1486 cattle from 160 herds in 14 villages were screened for the presence of tick-borne bacterial and protozoan pathogens using PCR with high-resolution melting analysis and sequencing. Standardized questionnaires were used to collect data on herd structure and herd management practices, and a mixed-effect logistic regression model to identify risk factors for tick-borne pathogens (TBPs). The application of chemical acaricide was the primary method for tick control (96.3%, 154/160), with the amidine group (mainly Triatix®, amitraz) being the most frequently used acaricides. Respondents identified East Coast fever as the most important disease and Butalex® (buparvaquone) was the most commonly administered drug in response to perceived TBD in cattle. The overall animal- and herd-level prevalence for TBPs were 24.2% (95% confidence interval (CI): 22.0–26.4%) and 75.6% (95% CI: 68.2–82.1%), respectively. Cattle were infected with Anaplasma marginale (10.9%, 95% CI: 9.4–12.6), Theileria parva (9.0%, 95% CI: 7.5–10.5), Anaplasma platys (2.6%, 95% CI: 1.9–3.6), Theileria velifera (1.1%, 95% CI: 0.7–1.8), Babesia bigemina (0.5%, 95% CI: 0.2–1.0), and Anaplasma sp. (0.1%, 95% CI: 0.0–0.4). Moreover, 21 cattle (1.4%) were co-infected with two TBPs. None of the assessed potential risk factors for the occurrence of either A. marginale or T. parva in cattle were statistically significant. The intra-herd correlation coefficients (lCCs) computed in this study were 0.29 (A. marginale) and 0.14 (T. parva). This study provides updated molecular-based information on the epidemiological status of TBPs of cattle and herd management practices in coastal Kenya. This information can be used in designing cost-effective control strategies for combating these TBD in the region.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Culture filtrate protein 32 as a potential target to attenuate the heterogeneous antibody response against Mycobacterium tuberculosis Antigens in different endemic settings.

We previously reported the development of an enzyme-linked immunosorbent assay for the detection of the immunoglobulin G (IgG) response to Mycobacterium tuberculosis virulence factor - culture filtrate protein 32 (CFP32). The assay achieved high performance in comparing healthy Bacillus Calmette-Guerin-vaccinated controls with active tuberculosis (TB) patients from the Tunisian population. Herein, we aimed to assess the anti-CFP32 IgG response in suspected or confirmed active pulmonary TB individuals in different endemic settings. Serum samples were obtained from 224 donors from African and Latin American countries with variable levels of TB endemicity and different ethnical origins. Receiver operating characteristic curve was used to evaluate the performance of the serological assay. The area under the curve was 0.70. The use of a cutoff level of 0.65 gave 67% and 68% sensitivity and specificity, respectively, regardless of ethnicity and endemicity. Except for the suspected Latin American group, overall multiple comparisons of medians pointed out the stability of the anti-CFP32 IgG response across the different endemic settings. Therefore, endemicity and ethnicity seem not to affect anti-CFP32 IgG response, mainly for detecting confirmed active TB individuals. These findings suggest that the inclusion of CFP32 epitopes in multi-antigen TB assay could attenuate serological differences related to heterogeneous endemicity and ethnicity. For this purpose, we further identified B-cell epitopes belonging to CFP32 by an in silico analysis.

An optimal control model for COVID-19, zika, dengue, and chikungunya co-dynamics with reinfection.

The co‐circulation of different emerging viral diseases is a big challenge from an epidemiological point of view. The similarity of symptoms, cases of virus co‐infection, and cross‐reaction can mislead in the diagnosis of the disease. In this article, a new mathematical model for COVID‐19, zika, chikungunya, and dengue co‐dynamics is developed and studied to assess the impact of COVID‐19 on zika, dengue, and chikungunya dynamics and vice‐versa. The local and global stability analyses are carried out. The model is shown to undergo a backward bifurcation under a certain condition. Global sensitivity analysis is also performed on the parameters of the model to determine the most dominant parameters. If the zika‐related reproduction number ℛ0Z is used as the response function, then important parameters are: the effective contact rate for vector‐to‐human transmission of zika (β2h, which is positively correlated), the human natural death rate (ϑh, positively correlated), and the vector recruitment rate (Ψv, also positively correlated). In addition, using the class of individuals co‐infected with COVID‐19 and zika (ℐCZh) as response function, the most dominant parameters are: the effective contact rate for COVID‐19 transmission (β1, positively correlated), the effective contact rate for vector‐to‐human transmission of zika (β2h, positively correlated). To control the co‐circulation of all the diseases adequately under an endemic setting, time dependent controls in the form of COVID‐19, zika, dengue, and chikungunya preventions are incorporated into the model and analyzed using the Pontryagin's principle. The model is fitted to real COVID‐19, zika, dengue, and chikungunya datasets for Espirito Santo (a city with the co‐circulation of all the diseases), in Brazil and projections made for the cumulative cases of each of the diseases. Through simulations, it is shown that COVID‐19 prevention could greatly reduce the burden of co‐infections with zika, dengue, and chikungunya. The negative impact of the COVID‐19 pandemic on the control of the arbovirus diseases is also highlighted. Furthermore, it is observed that prevention controls for zika, dengue, and chikungunya can significantly reduce the burden of co‐infections with COVID‐19.

Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study.

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of Plasmodium falciparum that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy. The genes encoding P. falciparum circumsporozoite protein (PfCSP) and the ookinete protein P25 (Pfs25) are expressed as a Pfs25–PfCSP fusion protein, and the heterologous m8Δ-prime/AAV-boost immunization regimen in mice provided both 100% protection against PfCSP-transgenic P. berghei sporozoites and up to 100% transmission blocking efficacy, as determined by a direct membrane feeding assay using parasites from P. falciparum-positive, naturally-infected donors from endemic settings. Remarkably, the persistence of vaccine-induced immune responses were over 7 months and additionally provided complete protection against repeated parasite challenge in a murine model. We propose that application of the m8Δ/AAV malaria multistage vaccine platform has the potential to contribute to the landmark goals of the malaria vaccine technology roadmap, to achieve life-long sterile protection and high-level transmission blocking efficacy.

Estimating the effect of the wMel release programme on the incidence of dengue and chikungunya in Rio de Janeiro, Brazil: a spatiotemporal modelling study

Introgression of genetic material from species of the insect bacteria Wolbachia into populations of Aedes aegypti mosquitoes has been shown in randomised and non-randomised trials to reduce the incidence of dengue; however, evidence for the real-world effectiveness of large-scale deployments of Wolbachia-infected mosquitoes for arboviral disease control in endemic settings is still scarce. A large Wolbachia (wMel strain) release programme was implemented in 2017 in Rio de Janeiro, Brazil. We aimed to assess the effect of this programme on the incidence of dengue and chikungunya in the city. 67 million wMel-infected mosquitoes were released across 28 489 locations over an area of 86·8 km² in Rio de Janeiro between Aug 29, 2017 and Dec 27, 2019. Following releases, mosquitoes were trapped and the presence of wMel was recorded. In this spatiotemporal modelling study, we assessed the effect of the release programme on the incidence of dengue and chikungunya. We used spatiotemporally explicit mathematical models applied to geocoded dengue cases (N=283 270) from 2010 to 2019 and chikungunya cases (N=57 705) from 2016 to 2019. On average, 32% of mosquitoes collected from the release zones between 1 month and 29 months after the initial release tested positive for wMel. Reduced wMel introgression occurred in locations and seasonal periods in which cases of dengue and chikungunya were historically high, with a decrease to 25% of mosquitoes testing positive for wMel during months in which disease incidence was at its highest. Despite incomplete introgression, we found that the releases were associated with a 38% (95% CI 32-44) reduction in the incidence of dengue and a 10% (4-16) reduction in the incidence of chikungunya. Stable establishment of wMel in the geographically diverse, urban setting of Rio de Janeiro seems to be more complicated than has been observed elsewhere. However, even intermediate levels of wMel seem to reduce the incidence of disease caused by two arboviruses. These findings will help to guide future release programmes. Bill &amp; Melinda Gates Foundation and the European Research Council.

Risk Factors of Noncompliance to Preventive Mass Drug Administration for Eliminating Lymphatic Filariasis: A Case-Control Study in Jawi District, Northwest Ethiopia.

Background High compliance is crucial for the success of a mass drug administration program to achieve lymphatic filariasis elimination. However, the presence of persistently noncompliant individuals might delay the elimination target. Besides, although context-based research is essential to designing effective strategies, only a few studies have focused on identifying factors that play a role in noncompliance with mass drug administration in Africa. Therefore, this study was conducted to identify the factors associated with noncompliance to prevent mass drug administration using ivermectin-with-albendazole for the elimination of lymphatic filariasis in Northwest Ethiopia. Methods A case-control study was conducted in Jawi District, Northwest Ethiopia. All individuals who are permanently living in the study area and registered on the annual chemotherapy registration book since 2015 were included in this study. A two-proportion formula was used to estimate the required sample size and 348 cases and 348 controls were selected by identification number on the village chemotherapy registration book using a systematic sampling technique. Data were collected by face-to-face interviews using a structured questionnaire developed through an intensive literature review. Then, data were entered and cleaned by using the EPI DATA software, and analyses were conducted using SPSS version 26. Finally, a logistic regression analysis technique was applied to identify the risk factors using adjusted odds ratio as measures of effect. Results A total of 690 (99.1%) participants, 345 cases and 345 controls, were included in the study. Younger age (AOR = 1.60; 95%CI: 1.10, 2.33), female sex (AOR = 1.56; 95%CI: 1.24, 3.93), thought of not being susceptible to the disease (AOR = 2.36, 95%CI: 1.80, 4.32), lack of disease knowledge (AOR = 1.88; 95% CI: 1.38, 3.81), fear of drug side effect (AOR = 2.45; 95% CI:1.23, 4.86), and not participating in community drug distributors selection (AOR = 2.58; 95% CI: 1.70, 3.91) were found to be the risk factors significantly associated with noncompliance. Conclusion Noncompliance with lymphatic filariasis mass drug administration therapy was associated with specific demographic, individual, program, and drug delivery characteristics. This finding has important implications for program effectiveness and would be used to accelerate the elimination of lymphatic filariasis in the study area and other endemic settings.

Optimizing Implementation of Preventive Chemotherapy against Soil-Transmitted Helminthiasis and Intestinal Schistosomiasis Using High-Resolution Data: Field-Based Experiences from Côte d'Ivoire.

Background: Despite efforts to control neglected tropical diseases (NTDs) using preventive chemotherapy (PC), soil-transmitted helminthiases and schistosomiasis remain widely prevalent in sub-Saharan Africa. The current PC regimen in endemic settings is defined based on health district-level prevalence. This work aims to highlight the need for high-resolution data when elimination, rather than morbidity control, is the targeted goal. Methodology: Cross-sectional parasitological surveys were conducted from July to August 2019 and from September to October 2019, respectively, across the entire Dabou and Jacqueville health districts in southern Côte d’Ivoire. From every village, 60 school-aged children (6–15 years) were randomly selected and invited to provide one fresh stool sample, whereof duplicate Kato–Katz thick smears were prepared and read by two independent technicians. Principal Findings: 4338 school-aged children from 77 villages were screened from the Dabou (n = 2174; 50.12%, 39 villages) and Jacqueville (n = 2164; 49.88%, 38 villages) health districts. The prevalence of any soil-transmitted helminth (STH) infection was 12.47% and 11.09% in the Dabou and Jacqueville health districts, respectively. Species-specific district-level prevalence remained below 10%, varying between 0.51% (hookworm in Jacqueville) and 9.06% (Trichuris trichiura in Dabou). However, when considering sub-districts or villages only, several STH infection hotspots (five sub-districts with ≥20% and four villages with more than 50% infected) were observed. Schistosoma mansoni infection was found in less than 1% of the examined children in each health district. Conclusions/Significance: We conclude that keeping health district-level prevalence as a reference for PC implementation leaves many high-risk sub-districts or villages requiring PC (≥20% prevalence) untreated. To avoid maintaining those high-risk villages as STH reservoirs by skipping control interventions and jeopardizing the successes already achieved in STH control through PC during the past two decades, precision mapping is required. Further investigation is needed to assess cost-efficient approaches to implement small-scale disease surveillance.

Standardization of Epidemiological Surveillance of Group A Streptococcal Impetigo

Impetigo is a highly contagious bacterial infection of the superficial layer of skin. Impetigo is caused by group A Streptococcus (Strep A) and Staphylococcus aureus, alone or in combination, with the former predominating in many tropical climates. Strep A impetigo occurs mainly in early childhood, and the burden varies worldwide. It is an acute, self-limited disease, but many children experience frequent recurrences that make it a chronic illness in some endemic settings. We present a standardized surveillance protocol including case definitions for impetigo including both active (purulent, crusted) and resolving (flat, dry) phases and discuss the current tests used to detect Strep A among persons with impetigo. Case classifications that can be applied are detailed, including differentiating between incident (new) and prevalent (existing) cases of Strep A impetigo. The type of surveillance methodology depends on the burden of impetigo in the community. Active surveillance and laboratory confirmation is the preferred method for case detection, particularly in endemic settings. Participant eligibility, surveillance population and additional considerations for surveillance of impetigo, including examination of lesions, use of photographs to document lesions, and staff training requirements (including cultural awareness), are addressed. Finally, the core elements of case report forms for impetigo are presented and guidance for recording the course and severity of impetigo provided.

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).

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. 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. 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. Pan African Clinical Trial Registry (www.pactr.org) PACTR202202766889963 on 01/02/2022 and ISCRTN (www.isrctn.com/) ISRCTN13334317 on 22/02/2022.

Vaccine efficacy trials for Crimean-Congo haemorrhagic fever: Insights from modelling different epidemiological settings

BackgroundCrimean-Congo haemorrhagic fever (CCHF) is a priority emerging pathogen for which a licensed vaccine is not yet available. We aim to assess the feasibility of conducting phase III vaccine efficacy trials and the role of varying transmission dynamics. MethodsWe calibrate models of CCHF virus (CCHFV) transmission among livestock and spillover to humans in endemic areas in Afghanistan, Turkey and South Africa. We propose an individual randomised controlled trial targeted to high-risk population, and use the calibrated models to simulate trial cohorts to estimate the minimum necessary number of cases (trial endpoints) to analyse a vaccine with a minimum efficacy of 60%, under different conditions of sample size and follow-up time in the three selected settings. ResultsA mean follow-up of 160,000 person-month (75,000–550,000) would be necessary to accrue the required 150 trial endpoints for a target vaccine efficacy of 60 % and clinically defined endpoint, in a setting like Herat, Afghanistan. For Turkey, the same would be achieved with a mean follow-up of 175,000 person-month (50,000–350,000). The results suggest that for South Africa the low endemic transmission levels will not permit achieving the necessary conditions for conducting this trial within a realistic follow-up time. In the scenario of CCHFV vaccine trial designed to capture infection as opposed to clinical case as a trial endpoint, the required person-months is reduced by 70 % to 80 % in Afghanistan and Turkey, and in South Africa, a trial becomes feasible for a large number of person-months of follow-up (>600,000). Increased expected vaccine efficacy > 60 % will reduce the required number of trial endpoints and thus the sample size and follow-time in phase III trials. ConclusionsUnderlying endemic transmission levels will play a central role in defining the feasibility of phase III vaccine efficacy trials. Endemic settings in Afghanistan and Turkey offer conditions under which such studies could feasibly be conducted.

An outbreak of Rift Valley fever among peri-urban dairy cattle in northern Tanzania.

Human and animal cases of Rift Valley fever (RVF) are typically only reported during large outbreaks. The occurrence of RVF cases that go undetected by national surveillance systems in the period between these outbreaks is considered likely. The last reported cases of RVF in Tanzania occurred during a large outbreak in 2007-2008. Samples collected between 2017 and 2019 from livestock suffering abortion across northern Tanzania were retrospectively tested for evidence of RVF virus infection using serology and reverse transcription quantitative polymerase chain reaction (RT-qPCR). A total of 14 RVF-associated cattle abortions were identified among dairy cattle in a peri-urban area surrounding the town of Moshi. RVF cases occurred from May to August 2018 and were considered to represent an undetected, small-scale RVF outbreak. Milk samples from 3 of 14 cases (21%) were found to be RT-qPCR positive. Genotyping revealed circulation of RVF viruses from two distinct lineages. RVF outbreaks can occur more often in endemic settings than would be expected on the basis of detection by national surveillance. The occurrence of RVF cases among peri-urban dairy cattle and evidence for viral shedding in milk, also highlights potentially emerging risks for RVF associated with increasing urban and peri-urban livestock populations.

Piloting and validating the linkage of routine ART and laboratory records in an HIV endemic setting.

ObjectivesIntegrating clinical and laboratory data systems offers opportunities to understand disease aetiology and improve patient outcomes. We developed and piloted a data linkage algorithm to link HIV patient treatment records with routine laboratory service records in an HIV endemic setting in rural South Africa. ApproachWe used data from the South Africa’s National Health Laboratory Service (NHLS) and Three Integrated Electronic Registers (TIER.Net) databases for 17 primary healthcare clinics from uMkhanyakude district, South Africa. The two databases contained data on key demographic variables such as patient first name, surname, date of birth, sex, and health facility, and national ID numbers for a subset of the data. We adapted a probabilistic record linkage algorithm we previously developed for linkage of laboratory results. We trained and validated our algorithm using two approaches: 1) firstly, we constructed a quasi-gold standard based on manual review of potential matches for 1,061 randomly selected patients; 2) secondly, we constructed a quasi-gold standard based on records that contained national ID numbers. We calculated the probabilities that the algorithm could correctly identify a true match (sensitivity) and the probabilities that the match identified by the algorithm was truly a match (positive predictive value) using the two approaches. ResultsBetween 2015 and 2020, 55,077 patients were recorded in the HIV treatment database and 386,577 laboratory tests were recorded in the laboratory service database. The sensitivity and positive predictive value in the manually reviewed data were estimated to be 94.4% and 81.2% respectively. The sensitivity and positive predictive value in the matched individual identifiers were estimated to be 99.6% and 99.7% respectively. ConclusionsRecords can be linked successfully, but estimated performance of record linkage depends on the validation set used. Manually reviewed data contain noise and may underestimate performance, while national ID numbers may overestimate performance due to non-random patterns of missingness.