A pilot study to develop assessment tools for Group A Streptococcus surveillance studies.

Introduction: Group A Streptococcus (GAS) causes pharyngitis (sore throat) and impetigo (skin sores) GAS pharyngitis triggers rheumatic fever (RF) with epidemiological evidence supporting that GAS impetigo may also trigger RF in Australian Aboriginal children. Understanding the concurrent burden of these superficial GAS infections is critical to RF prevention. This pilot study aimed to trial tools for concurrent surveillance of sore throats and skins sore for contemporary studies of RF pathogenesis including development of a sore throat checklist for Aboriginal families and pharynx photography. Methods: Yarning circle conversations and semi-structured interviews were performed with Aboriginal caregivers and used to develop the language and composition of a sore throat checklist. The sore throat story checklist was combined with established methods of GAS pharyngitis and impetigo surveillance (examination, bacteriological culture, rapid antigen detection and serological tests) and new technologies (photography) and used for a pilot cross-sectional surveillance study of Aboriginal children attending their health clinic for a routine appointment. Feasibility, acceptability, and study costs were compiled. Results: Ten Aboriginal caregivers participated in the sore-throat yarning circles; a checklist was derived from predominant symptoms and their common descriptors. Over two days, 21 Aboriginal children were approached for the pilot surveillance study, of whom 17 were recruited; median age was 9 years [IQR 5.5-13.5], 65% were female. One child declined throat swabbing and three declined finger pricks; all other surveillance elements were completed by each child indicating high acceptability of surveillance assessments. Mean time for screening assessment was 19 minutes per child. Transport of clinical specimens enabled gold standard microbiological and serological testing for GAS. Retrospective examination of sore throat photography concorded with assessments performed on the day. Conclusion: Yarning circle conversations were effective in deriving culturally appropriate sore throat questionnaires for GAS pharyngitis surveillance. New and established tools were feasible, practical and acceptable to participants and enable surveillance to determine the burden of superficial GAS infections in communities at high risk of RF. Surveillance of GAS pharyngitis and impetgio in remote Australia informs primary RF prevention with potential global translation.

Standardization of Epidemiological Surveillance of Invasive Group A Streptococcal Infections.

Invasive group A streptococcal (Strep A) infections occur when Streptococcus pyogenes, also known as beta-hemolytic group A Streptococcus, invades a normally sterile site in the body. This article provides guidelines for establishing surveillance for invasive Strep A infections. The primary objective of invasive Strep A surveillance is to monitor trends in rates of infection and determine the demographic and clinical characteristics of patients with laboratory-confirmed invasive Strep A infection, the age- and sex-specific incidence in the population of a defined geographic area, trends in risk factors, and the mortality rates and rates of nonfatal sequelae caused by invasive Strep A infections. This article includes clinical descriptions followed by case definitions, based on clinical and laboratory evidence, and case classifications (confirmed or probable, if applicable) for invasive Strep A infections and for 3 Strep A syndromes: streptococcal toxic shock syndrome, necrotizing fasciitis, and pregnancy-associated Strep A infection. Considerations of the type of surveillance are also presented, noting that most people who have invasive Strep A infections will present to hospital and that invasive Strep A is a notifiable disease in some countries. Minimal surveillance necessary for invasive Strep A infection is facility-based, passive surveillance. A resource-intensive but more informative approach is active case finding of laboratory-confirmed Strep A invasive infections among a large (eg, state-wide) and well defined population. Participant eligibility, surveillance population, and additional surveillance components such as the use of International Classification of Disease diagnosis codes, follow-up, period of surveillance, seasonality, and sample size are discussed. Finally, the core data elements to be collected on case report forms are presented.

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.

Missing Piece Study protocol: prospective surveillance to determine the epidemiology of group A streptococcal pharyngitis and impetigo in remote Western Australia.

INTRODUCTION: Group A ß-haemolytic Streptococcus (GAS), a Gram-positive bacterium, causes skin, mucosal and systemic infections. Repeated GAS infections can lead to autoimmune diseases acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Aboriginal and Torres Strait Islander peoples in Australia have the highest rates of ARF and RHD in the world. Despite this, the contemporaneous prevalence and incidence of GAS pharyngitis and impetigo in remote Australia remains unknown. To address this, we have designed a prospective surveillance study of GAS pharyngitis and impetigo to collect coincident contemporary evidence to inform and enhance primary prevention strategies for ARF. METHODS AND ANALYSIS: The Missing Piece Study aims to document the epidemiology of GAS pharyngitis and impetigo through collection of clinical, serological, microbiological and bacterial genomic data among remote-living Australian children. The study comprises two components: (1) screening of all children at school for GAS pharyngitis and impetigo up to three times a year and (2) weekly active surveillance visits to detect new cases of pharyngitis and impetigo. Environmental swabbing in remote schools will be included, to inform environmental health interventions. In addition, the application of new diagnostic technologies, microbiome analysis and bacterial genomic evaluations will enhance primary prevention strategies, having direct bearing on clinical care, vaccine development and surveillance for vaccine clinical trials. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Western Australian Aboriginal Health Ethics Committee (Ref: 892) and Human Research Ethics Committee of the University of Western Australia (Ref: RA/4/20/5101). Study findings will be shared with community members, teachers and children at participating schools, together with academic and medical services. Sharing findings in an appropriate manner is important and will be done in a suitable way which includes plain language summaries and presentations. Finally, findings and updates will also be disseminated to collaborators, researchers and health planners through peer-reviewed journal publications.

Spatial codistribution of HIV, tuberculosis and malaria in Ethiopia.

BACKGROUND: HIV, tuberculosis (TB) and malaria are the three most important infectious diseases in Ethiopia, and sub-Saharan Africa. Understanding the spatial codistribution of these diseases is critical for designing geographically targeted and integrated disease control programmes. This study investigated the spatial overlap and drivers of HIV, TB and malaria prevalence in Ethiopia. METHODS: HIV, TB and malaria data were obtained from different nationwide prevalence surveys, and geospatial covariates were obtained from publicly available sources. A Bayesian model-based geostatistical framework was applied to each survey leveraging the strength of high-resolution spatial covariates to predict continuous disease-specific prevalence surfaces and their codistribution. RESULTS: The national prevalence was 1.54% (95% CI 1.40 to 1.70) for HIV, 0.39% (95% CI 0.34 to 0.45) for TB and 1.1% (95%CI 0.95 to 1.32) for malaria. Substantial subnational variation was predicted with the highest HIV prevalence estimated in Gambela (4.52%), Addis Ababa (3.52%) and Dire Dawa (2.67%) regions. TB prevalence was highest in Dire Dawa (0.96%) and Gambela (0.88%), while malaria was highest in Gambela (6.1%) and Benishangul-Gumuz (3.8%). Spatial overlap of their prevalence was observed in some parts of the country, mainly Gambela region. Spatial distribution of the diseases was significantly associated with healthcare access, demographic, and climatic factors. CONCLUSIONS: The national distribution of HIV, TB and malaria was highly focal in Ethiopia, with substantial variation at subnational and local levels. Spatial distribution of the diseases was significantly associated with healthcare access, demographic and climatic factors. Spatial overlap of HIV, TB and malaria prevalence was observed in some parts of the country. Integrated control programmes for these diseases should be targeted to these areas with high levels of co-endemicity.

Modes of transmission and attack rates of group A Streptococcal infection: a protocol for a systematic review and meta-analysis.

BACKGROUND: Group A Streptococcus (Strep A) is an important cause of mortality and morbidity globally. This bacterium is responsible for a range of different infections and post-infectious sequelae. Summarising the current knowledge of Strep A transmission to humans will address gaps in the evidence and inform prevention and control strategies. The objective of this study is to evaluate the modes of transmission and attack rates of group A streptococcal infection in human populations. METHODS: This systematic review protocol was prepared according to the Preferred Reporting Items for Systematic reviews and Meta-analysis Protocols (PRISMA-P) 2015 Statement. Using a comprehensive search strategy to identify any transmission studies that have been published in English since 1980, full-text articles will be identified and considered for inclusion against predefined criteria. We will include all studies reporting on Strep A transmission, who have identified a mode of transmission, and who reported attack rates. Risk of bias will be appraised using an appropriate tool. Our results will be described narratively and where feasible and appropriate, a meta-analysis utilizing the random-effects model will be used to aggregate the incidence proportions (attack rates) for each mode of transmission. In addition, we will also evaluate the emm genotype variants of the M protein causing Strep A infection and the association with transmission routes and attack rates, if any, by setting, socioeconomic background and geographical regions. DISCUSSION: We anticipate that this review will contribute to elucidating Strep A modes of transmission which in turn, will serve to inform evidence-based strategies including environmental health activities to reduce the transmission of Strep A in populations at risk of severe disease. TRIAL REGISTRATION: Systematic review registration: PROSPERO ( CRD42019138472 ).

The incidence of sore throat and group A streptococcal pharyngitis in children at high risk of developing acute rheumatic fever: A systematic review and meta-analysis.

BACKGROUND: Group A streptococcal (GAS) pharyngitis has traditionally been considered the sole precursor of acute rheumatic fever (ARF). Evidence from Australia, however, suggests that GAS skin infections may contribute to the pathogenesis of ARF. A missing piece of evidence is the incidence of sore throat and GAS pharyngitis in this setting. We conducted a systematic review and meta-analysis of the incidence of sore throat and GAS pharyngitis in all children at risk of developing ARF. METHODS: Databases were systematically searched for studies reporting on the incidence of pharyngitis among children from low to upper-middle income countries, and Indigenous children living in high-income countries. Studies were subjected to data extraction by two independent reviewers. Following an assessment of the methodological quality of the studies, we extracted incidence rates (IRs) and conducted a meta-analysis. This systematic review is registered on PROSPERO (CRD42019113019). RESULTS: From 607 titles identified by the search, 11 articles met the predetermined inclusion criteria; ten studies reported IRs while for the remaining study, the incidence was calculated. The pooled incidence estimated for sore throat was 82.5 per 100 child-years (95% confidence interval [CI], 6.5 to 1044.4 per 100 child-years, I2 = 100%) and GAS pharyngitis was 10.8 per 100 child-years (95% CI, 2.3 to 50.0 per 100 child-years, I2 = 99.9%). CONCLUSIONS: The pooled IRs for sore throat in children at risk of developing ARF were higher than rates reported in developed nations (32.70-40 per 100 child-years) and similar for GAS pharyngitis (12.8-14 per 100 years). The limited Australian data lend support to the need for further studies to inform the role of GAS pharyngitis in the development of ARF in Australian Indigenous children, so as to inform local primary prevention strategies for ARF and Rheumatic Heart Disease (RHD).

Performance and Practicality of a Rapid Molecular Test for the Diagnosis of Strep A Pharyngitis in a Remote Australian Setting.

Over 5 days, 120 schoolchildren from two schools in the remote Kimberley region of Australia were screened for Strep A pharyngitis. Molecular point-of-care testing identified Strep A pharyngitis in 13/18 (72.2%) symptomatic children. The portability and feasibility of molecular point-of-care testing was highly practical for remote settings.

Prevalence of group A Streptococcal infection in Africa to inform GAS vaccines for rheumatic heart disease: A systematic review and meta-analysis.

BACKGROUND: The prevalence of group A streptococcal (GAS) disease is estimated at >18.1 million cases with an incidence of >1.78 million cases per year. While a significant cause of mortality and morbidity on the global scale, the burden of GAS disease in Africa is unknown. We conducted a systematic review on the prevalence of GAS disease among children and adults in Africa and the frequency and distribution of emm types among isolates. METHODS: We performed a comprehensive literature search in a number of databases, using an African search filter. Two reviewers independently selected articles meeting pre-specified criteria and extracted relevant data as per a data extraction form. We applied the random-effects meta-analysis model to aggregate GAS prevalence estimates with 95% CI for GAS prevalence, incorporating the Freeman-Tukey transformation to account for between-study variability. RESULTS: Twenty-five studies were included. Invasive GAS disease prevalence ranged from 0.6% to 10.8% in samples from normally-sterile sites including blood, CSF and soft tissue. A single study reported a prevalence of 74% in skin infections. Prevalence of emm types varied with up to 88 different strains reported, corresponding to a vaccine coverage of 28% to 65%. The pooled prevalence of GAS in persons presenting with pharyngitis was 21% (95% CI, 17% to 26%). CONCLUSIONS: The prevalence of GAS remains high among symptomatic individuals residing in Africa. Data on molecular strain characterisation of GAS in Africa is largely non-existent, thus the need for further studies is warranted to inform current prevention efforts including vaccine development.

Rationale and design of the African group A streptococcal infection registry: the AFROStrep study.

INTRODUCTION: Group A ß-haemolytic Streptococcus (GAS), a Gram-positive bacterium, also known as Streptococcus pyogenes, causes pyoderma, pharyngitis and invasive disease. Repeated GAS infections may lead to autoimmune diseases such as acute post-streptococcal glomerulonephritis, acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Invasive GAS (iGAS) disease is an important cause of mortality and morbidity worldwide. The burden of GAS infections is, however, unknown in Africa because of lack of surveillance systems. METHODS AND ANALYSIS: The African group A streptococcal infection registry (the AFROStrep study) is a collaborative multicentre study of clinical, microbiological, epidemiological and molecular characteristics for GAS infection in Africa. The AFROStrep registry comprises two components: (1) active surveillance of GAS pharyngitis cases from sentinel primary care centres (non-iGAS) and (2) passive surveillance of iGAS disease from microbiology laboratories. Isolates will also be subjected to DNA isolation to allow for characterisation by molecular methods and cryopreservation for long-term storage. The AFROStrep study seeks to collect comprehensive data on GAS isolates in Africa. The biorepository will serve as a platform for vaccine development in Africa. ETHICS AND DISSEMINATION: Ethics approval for the AFROStrep registry has been obtained from the Human Research Ethics Committee at the University of Cape Town (HREC/REF: R006/2015). Each recruiting site will seek ethics approval from their local ethics' committee. All participants will be required to provide consent for inclusion into the registry as well as for the storage of isolates and molecular investigations to be conducted thereon. Strict confidentiality will be applied throughout. Findings and updates will be disseminated to collaborators, researchers, health planners and colleagues through peer-reviewed journal articles, conference publications and proceedings.

Prevalence of group A streptococcal disease in North and Sub-Saharan Africa: a systematic review protocol.

INTRODUCTION: The true burden of group A streptococcal (GAS) disease in Africa is not known. GAS is a significant cause of mortality and morbidity on the global scale and in developing countries. According to Carapetis et al, the prevalence of severe GAS disease is at least 18.1 million cases with an incidence of at least 1.78 million cases per year. METHODS AND ANALYSES: We aim to provide a systematic review of studies measuring the prevalence of GAS infection among people in North and Sub-Saharan African countries. A comprehensive literature search of a number of databases will be undertaken, using an African search filter, to identify GAS prevalence studies that have been published. Full copies of articles will be identified by a defined search strategy and will be considered for inclusion against predefined criteria. Statistical analysis will include two steps: (1) identification of data sources and documenting of estimates, and (2) the application of the random-effects and fixed-effects meta-analysis model to aggregate prevalence estimates, and to account for between study variability in calculating the overall pooled estimates and 95% CI for GAS prevalence. Heterogeneity will be evaluated using the I(2) statistic to determine the extent of variation in effect estimates that is due to heterogeneity rather than chance. This systematic review protocol was prepared according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols (PRISMA-P) 2015 Statement. This review will provide updated evidence of a review published in 2009. Our data will have implications for the development of a GAS vaccine. ETHICS AND DISSEMINATION: Ethics approval is not required for this study given that this is a protocol for a systematic review of published studies. The results of this study will be disseminated through a peer-reviewed publication and conference presentation. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD4201401290 0. (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014012900).

Effect of distance to health facility on the maintenance of INR therapeutic ranges in rheumatic heart disease patients from Cape Town: no evidence for an association.

BACKGROUND: Lack of adherence to international normalised ratio (INR) monitoring in rheumatic heart disease (RHD) patients is a contributor to cardio-embolic complications. This population-based observational study investigated whether the distance between home and an INR clinic affects the maintenance of therapeutic INR in RHD patients on warfarin. METHODS: Residential addresses, INR clinics, and INR results of patients with RHD were extracted from the Cape Town component of the Global Rheumatic Heart Disease Registry (REMEDY) database. Addresses of homes and INR clinics were converted to geographical coordinates and verified in ArcGIS 10®. ArcGIS 10® and Google Maps® were used for spatial mapping and obtaining shortest road distances respectively. The travel distance between the home and INR clinic was correlated with time within therapeutic range (TTR) using the Rosendaal linear interpolation method, and with the fraction of INR within range, based on an average of three INR readings of patients and compared with recommended therapeutic ranges. RESULTS: RHD patients (n = 133) resided between 0.2 km and 50.8 km (median distance, 3.60 km) from one of 33 INR clinics. There was no significant difference in the achievement of the therapeutic INR between patients who travelled a shorter distance compared to those who travelled a longer distance (in range = 3.50 km versus out of range = 3.75 km, p = 0.78). This finding was the same for patients with mechanical valve replacement (n = 105) (3.50 km versus 3.90 km, p = 0.81), and native valves (3.45 km versus 2.75 km, p = 0.84). CONCLUSIONS: There is no association between the maintenance of INR within therapeutic range amongst RHD patients in Cape Town and distance from patients' residence to the INR clinic.