Jonathan R. Carapetis

Global emm type distribution of group A streptococci: systematic review and implications for vaccine development

emm sequence typing is the most widely used method for defining group A streptococcal (GAS) strains, and has been applied to isolates in all regions of the world. We did a systematic review of the global distribution of GAS emm types. 102 articles and reports were included (38 081 isolates). Epidemiological data from high-income countries were predominant, with sparse data from low-income countries. The epidemiology of GAS disease in Africa and the Pacific region seems to be different from that in other regions, particularly high-income countries. In Africa and the Pacific, there were no dominant emm types, a higher diversity of emm types, and many of the common emm types in other parts of the world were less common (including emm 1, 4, 6, and 12). Our data have implications for the development of GAS vaccines. On the basis of the available data, the current formulation of the experimental multivalent emm vaccine would provide good coverage in high-income countries, particularly USA, Canada, and Europe, but poor coverage in Africa and the Pacific, and only average coverage in Asia and the Middle East.

Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children

BACKGROUND Antibiotics are widely administered to children with the intention of preventing urinary tract infection, but adequately powered, placebo-controlled trials regarding efficacy are lacking. This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy prevents urinary tract infection in predisposed children. METHODS We randomly assigned children under the age of 18 years who had had one or more microbiologically proven urinary tract infections to receive either daily trimethoprim-sulfamethoxazole suspension (as 2 mg of trimethoprim plus 10 mg of sulfamethoxazole per kilogram of body weight) or placebo for 12 months. The primary outcome was microbiologically confirmed symptomatic urinary tract infection. Intention-to-treat analyses were performed with the use of time-to-event data. RESULTS From December 1998 to March 2007, a total of 576 children (of 780 planned) underwent randomization. The median age at entry was 14 months; 64% of the patients were girls, 42% had known vesicoureteral reflux (at least grade III in 53% of these patients), and 71% were enrolled after the first diagnosis of urinary tract infection. During the study, urinary tract infection developed in 36 of 288 patients (13%) in the group receiving trimethoprim-sulfamethoxazole (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% confidence interval, 0.40 to 0.93; P = 0.02 by the log-rank test). In the antibiotic group, the reduction in the absolute risk of urinary tract infection (6 percentage points) appeared to be consistent across all subgroups of patients (P > or = 0.20 for all interactions). CONCLUSIONS Long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children. The treatment effect appeared to be consistent but modest across subgroups. (Australian New Zealand Clinical Trials Registry number, ACTRN12608000470392.)

Contrasting Molecular Epidemiology of Group A Streptococci Causing Tropical and Nontropical Infections of the Skin and Throat

Disease caused by group A streptococci (GAS) in tropical regions often takes the form of impetigo, whereas pharyngitis tends to predominate in temperate zones. GAS derived from asymptomatic throat infections and pyoderma lesions of rural Aboriginal Australians were evaluated for phylogenetic distant emm genes, which represent ecological markers for tissue site preference. On the basis of the percentage of total isolates from a given tissue, emm pattern A-C organisms exhibited a stronger predilection for the throat, whereas pattern D organisms preferred the skin. Only 16% of isolates collected by active surveillance displayed pattern A-C, which reflects the low incidence of oropharyngeal infection. Importantly, most (70%) pattern A-C organisms were isolated from skin sores, despite their innate tendency to infect the throat. Combined with findings from nontropical populations, analysis of the data supports the hypothesis that GAS tissue preferences are genetically predetermined and that host risk factors for infection strongly influence the differential reproduction of individual clones.

Success of a scabies control program in an Australian Aboriginal community

OBJECTIVE To adapt, implement and evaluate a model of scabies control in an Australian Aboriginal community. METHODS After initially examining the population, we offered all residents treatment with 5% permethrin cream. Visits were made during the ensuing 25 months to rescreen and to treat new-cases of scabies and contacts. RESULTS The prevalence of scabies was reduced from 28.8% before the program to < 10% during the entire period (from 32.3% to < 10% in children) (P < 0.01 for each visit). The initial prevalence of pyoderma in children was 69.4%, which was reduced and maintained at approximately one-half that rate during the last 16 months (P < 0.004 for the last 4 visits). Residual pyoderma in children was significantly less severe and no longer scabies-related. CONCLUSIONS This simplified model of scabies control had a substantial effect on scabies prevalence and on pyoderma prevalence and severity which was sustained for > 2 years. It could prove useful for other communities with high rates of scabies and pyoderma.

Evaluation of a screening protocol using auscultation and portable echocardiography to detect asymptomatic rheumatic heart disease in Tongan schoolchildren

Background Rheumatic heart disease (RHD) is an important problem in developing countries; however, many cases are detected only when the disease has progressed to cardiac failure. Screening can detect cases earlier, but there are no screening guidelines.Methods We performed a cross-sectional screening study in Tonga among 5,053 primary school children, in whom auscultation followed by echocardiography of those with heart murmurs were used to identify RHD. We also analyzed whether a three-stage screening protocol of auscultation performed by a medical student to detect any heart murmur, second-stage auscultation performed by a local pediatrician to differentiate pathological from innocent murmurs and echocardiography of those with pathological murmurs altered outcomes.Results The prevalence of definite RHD was 33.2 per 1,000. The prevalence of RHD increased significantly with age, peaking at 42.6 per 1,000 in children aged 10–12 years. Most valve lesions (91 [54%] of 169) were mild. Auscultation to detect pathological murmurs was poorly sensitive (46.4%), and the finding of any murmur on auscultation did not affect the likelihood of detecting pathology on echocardiography. The finding of a pathological murmur did significantly increase the likelihood of detecting pathology on echocardiography, but still missed 54% of those with pathology (mainly RHD) detected on echocardiography.Conclusions Screening is a useful method for detecting asymptomatic RHD in regions of high prevalence and we report a high echocardiographically confirmed prevalence. The most appropriate screening strategy remains to be confirmed, however, and implementation will depend on the availability of echocardiography and trained staff.

Group a streptococcal diseases and their global burden

Group A streptococcus (GAS) or Streptococcus pyogenes has been recognised as an important human pathogen since early days of modern microbiology, and it remains among the top ten causes of mortality from an infectious disease. Clinical manifestations attributable to this organism are perhaps the most diverse of any single human pathogen. These encompass invasive GAS infections, with high mortality rates despite effective antimicrobials, toxin-mediated diseases including scarlet fever and streptococcal toxic shock syndrome, the autoimmune sequelae of rheumatic fever and glomerulonephritis with potential for long-term disability, and nuisance manifestations of superficial skin and pharyngeal infection, which continue to consume a sizable proportion of healthcare resources. Although an historical perspective indicates major overall reductions in GAS infection rates in the modern era, chiefly as a result of widespread improvements in socioeconomic circumstances, this pathogen remains as a leading infectious cause of global morbidity and mortality. More than 18 million people globally are estimated to suffer from serious GAS disease. This burden disproportionally affects least affluent populations, and is a major cause of illness and death among children and young adults, including pregnant women, in low-resource settings. We review GAS transmission characteristics and prevention strategies, historical and geographical trends and report on the estimated global burden disease attributable to GAS. The lack of systematic reporting makes accurate estimation of rates difficult. This highlights the need to support improved surveillance and epidemiological research in low-resource settings, in order to enable better assessment of national and global disease burdens, target control strategies appropriately and assess the success of control interventions.

A Systematic and Functional Classification of Streptococcus pyogenes That Serves as a New Tool for Molecular Typing and Vaccine Development

Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate for epidemiological typing is both a virulence factor and a vaccine antigen. Over 220 variants of this protein have been described, making comparisons between proteins difficult, and hindering M protein-based vaccine development. A functional classification based on 48 emm-clusters containing closely related M proteins that share binding and structural properties is proposed. The need for a paradigm shift from type-specific immunity against S. pyogenes to emm-cluster based immunity for this bacterium should be further investigated. Implementation of this emm-cluster-based system as a standard typing scheme for S. pyogenes will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development.

Rheumatic fever in a high incidence population: the importance of monoarthritis and low grade fever

AIMS To describe the clinical features of rheumatic fever and to assess the Jones criteria in a population and setting similar to that in many developing countries. METHODS The charts of 555 cases of confirmed acute rheumatic fever in 367 patients (97% Aboriginal) and more than 200 possible rheumatic fever cases from the tropical “Top End” of Australias Northern Territory were reviewed retrospectively. RESULTS Most clinical features were similar to classic descriptions. However, monoarthritis occurred in 17% of confirmed non-chorea cases and 35% of unconfirmed cases, including up to 27 in whom the diagnosis was missed because monoarthritis is not a major manifestation. Only 71% and 25% of confirmed non-chorea cases would have had fever using cut off values of 38°C and 39°C, respectively. In 17% of confirmed non-chorea cases, anti-DNase B titres were raised but antistreptolysin O titres were normal. Although features of recurrences tended to correlate with initial episodes, there were numerous exceptions. CONCLUSIONS Monoarthritis and low grade fever are important manifestations of rheumatic fever in this population. Streptococcal serology results may support a possible role for pyoderma in rheumatic fever pathogenesis. When recurrences of rheumatic fever are common, the absence of carditis at the first episode does not reliably predict the absence of carditis with recurrences.

Disease burden and health-care clinic attendances for young children in remote aboriginal communities of northern Australia

OBJECTIVE To determine the frequency of presentations and infectious-disease burden at primary health care (PHC) services in young children in two remote Aboriginal communities in tropical northern Australia. METHODS Children born after 1 January 2001, who were resident at 30 September 2005 and for whom consent was obtained, were studied. Clinic records were reviewed for all presentations between 1 January 2002 and 30 September 2005. Data collected included reason for presentation (if infectious), antibiotic prescription and referral to hospital. FINDINGS There were 7273 clinic presentations for 174 children aged 0-4.75 years, 55% of whom were male. The median presentation rate per child per year was 16 (23 in the first year of life). Upper-respiratory-tract infections (32%) and skin infections (18%) were the most common infectious reasons for presentation. First presentations for scabies and skin sores peaked at the age of 2 months. By 1 year of age, 63% and 69% of children had presented with scabies and skin sores, respectively. CONCLUSION These Aboriginal children average about two visits per month to PHC centres during their first year of life. This high rate is testament to the disease burden, the willingness of Aboriginal people to use health services and the high workload experienced by these health services. Scabies and skin sores remain significant health problems, with this study describing a previously undocumented burden of these conditions commencing within the first few months of life. Appropriate prevention and treatment strategies should encompass early infancy to reduce the high burden of infectious diseases in this population.

Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease

BackgroundTo determine the prevalence of carriage of respiratory bacterial pathogens, and the risk factors for and serotype distribution of pneumococcal carriage in an Australian Aboriginal population.MethodsSurveys of nasopharyngeal carriage of Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and Moraxella catarrhalis were conducted among adults (≥16 years) and children (2 to 15 years) in four rural communities in 2002 and 2004. Infant seven-valent pneumococcal conjugate vaccine (7PCV) with booster 23-valent pneumococcal polysaccharide vaccine was introduced in 2001. Standard microbiological methods were used.ResultsAt the time of the 2002 survey, 94% of eligible children had received catch-up pneumococcal vaccination. 324 adults (538 examinations) and 218 children (350 examinations) were enrolled. Pneumococcal carriage prevalence was 26% (95% CI, 22-30) among adults and 67% (95% CI, 62-72) among children. Carriage of non-typeable H. influenzae among adults and children was 23% (95% CI, 19-27) and 57% (95% CI, 52-63) respectively and for M. catarrhalis, 17% (95% CI, 14-21) and 74% (95% CI, 69-78) respectively. Adult pneumococcal carriage was associated with increasing age (p = 0.0005 test of trend), concurrent carriage of non-typeable H. influenzae (Odds ratio [OR] 6.74; 95% CI, 4.06-11.2) or M. catarrhalis (OR 3.27; 95% CI, 1.97-5.45), male sex (OR 2.21; 95% CI, 1.31-3.73), rhinorrhoea (OR 1.66; 95% CI, 1.05-2.64), and frequent exposure to outside fires (OR 6.89; 95% CI, 1.87-25.4). Among children, pneumococcal carriage was associated with decreasing age (p < 0.0001 test of trend), and carriage of non-typeable H. influenzae (OR 9.34; 95% CI, 4.71-18.5) or M. catarrhalis (OR 2.67; 95% CI, 1.34-5.33). Excluding an outbreak of serotype 1 in children, the percentages of serotypes included in 7, 10, and 13PCV were 23%, 23%, and 29% (adults) and 22%, 24%, and 40% (2-15 years). Dominance of serotype 16F, and persistent 19F and 6B carriage three years after initiation of 7PCV is noteworthy.ConclusionsPopulation-based carriage of S. pneumoniae, non-typeable H. influenzae, and M. catarrhalis was high in this Australian Aboriginal population. Reducing smoke exposure may reduce pneumococcal carriage. The indirect effects of 10 or 13PCV, above those of 7PCV, among adults in this population may be limited.