Malcolm I. McDonald

Acute rheumatic fever: a chink in the chain that links the heart to the throat?

Acute rheumatic fever (ARF) remains a major problem in tropical regions, resource-poor countries, and minority indigenous communities. It has long been thought that group A streptococcal (GAS) pharyngitis alone was responsible for acute rheumatic fever; this belief has been supported by laboratory and epidemiological evidence gathered over more than 60 years, mainly in temperate climates where GAS skin infection is uncommon. GAS strains have been characterised as either rheumatogenic or nephritogenic based on phenotypic and genotypic properties. Primary prevention strategies and vaccine development have long been based on these concepts. The epidemiology of ARF in Aboriginal communities of central and northern Australia challenges this view with reported rates of ARF and rheumatic heart disease (RHD) that are among the highest in the world. GAS throat colonisation is uncommon, however, and symptomatic GAS pharyngitis is rare; pyoderma is the major manifestation of GAS infection. Typical rheumatogenic strains do not occur. Moreover, group C and G streptococci have been shown to exchange key virulence determinants with GAS and are more commonly isolated from the throats of Aboriginal children. We suggest that GAS pyoderma and/or non-GAS infections are driving forces behind ARF in these communities and other high-incidence settings. The question needs to be resolved as a matter of urgency because current approaches to controlling ARF/RHD in Aboriginal communities have clearly been ineffective. New understanding of the pathogenesis of ARF would have an immediate effect on primary prevention strategies and vaccine development.

Low Rates of Streptococcal Pharyngitis and High Rates of Pyoderma in Australian Aboriginal Communities Where Acute Rheumatic Fever Is Hyperendemic

BACKGROUND Acute rheumatic fever is a major cause of heart disease in Aboriginal Australians. The epidemiology differs from that observed in regions with temperate climates; streptococcal pharyngitis is reportedly rare, and pyoderma is highly prevalent. A link between pyoderma and acute rheumatic fever has been proposed but is yet to be proven. Group C beta-hemolytic streptococci and group G beta-hemolytic streptococci have also been also implicated in the pathogenesis. METHODS Monthly, prospective surveillance of selected households was conducted in 3 remote Aboriginal communities. People were questioned about sore throat and pyoderma; swab specimens were obtained from all throats and any pyoderma lesions. Household population density was determined. RESULTS From data collected during 531 household visits, the childhood incidence of sore throat was calculated to be 8 cases per 100 person-years, with no cases of symptomatic group A beta-hemolytic streptococci pharyngitis. The median point prevalence for throat carriage was 3.7% for group A beta-hemolytic streptococci, 0.7% for group C beta-hemolytic streptococci, and 5.1% for group G beta-hemolytic streptococci. Group A beta-hemolytic streptococci were recovered from the throats of 19.5% of children at some time during the study. There was no seasonal trend or correlation with overcrowding. Almost 40% of children had pyoderma at least once, and the prevalence was greatest during the dry season. In community 1, the prevalence of pyoderma correlated with household crowding. Group C and G beta-hemolytic streptococci were rarely recovered from pyoderma lesions. CONCLUSIONS These data are consistent with the hypothesis that recurrent skin infections immunize against throat colonization and infection. High rates of acute rheumatic fever were not driven by symptomatic group A beta-hemolytic streptococci throat infection. Group G and C beta-hemolytic streptococci were found in the throat but rarely in pyoderma lesions.

Community-Associated Strains of Methicillin-Resistant Staphylococcus aureus and Methicillin-Susceptible S. aureus in Indigenous Northern Australia: Epidemiology and Outcomes

BACKGROUND Some strains of non-multidrug-resistant, methicillin-resistant Staphylococcus aureus (nmMRSA) in Australia are likely to have emerged from strains of methicillin-susceptible S. aureus (MSSA) in remote Aboriginal communities. OBJECTIVE To describe the clinical epidemiology of infection due to community-associated MRSA strains in an Australian tropical hospital setting with a significant Aboriginal population and to compare infections caused by community-associated strains of MRSA, health-care-associated strains of MRSA, and MSSA strains with respect to demographic risk factors and clinical outcomes. Methods. We queried the microbiology database for the Top End of the Northern Territory, Australia, to determine population incidences for S. aureus infection and conducted a prospective matched case-control study to compare infection due to nmMRSA, MSSA, or multidrug-resistant MRSA at the Royal Darwin Hospital. RESULTS The annual incidence of S. aureus bacteremia was 65 cases per 100,000 population, but in the Aboriginal population the incidence was 172 cases per 100,000 population (odds ratio [OR] compared with non-Aboriginal population, 5.8 [95% confidence interval {CI}, 3.8-8.9). Female sex (adjusted OR [aOR], 1.5 [95% CI, 1.1-2.0) and remote residence (aOR, 1.8 [95% CI, 1.2-2.5]) were associated with the isolation of nmMRSA rather than MSSA, but disease spectrum and outcomes were similar. Among those from whom nmMRSA was isolated, Aboriginal patients were younger (aOR for each additional year, 0.94 [95% CI, 0.92-0.96]), more likely to be female (aOR, 3.8 [95% CI, 1.7-8.5]), and more likely to reside in a remote community (aOR, 29 [95% CI, 8.9-94]) than non-Aboriginal patients. The presence of Panton-Valentine leukocidin in nmMRSA was associated with double the odds of sepsis (aOR, 2.2 [95% CI, 1.1-4.6]). CONCLUSIONS The association of nmMRSA infection with female sex and remote residence supports the hypothesis that nmMRSA arose from MSSA strains in remote Aboriginal communities where staphylococcal disease is highly prevalent. The similar clinical spectrum and outcomes for nmMRSA infection and MSSA infection suggest that virulence is not correlated with resistance phenotype.

Use of a Single-Nucleotide Polymorphism Genotyping System To Demonstrate the Unique Epidemiology of Methicillin-Resistant Staphylococcus aureus in Remote Aboriginal Communities

ABSTRACT Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major public health problem in Australia, as in many other parts of the world. High rates of CA-MRSA skin and soft tissue infection have been reported from Aboriginal communities. We used a single-nucleotide polymorphism (SNP) genotyping typing system based on the multilocus sequence type (MLST) database to investigate the epidemiology of CA-MRSA and methicillin-sensitive S. aureus (MSSA) over a 12-month period in three remote Aboriginal communities of Northern Australia. This was supplemented by real-time PCR for Panton-Valentine leukocidin (PVL) genes, staphylococcal cassette chromosome mec (SCCmec) typing, and antimicrobial susceptibility testing. S. aureus was recovered from pyoderma lesions on 221 occasions and throat swabs on 44 occasions. The median monthly recovery rate of S. aureus from skin sores was 58% (interquartile range, 62 to 78%), and there was no seasonal variation. Twenty-three percent of isolates were CA-MRSA; the proportion was similar across the communities and did not vary over the study period. Erythromycin resistance was found in 47% of CA-MRSA and 21% of MSSA. SNP-based typing identified 14 different clonal complexes (cc); however, cc75 was predominant, accounting for 71% of CA-MRSA isolates. These were confirmed as ST75-like by using an additional SNP and MLST of selected isolates. All but one of the cc75 isolates had SSCmec type IV (one had type V), and all were PVL negative. Monthly tracking of SNP-based cc types showed a highly dynamic process. ST75-MRSA-IV appears to be unique to the region and probably evolved de novo in remote Aboriginal communities.

Global Implications of the Emergence of Community-Associated Methicillin-Resistant Staphylococcus aureus in Indigenous Populations

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in Australia may have been facilitated by conditions in socially disadvantaged populations--particularly, remote Australian Aboriginal communities. The appearance of community-associated MRSA was first noticed in Australia during the early 1980s; subsequently, several genetically diverse strains have independently emerged from geographically distinct regions. Molecular and epidemiological studies support the role of genetic transfer of resistance determinants (SCCmecIV) in this process. Conditions in Aboriginal communities--namely, domestic crowding, poor hygiene, and high rates of scabies, pyoderma, and antibiotic use--have facilitated both the clonal expansion and de novo emergence of strains of community-associated MRSA. Combating the worldwide emergence and spread of community-associated MRSA may require novel community-level control strategies targeted at specific groups, such as remote Indigenous populations.

Clinical Correlates of Panton-Valentine Leukocidin (PVL), PVL Isoforms, and Clonal Complex in the Staphylococcus aureus Population of Northern Australia

BACKGROUND Regional differences in the prevalence of Panton-Valentine leukocidin (PVL) and PVL isoform-harboring strains as well as in the local population structure of Staphylococcus aureus may influence the clinical spectrum of S. aureus infections. METHODS Using a prospective collection of S. aureus isolates from northern Australia, we determined differences between infections caused by (1) PVL(+) and PVL(-) isolates, (2) PVL histidine (H) isoform- and PVL arginine (R) isoform-harboring isolates, and (3) different lineages, including the genetically divergent clonal complex (CC) 75 and the PVL(+) CC93. RESULTS PVL(+) isolates comprised 54% (128/239) of community-associated methicillin-resistant isolates and 40% (95/239) of methicillin-susceptible S. aureus (MSSA) isolates. There were 113 H isoform- and 110 R isoform-harboring isolates. PVL was associated with truly community-acquired disease, younger age, and presentation with sepsis. We found no differences in infections due to H isoform-harboring isolates, compared with R isoform-harboring isolates. CC93 was the most prevalent lineage. The genetically divergent CC75 caused clinical disease similar to that of other S. aureus clones. CONCLUSIONS PVL(+) and PVL(-) infections are clearly distinct. MSSA contributes a large but underrecognized burden of PVL(+) disease. Compared with elsewhere in the world, there is a relative abundance of the clade that contains CC93 and CC121 in both northern Australia and Asia.

Epidemiology of Streptococcus dysgalactiae subsp. equisimilis in tropical communities, Northern Australia.

This subspecies is common in communities with high rates of streptococcal disease, and its epidemiology differs from that of Streptococcus pyogenes.

Molecular typing of Streptococcus pyogenes from remote Aboriginal communities where rheumatic fever is common and pyoderma is the predominant streptococcal infection

Aboriginal Australians in remote communities have high rates of rheumatic heart disease (RHD); yet pharyngitis is reportedly rare whilst pyoderma is common. Some strains of group A streptococci (GAS) have preference for the throat and others for the skin depending on M protein type. A study in three remote communities provided 350 GAS isolates for emm sequence typing, 244 were also emm pattern typed. There was 100% correlation between emm sequence and pattern type. Patterns D and E (non-throat tropic) made up 71% of throat and 87% of skin isolates although patterns A-C (throat tropic) were more common in the throat than the skin (RR 2.3, 95% CI 1.4-3.8) whilst the opposite was found for pattern D (RR 2.2, 95% CI 1.7-3.0). Pattern E favoured the throat (RR 1.4, 95% CI 1.1-1.8). Where environmental factors predispose to skin infection, emm pattern types D and E prevail, whatever the recovery site.

The dynamic nature of group A streptococcal epidemiology in tropical communities with high rates of rheumatic heart disease

Prospective surveillance was conducted in three remote Aboriginal communities with high rates of rheumatic heart disease in order to investigate the epidemiology of group A beta-haemolytic streptococci (GAS). At each household visit, participants were asked about sore throat. Swabs were taken from all throats and any skin sores. GAS isolates were emm sequence and pattern-typed using standard laboratory methods. There were 531 household visits; 43 different emm types and subtypes (emmST) were recovered. Four epidemiological patterns were observed. Multiple emmST were present in the population at any one time and household acquisition rates were high. Household acquisition was most commonly via 5- to 9-year-olds. Following acquisition, there was a 1 in 5 chance of secondary detection in the household. Throat detection of emmST was brief, usually <2 months. The epidemiology of GAS in these remote Aboriginal communities is a highly dynamic process characterized by emmST diversity and turnover.

Assessment of a register-based rheumatic heart disease secondary prevention program in an Australian Aboriginal community

Objective: To assess specific performance indicators relating to a register‐based acute rheumatic fever and rheumatic heart disease (ARF/RHD) prevention program in a remote Australian Aboriginal community in order to identify the most appropriate avenues for improvements in delivery of services.