INTRODUCTION
Invasive group A streptococcal (iGAS) disease has a high fatality of 7–25% and is associated with three severe clinical outcomes: streptococcal toxic shock syndrome (STSS), necrotizing fasciitis and bacteraemia [Reference Davies1–Reference Steer7]. The USA, Australia, Fiji and New Zealand have reported disproportionately higher rates of iGAS disease in their Indigenous populations [Reference Hoge2, Reference Safar6–Reference Carapetis8]. In Australia, tropical regions of northern Queensland and the Northern Territory (NT) have the highest reported rates, with incidence in Indigenous populations ranging from 23·9 to 82·5/100 000 and non-Indigenous from 4·7 to 10·3/100 000 [Reference Carapetis8–Reference Norton10]. The state of Victoria in Australia and other developed countries report much lower incidence, ranging between 1·3 and 3·5/100 000 population [Reference Davies1, Reference Lepoutre3, Reference O'Loughlin5, Reference Lamagni11]. Reasons for this difference are not known but possible factors include climatic variations (tropical vs. temperate climates) and population composition (higher proportion of Indigenous population in northern Australia with high levels of socioeconomic disadvantage and household crowding) [12, Reference Bailie13]. Queensland and the NT have a much higher prevalence of other group A streptococcal (GAS)-associated infections including rheumatic heart disease and acute post-streptococcal glomerulonephritis [Reference Carapetis, Wolff and Currie14–Reference Marshall16]. To inform prevention strategies in the NT further data are needed to identify specific at-risk populations, burden of disease in tropical and semi-arid regions and molecular characterization of GAS strains causing invasive disease. Multivalent GAS vaccines are currently undergoing clinical trials and are expected to reduce the burden of GAS-associated diseases [Reference McMillan17, Reference Steer, Dale and Carapetis18]. As over 200 Streptococcus pyogenes emm types have been identified, confirmation of strains causing disease in the NT will inform efficacy of various vaccine formulations [Reference McMillan17].
METHODS
Study setting
This study was conducted in the NT of Australia, which encompasses a geographical area of 1 346 200 km2 and has a population of about 227 900 people [19]. The tropical ‘Top End’ comprises the northern third of the NT while the southern two-thirds, referred to as ‘Central Australia’ has a semi-arid climate. Indigenous people comprise 27% of the population with many living in remote communities [20]. By contrast, Indigenous people represent 2·5% of the total Australian population. In 2012, about 479 people were receiving haemodialysis in the NT, equating to a rate of 2·0/100 000 population; a rate four times higher than other Australian jurisdictions [21]. In the NT, haemodialysis patients are predominantly Indigenous (91%) and receive services through 10 haemodialysis units or home dialysis.
Design
A case series between 11 May 2011 and 11 May 2013 of NT residents reported to the NT Notifiable Diseases System. Notifications were made by laboratories following isolation of S. pyogenes from a normally sterile body site. Cases were excluded if S. pyogenes had been isolated from a sterile site in the same individual in the preceding 30 days.
Data collection
Data were collected from individual medical records and included demographic features, clinical presentation and outcome, chronic medical conditions, malignancy, immunosuppressive illnesses, history of tobacco smoking ⩾5 times per week, medications and known contact with a person infectious with iGAS disease in the 30 days preceding symptom onset. Dates of hospitalization, specimen collection and 10-day surgical, dialysis and childbirth history were recorded. Infection was classified as nosocomial if the first positive specimen was collected 72 h after admission to hospital, or if the person had undergone surgery, dialysis or given birth in the 10 days preceding symptom onset. Secondary transmission was defined as infection occurring in a person who had contact with an infectious case within the preceding 30 days. If a case was not identified as nosocomial or secondary transmission, it was assumed the S. pyogenes had been acquired in the community. STSS was defined according to criteria of the working group on severe streptococcal infections with only definite cases included. Fulfilment of the definite STSS case definition required hypotension and the presence of ⩾2 of the following: acute renal impairment, coagulopathy, liver abnormalities, acute respiratory distress syndrome, extensive tissue necrosis and/or rash [Reference Breiman22]. Mortality was identified if a person died within 30 days of laboratory isolation of GAS from a sterile site; and GAS infection or sepsis was included as a cause of death on the death certificate.
Characterization of GAS isolates
GAS isolates causing invasive disease were provided by the five NT public hospital laboratories. DNA was extracted from 1 ml of overnight broth culture using a QIAamp DNA mini-kit (Qiagen, Australia) with the addition of mutanolysin and hyaluronidase. emm polymerase chain reaction (PCR) was conducted according to the USA Centers for Disease Control and Prevention (CDC) protocol [23]. PCR products were purified using a Qiagen PCR purification kit and DNA sequencing was conducted by Macrogen Inc. (Korea). Sequences were compared with the CDC emm sequence database and new subtypes submitted to the moderator for assignment. emm types encoding proteins of similar binding and structural properties were grouped by cluster, details of which have been described previously [Reference Sanderson-Smith24].
Data analysis
Data were analysed using Stata v. 13.1 (StataCorp, USA). Incidence was calculated using NT population projections based on Australian Bureau of Statistics data [25]. Population estimates for dialysis patients were obtained from the Australian and New Zealand Dialysis and Transplant Registry [21]. The χ 2 test was used to compare proportions, while Fisher's exact test was used if any of the cells had <5 cases. Median age and length of hospital stay were compared using the Mann–Whitney U test. Annualized incidence was calculated by dividing the average number of cases per year by the study population.
Ethics
Ethical approval was gained from the Human Research Ethics Committees of Central Australia, NT Department of Health and Menzies School of Health Research, and the Australian National University.
RESULTS
Over the 2-year period, 128 episodes of iGAS disease occurred in 121 people. Indigenous people accounted for 99 (77%) episodes and haemodialysis patients for 21 (16%) episodes.
Site of specimen collection was blood (n = 118, 92%), joints (n = 7, 5%), peritoneal fluid (n = 2, 2%) and pleural fluid (n = 1, 1%).
Incidence
Annualized incidence for the non-Indigenous, Indigenous and haemodialysis populations are shown in Table 1 and were similar for both Top End and Central Australian regions. Incidence in the Indigenous population was significantly higher than the non-Indigenous [risk ratio 7·8, 95% confidence interval (CI) 4·4–13·8].
Number of cases (n) and annualized incidence of iGAS disease (per 100 000) in the Northern Territory by region for Indigenous, non-Indigenous and haemodialysis populations
iGAS, Invasive group A streptococcal; CI, Confidence interval.
Figure 1 shows frequency of cases and incidence by Indigenous status and age group. For Indigenous adults, incidence was higher in those aged >30 years while incidence in non-Indigenous adults was higher only after 65 years. In children, incidence was high in the Indigenous population aged <5 years (68·2/100 000, 95% CI 23·6–153·3), a pattern not observed in non-Indigenous children (4·1/100 000, 95% CI 0–38·6).
Frequency (bar graph) and annualized incidence (line graph) of iGAS disease by age group and Indigenous status in the NT.
Laboratory typing of GAS isolates and clinical presentation
Of the 128 isolates, 82 (64%) were available for emm typing. Figure 2 shows the 28 emm types and clusters identified by geographical region, and includes two previously unidentified subtypes (114·7 and 197·4). There was no predominant emm type and half the emm types appeared in both Central Australia and the Top End. No individual emm type was associated with greater severity of disease as identified by STSS (12/14 isolates from people with STSS were typed) or death (5/10 isolates from people who died were typed).
Frequency of GAS isolates causing invasive disease by geographical region, emm type and emm cluster.
Classification of isolates by emm cluster shows the majority of isolates 63/82 (77%) were from four emm clusters, i.e. A-C2, D4, E3 and E6 [Reference Sanderson-Smith24].
Table 2 shows the clinical presentation and outcome of cases by prevalence of the five most commonly identified emm types. Emm type was not a predictor of clinical presentation or death.
Clinical presentation and outcome of Northern Territory residents with iGAS disease by the five most commonly identified emm types
iGAS, Invasive group A streptococcal; STSS, streptococcal toxic shock syndrome.
* Severe disease is defined as iGAS disease presenting as pneumonia, meningitis, necrotizing fasciitis, STSS or any other manifestation requiring intensive care admission or causing death;
† Other emm types identified where clinical illness was complicated by STSS included 4·0 (1), 39·4 (1), 73·0 (1), 92·0 (1), 104·0 (1), 207·1 (2).
‡ Other emm types identified where outcome was death included 197·0 (1), 39·4 (1), 4·0 (1) and 87·0 (1).
The most common site of initial infection was skin. For haemodialysis patients, 6/21 (29%) had skin lesions specifically on the lower limb. In children aged <16 years, skin sores and infected scabies were predominant (9/15, 60%). All people with infected scabies were Indigenous.
Risk factors
In the majority of episodes (66%), the person had a chronic medical condition as shown in Table 3. Comorbidity with diabetes or renal disease was significantly more common in Indigenous people. No cases were reported following varicella infection [Reference Laupland26]. Repeat infection was identified in five people, two of whom had three episodes of iGAS disease within 2 years. Average time between episodes ranged from 78 to 532 days (average 273 days). Each episode in the same individual was associated with a different emm type except in one person where emm type 81·1 was isolated twice. In this individual the interval between infections was 14 months with presentation on both occasions being leg cellulitis.
Characteristics of Northern Territory patients diagnosed with iGAS disease by Indigenous status
iGAS, Invasive group A streptococcal; OR, odds ratio; CI, confidence interval; ICU, intensive care unit; STSS, streptococcal toxic shock syndrome.
* One or more chronic medical conditions.
† Includes people receiving haemodialysis.
‡ Includes chemotherapy (3) and radiotherapy (1).
§ Smoking status only known for 121 episodes.
For haemodialysis patients, presence of a comorbidity other than renal failure was reported in 18/21 (86%) episodes, most commonly diabetes 16/21 (76%). In 5/21 (24%) episodes the scheduled haemodialysis session prior to onset of illness was missed.
Outcome and severity of disease
The case-fatality ratio (8%) and occurrence of STSS (11% of episodes) was similar for Indigenous and non-Indigenous people (Table 3). All died within 22 days of specimen collection with median time to death 6 days. Age of those who died ranged from 21 to 83 years with half aged ⩾60 years. Of the 10 people who died, seven had a history of one or more chronic medical conditions, two had malignancy and one died post-partum. The fatality rate in people with STSS was 29% (4/14). Necrotizing fasciitis was diagnosed in three people of whom two died.
Overall 123 (96%) cases were admitted to hospital with median length of stay 7 days (interquartile range 4–16 days). Surgical intervention was documented in 23/128 (18%) cases, including 16 wound washouts with/without debridement of tissue; drainage of fluid collections for four people and five amputations. Number of surgical procedures per person ranged from 1 to 23.
Nosocomial transmission
In total, six (5%) episodes were acquired in hospital, two of which were acquired after vaginal births. Portals of entry for the remainder were an intravenous catheter site, toe wound and burn sites for two people.
Of 21 episodes in haemodialysis patients, 20 attended a dialysis unit within the 10 days prior to symptom onset. A cluster of three cases was identified in a single dialysis unit, of whom all had onset of symptoms within a 2-week period. This cluster, however, was not confirmed through laboratory testing as only one of the three isolates were available for typing.
Household transmission
Transmission occurred within a household between twin infants, clinical details of which have been reported previously [Reference Middleton, Morris and Carapetis27]. Onset of illness was 2 days apart with the common emm type 207·1 identified.
A further two separate episodes of iGAS disease occurred in household contacts, with onset of infection between index and secondary cases 4 and 28 days apart. Typing of isolates on both occasions revealed a different emm type in index and secondary cases and therefore transmission was not supported.
DISCUSSION
Our study provides the first report of the epidemiology of iGAS disease for tropical and semi-arid regions of the NT. Incidence was similar across both regions with over-representation of the Indigenous and haemodialysis populations. Skin infections were the most common sites of initial infection leading to invasive disease. We found evidence supporting transmission in healthcare settings and between infant twins. Typing of isolates showed that a very diverse range of emm types contributes to invasive disease in the NT and refuted direct transmission in two household case pairs.
Incidence
Similar to previous reports, we found a significantly higher rate of disease in the Indigenous population (69·7/100 000) compared to non-Indigenous (8·8/100 000) [Reference Hoge2, Reference Safar6–Reference Carapetis8, Reference Norton10]. This finding is similar to rates reported in tropical northern Queensland (Indigenous: 82·5, 95% CI 27·4–190·0/100 000 population; non-Indigenous: 10·3, 95% CI 5·5–17·6/100 000 population) [Reference Norton10]. It was speculated that the tropical conditions in northern Australia contribute to the higher rates of iGAS disease seen in these regions [Reference O Grady4, Reference Gear9]. Our findings, however, did not support this hypothesis with incidence in the tropical regions of the NT similar to the semi-arid regions of Central Australia. However, the high rate of iGAS disease in the Indigenous population across the NT is consistent with high rates of other GAS-associated diseases including acute post-streptococcal glomerulonephritis, acute rheumatic fever and rheumatic heart disease [Reference Carapetis, Wolff and Currie14–Reference Marshall16]. Causes are likely multifaceted and include socioeconomic and environmental factors (e.g. house overcrowding) and greater host susceptibility (e.g. higher prevalence of predisposing chronic diseases) [12, Reference Bailie13, 28–Reference McDonald30]. Moreover, onset of chronic diseases occurs at a younger age in Indigenous people. In particular, rates of chronic kidney disease and diabetes begin rising from age 25 years in the Indigenous population compared to 55 years in non-Indigenous people [12]. This is reflected in our cases where the incidence of iGAS disease was higher in those aged >30 and >65 years for the respective populations. A further age group contributing to the higher incidence in the Indigenous population were children aged <5 years. Scabies, which frequently underlies streptococcal pyoderma was described exclusively in Indigenous children and is endemic in many NT Indigenous communities [Reference Currie and Carapetis29–Reference Clucas31]. Improving the social determinants of health for Indigenous people, along with greater adherence to treatment, prevention of scabies, skin infections and chronic diseases are of vital importance for decreasing the burden of GAS-associated diseases.
Incidence of iGAS disease in haemodialysis patients is exceedingly high. While chronic kidney disease is a known risk factor for iGAS disease, the high rate (2205·9/100 000) in haemodialysis patients has not been reported outside the NT. A study between 2005 and 2009 reported that 17% of people with GAS bacteraemia in the Top End were on haemodialysis; a result consistent with our finding of 16% of people with iGAS disease [Reference Gear9]. Further, our study found a similar incidence in Top End and Central Australia; suggesting a more widespread phenomenon than a breach in infection control practices isolated to one or two dialysis units. Apart from one cluster of three cases within a single dialysis unit, we were unable to establish nosocomial or community-acquired disease in the haemodialysis cases. The high incidence in this population probably reflects both the high rates of GAS infections in the region and susceptibility of the haemodialysis population. Patients on haemodialysis generally had at least two risk factors for iGAS disease, i.e. chronic kidney disease and Indigenous background. Additionally, three-quarters had a third risk factor of diabetes for whom the most common site of initial infection was a skin lesion of the lower limb. Hence regular examination of the skin integrity of the lower limbs of these patients could limit disease progression through early detection and treatment. The susceptibility of this population also highlights the need for stringent implementation of infection control practices including regular auditing to prevent transmission.
It is possible we under-ascertained the total number of people with iGAS disease as people with milder symptoms receiving antibiotic treatment in primary care without collection of a specimen may not have been identified.
Typing
Similar to other GAS-associated diseases in the NT, molecular typing showed a very diverse range of emm types causing invasive disease [Reference Bessen32–Reference Richardson34]. These data are consistent with developing regions of the Pacific and Africa which also report high diversity of emm types causing GAS-associated diseases [Reference Steer35]. While Fiji reports a similar diversity of emm types causing invasive GAS disease, data from other developing countries regarding emm types that specifically contribute to invasive disease are limited [Reference Steer7]. By contrast, developed regions of southern Australia, Europe and the USA report a limited number of predominant emm types causing invasive disease [Reference Lepoutre3–Reference O'Loughlin5, Reference Steer35]. The reason for this differing molecular epidemiology is unclear. Potentially the diversity of emm types reflects the NT's demographic and geographical setting that supports a high proportion of Indigenous people, many of whom are of lower socioeconomic status and live in remote communities associated with household overcrowding [12, 20]. Overcrowding provides opportunity for circulation of GAS strains. We did not find tropical climate to be a contributing factor as a diverse range of emm types were found in both the tropical and semi-tropical regions of the NT. As our study was limited to a 2-year period and small sample size, further study is required to rule out tropical setting as a contributing factor. The diversity of emm types has implications for potential effectiveness of GAS vaccine formulations [Reference Steer, Dale and Carapetis18]. In rat trials, a 30-valent GAS vaccine has shown cross-protection against molecularly related non-vaccine emm types which has led to interest in the concept and use of emm clustering to further inform vaccine coverage [Reference Sanderson-Smith24, Reference Dale36]. As most isolates (77%) in our study fell within four emm clusters, introduction of a GAS vaccine formulation covering these clusters may potentially reduce the incidence of iGAS disease in the NT significantly. Nevertheless the theoretical cross-protection across emm clusters remains speculative and requires robust studies in diverse locations to justify support for a GAS vaccine that directly covers only a minority of emm types in regions with high rates of GAS-related disease [Reference Steer35]. Our study is the first to describe the difference between emm ST and emm cluster coverage in a whole population analysis, but our data were limited to a 2-year period and ongoing typing of isolates is required to inform the evolution of circulating emm types causing disease.
Risk factors predisposing to disease
Consistent with previous reports, the majority of people had a risk factor predisposing them to iGAS disease [Reference Davies1, Reference O Grady4, Reference O'Loughlin5, Reference Carapetis8]. Risk factors included Indigenous ethnicity, age >65 years, presence of an underlying chronic or immunosuppressive medical condition, history of smoking and previous episode of iGAS disease. A limitation of this study was the inability to quantify alcohol consumption due to variable recording of alcohol intake in medical records. Excessive alcohol consumption, however, has been identified as a risk factor for iGAS disease [Reference Davies1, Reference Lepoutre3–Reference O'Loughlin5], and is likely also to be a risk factor in the NT which reports a higher alcohol consumption per capita than other Australian jurisdictions [37]. Identification of risk factors alerts clinicians for early detection and treatment and identifies populations who should be considered for vaccination and education.
Public health response
We identified only one episode of secondary transmission to a household contact. Due to lack of evidence of the efficacy of chemoprophylaxis and uncertainty regarding the number of people needed to treat to prevent one case, recommendations for managing contacts vary from no follow-up of cases to chemoprophylaxis of household members with a predisposing risk factor [Reference Lepoutre3, Reference Moore38, 39]. In 2014, the NT adopted similar guidelines to Canada, restricting chemoprophylaxis to close contacts of people with severe iGAS disease [39, 40]. Accordingly, contacts of 37 cases in our study would have received chemoprophylaxis, including the secondary case identified in the same household. However, due to the short time-frame of 2 days between infection in the index and secondary cases it is doubtful that diagnosis and public health response would have occurred prior to the secondary infection. To rationalize deployment of scarce public health resources, further studies on the potential effectiveness of chemoprophylaxis are needed. Studies should encompass timeliness of response, potential virulence of the organism, carriage status and extent of likely transmission.
Outcomes
Invasive GAS disease continues to cause severe illness in the Indigenous population of the NT. Outcomes and clinical course were similar regardless of Indigenous status. The case-fatality ratio of 8% was comparable to other Australian reports of 7–8% and lower than the rates reported from the United States, Europe and Fiji which were between 13% and 32% [Reference Lepoutre3–Reference O'Loughlin5, Reference Steer7, Reference Lamagni11]. This potentially reflects universal access to advanced healthcare including intensive care facilities in Australia increasing the chance of survival. Severe complication of STSS in 11% of cases is similar to previous Australian findings, as were the large number of cases requiring hospital admission and surgical interventions [Reference O Grady4, Reference Carapetis8, Reference Norton10]. People who died were more often older and had a pre-existing chronic medical condition. Similar to previous reports, development of STSS or necrotizing fasciitis was associated with high mortality [Reference Lepoutre3–Reference O'Loughlin5]. Invasive GAS disease continues to place significant burden on the individual, community and healthcare system.
ACKNOWLEDGEMENTS
We thank Dr Peter Markey for his ongoing contributions to iGAS disease surveillance in the NT and provision of notification data. Thanks to Dr Mahesh Menon for his initial contributions to assessing iGAS disease in the NT and similarly to Dr Matthew Pittman who was instrumental in developing the NT guidelines for ‘Management of contacts of patients with invasive group A streptococcus'. Additional thanks go to NT public hospital laboratories and particularly Associate Professor Robert Baird for provision of GAS isolates.
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
DECLARATION OF INTEREST
None.
