Capturing the complete clinical spectrum and incidence of severe acute Group A Streptococcus (GAS) disease: a population-based study in Auckland, New Zealand

Summary

Background

The global health burden of Streptococcus pyogenes (Group A Streptococcus, GAS) disease has led the World Health Organization to declare GAS vaccine development an international priority. Severe acute GAS disease comprises hospitalised infections, toxin-mediated disease (scarlet fever and streptococcal toxic shock syndrome) and immune-mediated disease (acute rheumatic fever [ARF] and acute post-streptococcal glomerulonephritis). This study aimed to characterize the burden and spectrum of severe acute GAS disease in Auckland, New Zealand, to inform future GAS vaccine studies in this setting.

Methods

This prospective population-based multicentre cross-sectional observational study utilized laboratory data and ARF notifications to capture all hospitalised GAS infections and toxin- and immune-mediated disease cases associated with hospitalisation in Auckland during 2023. The epidemiology, clinical features, incidence and hospitalisation costs of these cases are described.

Findings

The complete clinical spectrum of severe acute GAS disease was observed, with 606 cases captured corresponding to 1:2000 people affected each year (52 cases/100,000 population/year). The burden is inequitably distributed across the population, greatest at the intersection of age, ethnicity and socioeconomic deprivation. In the most deprived areas, approximately 1:400 Pacific children <10-years and 1:200 Pacific adults ≥80-years are affected annually (261 and 483 cases/100,000 population/year, respectively). Direct hospitalisation costs exceeded $13·2 million New Zealand dollars.

Interpretation

This study demonstrates that the complete clinical spectrum of severe acute GAS disease occurs in Auckland and is associated with a substantial health and economic burden. The high incidence and entire range of severe acute GAS disease present make Auckland an ideal location for future vaccine studies.

Funding

Ministry of Health New Zealand, Health Research Council of New Zealand (HRC-NZ), Royal College of Pathologists of Australasia (RCPA) Foundation.

Research in context.

Evidence before this study

The global health burden of Streptococcus pyogenes (Group A Streptococcus, GAS) disease has led the World Health Organization to declare GAS vaccine development an international public health priority. The clinical spectrum of GAS disease is arguably the broadest of any infectious pathogen, and includes asymptomatic carriage/colonisation, acute infections of varying severity, infection-associated toxin-mediated disease, post-infection immune-mediated disease (acute rheumatic fever [ARF] and acute post-streptococcal glomerulonephritis) and post-immune chronic disease (rheumatic heart disease and chronic kidney disease). The complexity of GAS disease and lack of a single disease entity make it difficult to measure the burden of disease, and the true impact of this pathogen on global human health remains underappreciated. Most published clinico-epidemiological GAS studies describe single clinical entities (e.g. ARF or invasive GAS infections). We searched PubMed from database inception to 28 Jan 2025 for clinical and epidemiological studies describing important infectious, toxin- and immune-mediated GAS disease manifestations, using the search “(Group A Streptococcus OR Group A Streptococcal OR S. pyogenes) AND invasive AND scarlet fever AND toxic shock AND rheumatic fever AND glomerulonephritis”. Review articles were excluded. The search returned a single study describing discrete GAS outbreaks occurring over 30 years ago at US military training facilities. There were no contemporary broad-spectrum clinico-epidemiological studies of GAS disease.

Added value of this study

This prospective population-based multicentre cross-sectional observational study comprehensively describes the burden and spectrum of severe acute GAS disease in Auckland, New Zealand, to inform future GAS vaccine studies. By utilising a novel microbiology laboratory-led enhanced surveillance approach, this study demonstrates that the complete clinical spectrum of severe acute GAS disease occurs in this single city in a single year, and is associated with a substantial health and economic burden. Importantly, GAS disease burden is inequitably distributed across the population, greatest at the intersection of age, ethnicity and socioeconomic deprivation, with the highest disease incidence observed in elderly Pacific peoples living in the most deprived areas. The present study utilised a unique microbiological approach to comprehensively capture hospitalised GAS-attributable infection episodes, supplemented with ARF case notifications, and provides a useful blueprint for future studies in other high burden settings.

Implications of all the available evidence

As GAS vaccine candidates approach clinical trials, pre- and post-vaccine implementation burden of disease data of a comprehensive nature, as presented by this study, is essential for determining how well a GAS vaccine protects against the many varied forms of GAS disease in real-world populations. Vaccine impact on common non-severe acute disease (e.g. pharyngitis and impetigo) and rarer severe acute GAS disease (e.g. hospitalised invasive and severe non-invasive infections, toxin-mediated disease and immune-mediated disease) will need to be assessed. An ideal vaccine would provide protection against all forms of acute GAS disease, and in doing so also prevent post-immune chronic diseases and their complications (e.g. rheumatic heart disease and chronic kidney disease). Following vaccine introduction, disease surveillance will need to be mirrored by bacteriological surveillance to monitor the effect of vaccine-induced host-immune selective pressure on circulating GAS strains and the potential emergence of ‘vaccine escape’ strains not covered by the vaccine. The present study shows that in Auckland it would be possible for vaccine impact to be measured across a range of clinical endpoints in a single urban population.

Introduction

Streptococcus pyogenes (Group A Streptococcus, GAS) is a major global pathogen, accounting for an estimated 800 million infections and 639,000 deaths annually.¹ Disease manifestations are diverse, including colonisation, acute disease and chronic disease (Fig. 1A).¹ The are three main types of acute GAS disease: infections (non-severe and severe); infection-associated toxin-mediated disease (scarlet fever (SF) and streptococcal toxic shock syndrome (STSS)); and post-infection immune-mediated disease (acute rheumatic fever (ARF) and acute post-streptococcal glomerulonephritis (APSGN)).¹ Acute GAS disease comprises severe acute disease requiring hospital management (e.g. invasive and severe non-invasive infections, toxin-mediated and immune-mediated disease) and non-severe disease managed in the community (e.g. pharyngitis, impetigo and other superficial infections). Chronic disease is a direct sequela of acute immune-mediated disease and consists of rheumatic heart disease (RHD) following ARF and chronic kidney disease following APSGN.¹ Deaths attributable to GAS are primarily due to invasive GAS (iGAS) infections and RHD complications.¹

Fig. 1.

Clinical manifestations of Group A Streptococcus (GAS) disease and clinical spectrum of severe acute GAS disease observed in Auckland, New Zealand. A) Clinical manifestations of GAS disease, ranging from colonization and asymptomatic infection, through non-severe and severe acute disease, to chronic post-immune disease and its complications. B) The complete clinical spectrum of severe acute GAS disease as observed in Auckland, New Zealand in a single year, including severe infections (invasive and non-invasive), toxin-mediated disease, and immune-mediated disease. STSS and APSGN cases have been listed separately for descriptive purposes but were diagnosed in the context of severe infections, making a total of 518 severe infections. Abbreviations: asymp, asymptomatic; APSGN, acute post-streptococcal glomerulonephritis; STSS, streptococcal toxic shock syndrome.

In New Zealand (NZ), ARF has been nationally notifiable since 1986 and iGAS infections became nationally notifiable on 1 October 2024.^2,3 NZ has a high incidence of iGAS infections, ARF and RHD compared with other high-income countries,4, 5, 6, 7 with ARF rates in Māori and Pacific children comparable to rates in many low- and middle-income countries (LMICs).⁷ The overall health and economic burden from GAS-related diseases in NZ is significant, with 1·5% of the population affected each year resulting in direct healthcare costs of 29·2 million NZ dollars (NZD) (calculated using 2015 prices, equivalent to 20·4 million US dollars (USD) based on average 2015 exchange rate).^8,9 The multinational iGAS surge following the COVID-19 pandemic (mid-2022 onwards) also occurred in NZ,^6,10 with the 2023 iGAS incidence exceeding pre-pandemic levels in many NZ health districts (national passive surveillance data prior to iGAS becoming notifiable).¹¹

The substantial global health burden of GAS disease has led the World Health Organization to declare GAS vaccine development an international public health priority.¹² In NZ and Australia, recognition of the health burden of GAS disease led to governmental support for a Trans-Tasman Coalition to Advance New Vaccines for Group A Streptococcus (CANVAS) 10 years ago.¹³ Recently formed government-funded initiatives advancing GAS vaccine development are active in the region.^14,15 The NZ-based project ‘Rapua te mea ngaro ka tau’ (Rapua), which translates as ‘The end to seeking that which was hidden’, is one such initiative aimed at enhancing GAS disease surveillance and progressing GAS vaccine development.¹⁴

As with any vaccine, implementation of a successful vaccine against GAS will involve efficacy studies in controlled clinical trials. Post-licensure effectiveness studies in real-world settings will also be required to address clinical trial evidence gaps and determine how well a GAS vaccine protects against the varied forms of GAS disease, including rarer severe GAS diseases. As part of the Rapua GAS vaccine development initiative, this study sought to describe the epidemiology, clinical features, and cost of severe acute GAS disease in central and south Auckland, NZ, with a view to informing future vaccine studies.

Methods

Study setting and design

NZ is an island nation in the South Pacific Ocean with a 2023 population of ∼5 million.¹⁶ Auckland, population ∼1·7 million, is NZ's largest and most ethnically diverse city.¹⁶ The Auckland region is covered by three health districts: Auckland (central Auckland), Counties Manukau (south Auckland) and Waitematā (north and west Auckland).¹⁷ This study was conducted at the three public hospitals (sites A, B and C) covering the central and south Auckland health districts. Sites A and B refer to Auckland City Hospital and Starship Children's Hospital, respectively, both covering central Auckland. Site C refers to Middlemore Hospital, covering south Auckland. The combined catchment population of these three hospitals is approximately 1·1 million people. This represents around two-thirds (63%) of the Auckland population and one fifth (21%) of the total NZ population, and includes the greatest number of people living in socioeconomic deprivation nationally.¹⁸

This prospective population-based multicentre cross-sectional observational study utilised hospital clinical microbiology laboratory (CML) data supplemented with ARF notifications to identify all cases of hospitalised GAS infection and ARF, plus any cases of toxin- and immune-mediated disease associated with hospitalised infections. See Supplementary Methods for more detail.

Enhanced surveillance

For the 12-month study period of 1 January to 31 December 2023, a prospective monthly data extract was generated by the two CMLs serving sites A, B and C, detailing all GAS-positive microbiological specimens (in which GAS was detected by culture or nucleic acid testing). Specimen data were compiled into a secure laboratory database. Patients of all ages were included. Specimens were grouped into discrete infection episodes (cases), with specimens collected within 30 days of each other considered part of the same episode¹⁹ unless careful review of the electronic medical record (EMR) showed distinct infection episodes within a 30-day period. Individual patients could have multiple infection episodes during the study period. Cases were included if the initial GAS-positive specimen was collected during the study period. Each case was assigned a unique identifier, and demographic, clinical, and hospitalisation data were obtained from the EMR. De-identified data were recorded in a secure REDCap (Research Electronic Data Capture) clinical database. Each case was allocated a single ethnicity based on ‘prioritised ethnicity’ as recorded in the EMR.²⁰

At the end of the study, an additional laboratory data extract of all GAS-positive specimens for the study period was generated to ensure completeness of case ascertainment. Specimens not captured during prospective data collection were reviewed and corresponding missed cases added to the clinical database. Notified cases of ARF presenting to study sites during the study period were added to the clinical database. Cases of APSGN were included if they were associated with a hospitalised GAS infection episode. See Supplementary Methods for more detail.

Microbiological inclusion criteria

GAS was detected in clinical specimens primarily by culture, and occasionally by nucleic acid testing (e.g. polymerase chain reaction, PCR). Culture was undertaken as per standard laboratory protocols using routine bacterial culture media.^19,21,22 Cultured GAS isolates were identified to the species level by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Commercial PCR assays were used on selected clinical specimens as per standard laboratory protocols: Xpert Xpress Strep A (Cepheid) and BioFire Blood Culture Identification 2 (BCID2) Panel (bioMérieux).

Infection episodes were classified as confirmed iGAS infections, probable iGAS infections, or severe non-invasive GAS (sniGAS) infections based on the most sterile GAS-positive specimen temporally and anatomically associated with the infection episode. The following order of sterility priority was used: blood culture (sterile) >> internal body fluid (sterile) >> tissue/pus/body interior swab from sterile site (sterile) >> tissue/pus/body interior swab from non-sterile site (non-sterile) >> body surface swab/respiratory/urine/other (non-sterile). Infections were microbiologically attributed to GAS if evidenced by GAS detection in ≥1 associated sterile site specimens (confirmed iGAS infections) or if GAS was the only causative pathogen detected in ≥1 associated non-sterile site specimens (probable iGAS and sniGAS infections). To be included, probable iGAS and sniGAS infections also needed to meet clinical case definitions (Table 1).

Table 1.

Clinical case definitions.

GAS disease type/clinical syndrome	Case definition (for full wording see refenced published case definitions)	Organization/Ref.
Severe infection
iGAS—confirmed	Clinical illness with GAS detected in ≥1 associated sterile site specimens	SAVAC19
iGAS—probable	Septic shock, STSS, maternal sepsis, or necrotising fasciitis with GAS detected in the absence of other causative pathogens in ≥1 associated non-sterile site specimens, not meeting the confirmed iGAS case definition	SAVAC19
sniGAS	Non-invasive non-pharyngitis GAS-attributable infection hospitalised for ≥24 h with GAS detected in the absence of other causative pathogens in ≥1 associated non-sterile site specimens, not meeting the confirmed or probable iGAS case definitions	Study specific
Necrotising fasciitis—confirmed	Surgical and/or histopathological evidence of fascial necrosis with GAS detected in ≥1 associated sterile site specimens	SAVAC19
Necrotising fasciitis—probable	Surgical and/or histopathological evidence of fascial necrosis with GAS detected in ≥1 associated non-sterile site specimens, not meeting the confirmed case definition	SAVAC19
Peripartum infection—confirmed	Pregnancy-associated infection that occurs in the peripartum period (intrapartum or postpartum) with GAS detected in ≥1 associated sterile site specimens	SAVAC19
Peripartum infection—probable	Pregnancy-associated infection that occurs in the peripartum period (intrapartum or postpartum) with GAS detected in ≥1 associated non-sterile site specimens, not meeting the confirmed case definition	SAVAC19
Primary bacteraemia	GAS-positive blood cultures without an identifiable source	SAVAC19
Cellulitis	Clinical diagnosis of cellulitis with GAS detection in blood culture or a specimen from the affected site	SAVAC21
Pharyngitis	Clinical diagnosis of pharyngitis with GAS detection in a throat specimen	SAVAC22
Toxin-mediated
STSS—confirmed	Hypotension and multiorgan involvement with GAS detected in ≥1 associated sterile site specimens	CDC/CSTE23
STSS—probable	Hypotension and multiorgan involvement with GAS detected in ≥1 associated non-sterile site specimens, not meeting the confirmed case definition	CDC/CSTE23
Scarlet fever	A clinical diagnosis of scarlet fever with GAS detected in ≥1 associated throat specimens	SAVAC22
Immune-mediated
ARF	Major and/or minor clinical criteria plus evidence of preceding GAS infection	NHFNZ24
APSGN	Clinical and laboratory evidence	SAVAC25

Abbreviations: GAS, Group A Streptococcus (Streptococcus pyogenes); iGAS, invasive GAS infection; sniGAS, severe non-invasive GAS infection; STSS, streptococcal toxic shock syndrome; ARF, acute rheumatic fever; APSGN, acute post-streptococcal glomerulonephritis; SAVAC, Strep A Vaccine Global Consortium; CDC, Centers for Disease Control and Prevention; CSTE, Council of State and Territorial Epidemiologists; NHFNZ, National Heart Foundation of New Zealand; Ref, reference.

For probable iGAS and sniGAS infections (GAS detection in non-sterile site specimens only) all matching GAS-positive microbiological specimens from the same infection episode underwent microbiological assessment to determine the whether the infection episode could reasonably be attributed to GAS. Microbiological testing results (culture and nucleic acid testing) of GAS-positive non-sterile site specimens were used to classify individual specimens as unmixed (GAS was the only causative pathogen detected) or mixed (GAS was detected along with other potentially causative pathogens). Mixed specimens were excluded, and an infection episode was only attributed to GAS if there remained ≥1 temporally and anatomically associated unmixed specimen, i.e. detection of GAS as the only causative pathogen in at least one matching clinical specimen for a given infection episode. See Supplementary Table S1 and Fig. 1 for examples.

Clinical case definitions

Strep A Vaccine Global Consortium (SAVAC) standardised surveillance case definitions were used where available,^1,19,21,22 with other standardised case definitions applied as needed23, 24, 25 (Table 1). Confirmed iGAS infections were clinically defined as any infection with GAS detected in ≥1 associated sterile site specimens.¹⁹ Probable iGAS infections were clinically defined as any combination of septic shock, STSS, maternal sepsis, or necrotising fasciitis, not meeting the confirmed iGAS case definition, with GAS detected in the absence of other causative pathogens in ≥1 associated non-sterile site specimens.¹⁹ Severe non-invasive GAS infections were defined for the purposes of this study as non-invasive (i.e. not meeting confirmed or probable iGAS case definitions) non-pharyngitis infections hospitalised for ≥24 h, with GAS detected in the absence of other causative pathogens in ≥1 associated non-sterile site specimens.

Clinical inclusion criteria

Electronic medical records were interrogated to classify cases by their primary clinical presentation. Infections attributable to GAS were further categorised by infectious syndrome (i.e. cellulitis) and infection type (i.e. skin and soft tissue infection). Where cases had GAS infection in multiple anatomical sites, the most severe/invasive infection was designated as the primary clinical presentation. To capture all cases of toxin-mediated and immune-mediated disease, these disease types were prioritised for disease classification purposes. Death due to GAS was defined as GAS-attributable in-hospital mortality occurring within 30 days.

Cases were included if they had a documented hospitalisation due to GAS disease, met microbiological inclusion criteria, and met the case definition for either iGAS infection, sniGAS infection, SF or ARF. STSS or APSGN could be diagnosed in the context of iGAS or sniGAS infections. Regardless of hospitalisation duration, SF cases were included as a toxin-mediated disease of public health importance whilst uncomplicated pharyngitis was excluded.

Incidence rate calculations

Incidence rates are expressed as cases/100,000 population/year and were calculated by taking the number of cases over the study period (one year) divided by the population at risk and multiplied by 100,000. Health district population denominators were derived from 2018 Census-based medium-series projections (using the cohort component method) for the 2023 year ending June, based on 2022 Stats NZ health district boundaries.

Direct hospitalisation costs and deprivation scores

Study site health intelligence departments provided data on direct hospitalisation costs and NZ Index of Deprivation (NZDep) score based on patient residential address.

Direct hospitalisation costs were defined as patient level costs attributed to an individual patient hospitalisation episode due to GAS-disease (i.e. a hospital admission). Exact patient level costs for each case hospitalisation episode were obtained from the health intelligence and informatics departments of the included study sites. Direct hospitalisation costs did not include healthcare encounters prior to or subsequent to the index hospitalisation episode. See Supplementary Methods for more detail.

The NZDep score is a national area-based measure of socioeconomic deprivation in which defined small geographical areas are allocated a level of deprivation based on a weighted combination of key deprivation dimensions.²⁶ NZDep quintile 1 represents the least deprived areas nationally, whilst quintile 5 represents the most deprived areas.^11,18 See Supplementary Methods for more detail.

Data analysis and visualisation

Analysis was performed with R (R Foundation for Statistical Computing, Vienna). Data visualisations were created using Microsoft Office (v2409) and R (v4·4·0) with R studio (v2024·04·2 + 764) using ggplot2 (v3·5·1).

Ethics

This study was approved by the Auckland Health Research Ethics Committee (AHREC) reference AH24595, and study site research offices. The ethics, study design, and operation were also reviewed by Māori and Pacific Governance Groups. Individual patient consent was not required as all data was derived from routine clinical care.

Role of the funding source

The funders of this study had no role in the study design, data collection, data analysis, interpretation, writing of the manuscript or the decision to submit for publication.

Results

Case ascertainment

A total of 3552 GAS-positive microbiological specimens were collected, corresponding to 2922 distinct clinical episodes (cases) in 2746 individual patients (148 patients had multiple episodes during the study period) (Fig. 2). Excluded cases numbered 2338 (i.e. non-severe GAS infection episodes, episodes not attributable to GAS, or GAS detection without a documented hospitalisation). After addition of 22 notified ARF cases without accompanying GAS-positive specimens, 606 cases were included in the final analysis (Figs. 1B and 2). Included cases comprised 243 iGAS cases, 275 sniGAS cases, 68 ARF cases and 20 SF cases. STSS was diagnosed in the context of six iGAS cases and APSGN was diagnosed in the context of one iGAS case and four sniGAS cases. Of the 243 iGAS cases, 213 (87·7%) were microbiologically confirmed cases and 30 (12·3%) were probable cases (see Supplementary Results).

Fig. 2.

Study summary of severe acute Group A Streptococcus (GAS) disease in Auckland, New Zealand. ^aExcluded cases comprised cases not meeting the case definitions for iGAS, sniGAS, SF or ARF. ^bIncluded cases constituted 584 cases with GAS-positive microbiological specimens and 22 additional notified ARF cases without GAS-positive specimens. ^cListed iGAS cases do not include the 6 STSS cases and 1 APSGN case, making a total of 243 iGAS cases. ^dListed sniGAS cases do not include 4 APSGN cases, making a total of 275 sniGAS cases. ^eSTSS cases have been listed separately for descriptive purposes but also constitute iGAS cases. ^fPSGN cases have been listed separately for descriptive purposes but were diagnosed in the context of one iGAS case and four sniGAS cases. Abbreviations: GAS, Group A Streptococcus (Streptococcus pyogenes); iGAS, invasive GAS infection; sniGAS, severe non-invasive GAS infection; SF, scarlet fever; STSS, streptococcal toxic shock syndrome; ARF, acute rheumatic fever; APSGN, acute post-streptococcal glomerulonephritis.

Clinical characteristics and outcomes

The complete clinical spectrum of severe acute GAS disease was present in the study population, comprising severe infections (84% of included cases), toxin-mediated disease (4%), and immune-mediated disease (12%) (Fig. 1B, Table 2). Among 26 cases of toxin-mediated disease, 20 had SF (76·9%) and six had STSS (23·1%). Most immune-mediated disease cases were ARF (68/73, 93·2%), with five APSGN cases (6·8%) captured.

Table 2.

Clinical characteristics and outcomes of severe acute Group A Streptococcus (GAS) disease in Auckland, New Zealand.

	n	(%)
Primary clinical presentationa
Severe infection (iGAS and sniGAS)a	507	(83·7)
Skin and soft tissue infections	344	(67·9)
Ear, nose and throat infections	35	(6·9)
Lower respiratory tract infections	30	(5·9)
Primary bacteraemia	26	(5·1)
Peripartum infections	22	(4·3)
Bone and joint infections	22	(4·3)
Healthcare-associated infections	18	(3·6)
Other infections	10	(2·0)
Toxin-mediated disease	26	(4·3)
Scarlet fever	20	(76·9)
STSS	6	(23·1)
Immune-mediated disease	73	(12·0)
Acute rheumatic fever	68	(93·2)
APSGN	5	(6·8)
Co-morbidities in severe infection cases
Diabetes	110	(21·7)
Chronic skin conditions	53	(10·5)
Chronic kidney disease	37	(7·3)
Immunodeficiency/immunosuppression	12	(2·4)
Hospitalisation duration, days (median, IQR)
Severe infectionb	4	(3–9)
iGASc	8	(4–15)
sniGAS	3	(2–5)
Toxin-mediated disease
Scarlet fever	0·2	(0·1–0·3)
STSS	17	(11–32)
Immune-mediated disease
Acute rheumatic fever	9	(4–20)
APSGN	3	(3–15)
Surgical management
Severe infectionb	201/518	(38·8)
iGAS	76/243	(31·3)
sniGAS	125/275	(45·5)
Toxin-mediated disease
STSS	2/6	(33·3)
ICU admission
Severe infectionb	47/518	(9·1)
iGAS	46/243	(18·9)
sniGAS	1/275	(0·4)
Toxin-mediated disease
Scarlet fever	0/20	(0·0)
STSS	6/6	(100·0)
Immune-mediated disease
Acute rheumatic fever	2/68	(2·9)
APSGN	0/5	(0·0)
Case fatality rated
Severe infection	19/496	(3·8)
iGAS	18/228	(7·9)
Invasive pneumonia	5/13	(38·5)
Primary bacteraemia	3/28	(10·7)
All infections with bacteraemia	15/163	(9·2)
Invasive cellulitis	8/75	(10·7)
Necrotizing fasciitis	1/11	(9·1)
sniGAS	1/268	(0·4)
Toxin-mediated disease
STSS	1/6	(16·7)

Abbreviations: iGAS, invasive GAS infection; sniGAS, severe non-invasive GAS infection; IQR, interquartile range; ICU, intensive care unit; STSS, streptococcal toxic shock syndrome; APSGN, acute post-streptococcal glomerulonephritis.

^aFor primary clinical presentation description, severe infection cases do not include those in which toxin-mediated disease and immune-mediated disease was also diagnosed (n = 11).

^bFor hospitalisation duration, surgical management proportion, ICU admission proportion and case fatality rate calculations, severe infection cases include those in which STSS and APSGN was also diagnosed (n = 11).

^cHospitalisation duration medians and IQRs for iGAS exclude patients who died (n = 18).

^dDeath due to GAS was defined as GAS-attributable in-hospital mortality occurring within 30 days. Case fatality rate calculations excluded non-Auckland residents (n = 22) to remove bias towards increased mortality due to counting critically ill non-Auckland residents transferred to Auckland hospitals for specialist care.

Skin and soft tissue infections (SSTIs) accounted for approximately two-thirds (67·9%) of all severe infections (Fig. 1B, Table 2). Cellulitis and abscesses were the most common SSTIs, together accounting for three quarters of SSTIs (47·7% and 27·9%, respectively). There were 14 cases of necrotising fasciitis. Peripartum infections were primarily postpartum endometritis (16/22, 72·3%), occurred in women aged 15–40 years, and accounted for around half of iGAS infections in women in this age group (22/42, 52·4%).

Distribution of GAS disease type varied with age (Fig. 3A). Severe infections were the primary cause of severe acute GAS disease across all age groups, whilst toxin-mediated disease (mainly SF) primarily occurred in under 20-year-olds (22/26, 84·6%) and immune-mediated disease (mainly ARF) primarily occurred in those aged under 30-years (68/73, 93·2%).

Fig. 3.

Severe acute Group A Streptococcus (GAS) disease type case numbers and infection type proportions in Auckland, New Zealand. A) Severe acute GAS disease by disease type and age group. B) Severe GAS infection type proportions by infection type and age group. Dashed boxes indicate paediatric age subgroups included within the under-10-year-old age group. Abbreviations: SSTI, skin and soft tissue infections; ENTI, ear, nose and throat infections; LRTI, lower respiratory tract infections; BSI, bloodstream infections (primary bacteraemia, i.e. bacteraemia without an identifiable source); BJI, bone and joint infections; PPI, peripartum infections; HCAI, healthcare-associated infections.

The predominant types of severe infection also varied by age (Fig. 3B). Primary bacteraemia was the second most common type of severe infection at the extremes of life, accounting for around a third (35·3%) and a fifth (19·0%) of severe infections in under 1-year-olds and over 80-year-olds, respectively. Perinatal infections were most frequent in 20–29-year-old women (16·1% of severe infections in this age group). Ear, nose and throat infections (ENTIs) accounted for 7–16% of severe infections in under 50-year-olds.

Diabetes mellitus was the most common pre-disposing condition and was present in 21·8% of severe infection cases (Table 2) and only in adults. Median hospitalisation duration was eight days for iGAS, three days for sniGAS, 0·2 days for SF, 17 days for STSS, nine days for ARF cases, and three days for APSGN. Almost half (125/275, 45·5%) of sniGAS cases required surgical management compared with around a third (76/243, 31·3%) of iGAS cases. Of iGAS cases, nearly one fifth (46/243, 18·9%) required ICU admission and the overall case fatality rate (CFR) was 7·9% (18/228 cases, excluding non-Auckland residents). Invasive pneumonia (pneumonia with bacteraemia) had the highest CFR of any infection type (5/13, 38·5%, excluding non-Auckland residents).

Demographics and incidence rates

Of the 606 included cases with severe acute GAS disease, the median age was 30 years (range 0–104 years) and 272 (44·9%) of cases were female. In NZ, an individual is medially considered a child until their 15th birthday.²⁷ By this definition, 200 of the included cases (33·0%) were children. Pacific peoples accounted for half of cases (n = 303, 50·0%), 116 (19·1%) were Māori, and 187 (30·9%) were from other ethnicities. Nearly two thirds (60·7%, 368/606) of included cases resided in the most socioeconomically deprived areas (quintile 5).

Excluding non-Auckland residents (n = 22) the annual incidence rate of severe acute GAS disease (all types) was 52·3 cases/100,000 population/year, equivalent to over 1:2000 people per year affected (Supplementary Tables S2–S4). By disease type, the annual incidence rate was 44·4 for severe infections, 2·3 for toxin-mediated disease, and 6·5 for immune-mediated disease. The annual incidence of iGAS infections was 20·4 cases/100,000 population/year (Supplementary Tables S5–S7). The annual rate of invasive perinatal infections was 1·6 cases/1000 live births.

By ethnicity, the annual incidence rate of severe acute GAS disease was 150·5 for Pacific peoples and 79·1 for Māori, compared with 22·5 for other ethnicities. Severe acute GAS disease incidence rates were higher in Pacific peoples and Māori compared with other ethnicities for almost all age groups (Fig. 4, Supplementary Table S3). A similar pattern was seen for iGAS, with rates of 56·2, 31·8 and 9·3 observed in Pacific peoples, Māori and other ethnicities, respectively (Supplementary Table S6).

Fig. 4.

Annual incidence of severe acute Group A Streptococcus (GAS) disease (all types) and invasive GAS (iGAS) infections by ethnicity, age and deprivation level. Annual incidence rates are expressed as number of cases/100,000 population/year. Incidence rates exclude non-Auckland residents (n = 22) to remove bias towards increased incidence due to counting critically ill non-Auckland residents transferred to Auckland hospitals for specialist care. White boxes indicate zero cases in the relevant group.

Severe acute GAS disease incidence varied with age, with the highest incidence seen in <1-year-olds followed by < 10-year-olds (all ethnicities, 123·3 and 99·3 cases/100,000 population/year, respectively) (Supplementary Table S2). Incidence also increased in Pacific peoples towards the extremes of life, with rates of 387·1 and 397·9 cases/100,000 population/year observed in <1-year-olds and ≥80-year-olds, respectively. The iGAS incidence was also highest in <1-year-olds and ≥80-year-olds (all ethnicities, 65·3 and 56·3 cases/100,000 population/year, respectively) (Supplementary Table S5).

Increased deprivation was also associated with higher disease incidence (Fig. 4, Supplementary Tables S4 and S7). In the most deprived areas (quintile 5) the incidence of severe acute GAS disease and iGAS infections was 113·1 and 44·9 cases/100,000 population/year respectively, compared with 22·5 and 10·7 in the least deprived areas (quintile 1).

The highest incidence rates of both severe acute GAS disease and iGAS infections were observed in Pacific adults ≥80-years-old living in the most deprived areas, with rates of 483·2 and 422·8 cases/100,000 population/year, respectively (Fig. 4).

Direct hospitalisation costs

The median direct hospitalisation cost in NZD for any severe acute GAS clinical episode (case) was $9111 (interquartile range (IQR) $5248–$19,750), which varied depending on disease type (Supplementary Table S8). The median cost per case was similar for iGAS and ARF, at $13,295 ($7611–$39,448) and $13,596 ($7677–$27,015), respectively. The median cost per sniGAS case was roughly half that of iGAS cases, at $7337 ($4535–$11,321), whilst the median cost per day per case was similar for iGAS and sniGAS cases, at $2066 ($1588–$3443) and $2161 ($1753–$2601), respectively, reflecting the relative hospitalisation durations of these infections (Table 1). The cumulative cost of paediatric cases was $4,546,575 (34·5%) whilst the cumulative cost of adult cases was $8,642,989 (65·5%), corresponding to the relative proportion of child and adult cases included (33·0% and 67·0%, respectively). Altogether, direct hospitalisation costs of severe acute GAS disease cases included in this study exceeded $13·2 million NZD (equivalent to $8·1 million USD, based on average 2023 exchange rate).⁹

Discussion

By using enhanced prospective laboratory-based surveillance, this study demonstrates that the complete clinical spectrum of severe acute GAS disease occurred in Auckland within a single year. Broad spectrum burden of disease data of this nature, encompassing all manifestations of severe acute disease, provides essential baseline data to inform future GAS vaccine trials. Despite the importance of such data, contemporary broad-spectrum clinico-epidemiologic studies of GAS disease have been lacking. This study complements existing research on non-severe acute GAS disease in the Auckland region of NZ (e.g. pharyngitis and impetigo)28, 29, 30 and chronic GAS disease and its long-term complications (e.g. RHD and post-APSGN complications).31, 32, 33, 34

This study demonstrates high rates of severe acute GAS disease in Auckland, with approximately 1:2000 people affected per year (52·3 cases/100,000 population). This disease burden was inequitably distributed across the population, greatest at the intersection of age, ethnicity and socioeconomic deprivation. Extremes of incidence were primarily seen in young and elderly Pacific peoples living in the most deprived areas, with approximately 1:400 Pacific children <10-years-old and 1:200 Pacific adults ≥80-years-old affected by severe acute GAS disease each year (261·0 and 483·2 cases/100,000 population per year, respectively).

Severe acute GAS disease in Auckland was also associated with a substantial economic burden, with direct hospitalisation costs in one year exceeding $13·2 million NZD. This estimate is conservative, in that it only includes costs associated with the index hospitalisation episode for each case and does not include costs for associated pre- or post-admission healthcare encounters. In in one study of paediatric iGAS, associated pre- and post-admission healthcare costs added an estimated additional 10% to the index hospitalisation cost.³⁵ The total annual healthcare costs for all forms of GAS disease nationally, including non-severe infections managed in primary care and RHD and its complications, were previously estimated at $29·2 million NZD (calculated using 2015 price levels).⁸ The sizable direct hospitalisation costs from the present study highlight the disproportionate extent of GAS disease in the Auckland region.

Although comprehensive, the true extent of severe acute GAS disease in the studied population was likely underestimated and is a limitation. Stringent microbiological inclusion criteria were applied to ensure sniGAS infections were reasonably attributed to GAS. In doing so, co-infections involving GAS (primarily GAS-Staphylococcus aureus coinfections) were not captured though these still form part of the overall burden of GAS disease. With the exception of SF, the present study intentionally only included non-invasive infections hospitalised for ≥24, and future studies will be needed to estimate the burden of non-severe GAS infections managed in the community, emergency department and through brief hospital admissions. In using a microbiological surveillance approach, a small number of APSGN and suspected SF cases may have been missed. Cases resident in the central and south Auckland health district study catchment area but hospitalised at one of the two hospitals serving the north and west Auckland health district would not have been captured.

Compared to other high-income settings, Auckland has a high incidence of iGAS and non-invasive GAS infections, ARF and RHD.5, 6, 7^,28, 29, 30, 31^,36 Despite a global post-COVID-19 pandemic increase in iGAS incidence,^6,10,11 the post-pandemic incidence in this Auckland subpopulation was similar to peak pre-pandemic years. For example, iGAS incidence rates per 100,000 population/year in central and south Auckland were 11·8 and 18·9 in 2023 compared with 11·4 and 18·7 in 2018, respectively.¹¹ This indicates a consistently high burden of iGAS in Auckland. Similarly, ARF rates in south Auckland are the highest nationally.³⁷ This high severe acute disease concentration in a single city contrasts with settings such as Australia, where the burden of invasive and immune-mediated disease is dispersed across rural and remote populations.38, 39, 40 Auckland also displays unique GAS ecology, having a high strain diversity similar to LMICs whilst also harbouring strains associated with outbreaks and antimicrobial resistance found in high-income countries.²⁸ Additionally, iGAS and ARF are nationally notifiable in NZ, meaning reliable long-term incidence data is collected.

Most GAS disease clinico-epidemiologic studies describe a single disease entity, whilst this study uniquely captures all hospitalised severe acute GAS disease cases. It clearly demonstrates that the complete clinical spectrum of severe acute GAS disease is present in Auckland, including the rarer clinical endpoints of iGAS, STSS, SF, ARF and APSGN. This breadth of GAS disease makes Auckland ideal for post-licensure vaccine trials designed to demonstrate effectiveness in a real-world population, including prevention of rarer clinical endpoints. Finally, with a GAS strain diversity intermediate between regions of low-medium and high human development,^28,41 Auckland would be an excellent vaccine ‘sentinel site’ for undertaking bacteriological surveillance to monitor the impact of widespread vaccination on circulating GAS strains over time.

Contributors

Conceptualisation: AFL, NJM, RW. Funding acquisition: NJM, AA, RHW, AFL. Project management: JB. Supervision: NJM, RW. Methodology: AFL, NJM, RW. Investigation (data collection): AFL, KWS, EWS, AS, SAR, SCM, ST. Data curation: AFL, KWS. Formal analysis: AFL. Validation: AFL, NJM, RW. Visualization: AFL. Writing—original draft: AFL, NJM, RW. Writing—review & editing: all authors. The corresponding authors, AFL and RW, directly accessed and verified the underlying data reported in the manuscript. The first author AFL and supervising authors NJM and RW had final responsibility for the decision to submit for publication.

Data sharing statement

Fully de-identified clinical data may be made available from the corresponding author on reasonable request and subject to ethical approval.

Declaration of interests

SCM received personal payments for work on ASCOT, REMAP-CAP and BALANCE trials and consulting fees for PHARMAC anti-infectives committee membership, and payments to their institution for work on the SNAP trial.