doi:10.1111/j.1440-1754.2007.01051.

ANNOTATION

Group A streptococcal infections in children

Andrew C Steer,1 Margaret H Danchin1 and Jonathan R Carapetis1,2
1

Centre for International Child Health, University of Melbourne, Department of Paediatrics, Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne, Victoria and 2Menzies School of Health Research, Darwin, Northern Territory, Australia

Abstract: The group A streptococcus causes the widest range of disease in humans of all bacterial pathogens. Group A streptococcal diseases are more common in children than adults with diseases ranging from pharyngitis and impetigo to invasive infections and the poststreptococcal sequelae acute rheumatic fever and acute post-streptococcal glomerulonephritis. The global burden of severe group A streptococcal disease is concentrated largely in developing countries and Indigenous populations such as Aboriginal Australians. Control of group A streptococcal disease is poor in these settings and the need for a vaccine has been argued. With an ever-increasing understanding of the group A streptococcus at a molecular level, new and sophisticated vaccines are currently in human trials and the next decade holds exciting prospects for curbing group A streptococcal diseases. Key words: acute rheumatic fever; epidemiology; group A streptococcus; impetigo; pharyngitis; post-streptococcal glomerulonephritis.

The group A beta-haemolytic streptococcus (GAS) is a common infective agent in children that causes the widest range of clinical disease in humans of any bacterium. The spectrum of GAS diseases can be divided into supercial, invasive, toxinmediated and post-infectious diseases (Table 1). The GAS has a large armamentarium of virulence factors responsible for this broad range of human disease. The most common infections caused by GAS are pharyngitis and pyoderma, which occur particularly in children. Invasive disease is less common but has a high rate of mortality and long-term morbidity. Group A streptococcal toxin-mediated diseases are scarlet fever and streptococcal toxic shock syndrome (STSS), the latter of which is usually found in association with invasive disease and has a high case fatality rate. The post-infectious auto-immune sequelae of GAS infection, acute rheumatic fever (ARF) and acute post-streptococcal glomerulonephritis (APSGN), are the Key Points 1 The group A streptococcus is a major bacterial pathogen affecting children globally; the greatest burden of disease, particularly invasive disease and post-streptococcal sequelae, is in children in resource-poor areas. 2 Penicillin remains the treatment of choice for GAS disease; intravenous immunoglobulin and clindamycin are important adjuncts in treating invasive disease. 3 Vaccines against the GAS are in development, but an effective and widely available vaccine is several years away; effective treatment and control strategies against GAS disease are available to clinicians and public health specialists.
Correspondence: Professor Jonathan Carapetis, Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811, Australia. Fax: +61 88922 8999; email: jonathan.carapetis@menzies.edu.au Accepted for publication 19 April 2006.

major global causes of GAS-related morbidity and mortality, and pose challenging questions about pathogenesis and control. Around the world, an estimated 18 million people currently suffer from a serious GAS disease with over 1.7 million new cases per year and 500 000 deaths per year. In addition to serious diseases, there are over 100 million prevalent cases of pyoderma and over 600 million new cases of GAS pharyngitis per year.3 Reports of outbreaks of ARF and an increasing incidence of invasive disease in industrialised countries since the 1980s have highlighted GAS as a cause of disease in children in these areas. However, the burden of severe GAS disease is predominantly in developing countries and impoverished populations living in wealthy countries.

Microbiology and Pathogenesis

One hundred and twenty years after its discovery by Louis Pasteur in 1879 the entire genome of an M1 strain of GAS was sequenced in 2001,4 and a further eight strains sequenced since.5 The GAS is a Gram-positive organism that is seen in chains on Gram stain. On blood agar, GAS displays characteristic beta-haemolysis due to the haemolysin streptolysin S. It is differentiated from other streptococci by Lanceeld grouping based on serological specicity of cell wall group-specic carbohydrates.6 The GAS has numerous surface and extracellular factors that confer virulence (Fig. 1). With genetic sequencing more than 40 virulence associated genes have been revealed to date.4 The cell surface M protein is the main antigenic determinant of GAS.7 It aids in adherence but most importantly enables the bacterium to evade phagocytosis which is the major defense of the human host.7 Lipoteichoic acid, bronectin binding proteins and the hyaluronic acid capsule aid in adherence to epithelial cells. M protein, capsule, streptokinase, the DNases, hyaluronidase and SpeB are all responsible for the tissue
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Table 1 The spectrum of clinical disease caused by the group A streptococcus in children (adapted from Curtis1 with permission) Asymptomatic colonisation Throat Skin (immediately preceding infection) Also vagina, anus, scalp Supercial infection Pharyngitis and pharyngotonsillitis Pyoderma Invasive disease Bacteraemia/septicaemia Skin/soft tissue suppurative disease Erysipelas Cellulitis (including perianal cellulitis) Wound infection Varicella superinfection Necrotising fasciitis Pyomyositis Puerperal sepsis Neonatal omphalitis Suppurative respiratory disease Peritonsillar abscess Retropharyngeal abscess Cervical lymphadenitis Sinusitis Otitis media Pneumonia Empyema Central nervous system Meningitis Brain abscess Musculoskeletal Osteomyelitis Septic arthritis Cardiac Endocarditis Gastrointestinal Peritonitis Hepatic Liver abscess Genitourinary Urinary tract infection Toxin-mediated disease Scarlet fever Streptococcal toxic shock syndrome Post-infectious sequelae Rheumatic fever Acute post-streptococcal glomerulonephritis Reactive arthritis Erythema nodusum PANDAS PANDAS, Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections the existence of this syndrome as a distinct entity has been questioned.2

invasive capacity of GAS. C5a peptidase limits recruitment of phagocytes.8 Streptococcal inhibitor of complement aids in evading complement mediated killing.9 Streptococcal pyrogenic exotoxins are responsible for the clinical features of STSS and scarlet fever by acting as superantigens, which stimulate around 20% of the T-cell population by binding directly to the T-cell receptor rather than having to be presented in the MHC II binding groove. Rheumatic fever is the result of an interaction between a GAS strain with certain undened features that confer an ability to cause ARF and a host with inherited susceptibility. This interaction leads to an autoimmune response directed against cardiac, synovial, subcutaneous, epidermal and neuronal tissues. Traditional teaching states that ARF follows pharyngitis but not pyoderma, although this has recently been questioned.10 An auto-immune response to GAS infection is also responsible for APSGN, probably due to deposition of a streptococcal antigen directly in the glomerulus.7 Group A streptococcal typing is mainly based on the M protein in the past, serotyping was used but in recent years genotyping of the amino-terminal portion of the M protein gene (emm sequence typing) has largely replaced serotyping. There are currently around 180 emm sequence types and 800 emm subtypes described, but new types and subtypes are being identied regularly.

Supercial Infections
Pharyngitis
Epidemiology
The GAS is the main bacterial cause of pharyngitis and is responsible for around 1530% of cases of acute pharyngitis in children.11 The incidence of GAS culture-positive pharyngitis in school-aged children ranges from 0.95 per child-year in an urban slum area of northern12 India to 0.13 per child year in urban Melbourne.13

Clinical features
The features suggestive of GAS pharyngitis include age 5 12 years (although with the advent of day care, rates in children aged 25 years appear to be increasing), fever, tender and enlarged anterior cervical nodes and tonsillopharyngeal erythema and exudate.11 However, they are not sufcient to allow an accurate diagnosis to be made without microbiological conrmation. Features suggestive of a viral aetiology include absence of fever, conjunctivitis, coryza and diarrhoea.14 Attempts to combine these features into a clinical algorithm for the diagnosis of GAS pharyngitis have been unsuccessful with a relatively low sensitivity and specicity compared with bacteriological diagnosis.15

Diagnosis
Inoculation of a throat swab onto sheep-blood agar remains the gold standard for diagnosis, with a sensitivity of 9095%.16 Rapid antigen tests are now also highly sensitive and specic,17 but they are not used widely in Australia.

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Cytoplasmic membrane

Fibronectin binding proteins protein F, opacity factor and others

Cytoplasm Other extracellular virulence factors Streptolysin S Streptolysin O DNase A-D Hyaluronidase Streptokinase NADase C5a peptidase Spe-B (Streptococcal proteinase) Spe-A,C,G,H,J-M SSA SMEZ and SMEZ-2 SIC GRAB SOD Mac Sc1A and 1B EndoS and IdeS

Fig. 1 The basic outer cell antigenic structure of the group A streptococcus. Dnase, deoxyribonuclease; NADase, NAD glycohydrolase; Spe, streptococcal pyrogenic exotoxin; SSA, streptococcal superantigen; SMEZ, streptococcal mitogenic exotoxin Z; SIC, streptococcal inhibitor of complement; GRAB, a surface protein which binds the proteinase inhibitor 2-macroglobulin; SOD, superoxide dismutase; Mac, a homologue of human CD11b that inhibits opsonophagocytosis; Sc1A and 1B, cell wall-attached proteins that aid in adherence to human cells; EndoS and IdeS, 2 secreted enzymes that have specic effects on IgG.

Peptidoglycan layer Group specific carbohydrate Hyaluronic acid capsule

-helical M protein and M-related protein

Management
In populations with a low incidence of ARF the need to investigate and treat GAS pharyngitis has been questioned.18,19 Reasons to treat GAS pharyngitis include prevention of ARF, prevention of suppurative complications, reduction of the severity or duration of symptoms and reduction of secondary transmission of GAS.19,20 Balanced against this are the side effects of antibiotic therapy, the risk of treatment failure (around 1015% bacteriological failure using penicillin)21 and promotion of antibiotic resistance. The reduction in duration of illness using antibiotic treatment is said to be modest, although this has been underestimated because very few studies have been conducted in children with proven GAS pharyngitis or those with severe symptoms, the group in whom the benets of antibiotic treatment may be greatest.19,22,23 A recent clinical trial also found a high rate of quinsy in placebo-treated children, raising the possibility that suppurative complications may increase if antibiotic treatment of sore throat is abandoned.22 Until better data are available, we recommend antibiotic treatment for sore throat of more than mild severity in patients with features consistent with GAS pharyngitis, with the main aim of symptomatic relief, and secondary aims of preventing suppurative and non-suppurative sequelae and reducing transmission of virulent strains (Fig. 2). All treated cases should have a throat culture (or rapid antigen test) performed and antibiotics should be discontinued if these tests are negative. Investigation and antibiotic treatment are not indicated if the sore throat is of mild severity and there are no or minimal concerns about the other aims of treatment. Antibiotic treatment should not be based on clinical features alone. These recommendations do not relate to populations at high risk of ARF (e.g. Indigenous Australians living in tropical and subtropical areas) as these patients should always have antibiotic treatment,24 and ideally culture conrmation if available.

Presenting complaint with sore throat Clinical examination

No features of GAS pharyngitis

Features suggest GAS pharyngitis: - Age 415 years - Fever - Tonsillopharyngeal erythema or exudate - Tender or enlarged anterior cervical lymph nodes - Absence of viral symptoms (cough, coryza, conjunctivitis)

Throat swab and culture Penicillin V 250 mg children / 500 mg adults bd (or IM benzathine penicillin G single dose*) Culture negative for GAS No investigations No antibiotics Culture positive for GAS

Cease antibiotics

Continue antibiotics for 10 days

Fig. 2 Recommendations for the management of acute pharyngitis in populations at low risk of acute rheumatic fever (adapted from Danchin23 with permission). *Erythromycin may be used for proven penicillin-allergic patients. GAS, group A streptococcus; IM, intramuscular.

Penicillin is the rst-line agent most commonly recommended for GAS pharyngitis.14,21,24 However, there is generally a 20% to 25% higher eradication rate after the use of more broad spectrum agents, such as cephalosporins25 and azithromycin,26 compared with penicillin. A recent meta-analysis suggested an increased likelihood of bacteriological and clinical failure in adult patients with GAS pharyngitis treated with oral
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penicillin compared with oral cephalosporins,27 although this claim has been strongly refuted.28,29 Given its record of success over several decades for both treatment of GAS pharyngitis and primary prevention of ARF, and that there has never been a clinical isolate of GAS resistant to it, we recommend that penicillin remains the antibiotic of choice for this indication.

Pyoderma
Epidemiology
Pyoderma refers to localised purulent infection of the skin. It is an umbrella term for non-bullous impetigo, bullous impetigo and folliculitis.30 Non-bullous impetigo is the most common form of pyoderma and is usually due to GAS, whereas bullous impetigo and folliculitis are usually due to Staphylococcus aureus. The aetiology of pyoderma differs between developing and industrialised nations. In tropical developing countries and other impoverished populations such as the Aboriginal population in Australia, GAS is the major pathogen, while S. aureus appears to predominate in temperate, industrialised countries.31 Pyoderma is endemic in children in many developing countries with prevalence rates averaging 7%.3 The exception is that in Aboriginal Australians and in Pacic nations prevalence rates of pyoderma are often over 50%.3,32 Infestation by the scabies mite is commonly an underlying cause in these populations.33

In addition, the possible but unproven link between GAS skin disease and ARF10 increases the importance of adequate treatment. In remote Aboriginal communities, widespread use of mupirocin for impetigo resulted in rapid emergence of methicillin-resistant S. aureus.38 Intramuscular benzathine penicillin G is currently the treatment of choice for streptococcal impetigo,39 although oral antibiotics such as ucloxacillin or cephalexin are good alternatives when adherence can be assured. The effectiveness of benzathine penicillin G may be reduced if S. aureus emerges as a major cause of impetigo in developing countries and Indigenous populations. It is important to ensure that underlying scabies is appropriately treated, and that family members and other close contacts are also examined and treated for pyoderma and scabies. In populations with high rates of scabies-related pyoderma, community treatment with scabicides alone has been shown to reduce rates of pyoderma.40

Invasive Disease and ToxinMediated Disease

Invasive GAS disease occurs when the bacterium infects a normally sterile site (Table 1). STSS occurs when an infecting GAS strain produces toxins that lead to a characteristic set of clinical features.

Epidemiology
From the 1980s onwards, severe GAS diseases were reported to increase in incidence and severity North America, Europe and Australia.4143 This change in epidemiology may relate to the emergence of virulent strains of GAS. The incidence of invasive GAS disease in most industrialised countries is between 2.5 and 3 per 100 000 and mortality rates vary between 10% and 20%.3 Recent data suggest that invasive GAS infections occur at increased rates in developing countries. It is estimated that more than 660 000 cases of invasive disease resulting in more than 160 000 deaths occur globally each year, most in developing countries.3 The peak incidence of these infections occurs in infants and elderly adults. Data from developing countries suggest that GAS is the most common cause of invasive bacterial disease in young infants aged 759 days.44 A Kenyan study found that the incidence of GAS bacteraemia in children <15 years was 13 per 100 000 with a comparatively high mortality rate of 25%.3,45 Aboriginal Australians are at particularly high risk of invasive infections with crude hospital-based incidence rates of invasive GAS disease in the Northern Territory of 23.8 per 100 00037 and in north Queensland 82.5 per 100 000.46 Invasive GAS infections are more common in adults with other comorbidities although many cases (and almost all in children) occur in otherwise healthy individuals. Varicella infection is the most commonly identied precipitating factor in children. There also may be an association between the use of non-steroidal anti-inammatory drugs and necrotising fasciitis or STSS.47

Clinical features
Clinically, GAS non-bullous impetigo is usually indistinguishable from non-bullous impetigo caused by S. aureus. The infection commonly presents as a small pimple which evolves to a purulent lesion covered by a honey-coloured crust. Lesions are most commonly found on the arms or legs, at the sites of minor trauma that are invariably needed for the organism to establish an infection.34 The organism is highly transmissible, so affected children may develop lesions elsewhere on their body, and multiple cases within the same household or classroom are quite common (hence the term school sores).

Management
In industrialised countries where supercial bacterial skin disease is less common, where the causative organism is often S. aureus, and where local complications and post-streptococcal sequelae are less common, most mild cases will respond to topical treatment with mupirocin. Moderate cases can be treated successfully with oral anti-staphylococcal antibiotics such as ucloxacillin or cephalexin. A recent Cochrane review of 57 trials suggested that topical mupirocin or fusidic acid is at least as effective as oral anti-staphylococcal antibiotics.35 However, the results of the Cochrane review are not easily applicable to developing countries and populations such as remote Aboriginal people. The trials included in the review did not come from these settings, where streptococcal impetigo is most common and often severe, outbreaks of APSGN due to virulent skin strains of GAS may occur, and invasive GAS disease occurs at high rates, often as a result of skin infection.36,37
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Clinical features
The GAS causes a wide range of focal invasive infections including soft tissue infections (in approximately 60% of cases),

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pneumonia, meningitis and others (Table 1). Bacteremia without focus occurs in approximately 15% of cases of invasive GAS disease. Usually there is little to distinguish GAS from other bacterial causes of focal invasive disease, except that GAS infections are usually severe, more likely to cause complications, and often slower to respond to treatment than other bacteria. Necrotising fasciitis is a severe infection of muscle fascia, subcutaneous fat and epidermis that rapidly leads to necrosis of muscle fascia usually progressing to limb and life-threatening disease within 24 h.48 In children, 90% of deaths occur in the rst 48 h after presentation.49 The recognition of infection beyond the dermis is critical in diagnosing necrotising fasciitis severe pain and tenderness disproportionate to the physical ndings as well as skin bullae and blistering are the clinical hallmarks that differentiate necrotising fasciitis from more supercial infection.48 Survivors frequently require amputation or reconstructive surgery, and many are left with permanent disability. Pneumonia comprises around 10% of invasive GAS disease.50 Pneumonia due to GAS is often severe and empyema is very common in one earlier series 100% of children with GAS pneumonia had empyema.51 The exudate is often thick, persists for several days and patients invariably require re-drainage or surgical decortication. Children usually require 3 weeks or more of antibiotics and persistence of fever for up to 10 days is common. In the 1930s GAS was the second most common cause of meningitis after pneumococcus.52 Today, GAS meningitis is uncommon in industrialised countries, but it remains common in children in developing countries, particularly in young infants and neonates.44,53 In children, approximately 50% of patients have a distant primary focus of infection, usually pharyngotonsillitis. Rates of neurological sequelae after GAS meningitis are between 36% and 46%, the highest among the major bacterial causes of meningitis.53,54

Table 2 Diagnostic criteria for streptococcal toxic shock syndrome55 Streptococcal toxic shock syndrome case denition 1 Isolation of the group A streptococcus A From a sterile site (denite case) B From a non-sterile site (probable case) 2 Clinical signs of severity A Hypotension B Two or more of the following clinical and laboratory abnormalities: a Fever (>38.5C) b Rash (diffuse macular erythema with subsequent desquamation) c Renal impairment d Coagulopathy (platelets <100 or disseminated intravascular coagulation) e Liver abnormalities f Adult respiratory distress syndrome g Extensive tissue necrosis (including necrotising fasciitis)

contrast, in staphylococcal toxic shock syndrome, S. aureus is cultured from the blood in only 3% of patients.59 The case fatality rate of STSS is approximately 50%,41 although recent data suggest that this is substantially lower in Australia (J Carapetis, unpubl. data, 2005).

Management of invasive group A streptococcal disease and STSS

The absence of sufcient features to full the formal diagnostic criteria should not deter early provisional diagnostic and empiric treatment of STSS. Factors to consider in the management of severe GAS disease are (i) aggressive supportive care; (ii) early surgical debridement of necrotic tissue; (iii) correct use of antibiotics; and (iv) intravenous immunoglobulin (IVIG). Aggressive supportive care is the most important aspect of management of severe GAS disease, particularly in STSS. Patients often require massive uid resuscitation due to the capillary leak syndrome. Wide surgical debridement of non-viable tissue in necrotising fasciitis has been shown to improve outcome.60 However, if the diagnosis is made before extensive tissue destruction or shock has occurred, correct use of antibiotics and early administration of IVIG may reduce the need for, or extent of, debridement.61 Penicillin is the antibiotic of choice for all GAS infections, including severe invasive disease. There has never been a clinical isolate of GAS resistant to penicillin. In the early stages of severe invasive disease, particularly in impending or established STSS or necrotising fasciitis, clindamycin should be added to penicillin. Clindamycin has the theoretical benets of circumventing the Eagle effect, reducing GAS toxin production, potentiating phagocytosis, possessing superior tissue penetration and having a longer post-antibiotic effect.6264 However, clindamycin should not be used alone because of the possibility of resistance, and only needs to be used for the rst days of management until the patient is stabilised.
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Streptococcal toxic shock syndrome

Streptococcal toxic shock syndrome occurs when the infecting strain of GAS produces superantigens. The clinical features of STSS include fever and rash with rapid progression to shock and multiorgan failure (Table 255). Most patients have fever and 50% have hypotension at presentation; the other 50% will develop hypotension within 4 h.47 The typical sunburn type rash in STSS is widespread, erythematous, macular and blanching. Characteristically, there is subsequent desquamation about 2 weeks after the initial illness. Scarlet fever shares these clinical features of erythematous rash and desquamation scarlet fever and STSS are at extreme ends of the spectrum of streptococcal toxin-mediated diseases. Scarlet fever was widely feared in the nineteenth and early twentieth centuries with cyclic pandemics of severe disease with high mortality. Although STSS was rst described in the mid 1980s,56 it almost certainly existed before this time and it is likely that these early descriptions of severe or septic scarlet fever were in fact cases of STSS.57 Streptococcal toxic shock syndrome has been described in association with numerous foci of infection but soft tissue infection, usually necrotising fasciitis, is the most common focus (approximately 60% of STSS cases).58 The GAS is isolated in blood cultures in approximately 6080% of cases of STSS.41 In

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Neutralising antibodies to GAS and streptococcal toxins have been found in IVIG and humoral immunity is known to be important in protecting against GAS disease.65 A randomised controlled trial of the use of IVIG in STSS was stopped prematurely before statistically signicant results were obtained because of slow patient recruitment.66 However, the limited data from this trial and a historically controlled observational study67 suggest benet in the use of IVIG in STSS. With this in mind most experts recommend the use of IVIG in severe GAS disease. It should be given early after presentation. There are a number of dosing regimens but we recommend 2 g/kg as a single infusion.

Clinical features
Acute rheumatic fever begins approximately 3 weeks after a GAS infection (range 15 weeks), which is often asymptomatic. The clinical features of ARF are outlined in the Jones Criteria which were most recently updated in 1992.72 A World Health Organization (WHO) expert advisory group has recently suggested how the Jones Criteria should be applied to rst and recurrent episodes (Table 3).73 In particular, the WHO criteria note that recurrent ARF can be diagnosed in a patient with RHD based only on minor criteria, provided other more likely diagnoses have been excluded. A diagnosis of ARF can be made without other manifestations or evidence of recent streptococcal infection in cases of isolated chorea or subacute carditis. In addition, the WHO revisions have also allowed special consideration to be given to patients in high incidence areas who present with polyarthralgia or monoarthritis, fever and elevated acute phase reactants to be considered as probable rheumatic fever and be commenced on secondary prophylaxis. Recently published guidelines on the diagnosis and management of ARF and RHD in Australia recommend that polyarthralgia or monoarthritis be considered as major criteria in high-risk populations such as Aboriginal Australians.74 In experienced hands, echocardiography can help to identify and characterise rheumatic valvular disease, including subclinical valve lesions.75,76 The signicance of these ndings is not certain and as such the American Heart Association and the WHO decided not to include echocardiographic evidence of rheumatic valvular disease in their versions of the ARF diagnostic criteria. However, clinicians serving populations with high rates of ARF and RHD commonly use echocardiographically diagnosed rheumatic valvular disease as a major manifestation in interpreting the Jones criteria. The recently published Australian ARF and RHD guidelines recommend that all patients with suspected ARF should have an echocardiogram and that subclinical carditis, based upon standard criteria, be considered as a major criterion in high-risk populations such as Aboriginal Australians.74

Post-streptococcal Diseases
The process by which GAS causes post-streptococcal disease is poorly understood. Post-streptococcal diseases include ARF and rheumatic heart disease (RHD), APSGN, erythema nodosum and post-streptococcal reactive arthritis (PSRA). Post-streptococcal reactive arthritis does not full the Jones Criteria for the diagnosis of ARF, and patients are said not to be at risk of cardiac valvular damage. However, because some patients with this diagnosis have later developed conrmed episodes of ARF, the clinician should be very cautious about making a diagnosis of PSRA. In populations with a high incidence of ARF, the diagnosis of PSRA should rarely, if ever, be made. Even in populations with low rates of ARF, it is recommended that penicillin prophylaxis be administered for 1 year and then discontinued if there is no evidence of valvular disease.68

Acute rheumatic fever and rheumatic heart disease

Epidemiology
Coinciding with the apparent resurgence of invasive GAS disease in the developed world, ARF also re-appeared in middle class areas of the USA.69 This change in epidemiology has been attributed to changes in the virulence of circulating strains of GAS and possibly susceptibility in the host. In addition, changing patterns of antibiotic use, in particular the movement away from using antibiotics for treating GAS pharyngitis in countries with low rates of ARF, may also have affected the epidemiology of GAS diseases. The major burden of ARF and RHD is in developing countries and in populations of Indigenous people living in poverty in industrialised countries.3,70 More than 2.4 million children aged 514 years have RHD world-wide and 94% of these are in developing countries.3 There are over 330 000 new cases of ARF each year in children aged 514 years world-wide.3 In Australia, Indigenous people bear almost the entire brunt of ARF and RHD, and have among the highest documented rates in the world. The incidence of ARF in Northern Territory Aboriginal children aged 514 years ranges from 250 to 350 per 100 000. The prevalence of RHD in Aboriginal people of all ages in the same region is 1317 per 1000.71 Recent data from the Top End of the Northern Territory suggest that the prevalence in Aboriginal people is almost 20 per 1000.72
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Rheumatic heart disease

Rheumatic heart disease is the chronic valvular pathology that can follow ARF. Chronic valvular damage is most likely when the rst attack of ARF is severe and in the young patient, and when there are recurrent attacks of ARF.77 The mitral valve is involved in more than 90% of cases with mitral incompetence the predominant lesion in young people and mitral stenosis occurring in around 25% of patients in adolescence or adulthood.78 The aortic valve may also be affected damage to the tricuspid or pulmonary valves in RHD is always due to increased pressures from mitral or aortic valvular disease, not because of direct rheumatic inammation to the right-sided heart valves.

Management
Management of ARF primarily involves conrming the diagnosis, relieving the pain of arthritis, and managing cardiac failure with medication or, rarely, surgery. All patients with ARF should receive a dose of intramuscular benzathine penicillin G

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Table 3 20022003 World Health Organization criteria for the diagnosis of rheumatic fever and rheumatic heart disease73 The Jones Criteria (1992 Update): Major manifestations

Minor manifestations

Evidence of antecedent GAS infection Diagnostic categories: Primary episode of ARF

Recurrent attack of ARF in a patient without established RHD

Recurrent attack of ARF in a patient with established RHD

Rheumatic chorea Insidious onset rheumatic carditis Chronic valve lesions of RHD (patients presenting for the rst time with pure mitral stenosis or mixed mitral valve disease and/oraortic valve disease)

Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules Clinical: Arthralgia Fever Laboratory: Elevated acute phase reactants (erythrocyte sedimentation rate, leukocyte count) ECG: Prolonged PR interval Elevated or rising streptococcal antibody titres (anti-streptolysin-O or anti-DNase B titre) Positive throat culture or rapid streptococcal antigen test Recent scarlet fever Criteria (using above Jones Criteria): Two major manifestations, or One major and two minor manifestations Plus Evidence of antecedent GAS infection Two minor manifestations Plus Evidence of antecedent GAS infection Two major manifestations, or One major and two minor manifestations Plus Evidence of antecedent GAS infection Other major manifestations or evidence of antecedent GAS infection not required Do not require any other criteria to be diagnosed as having RHD

ARF, acute rheumatic fever; GAS, group A streptococcus; RHD, rheumatic heart disease.

or 10 days of oral penicillin V, although there is little empirical evidence to suggest that this affects the outcome.79 Salicylates or non-steroidal anti-inammatory drugs are used only for symptomatic relief of joint inammation and fever; they have no role in the treatment of carditis.80 Corticosteroids are sometimes used for the treatment of severe cardiac failure, although there is no evidence that they affect the likelihood of developing, or the severity of, subsequent RHD.81 Most cases of Sydenhams chorea can be treated without medication; more severe cases should be treated with either carbamazepine or valproic acid.82 Management of RHD primarily involves close follow-up, ensuring adherence to secondary prophylaxis, and medical or surgical treatment of cardiac failure if it develops. In recent years, there has been a trend toward operating earlier in the natural history of disease, when valvular tissue is not severely scarred and calcied.83 This may allow the surgeon to repair rather than replace the valve leaets, which in turn provides a good functional result without the need for long-term anticoagulation.84 The prognosis after mechanical valve replacement in remote Aboriginal people is particularly poor, with only 52% of patients remaining alive without a major complication 5 years after surgery.85

There are two recognised methods of control of ARF and RHD primary and secondary prophylaxis. Primary prophylaxis is the prompt and accurate diagnosis of GAS pharyngitis and treatment with 10 days of oral penicillin V or a single dose of intramuscular benzathine penicillin G. This method can prevent ARF.19,86 However, in practice it has had little impact on ARF incidence in developing countries, because of difculties in providing diagnostic services, the poor performance of clinical diagnostic algorithms for GAS pharyngitis, problems with the availability and quality of antibiotics, different health-seeking behaviour for sore throats, and the fact that only one-third of people with ARF report a previous sore throat severe enough for them to seek medical care, even in industrialised countries.87 Secondary prophylaxis involves regular administration of penicillin (usually 4-weekly benzathine penicillin G) for many years. This strategy prevents recurrent ARF, avoids further damage to heart valves, and has been demonstrated to lead to regression of existing heart valve lesions and reduce RHD mortality.88 This is the only intervention that has proven to be practical and costeffective in all settings, and should be the mainstay of efforts to control RHD.73 Secondary prophylaxis and other aspects of RHD care and control are most effectively delivered as part of a coordinated, register-based RHD control programme.
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Acute post-streptococcal glomerulonephritis

Epidemiology
There are over 470 000 cases of APSGN that occur annually leading to approximately 5000 deaths, with 97% of these cases in less developed countries.3 APSGN, unlike ARF, tends to occur in outbreaks that are associated with virulent skin strains of GAS.89 Several outbreaks have been described in Aboriginal children in northern Australia associated with GAS pyoderma.90

Clinical features
The symptoms and signs of APSGN appear 13 weeks after GAS pharyngitis and 36 weeks after GAS pyoderma. Whereas ARF rarely occurs in children aged less than 4 years, APSGN may occur in younger children, sometimes in the rst 2 years of life. The most common presentation of APSGN is dark urine and facial oedema (Table 4). Hypertension occurs in around 60 70% of cases, primarily as a result of water and salt retention, although in some cases a nephrotic syndrome may occur. With the activation of the alternative pathway of the complement system, C3 levels are almost always diminished early in the disease this is an important diagnostic test in APSGN.92 Other causes of nephritis including systemic lupus erythematosus which can present with similar clinical features and low serum complement levels. In APSGN the depression of C3 is transient and should return to normal at 68 weeks.93 The C3 level should therefore be re-checked at 68 weeks and if it remains depressed then other diagnoses including systemic lupus erythematosus must be considered. Renal biopsy is generally not required if the diagnosis is clear indications for biopsy may include the development of acute renal failure, nephrotic syndrome, insufcient evidence of antecedent streptococcal infection and a persistently low serum C3 level. In most cases of APSGN the clinical course is benign, but overwhelming acute renal failure with crescent formation does occur.93 Acute mortality is low in settings where high quality medical care is available. Management of oedema and hypertension is important and is usually able to be controlled with

uid restriction and frusemide. Serum potassium should be monitored as patients may present with hyperkalemia. Angiotensin-converting enzyme inhibitors such as captopril can be considered as second line agents. There is no evidence that primary prophylaxis (i.e. treatment of a person already infected with a nephritogenic strain to prevent the development of APSGN) is effective. However, on a public health level mass benzathine penicillin administration in the setting of an outbreak may contain further cases particularly by targeting treatment of children with skin sores and household contacts of cases.94 There are now a number of reports in northern Australia documenting the success of mass benzathine penicillin administration in the setting of an epidemic, including one program that focused on treating those with pyoderma only.90,91 Epidemic APSGN in children has a very favourable outcome with a 10-year renal survival rate of 92% and minimal risk of hypertension.95,96 However, the coexistence in Aboriginal Australians in the Northern Territory of endemic pyoderma, high rates of APSGN and high rates of end-stage renal failure have raised the question of whether childhood APSGN could be a risk factor for chronic renal failure later in life.97

Vaccine Development
Group A streptococcal vaccine development has fallen into two groups focused on either M protein antigens or non-M protein antigens. Among the non-M protein antigens being investigated are GAS carbohydrate, C5a peptidase and bronectin binding proteins; none of these has progressed to clinical trials. M protein vaccines are either based upon the variable aminoterminus region these vaccines are multivalent and typespecic or the C-terminal conserved region these antigens are thought to be common to most or all GAS strains (Fig. 3). The most advanced vaccine candidate is one based upon the aminoterminus region. An N-terminal vaccine based on 26 emm types has undergone phase I and II clinical trials in adults, with good evidence of safety and immunogenicity.99 It is estimated

Table 4 The diagnostic glomerulonephritis91

criteria

for

acute

post-streptococcal

Aminoterminus A repeat region

Variable between strains

The presence of two or more of the following: 1 Macroscopic or microscopic haematuria (>10 red blood cells/mm3 on urine microscopy or 2+ on urine dipstick) 2 Oedema (any of denite facial pufness, pitting peripheral oedema, ascites, or other clear evidence of oedema) 3 Hypertension (diastolic blood pressure >90 mmHg in children 13 years and older or >80 mmHg in children <13 years) And Reduced serum C3 level And Evidence of antecedent streptococcal infection (Elevated or rising antistreptolysin-O titre or anti-DNase B titre or isolation of GAS from throat or skin sore culture or positive rapid antigen test from throat swab)

B repeat region

C repeat region

Conserved between strains

D repeat region or transmembrane region

Fig. 3 Schematic drawing of the M protein (adapted from Good98).

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that this 26 valent vaccine will provide protection against 80 90% of invasive GAS isolates in North America.100 However, there are many circulating emm types of GAS, and the dominant strains can change rapidly, even in afuent communities.101 The diversity of emm types in developing countries is even greater, and new emm types emerge frequently.102 Therefore, while typespecic vaccines hold promise in afuent communities, they may prove to have limited effectiveness in developing countries and other settings with high rates of GAS diseases. Vaccines based on the conserved region of the M protein may potentially provide protection against all GAS strains. Researchers in Australia have identied a peptide in the conserved C repeat region that induces antibodies that are opsonic and protective in mice.103 Clinical trials of this candidate are currently in preparation. Any GAS vaccine will be required to undergo strict safety evaluation because of the possibility that the vaccine itself could induce autoimmunity. This concern arose after a crude Mprotein-based vaccine appeared to be associated with cases of ARF when administered to siblings of ARF patients in the 1970s.104 Although this study provided no conclusive proof that the vaccine was dangerous, and numerous other GAS vaccine trials have not been associated with any cases of ARF, the US Food and Drug Administration disallowed the administration of GAS vaccines to humans. GAS vaccine development is now proceeding following review of this legislation. However, a GAS vaccine remains at least several years away, and a vaccine that is effective and affordable in developing countries is an even more distant possibility. Therefore, there is an urgent need to institute effective public health control measures, particularly in developing countries.

Acknowledgement
The authors would like to thank Dr Michael Batzloff, Queensland Institute of Medical Research, Brisbane, Australia, for his kind assistance in developing Figure 1.

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