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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 post-
streptococcal 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 major global causes of GAS-related morbidity and mortality, and
infective agent in children that causes the widest range of clini- pose challenging questions about pathogenesis and control.
cal disease in humans of any bacterium. The spectrum of GAS Around the world, an estimated 18 million people currently
diseases can be divided into superficial, invasive, toxin- suffer from a serious GAS disease with over 1.7 million new
mediated and post-infectious diseases (Table 1). The GAS has a cases per year and 500 000 deaths per year. In addition to
large armamentarium of virulence factors responsible for this serious diseases, there are over 100 million prevalent cases of
broad range of human disease. The most common infections pyoderma and over 600 million new cases of GAS pharyngitis
caused by GAS are pharyngitis and pyoderma, which occur per year.3 Reports of outbreaks of ARF and an increasing inci-
particularly in children. Invasive disease is less common but has dence of invasive disease in industrialised countries since the
a high rate of mortality and long-term morbidity. Group A 1980s have highlighted GAS as a cause of disease in children in
streptococcal toxin-mediated diseases are scarlet fever and these areas. However, the burden of severe GAS disease is
streptococcal toxic shock syndrome (STSS), the latter of which predominantly in developing countries and impoverished popu-
is usually found in association with invasive disease and has lations living in wealthy countries.
a high case fatality rate. The post-infectious auto-immune
sequelae of GAS infection, acute rheumatic fever (ARF) and Microbiology and Pathogenesis
acute post-streptococcal glomerulonephritis (APSGN), are the
One hundred and twenty years after its discovery by Louis
Key Points Pasteur in 1879 the entire genome of an M1 strain of GAS was
1 The group A streptococcus is a major bacterial pathogen affect- sequenced in 2001,4 and a further eight strains sequenced
ing children globally; the greatest burden of disease, particu- since.5 The GAS is a Gram-positive organism that is seen in
larly invasive disease and post-streptococcal sequelae, is in chains on Gram stain. On blood agar, GAS displays characteristic
children in resource-poor areas. beta-haemolysis due to the haemolysin streptolysin S. It is dif-
ferentiated from other streptococci by Lancefield grouping
2 Penicillin remains the treatment of choice for GAS disease;
based on serological specificity of cell wall group-specific
intravenous immunoglobulin and clindamycin are important
carbohydrates.6
adjuncts in treating invasive disease.
The GAS has numerous surface and extracellular factors that
3 Vaccines against the GAS are in development, but an effective
confer virulence (Fig. 1). With genetic sequencing more than
and widely available vaccine is several years away; effective
40 virulence associated genes have been revealed to date.4 The
treatment and control strategies against GAS disease are avail-
cell surface M protein is the main antigenic determinant of
able to clinicians and public health specialists.
GAS.7 It aids in adherence but most importantly enables the
bacterium to evade phagocytosis which is the major defense
Correspondence: Professor Jonathan Carapetis, Menzies School of of the human host.7 Lipoteichoic acid, fibronectin binding
Health Research, PO Box 41096, Casuarina, NT 0811, Australia. Fax: proteins and the hyaluronic acid capsule aid in adherence to
+61 88922 8999; email: jonathan.carapetis@menzies.edu.au
epithelial cells. M protein, capsule, streptokinase, the DNases,
Accepted for publication 19 April 2006. hyaluronidase and SpeB are all responsible for the tissue

Journal of Paediatrics and Child Health 43 (2007) 203213 203


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Group A streptococcal infections in children AC Steer et al.

invasive capacity of GAS. C5a peptidase limits recruitment of


Table 1 The spectrum of clinical disease caused by the group A strep- phagocytes.8 Streptococcal inhibitor of complement aids in
tococcus in children (adapted from Curtis1 with permission) evading complement mediated killing.9
Asymptomatic colonisation Streptococcal pyrogenic exotoxins are responsible for the
Throat clinical features of STSS and scarlet fever by acting as superan-
Skin (immediately preceding infection) tigens, which stimulate around 20% of the T-cell population by
Also vagina, anus, scalp binding directly to the T-cell receptor rather than having to be
Supercial infection presented in the MHC II binding groove. Rheumatic fever is the
Pharyngitis and pharyngotonsillitis result of an interaction between a GAS strain with certain unde-
Pyoderma fined features that confer an ability to cause ARF and a host
Invasive disease with inherited susceptibility. This interaction leads to an auto-
Bacteraemia/septicaemia immune response directed against cardiac, synovial, subcutane-
Skin/soft tissue suppurative disease ous, epidermal and neuronal tissues. Traditional teaching states
Erysipelas that ARF follows pharyngitis but not pyoderma, although this
Cellulitis (including perianal cellulitis)
has recently been questioned.10 An auto-immune response to
Wound infection
GAS infection is also responsible for APSGN, probably due to
Varicella superinfection
deposition of a streptococcal antigen directly in the glomerulus.7
Necrotising fasciitis
Group A streptococcal typing is mainly based on the M pro-
Pyomyositis
tein in the past, serotyping was used but in recent years
Puerperal sepsis
Neonatal omphalitis
genotyping of the amino-terminal portion of the M protein gene
Suppurative respiratory disease (emm sequence typing) has largely replaced serotyping. There
Peritonsillar abscess are currently around 180 emm sequence types and 800 emm
Retropharyngeal abscess subtypes described, but new types and subtypes are being iden-
Cervical lymphadenitis tified regularly.
Sinusitis
Otitis media
Pneumonia Supercial Infections
Empyema
Pharyngitis
Central nervous system
Meningitis Epidemiology
Brain abscess
Musculoskeletal The GAS is the main bacterial cause of pharyngitis and is
Osteomyelitis responsible for around 1530% of cases of acute pharyngitis in
Septic arthritis children.11 The incidence of GAS culture-positive pharyngitis in
Cardiac school-aged children ranges from 0.95 per child-year in an
Endocarditis urban slum area of northern12 India to 0.13 per child year in
Gastrointestinal urban Melbourne.13
Peritonitis
Hepatic
Liver abscess Clinical features
Genitourinary
The features suggestive of GAS pharyngitis include age 5
Urinary tract infection
12 years (although with the advent of day care, rates in children
Toxin-mediated disease
Scarlet fever
aged 25 years appear to be increasing), fever, tender and
Streptococcal toxic shock syndrome enlarged anterior cervical nodes and tonsillopharyngeal
Post-infectious sequelae erythema and exudate.11 However, they are not sufficient to
Rheumatic fever allow an accurate diagnosis to be made without microbiological
Acute post-streptococcal glomerulonephritis confirmation. Features suggestive of a viral aetiology include
Reactive arthritis absence of fever, conjunctivitis, coryza and diarrhoea.14
Erythema nodusum Attempts to combine these features into a clinical algorithm for
PANDAS the diagnosis of GAS pharyngitis have been unsuccessful with
a relatively low sensitivity and specificity compared with bacte-
PANDAS, Paediatric Autoimmune Neuropsychiatric Disorders Associ- riological diagnosis.15
ated with Streptococcal infections the existence of this syndrome as a
distinct entity has been questioned.2
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 specific,17
but they are not used widely in Australia.

204 Journal of Paediatrics and Child Health 43 (2007) 203213


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
AC Steer et al. Group A streptococcal infections in children

Cytoplasmic Fibronectin binding


membrane proteins protein F,
opacity factor and others

Cytoplasm

Other extracellular
virulence factors
Streptolysin S
Streptolysin O
DNase A-D
Fig. 1 The basic outer cell antigenic structure
Hyaluronidase
of the group A streptococcus. Dnase, deoxyribo- Streptokinase
nuclease; NADase, NAD glycohydrolase; Spe, NADase
streptococcal pyrogenic exotoxin; SSA, strepto- C5a peptidase
coccal superantigen; SMEZ, streptococcal mito- Spe-B (Streptococcal
proteinase)
genic exotoxin Z; SIC, streptococcal inhibitor of
Spe-A,C,G,H,J-M
complement; GRAB, a surface protein which SSA
binds the proteinase inhibitor 2-macroglobulin; Peptidoglycan
SMEZ and SMEZ-2
layer
SOD, superoxide dismutase; Mac, a homologue SIC
of human CD11b that inhibits opsonophagocyto- Group specific carbohydrate GRAB
sis; Sc1A and 1B, cell wall-attached proteins that SOD
Mac
aid in adherence to human cells; EndoS and IdeS, Hyaluronic acid capsule Sc1A and 1B
2 secreted enzymes that have specic effects on -helical M protein and EndoS and IdeS
IgG. M-related protein

Management Presenting complaint with sore throat


Clinical examination
In populations with a low incidence of ARF the need to inves-
tigate and treat GAS pharyngitis has been questioned.18,19 Rea-
sons to treat GAS pharyngitis include prevention of ARF,
prevention of suppurative complications, reduction of the No features of Features suggest GAS pharyngitis:
severity or duration of symptoms and reduction of secondary GAS - Age 415 years
pharyngitis - Fever
transmission of GAS.19,20 Balanced against this are the side - Tonsillopharyngeal erythema or exudate
effects of antibiotic therapy, the risk of treatment failure - Tender or enlarged anterior cervical
lymph nodes
(around 1015% bacteriological failure using penicillin)21 and
- Absence of viral symptoms (cough,
promotion of antibiotic resistance. The reduction in duration of coryza, conjunctivitis)
illness using antibiotic treatment is said to be modest, although
this has been underestimated because very few studies have Throat swab and culture
been conducted in children with proven GAS pharyngitis or Penicillin V 250 mg children / 500 mg adults bd
those with severe symptoms, the group in whom the benefits (or IM benzathine penicillin G single dose*)

of antibiotic treatment may be greatest.19,22,23 A recent clinical


Culture negative for Culture positive for
trial also found a high rate of quinsy in placebo-treated children, GAS GAS
raising the possibility that suppurative complications may
increase if antibiotic treatment of sore throat is abandoned.22 No
Until better data are available, we recommend antibiotic investigations Cease antibiotics Continue antibiotics
No antibiotics for 10 days
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 Fig. 2 Recommendations for the management of acute pharyngitis in
suppurative and non-suppurative sequelae and reducing trans- populations at low risk of acute rheumatic fever (adapted from Danchin23
mission of virulent strains (Fig. 2). All treated cases should have with permission). *Erythromycin may be used for proven penicillin-allergic
a throat culture (or rapid antigen test) performed and antibiotics patients. GAS, group A streptococcus; IM, intramuscular.
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 Penicillin is the first-line agent most commonly recom-
the other aims of treatment. Antibiotic treatment should not be mended for GAS pharyngitis.14,21,24 However, there is generally
based on clinical features alone. These recommendations do not a 20% to 25% higher eradication rate after the use of more
relate to populations at high risk of ARF (e.g. Indigenous Aus- broad spectrum agents, such as cephalosporins25 and azithromy-
tralians living in tropical and subtropical areas) as these patients cin,26 compared with penicillin. A recent meta-analysis sug-
should always have antibiotic treatment,24 and ideally culture gested an increased likelihood of bacteriological and clinical
confirmation if available. failure in adult patients with GAS pharyngitis treated with oral

Journal of Paediatrics and Child Health 43 (2007) 203213 205


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Group A streptococcal infections in children AC Steer et al.

penicillin compared with oral cephalosporins,27 although this In addition, the possible but unproven link between GAS skin
claim has been strongly refuted.28,29 Given its record of success disease and ARF10 increases the importance of adequate treat-
over several decades for both treatment of GAS pharyngitis and ment. In remote Aboriginal communities, widespread use of
primary prevention of ARF, and that there has never been a mupirocin for impetigo resulted in rapid emergence of methi-
clinical isolate of GAS resistant to it, we recommend that pen- cillin-resistant S. aureus.38 Intramuscular benzathine penicillin G
icillin remains the antibiotic of choice for this indication. is currently the treatment of choice for streptococcal impetigo,39
although oral antibiotics such as flucloxacillin or cephalexin are
good alternatives when adherence can be assured. The effec-
Pyoderma tiveness of benzathine penicillin G may be reduced if S. aureus
Epidemiology emerges as a major cause of impetigo in developing countries
and Indigenous populations. It is important to ensure that
Pyoderma refers to localised purulent infection of the skin. It underlying scabies is appropriately treated, and that family
is an umbrella term for non-bullous impetigo, bullous impe- members and other close contacts are also examined and treated
tigo and folliculitis.30 Non-bullous impetigo is the most com- for pyoderma and scabies. In populations with high rates of
mon form of pyoderma and is usually due to GAS, whereas scabies-related pyoderma, community treatment with scabi-
bullous impetigo and folliculitis are usually due to Staphylococ- cides alone has been shown to reduce rates of pyoderma.40
cus aureus. The aetiology of pyoderma differs between develop-
ing and industrialised nations. In tropical developing countries Invasive Disease and Toxin-
and other impoverished populations such as the Aboriginal Mediated Disease
population in Australia, GAS is the major pathogen, while
S. aureus appears to predominate in temperate, industrialised Invasive GAS disease occurs when the bacterium infects a nor-
countries.31 mally sterile site (Table 1). STSS occurs when an infecting GAS
Pyoderma is endemic in children in many developing coun- strain produces toxins that lead to a characteristic set of clinical
tries with prevalence rates averaging 7%.3 The exception is that features.
in Aboriginal Australians and in Pacific nations prevalence rates
of pyoderma are often over 50%.3,32 Infestation by the scabies Epidemiology
mite is commonly an underlying cause in these populations.33
From the 1980s onwards, severe GAS diseases were reported to
Clinical features increase in incidence and severity North America, Europe and
Australia.4143 This change in epidemiology may relate to the
Clinically, GAS non-bullous impetigo is usually indistinguish- emergence of virulent strains of GAS. The incidence of invasive
able from non-bullous impetigo caused by S. aureus. The infec- GAS disease in most industrialised countries is between 2.5 and
tion commonly presents as a small pimple which evolves to a 3 per 100 000 and mortality rates vary between 10% and 20%.3
purulent lesion covered by a honey-coloured crust. Lesions are Recent data suggest that invasive GAS infections occur at
most commonly found on the arms or legs, at the sites of minor increased rates in developing countries. It is estimated that more
trauma that are invariably needed for the organism to establish than 660 000 cases of invasive disease resulting in more than
an infection.34 The organism is highly transmissible, so affected 160 000 deaths occur globally each year, most in developing
children may develop lesions elsewhere on their body, and countries.3 The peak incidence of these infections occurs in
multiple cases within the same household or classroom are infants and elderly adults. Data from developing countries sug-
quite common (hence the term school sores). gest that GAS is the most common cause of invasive bacterial
disease in young infants aged 759 days.44 A Kenyan study found
Management that the incidence of GAS bacteraemia in children <15 years was
13 per 100 000 with a comparatively high mortality rate of
In industrialised countries where superficial bacterial skin dis- 25%.3,45 Aboriginal Australians are at particularly high risk of
ease is less common, where the causative organism is often invasive infections with crude hospital-based incidence rates
S. aureus, and where local complications and post-streptococcal of invasive GAS disease in the Northern Territory of 23.8 per
sequelae are less common, most mild cases will respond to 100 00037 and in north Queensland 82.5 per 100 000.46
topical treatment with mupirocin. Moderate cases can be Invasive GAS infections are more common in adults with
treated successfully with oral anti-staphylococcal antibiotics other comorbidities although many cases (and almost all in
such as flucloxacillin or cephalexin. A recent Cochrane review children) occur in otherwise healthy individuals. Varicella infec-
of 57 trials suggested that topical mupirocin or fusidic acid is at tion is the most commonly identified precipitating factor in
least as effective as oral anti-staphylococcal antibiotics.35 children. There also may be an association between the use of
However, the results of the Cochrane review are not easily non-steroidal anti-inflammatory drugs and necrotising fasciitis
applicable to developing countries and populations such as or STSS.47
remote Aboriginal people. The trials included in the review did
not come from these settings, where streptococcal impetigo is Clinical features
most common and often severe, outbreaks of APSGN due to
virulent skin strains of GAS may occur, and invasive GAS dis- The GAS causes a wide range of focal invasive infections includ-
ease occurs at high rates, often as a result of skin infection.36,37 ing soft tissue infections (in approximately 60% of cases),

206 Journal of Paediatrics and Child Health 43 (2007) 203213


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Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
AC Steer et al. Group A streptococcal infections in children

pneumonia, meningitis and others (Table 1). Bacteremia with-


out focus occurs in approximately 15% of cases of invasive GAS Table 2 Diagnostic criteria for streptococcal toxic shock syndrome55
disease. Usually there is little to distinguish GAS from other Streptococcal toxic shock syndrome case denition
bacterial causes of focal invasive disease, except that GAS infec- 1 Isolation of the group A streptococcus
tions are usually severe, more likely to cause complications, and A From a sterile site (denite case)
often slower to respond to treatment than other bacteria. B From a non-sterile site (probable case)
Necrotising fasciitis is a severe infection of muscle fascia, 2 Clinical signs of severity
subcutaneous fat and epidermis that rapidly leads to necrosis of A Hypotension
muscle fascia usually progressing to limb and life-threatening B Two or more of the following clinical and laboratory
disease within 24 h.48 In children, 90% of deaths occur in the abnormalities:
first 48 h after presentation.49 The recognition of infection beyond a Fever (>38.5C)
the dermis is critical in diagnosing necrotising fasciitis severe b Rash (diffuse macular erythema with subsequent
pain and tenderness disproportionate to the physical findings as desquamation)
well as skin bullae and blistering are the clinical hallmarks that c Renal impairment
d Coagulopathy (platelets <100 or disseminated intravascular
differentiate necrotising fasciitis from more superficial infec-
coagulation)
tion.48 Survivors frequently require amputation or reconstructive
e Liver abnormalities
surgery, and many are left with permanent disability.
f Adult respiratory distress syndrome
Pneumonia comprises around 10% of invasive GAS disease.50
g Extensive tissue necrosis (including necrotising fasciitis)
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 contrast, in staphylococcal toxic shock syndrome, S. aureus is
common. cultured from the blood in only 3% of patients.59 The case
In the 1930s GAS was the second most common cause of fatality rate of STSS is approximately 50%,41 although recent
meningitis after pneumococcus.52 Today, GAS meningitis is data suggest that this is substantially lower in Australia (J
uncommon in industrialised countries, but it remains common Carapetis, unpubl. data, 2005).
in children in developing countries, particularly in young
infants and neonates.44,53 In children, approximately 50% of Management of invasive group A streptococcal
patients have a distant primary focus of infection, usually disease and STSS
pharyngotonsillitis. Rates of neurological sequelae after GAS
meningitis are between 36% and 46%, the highest among the The absence of sufficient features to fulfil the formal diagnostic
major bacterial causes of meningitis.53,54 criteria should not deter early provisional diagnostic and
empiric treatment of STSS. Factors to consider in the manage-
Streptococcal toxic shock syndrome ment of severe GAS disease are (i) aggressive supportive care;
(ii) early surgical debridement of necrotic tissue; (iii) correct use
Streptococcal toxic shock syndrome occurs when the infecting of antibiotics; and (iv) intravenous immunoglobulin (IVIG).
strain of GAS produces superantigens. The clinical features of Aggressive supportive care is the most important aspect of
STSS include fever and rash with rapid progression to shock and management of severe GAS disease, particularly in STSS.
multiorgan failure (Table 255). Most patients have fever and Patients often require massive fluid resuscitation due to the
50% have hypotension at presentation; the other 50% will capillary leak syndrome.
develop hypotension within 4 h.47 The typical sunburn type Wide surgical debridement of non-viable tissue in necrotising
rash in STSS is widespread, erythematous, macular and blanch- fasciitis has been shown to improve outcome.60 However, if the
ing. Characteristically, there is subsequent desquamation about diagnosis is made before extensive tissue destruction or shock
2 weeks after the initial illness. Scarlet fever shares these clinical has occurred, correct use of antibiotics and early administration
features of erythematous rash and desquamation scarlet fever of IVIG may reduce the need for, or extent of, debridement.61
and STSS are at extreme ends of the spectrum of streptococcal Penicillin is the antibiotic of choice for all GAS infections,
toxin-mediated diseases. Scarlet fever was widely feared in the including severe invasive disease. There has never been a clini-
nineteenth and early twentieth centuries with cyclic pandemics cal isolate of GAS resistant to penicillin. In the early stages of
of severe disease with high mortality. Although STSS was first severe invasive disease, particularly in impending or established
described in the mid 1980s,56 it almost certainly existed before STSS or necrotising fasciitis, clindamycin should be added to
this time and it is likely that these early descriptions of severe penicillin. Clindamycin has the theoretical benefits of circum-
or septic scarlet fever were in fact cases of STSS.57 venting the Eagle effect, reducing GAS toxin production, poten-
Streptococcal toxic shock syndrome has been described in tiating phagocytosis, possessing superior tissue penetration and
association with numerous foci of infection but soft tissue infec- having a longer post-antibiotic effect.6264 However, clindamycin
tion, usually necrotising fasciitis, is the most common focus should not be used alone because of the possibility of resistance,
(approximately 60% of STSS cases).58 The GAS is isolated in and only needs to be used for the first days of management until
blood cultures in approximately 6080% of cases of STSS.41 In the patient is stabilised.

Journal of Paediatrics and Child Health 43 (2007) 203213 207


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Group A streptococcal infections in children AC Steer et al.

Neutralising antibodies to GAS and streptococcal toxins have Clinical features


been found in IVIG and humoral immunity is known to be
Acute rheumatic fever begins approximately 3 weeks after a
important in protecting against GAS disease.65 A randomised
GAS infection (range 15 weeks), which is often asymptomatic.
controlled trial of the use of IVIG in STSS was stopped prema-
The clinical features of ARF are outlined in the Jones Criteria
turely before statistically significant results were obtained
which were most recently updated in 1992.72 A World Health
because of slow patient recruitment.66 However, the limited
Organization (WHO) expert advisory group has recently sug-
data from this trial and a historically controlled observational
gested how the Jones Criteria should be applied to first and
study67 suggest benefit in the use of IVIG in STSS. With this in
recurrent episodes (Table 3).73 In particular, the WHO criteria
mind most experts recommend the use of IVIG in severe GAS
note that recurrent ARF can be diagnosed in a patient with RHD
disease. It should be given early after presentation. There are a
based only on minor criteria, provided other more likely diag-
number of dosing regimens but we recommend 2 g/kg as a
noses have been excluded. A diagnosis of ARF can be made
single infusion.
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 consid-
Post-streptococcal Diseases eration to be given to patients in high incidence areas who
present with polyarthralgia or monoarthritis, fever and elevated
The process by which GAS causes post-streptococcal disease is
acute phase reactants to be considered as probable rheumatic
poorly understood. Post-streptococcal diseases include ARF and
fever and be commenced on secondary prophylaxis. Recently
rheumatic heart disease (RHD), APSGN, erythema nodosum
published guidelines on the diagnosis and management of ARF
and post-streptococcal reactive arthritis (PSRA). Post-strepto-
and RHD in Australia recommend that polyarthralgia or
coccal reactive arthritis does not fulfil the Jones Criteria for the
monoarthritis be considered as major criteria in high-risk popu-
diagnosis of ARF, and patients are said not to be at risk of cardiac
lations such as Aboriginal Australians.74
valvular damage. However, because some patients with this
In experienced hands, echocardiography can help to identify
diagnosis have later developed confirmed episodes of ARF, the
and characterise rheumatic valvular disease, including subclin-
clinician should be very cautious about making a diagnosis of
ical valve lesions.75,76 The significance of these findings is not
PSRA. In populations with a high incidence of ARF, the diag-
certain and as such the American Heart Association and the
nosis of PSRA should rarely, if ever, be made. Even in popula-
WHO decided not to include echocardiographic evidence of
tions with low rates of ARF, it is recommended that penicillin
rheumatic valvular disease in their versions of the ARF diagnos-
prophylaxis be administered for 1 year and then discontinued
tic criteria. However, clinicians serving populations with high
if there is no evidence of valvular disease.68
rates of ARF and RHD commonly use echocardiographically
diagnosed rheumatic valvular disease as a major manifestation
in interpreting the Jones criteria. The recently published Aus-
Acute rheumatic fever and rheumatic heart disease tralian ARF and RHD guidelines recommend that all patients
with suspected ARF should have an echocardiogram and that
Epidemiology subclinical carditis, based upon standard criteria, be considered
as a major criterion in high-risk populations such as Aboriginal
Coinciding with the apparent resurgence of invasive GAS dis-
Australians.74
ease 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 Rheumatic heart disease
GAS and possibly susceptibility in the host. In addition, chang-
ing patterns of antibiotic use, in particular the movement away Rheumatic heart disease is the chronic valvular pathology that
from using antibiotics for treating GAS pharyngitis in countries can follow ARF. Chronic valvular damage is most likely when
with low rates of ARF, may also have affected the epidemiology the first attack of ARF is severe and in the young patient, and
of GAS diseases. when there are recurrent attacks of ARF.77 The mitral valve is
The major burden of ARF and RHD is in developing countries involved in more than 90% of cases with mitral incompetence
and in populations of Indigenous people living in poverty in the predominant lesion in young people and mitral stenosis
industrialised countries.3,70 More than 2.4 million children aged occurring in around 25% of patients in adolescence or adult-
514 years have RHD world-wide and 94% of these are in hood.78 The aortic valve may also be affected damage to the
developing countries.3 There are over 330 000 new cases of ARF tricuspid or pulmonary valves in RHD is always due to increased
each year in children aged 514 years world-wide.3 pressures from mitral or aortic valvular disease, not because of
In Australia, Indigenous people bear almost the entire brunt direct rheumatic inflammation to the right-sided heart valves.
of ARF and RHD, and have among the highest documented
rates in the world. The incidence of ARF in Northern Territory Management
Aboriginal children aged 514 years ranges from 250 to 350 per
100 000. The prevalence of RHD in Aboriginal people of all ages Management of ARF primarily involves confirming the diagno-
in the same region is 1317 per 1000.71 Recent data from the sis, relieving the pain of arthritis, and managing cardiac failure
Top End of the Northern Territory suggest that the prevalence with medication or, rarely, surgery. All patients with ARF
in Aboriginal people is almost 20 per 1000.72 should receive a dose of intramuscular benzathine penicillin G

208 Journal of Paediatrics and Child Health 43 (2007) 203213


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
AC Steer et al. Group A streptococcal infections in children

Table 3 20022003 World Health Organization criteria for the diagnosis of rheumatic fever and rheumatic heart disease73

The Jones Criteria (1992 Update):


Major manifestations Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Minor manifestations Clinical: Arthralgia
Fever
Laboratory: Elevated acute phase reactants (erythrocyte sedimentation rate,
leukocyte count)
ECG: Prolonged PR interval
Evidence of antecedent Elevated or rising streptococcal antibody titres (anti-streptolysin-O or anti-DNase B titre)
GAS infection Positive throat culture or rapid streptococcal antigen test
Recent scarlet fever
Diagnostic categories: Criteria (using above Jones Criteria):
Primary episode of ARF Two major manifestations, or
One major and two minor manifestations
Plus
Evidence of antecedent GAS infection
Recurrent attack of ARF in a patient without established RHD Two minor manifestations
Plus
Evidence of antecedent GAS infection
Recurrent attack of ARF in a patient with established RHD Two major manifestations, or
One major and two minor manifestations
Plus
Evidence of antecedent GAS infection
Rheumatic chorea Insidious onset rheumatic carditis Other major manifestations or evidence of antecedent
GAS infection not required
Chronic valve lesions of RHD (patients presenting for the rst Do not require any other criteria to be diagnosed as having RHD
time with pure mitral stenosis or mixed mitral valve disease
and/oraortic valve disease)

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

or 10 days of oral penicillin V, although there is little empirical There are two recognised methods of control of ARF and RHD
evidence to suggest that this affects the outcome.79 Salicylates primary and secondary prophylaxis. Primary prophylaxis is
or non-steroidal anti-inflammatory drugs are used only for the prompt and accurate diagnosis of GAS pharyngitis and treat-
symptomatic relief of joint inflammation and fever; they have ment with 10 days of oral penicillin V or a single dose of intra-
no role in the treatment of carditis.80 Corticosteroids are some- muscular benzathine penicillin G. This method can prevent
times used for the treatment of severe cardiac failure, although ARF.19,86 However, in practice it has had little impact on ARF
there is no evidence that they affect the likelihood of develop- incidence in developing countries, because of difficulties in pro-
ing, or the severity of, subsequent RHD.81 Most cases of Syden- viding diagnostic services, the poor performance of clinical diag-
hams chorea can be treated without medication; more severe nostic algorithms for GAS pharyngitis, problems with the
cases should be treated with either carbamazepine or valproic availability and quality of antibiotics, different health-seeking
acid.82 behaviour for sore throats, and the fact that only one-third of
Management of RHD primarily involves close follow-up, people with ARF report a previous sore throat severe enough
ensuring adherence to secondary prophylaxis, and medical or for them to seek medical care, even in industrialised countries.87
surgical treatment of cardiac failure if it develops. In recent Secondary prophylaxis involves regular administration of pen-
years, there has been a trend toward operating earlier in the icillin (usually 4-weekly benzathine penicillin G) for many years.
natural history of disease, when valvular tissue is not severely This strategy prevents recurrent ARF, avoids further damage to
scarred and calcified.83 This may allow the surgeon to repair heart valves, and has been demonstrated to lead to regression
rather than replace the valve leaflets, which in turn provides a of existing heart valve lesions and reduce RHD mortality.88 This
good functional result without the need for long-term anti- is the only intervention that has proven to be practical and cost-
coagulation.84 The prognosis after mechanical valve replace- effective in all settings, and should be the mainstay of efforts to
ment in remote Aboriginal people is particularly poor, with only control RHD.73 Secondary prophylaxis and other aspects of RHD
52% of patients remaining alive without a major complication care and control are most effectively delivered as part of a
5 years after surgery.85 coordinated, register-based RHD control programme.

Journal of Paediatrics and Child Health 43 (2007) 203213 209


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Group A streptococcal infections in children AC Steer et al.

Acute post-streptococcal glomerulonephritis fluid restriction and frusemide. Serum potassium should be
monitored as patients may present with hyperkalemia. Angio-
Epidemiology tensin-converting enzyme inhibitors such as captopril can be
There are over 470 000 cases of APSGN that occur annually considered as second line agents.
leading to approximately 5000 deaths, with 97% of these cases There is no evidence that primary prophylaxis (i.e. treatment
in less developed countries.3 APSGN, unlike ARF, tends to occur of a person already infected with a nephritogenic strain to
in outbreaks that are associated with virulent skin strains of prevent the development of APSGN) is effective. However, on
GAS.89 Several outbreaks have been described in Aboriginal a public health level mass benzathine penicillin administration
children in northern Australia associated with GAS pyoderma.90 in the setting of an outbreak may contain further cases partic-
ularly by targeting treatment of children with skin sores and
household contacts of cases.94 There are now a number of
Clinical features reports in northern Australia documenting the success of mass
The symptoms and signs of APSGN appear 13 weeks after GAS benzathine penicillin administration in the setting of an epi-
pharyngitis and 36 weeks after GAS pyoderma. Whereas ARF demic, including one program that focused on treating those
rarely occurs in children aged less than 4 years, APSGN may with pyoderma only.90,91
occur in younger children, sometimes in the first 2 years of life. Epidemic APSGN in children has a very favourable outcome
The most common presentation of APSGN is dark urine and with a 10-year renal survival rate of 92% and minimal risk of
facial oedema (Table 4). Hypertension occurs in around 60 hypertension.95,96 However, the coexistence in Aboriginal Aus-
70% of cases, primarily as a result of water and salt retention, tralians in the Northern Territory of endemic pyoderma, high
although in some cases a nephrotic syndrome may occur. rates of APSGN and high rates of end-stage renal failure have
With the activation of the alternative pathway of the comple- raised the question of whether childhood APSGN could be a risk
ment system, C3 levels are almost always diminished early in factor for chronic renal failure later in life.97
the disease this is an important diagnostic test in APSGN.92
Other causes of nephritis including systemic lupus erythemato- Vaccine Development
sus which can present with similar clinical features and low
serum complement levels. In APSGN the depression of C3 is Group A streptococcal vaccine development has fallen into two
transient and should return to normal at 68 weeks.93 The C3 groups focused on either M protein antigens or non-M protein
level should therefore be re-checked at 68 weeks and if it antigens. Among the non-M protein antigens being investigated
remains depressed then other diagnoses including systemic are GAS carbohydrate, C5a peptidase and fibronectin binding
lupus erythematosus must be considered. proteins; none of these has progressed to clinical trials.
Renal biopsy is generally not required if the diagnosis is clear M protein vaccines are either based upon the variable ami-
indications for biopsy may include the development of acute noterminus region these vaccines are multivalent and type-
renal failure, nephrotic syndrome, insufficient evidence of ante- specific or the C-terminal conserved region these antigens
cedent streptococcal infection and a persistently low serum C3 are thought to be common to most or all GAS strains (Fig. 3).
level. In most cases of APSGN the clinical course is benign, but The most advanced vaccine candidate is one based upon the
overwhelming acute renal failure with crescent formation does aminoterminus region. An N-terminal vaccine based on 26 emm
occur.93 Acute mortality is low in settings where high quality types has undergone phase I and II clinical trials in adults, with
medical care is available. Management of oedema and hyper- good evidence of safety and immunogenicity.99 It is estimated
tension is important and is usually able to be controlled with

Variable
Table 4 The diagnostic criteria for acute post-streptococcal Aminoterminus between
glomerulonephritis91 strains

The presence of two or more of the following: A repeat region


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,
B repeat region
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 Conserved
C repeat region between
Reduced serum C3 level
And strains
Evidence of antecedent streptococcal infection (Elevated or rising anti- D repeat region or
streptolysin-O titre or anti-DNase B titre or isolation of GAS from throat transmembrane region
or skin sore culture or positive rapid antigen test from throat swab)

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

210 Journal of Paediatrics and Child Health 43 (2007) 203213


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
AC Steer et al. Group A streptococcal infections in children

that this 26 valent vaccine will provide protection against 80 8 Ji Y, McLandsborough L, Kondagunta A, Cleary PP. C5a peptidase
90% of invasive GAS isolates in North America.100 However, alters clearance and trafcking of group A streptococci by infected
there are many circulating emm types of GAS, and the dominant mice. Infect. Immun. 1996; 64: 50310.
strains can change rapidly, even in affluent communities.101 The 9 Akesson P, Sjoholm AG, Bjorck L. Protein SIC, a novel extracellular
protein of Streptococcus pyogenes interfering with complement
diversity of emm types in developing countries is even greater,
function. J. Biol. Chem. 1996; 271: 10818.
and new emm types emerge frequently.102 Therefore, while type-
10 McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink
specific vaccines hold promise in affluent communities, they in the chain that links the heart to the throat? Lancet Infect. Dis. 2004;
may prove to have limited effectiveness in developing countries 4: 2405.
and other settings with high rates of GAS diseases. 11 Edmond KM, Grimwood K, Carlin JB, Chondros P, Hogg GG, Barnett PL.
Vaccines based on the conserved region of the M protein may Streptococcal pharyngitis in a paediatric emergency department.
potentially provide protection against all GAS strains. Research- Med. J. Aust. 1996; 165: 4203.
ers in Australia have identified a peptide in the conserved C 12 Nandi S, Kumar R, Ray P, Vohra H, Ganguly NK. Group A streptococcal
repeat region that induces antibodies that are opsonic and pro- sore throat in a periurban population of northern India: a one-year
tective in mice.103 Clinical trials of this candidate are currently prospective study. Bull. World Health Organ. 2001; 79: 52833.
13 Danchin MH, Rogers S, Selvaraj G et al. The burden of group A
in preparation.
streptococcal pharyngitis in Melbourne families. Indian J. Med. Res.
Any GAS vaccine will be required to undergo strict safety
2004; 119 (Suppl.): 1447.
evaluation because of the possibility that the vaccine itself could 14 Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH. Practice
induce autoimmunity. This concern arose after a crude M- guidelines for the diagnosis and management of group A
protein-based vaccine appeared to be associated with cases of streptococcal pharyngitis. Infectious Diseases Society of America.
ARF when administered to siblings of ARF patients in the Clin. Infect. Dis. 2002; 35: 11325.
1970s.104 Although this study provided no conclusive proof that 15 McIsaac WJ, Kellner JD, Aufricht P, Vanjaka A, Low DE. Empirical
the vaccine was dangerous, and numerous other GAS vaccine validation of guidelines for the management of pharyngitis in children
trials have not been associated with any cases of ARF, the US and adults. JAMA 2004; 291: 158795.
Food and Drug Administration disallowed the administration of 16 Gerber MA. Comparison of throat cultures and rapid strep tests for
diagnosis of streptococcal pharyngitis. Pediatr. Infect. Dis. J. 1989; 8:
GAS vaccines to humans. GAS vaccine development is now
8204.
proceeding following review of this legislation. However, a GAS
17 Gerber MA, Tanz RR, Kabat W et al. Optical immunoassay test for
vaccine remains at least several years away, and a vaccine that group A beta-hemolytic streptococcal pharyngitis. An ofce-based,
is effective and affordable in developing countries is an even multicenter investigation. JAMA 1997; 277: 899903.
more distant possibility. Therefore, there is an urgent need to 18 Del Mar C. Managing sore throat: a literature review. I. Making the
institute effective public health control measures, particularly diagnosis. Med. J. Aust. 1992; 156: 5725.
in developing countries. 19 Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat.
Cochrane Database Syst. Rev. 2006; (4): CD000023.
20 Krober MS, Bass JW, Michels GN. Streptococcal pharyngitis. Placebo-
Acknowledgement controlled double-blind evaluation of clinical response to penicillin
therapy. JAMA 1985; 253: 12714.
The authors would like to thank Dr Michael Batzloff, Queen-
21 Markowitz M, Gerber MA, Kaplan EL. Treatment of streptococcal
sland Institute of Medical Research, Brisbane, Australia, for his
pharyngotonsillitis: reports of penicillins demise are premature. J.
kind assistance in developing Figure 1. Pediatr. 1993; 123: 67985.
22 Zwart S, Rovers MM, de Melker RA, Hoes AW. Penicillin for acute
References sore throat in children: randomised, double blind trial. BMJ 2003;
327: 1324.
1 Curtis N. Invasive group A streptococcal infection. Curr. Opin. Infect. 23 Danchin MH, Curtis N, Nolan TM, Carapetis JR. Treatment of sore
Dis. 1996; 9: 1912. throat in light of the Cochrane verdict: is the jury still out? Med. J. Aust.
2 Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric 2002; 177: 5125.
disorders associated with streptococcal infection (PANDAS) etiology 24 Anonymous. Sore throat (pharyngitis). In: Ewald D, ed. CARPA
for tics and obsessivecompulsive symptoms: hypothesis or entity? Standard Treatment Manual, 4th edn. Alice Springs: Central
Practical considerations for the clinician. Pediatrics 2004; 113: Australian Rural Practitioners Association, 2003; 322.
8836. 25 Pichichero ME, Margolis PA. A comparison of cephalosporins and
3 Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of penicillins in the treatment of group A beta-hemolytic streptococcal
group A streptococcal diseases. Lancet Infect. Dis. 2005; 5: 68594. pharyngitis: a meta-analysis supporting the concept of microbial
4 Ferretti JJ, McShan WM, Ajdic D et al. Complete genome sequence of copathogenicity. Pediatr. Infect. Dis. J. 1991; 10: 27581.
an M1 strain of Streptococcus pyogenes. Proc. Natl. Acad. Sci. USA 26 Still J. Management of pediatric patients with group A beta-hemolytic
2001; 98: 465863. Streptococcus pharyngitis: treatment options. Pediatr. Infect. Dis. J.
5 McShan WM, Savic DJ, Ferretti JJ. Genome sequence of M49 Strain 1995; 14: S57S61.
of Streptococcus pyogenes. The XVIth Lanceeld International 27 Casey JR, Pichichero ME. Meta-analysis of cephalosporins versus
Symposium on Streptococci and Streptococcal Diseases 2005, Palm penicillin for treatment of group A streptococcal tonsillopharyngitis in
Cove, Australia. adults. Clin. Infect. Dis. 2004; 38: 152634.
6 Lanceeld RC. The antigenic complex of Streptococcus hemolyticus. 28 Shulman ST, Tanz RR, Kabat W et al. Group A streptococcal pharyngitis
I. Demonstration of a type-specic substance in extracts of serotype surveillance in North America, 20002002. Clin. Infect. Dis.
Streptococcus hemolyticus. J. Exp. Med. 1928; 47: 910. 2004; 39: 32532.
7 Cunningham MW. Pathogenesis of group A streptococcal infections. 29 Bisno AL. Are cephalosporins superior to penicillin for treatment of
Clin. Microbiol. Rev. 2000; 13: 470511. acute streptococcal pharyngitis? Clin. Infect. Dis. 2004; 38: 153557.

Journal of Paediatrics and Child Health 43 (2007) 203213 211


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Group A streptococcal infections in children AC Steer et al.

30 Stevens DL. Cellulitis, pyoderma, abscesses and other skin and 50 Muller MP, Low DE, Green KA et al. Clinical and epidemiologic features
subcutaneous infections. In: Cohen J, ed. Infectious Diseases. of group A streptococcal pneumonia in Ontario, Canada. Arch. Intern.
Philadelphia: Mosby, 2003; 13343. Med. 2003; 163: 46772.
31 Rogers M, Dorman DC, Gapes M, Ly J. A three-year study of impetigo 51 Kevy SV, Lowe BA. Streptococcal pneumonia and empyema in
in Sydney. Med. J. Aust. 1987; 147: 635. childhood. N. Engl. J. Med. 1961; 264: 73843.
32 Steer AC, Adams J, Carlin J, Nolan T, Shann F. Rheumatic heart disease 52 Finland M, Jones WF Jr, Barnes MW. Occurrence of serious bacterial
in school children in Samoa. Arch. Dis. Child. 1999; 81: 372. infections since introduction of antibacterial agents. JAMA 1959; 170:
33 Carapetis JR, Johnston F, Nadjamerrek J, Kairupan J. Skin sores in 218897.
Aboriginal children. J. Paediatr. Child Health 1995; 31: 563. 53 Shetty AK, Frankel LR, Maldonado Y, Falco DA, Lewis DB. Group A
34 Ferrieri P, Dajani AS, Wannamaker LW, Chapman SS. Natural history streptococcal meningitis: report of a case and review of literature
of impetigo. I. Site sequence of acquisition and familial patterns of since 1976. Pediatr. Emerg. Care 2001; 17: 4304.
spread of cutaneous streptococci. J. Clin. Invest. 1972; 51: 285162. 54 Chow JW, Muder RR. Group A streptococcal meningitis. Clin. Infect.
35 Koning S, Verhagen AP, van Suijlekom-Smit LW, Morris A, Butler CC, Dis. 1992; 14: 41821.
van der Wouden JC. Interventions for impetigo. Cochrane Database 55 The Working Group on Severe Streptococcal Infections. Dening the
Syst. Rev. 2004; 2: CD003261. group A streptococcal toxic shock syndrome. Rationale and
36 Evans C. Acute post streptococcal glomerulonephritis in the consensus denition. JAMA 1993; 269: 3901.
Northern Territory 19802000. Northern Territory Dis. Control Bull. 56 Cone LA, Woodard DR, Schlievert PM, Tomory GS. Clinical and
2001; 8: 140. bacteriologic observations of a toxic shocklike syndrome due to
37 Carapetis JR, Walker AM, Hibble M, Sriprakash KS, Currie BJ. Clinical Streptococcus pyogenes. N. Engl. J. Med. 1987; 317: 1469.
and epidemiological features of group A streptococcal bacteraemia in 57 Katz AR, Morens DM. Severe streptococcal infections in historical
a region with hyperendemic supercial streptococcal infection. perspective. Clin. Infect. Dis. 1992; 14: 298307.
Epidemiol. Infect. 1999; 122: 5965. 58 Davies HD, McGeer A, Schwartz B et al. Invasive group A streptococcal
38 Maguire GP, Arthur AD, Boustead PJ, Dwyer B, Currie BJ. Emerging infections in Ontario, Canada. Ontario Group A Streptococcal Study
epidemic of community-acquired methicillin-resistant Staphylococcus Group. N. Engl. J. Med. 1996; 335: 54754.
aureus infection in the Northern Territory. Med. J. Aust. 1996; 164: 59 Reingold AL, Hargrett NT, Dan BB et al. Nonmenstrual toxic shock
7213. syndrome: a review of 130 cases. Ann. Intern. Med. 1982; 96: 8714.
39 Ferrieri P, Dajani AS, Wannamaker LW. A controlled study of penicillin 60 Bilton BD, Zibari GB, McMillan RW, Aultman DF, Dunn G, McDonald JC.
prophylaxis against streptococcal impetigo. J. Infect. Dis. 1974; 129: Aggressive surgical management of necrotizing fasciitis serves to
42938. decrease mortality: a retrospective study. Am. Surg. 1998; 64: 397
40 Lawrence GW, Leafasia J, Sheridan J et al. Control of scabies, skin sores 400; discussion 4001.
and haematuria in children in the Solomon Islands: another role for 61 Muller MP, McGeer A, Low DE, Ontario Group A Streptococcal Study.
ivermectin. Bull. World Health Organ. 2005; 83: 3442. Successful outcome in six patients treated conservatively for
41 Hoge CW, Schwartz B, Talkington DF, Breiman RF, MacNeill EM, suspected necrotizing fasciitis (NF) due to group A streptococcus
Englender SJ. The changing epidemiology of invasive group A (GAS) [abstract]. 41st Interscience Conference on Antimicrobial
streptococcal infections and the emergence of streptococcal toxic Agents and Chemotherapy, December 2001, Chicago.
shock-like syndrome. A retrospective population-based study. JAMA 62 Eagle H. Experimental approach to the problem of treatment failure
1993; 269: 3849. with penicillin. I. Group A streptococcal infection in mice. Am. J. Med.
42 Eriksson BK, Norgren M, McGregor K, Spratt BG, Normark BH. Group 1952; 13: 38999.
A streptococcal infections in Sweden: a comparative study of invasive 63 Gemmell CG, Peterson PK, Schmeling D et al. Potentiation of
and noninvasive infections and analysis of dominant T28 emm28 opsonization and phagocytosis of Streptococcus pyogenes following
isolates. Clin. Infect. Dis. 2003; 37: 118993. growth in the presence of clindamycin. J. Clin. Invest. 1981; 67: 1249
43 Carapetis J, Robins-Browne R, Martin D, Shelby-James T, Hogg G. 56.
Increasing severity of invasive group A streptococcal disease in 64 Zimbelman J, Palmer A, Todd J. Improved outcome of clindamycin
Australia: clinical and molecular epidemiological features and compared with beta-lactam antibiotic treatment for invasive
identication of a new virulent M-nontypeable clone. Clin. Infect. Dis. Streptococcus pyogenes infection. Pediatr. Infect. Dis. J. 1999; 18:
1995; 21: 12207. 1096100.
44 The WHO Young Infants Study Group. Bacterial etiology of serious 65 Norrby-Teglund A, Kaul R, Low DE et al. Evidence for the presence
infections in young infants in developing countries: results of a of streptococcal-superantigen-neutralizing antibodies in normal
multicenter study. Pediatr. Infect. Dis. J. 1999; 18 (10 Suppl.): S17 polyspecic immunoglobulin G. Infect. Immun. 1996; 64: 53958.
22. 66 Darenberg J, Ihendyane N, Sjolin J et al. Intravenous immunoglobulin
45 Berkley JA, Lowe BS, Mwangi I et al. Bacteremia among children G therapy in streptococcal toxic shock syndrome: a European
admitted to a rural hospital in Kenya. N. Engl. J. Med. 2005; 352: randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis.
3947. 2003; 37: 33340.
46 Norton R, Smith HV, Wood N, Siegbrecht E, Ross A, Ketheesan N. 67 Kaul R, McGeer A, Norrby-Teglund A et al. Intravenous
Invasive group A streptococcal disease in North Queensland (1996 immunoglobulin therapy for streptococcal toxic shock syndrome a
2001). Indian J. Med. Res. 2004; 119 (Suppl.): 14851. comparative observational study. The Canadian Streptococcal Study
47 Stevens DL. Invasive group A streptococcus infections. Clin. Infect. Dis. Group. Clin. Infect. Dis. 1999; 28: 8007.
1992; 14: 211. 68 Shulman ST, Ayoub EM. Poststreptococcal reactive arthritis. Curr.
48 Chelsom J, Halstensen A, Haga T, Hoiby EA. Necrotising fasciitis due Opin. Rheumatol. 2002; 14: 5625.
to group A streptococci in western Norway: incidence and clinical 69 Veasy LG, Wiedmeier SE, Orsmond GS et al. Resurgence of acute
features. Lancet 1994; 344: 11115. rheumatic fever in the intermountain area of the United States. N. Engl.
49 Laupland KB, Davies HD, Low DE, Schwartz B, Green K, McGeer A. J. Med. 1987; 316: 4217.
Invasive group A streptococcal disease in children and association 70 Carapetis JR. A Review of WHO, Activities in, the Burden of, and the
with varicella-zoster virus infection. Ontario Group A Streptococcal Evidence for Strategies to Control Group A Streptococcal Diseases:
Study Group. Pediatrics 2000; 105: E60. Part 4: A Review of the Technical Basis for the Current WHO, Approach

212 Journal of Paediatrics and Child Health 43 (2007) 203213


2007 The Authors
Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
AC Steer et al. Group A streptococcal infections in children

to the Control of Conditions Associated with GAS Infections. Geneva: 87 Snitcowsky R. Rheumatic fever prevention in industrializing countries:
World Health Organization, 2004; 146. problems and approaches. Pediatrics 1996; 97: 9968.
71 Kelly A. Top end rheumatic heart disease program. A report to the 88 Feinstein AR, Stern EK, Spagnuolo M. The prognosis of acute
Commonwealth. FebruaryNovember 2002 (abbreviated). Northern rheumatic fever. Am. Heart J. 1964; 68: 81734.
Territory Dis. Control. Bull. 2003; 10: 911. 89 Dillon HC Jr. Post-streptococcal glomerulonephritis following
72 Special Writing Group of the Committee on Rheumatic Fever E, and pyoderma. Rev. Infect. Dis. 1979; 1: 93545.
Kawasaki Disease of the Council on Cardiovascular Disease in the 90 Streeton CL, Hanna JN, Messer RD, Merianos A. An epidemic of acute
Young of the American Heart Association. Guidelines for the diagnosis post-streptococcal glomerulonephritis among aboriginal children. J.
of rheumatic fever. Jones Criteria, 1992 update. JAMA 1992; 268: Paediatr. Child Health 1995; 31: 2458.
206973. 91 Kearns T, Evans C, Krause V. Outbreak of acute post-streptococcal
73 World Health Organization (WHO). Rheumatic Fever and Rheumatic glomerulonephritis in the Northern Territory 2000. Northern
Heart Disease: Report of a WHO Expert Consultation Geneva. WHO Territory Dis. Control. Bull. 2000; 8: 614.
Technical report series. Geneva: WHO, 2004; 122. 92 Wyatt RJ, Forristal J, West CD, Sugimoto S, Curd JG. Complement
74 National Heart Foundation of Australia and the Cardiac Society of proles in acute post-streptococcal glomerulonephritis. Pediatr.
Australia and New Zealand. Diagnosis and Management of Acute Nephrol. 1988; 2: 21923.
Rheumatic Fever and Rheumatic Heart Disease in Australiaan 93 Jordan SC, Lemire JM. Acute glomerulonephritis. Diagnosis and
Evidence-Based Review. Sydney: National Heart Foundation of treatment. Pediatr. Clin. North Am. 1982; 29: 85773.
Australia and Cardiac Society of Australia and New Zealand, 2006. 94 Johnston F, Carapetis J, Patel MS, Wallace T, Spillane P.
75 Veasy LG. Time to take soundings in acute rheumatic fever. Lancet Evaluating the use of penicillin to control outbreaks of acute
2001; 357: 19945. poststreptococcal glomerulonephritis. Pediatr. Infect. Dis. J. 1999;
76 Narula J, Kaplan EL. Echocardiographic diagnosis of rheumatic fever. 18: 32732.
Lancet 2001; 358: 2000. 95 Bohle A, Wehrmann M, Bogenschutz O et al. The long-term
77 Thakur JS, Negi PC, Ahluwalia SK, Vaidya NK. Epidemiological survey prognosis of the primary glomerulonephritides. A morphological
of rheumatic heart disease among school children in the Shimla Hills and clinical analysis of 1747 cases. Pathol. Res. Pract. 1992; 188:
of northern India: prevalence and risk factors. J. Epidemiol. Commun. 90824.
Health 1996; 50: 627. 96 Potter EV, Lipschultz SA, Abidh S, Poon-King T, Earle DP. Twelve to
78 Carapetis JR, Wolff DR, Currie BJ. Acute rheumatic fever and rheumatic seventeen-year follow-up of patients with poststreptococcal acute
heart disease in the Top End of Australias Northern Territory. Med. J. glomerulonephritis in Trinidad. N. Engl. J. Med. 1982; 307: 7259.
Aust. 1996; 164: 1469. 97 White AV, Hoy WE, McCredie DA. Childhood post-streptococcal
79 Mortimer EA Jr, Vaisman S, Vigneau A. The effect of penicillin on acute glomerulonephritis as a risk factor for chronic renal disease later in
rheumatic fever and valvular heart disease. N. Engl. J. Med. 1959; 260: life. Med. J. Aust. 2001, 2005; 174: 4926.
10112. 98 Good M, Brandt E. Vaccines to protect the heart. Microbiol. Aust.
80 Bywaters EGL, Thomas GT. Bed rest, salicylates and steroid in 1997; 18: 302.
rheumatic fever. BMJ 1961; 1: 162834. 99 McNeil SA, Halperin SA, Langley JB et al. A double-blinded,
81 Cilliers AM, Manyemba J, Saloojee H. Anti-inammatory treatment for randomized, controlled phase II trial of the safety and immunogenicity
carditis in acute rheumatic fever. Cochrane Database Syst. Rev. 2003; of a 26 valent group A streptococcus vaccine in healthy adults. The
(2): CD003176. XVIth Lanceeld International Symposium on Streptococci and
82 Pena J, Mora E, Cardozo J, Molina O, Montiel C. Comparison of the Streptococcal Diseases 2005, Palm Cove, Australia.
efcacy of carbamazepine, haloperidol and valproic acid in the 100 Kotloff KL, Dale JB. Progress in group A streptococcal vaccine
treatment of children with Sydenhams chorea: clinical follow-up of 18 development. Pediatr. Infect. Dis. J. 2004; 23: 7656.
patients. Arq. Neuropsiquiatr. 2002; 60: 3747. 101 Kaplan EL, Wotton JT, Johnson DR. Dynamic epidemiology of group A
83 Thourani VH, Weintraub WS, Guyton RA et al. Outcomes and long- streptococcal serotypes associated with pharyngitis. Lancet 2001;
term survival for patients undergoing mitral valve repair versus 358: 13347.
replacement: effect of age and concomitant coronary artery bypass 102 Bessen DE, Carapetis JR, Beall B et al. Contrasting molecular
grafting. Circulation 2003; 108: 298304. epidemiology of group A streptococci causing tropical and
84 Carapetis JR, Powers JR, Currie BJ. Outcomes of cardiac valve nontropical infections of the skin and throat. J. Infect. Dis. 2000; 182:
replacement for rheumatic heart disease in Aboriginal Australians. 110916.
Asia Pac. Heart J. 1999; 8: 13847. 103 Batzloff M, Yan H, Davies M, Hartas J, Good M. Preclinical evaluation
85 Carapetis JR, Powers JR, Currie BJ et al. Outcomes of cardiac valve of a vaccine based on conserved region of M protein that prevents
replacement for rheumatic heart disease in Aboriginal Australians. group A streptococcal infection. Indian J. Med. Res. 2004; 119
Asia Pac. Heart J. 2000; 8: 13847. (Suppl.): 1047.
86 Denny F, Wannamaker LW, Brink WR, Rammelkamp CH Jr, Custer EA. 104 Massell BF, Honikman LH, Amezcua J. Rheumatic fever following
Prevention of rheumatic fever; treatment of preceding streptococci streptococcal vaccination. Report of three cases. JAMA 1969; 207:
infection. JAMA 1950; 143: 1513. 11159.

Journal of Paediatrics and Child Health 43 (2007) 203213 213


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Journal compilation 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)