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Pathogens 2024, 13, 350. https://doi.org/10.3390/pathogens13050350 www.mdpi.com/journal/pathogens
Review
Group A Streptococcal Infections in Pediatric Age: Updates
about a Re-Emerging Pathogen
Giada Maria Di Pietro
1,
*, Paola Marchisio
2
, Pietro Bosi
2
, Massimo Luca Castellazzi
3
and Paul Lemieux
2
1
Pediatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
2
Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy;
paul.lemieux@unimi.it (P.L.)
3
Pediatric Emergency Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico,
20122 Milan, Italy; luca.castellazzi@policlinico.mi.it
* Correspondence: giada.dipietro@policlinico.mi.it; Tel.: +39-025-5034275
Abstract: Group A Streptococcus (GAS) presents a significant global health burden due to its diverse
clinical manifestations ranging from mild infections to life-threatening invasive diseases. While
historically stable, the incidence of GAS infections declined during the COVID-19 pandemic but
resurged following the relaxation of preventive measures. Despite general responsiveness to β-lactam
antibiotics, there remains an urgent need for a GAS vaccine due to its substantial global disease
burden, particularly in low-resource settings. Vaccine development faces numerous challenges,
including the extensive strain diversity, the lack of suitable animal models for testing, potential
autoimmune complications, and the need for global distribution, while addressing socioeconomic
disparities in vaccine access. Several vaccine candidates are in various stages of development, offering
hope for effective prevention strategies in the future.
Keywords: Streptococcus pyogenes; group A Streptococcus (GAS); pharyngitis; invasive group A
streptococcal infection (iGAS); vaccines
1. Epidemiology
Streptococcus pyogenes
(also known as Group A Streptococcus (GAS)) is a major human-
specific Gram-positive coccus responsible for a wide range of diseases differing in clinical
presentation and severity [1]. GAS can colonize the skin and throat, causing asymptomatic
and self-limited conditions or symptomatic infections. The latter can vary from superficial
infections of the throat (pharyngitis and tonsillitis) and skin (impetigo, pyoderma, and
cellulitis) to serious life-threatening invasive infections, collectively termed invasive group
A streptococcal (iGAS) diseases and defined as severe illnesses associated with the isolation
of GAS from a normally sterile site, such as blood, cerebrospinal fluid, deep muscle, or
pleural fluid (causing necrotizing fasciitis, osteomyelitis, and bacteremia) [2,3]. GAS
infections can also cause autoimmune sequelae after the production of specific antibodies,
such as acute rheumatic fever (ARF) and rheumatic heart disease (RHD), both of which are
related to antibody-directed molecular mimicry with abnormal host immune response, as
well as post-streptococcal glomerulonephritis (APSGN) consequent to the deposition of
immune complexes [4].
The variety of the clinical manifestations may originate from the large strain diversity,
as more than 250 emm-types have been described. The highest genetic diversity of
circulating strains has been observed in developing countries, while Europe and North
America show the lowest strain heterogeneity. Recent studies conducted in Europe and
Australia in 2022 and 2023, respectively, identified emm-type 1 and emm-type 12 as more
associated with invasive disease, while a systematic review of studies on bacterial samples
originating from 55 countries and collected from 1990 to 2023 demonstrated that emm-type
Citation: Di Pietro, G.M.; Marchisio,
P.; Bosi, P.; Castellazzi, M.L.;
Lemieux, P. Group A Streptococcal
Infections in Pediatric Age: Updates
about a Re-Emerging Pathogen.
Pathogens 2024, 13, 350.
https://doi.org/10.3390/
pathogens13050350
Academic Editor: Jens Kreth
Received: 14 March 2024
Revised: 16 April 2024
Accepted: 23 April 2024
Published: 24 April 2024
Copyright: © 2024 by the authors.
Submitted for possible open access
publication under the terms and
conditions of the Creative Commons
Attribution (CC BY) license
(https://creativecommons.org/licenses
/by/4.0/).
Pathogens 2024, 13, 350 2 of 13
1 ranked 39th among all emm-types associated with invasive disease and identified other
emm-types as emergent causes of iGAS in the world. The same authors recognized 15 emm-
clusters that accounted for 95.6% of the strain diversity in the global, population-weighted,
emm-type dataset and concluded that the development of a vaccine protective against them
would theoretically protect against more than 95% of the disease-causing strains,
underlining the importance of knowledge of the emm-type distribution worldwide [5–9].
GAS is the principal bacterial cause of tonsillopharyngitis in children all over the world:
in 2005, the global burden of Streptococcus pyogenes sore throat among children aged 5–14
years was 446 million episodes each year, which decreased to 288.6 million in 2022 [10].
Usually, the incidence of GAS pharyngitis peaks during winter and in the first part of spring
[11]. GAS tonsillitis predominantly affects school-age children, though younger children,
especially those in contact with school-age children, are also susceptible to infection [12].
Prompt antibiotic treatment of GAS in children, after microbiologic confirmation, is
necessary to prevent complications, further disease transmission, and deaths. Invasive GAS
infections can rapidly worsen if left untreated, often necessitating surgical intervention to
be fully controlled [13]. A recent multicenter cohort study including 320 children with iGAS
infections reported an overall mortality rate of 2%, with 12% experiencing survival with
neurodisability, amputation, skin grafts, hearing loss, and the need for surgery [14].
The annual burden of iGAS disease and RHD is 663,000 and 282,000 new cases
worldwide, respectively. Based on data for the 2010s, each year, Group A Streptococcus is
responsible for 163,000 deaths due to iGAS and 345,000 deaths due to RHD, making it the
fifth most lethal pathogen in the world [2]. While the incidence of GAS infections has
historically remained stable, there was a decline during the pandemic period. However,
following the relaxation of preventive measures against COVID-19, a significant resurgence
of GAS infections was observed worldwide. In late 2022, many countries reported a
considerable increase in scarlet fever and iGAS infections, particularly affecting children
under 10 years of age, raising concerns about the high iGAS incidence and mortality among
children [15,16]. Between late 2022 and early 2023, an increased incidence of iGAS infections
was also reported in the Milan area [17].
Two years of social distancing and barrier measures needed to fight the COVID-19
pandemic caused a decrease in exposure to pathogens, including GAS [18]. This reduction
may have resulted in a state of reduced immunity, termed “immune debt”, potentially
contributing to increased iGAS infection incidence among susceptible children [19].
The upsurge in incidence appears unrelated to any predominant GAS strain but rather
correlates with this “immune debt” following reduced exposure to both GAS and common
viral respiratory infections [20]. The recrudescence of predisposing viral infections after
COVID-19 has increased the prevalence of iGAS infections; most reported cases are
superinfections of viral respiratory infections [18,21]. Recent studies showed that a
coexistent viral respiratory tract infection was present in up to 60% of iGAS cases in children
[22]. A link with preceding or coinciding varicella was highlighted in a recent Dutch study
[5].
Supporting this trend, an increased number of cases of acute otitis media (AOM) with
otorrhea have been noted in children regularly followed for recurrent AOM at our tertiary
outpatient clinic for upper respiratory tract infections since late 2022 [23]. We retrospectively
analyzed ear swab results obtained for otorrhea in our Pediatric Emergency Room and
outpatient clinics from 1 December 2022 to 30 June 2023. We considered children from 1
month to 6 years of age due to the predominant prevalence of AOM in the first years of life
[24]. Comparison with results from the same months of previous years revealed a significant
rise in the prevalence of GAS-positive ear swabs during the 2022–2023 season (Figure 1).
Using the chi-squared test, we also compared the proportion of GAS-positive ear swabs
during the 2022–2023 season with the overall proportion for the previous five seasons (GAS-
positive swabs in the five seasons divided by total swabs in the same period), which
revealed a significant percent increase in the 2022–2023 season (23% vs. 10%, p < 0.01).
Pathogens 2024, 13, 350 3 of 13
Corroborating previously published findings, we also noticed a significant drop in
AOM with otorrhea cases during the COVID-19 pandemic as a result of the global
improvement of otitis-prone children in Milan during lockdown [25]. Additionally, the
prevalence of Streptococcus pyogenes-positive ear swabs during the pandemic significantly
decreased, likely as a result of reduced exposure of children to GAS.
Figure 1. Ear swabs positive for GAS in a tertiary care hospital in northern Italy in five consecutive
seasons (2018–2023).
2. Clinical Features
GAS causes a wide range of clinical infections ranging from mild to severe and
potentially fatal, affecting various organ systems and encompassing superficial, invasive,
and toxin-mediated diseases. The clinical manifestations of GAS infection are discussed in
the following subsections and broken down by clinical diagnosis [26].
3. Non-Invasive Group A Streptococcal Infections
3.1. Streptococcus pyogenes Pharyngitis
Strepyococcus pyogenes throat is a prevalent respiratory infection, predominantly
affecting children aged 5 to 15 years. Streptococcal pharyngitis typically presents with an
abrupt onset of symptoms, including pharyngodynia, malaise, fever, and headache. In
children under 5, common symptoms also include abdominal pain, nausea, and vomiting.
Cough, coryza, and conjunctivitis are atypical symptoms of streptococcal pharyngitis and
are more often indicative of a viral etiology [27]. The use of clinical scores, such as the Centor
score, in aiding diagnosis remains controversial due to their limited sensitivity and
specificity. The Centor criteria include four clinical parameters, each scoring one point:
tonsillar exudate, tender anterior cervical lymphadenopathy or lymphadenitis, fever (over
38 °C), and absence of cough. The modified Centor criteria, also called the Mc Isaac score,
include age as an additional criterion and are a clinical aid for physicians to determine who
to test and treat when GAS pharyngitis is suspected [28]. Pharyngodynia in streptococcal
pharyngitis is often asymmetric and may be severe. The presence of intense unilateral pain
or difficulty swallowing, especially more than 3–5 days after the onset of fever, should
0%
5%
10%
15%
20%
25%
9/ 78 12/94 3/36 1/19 1/27 19/83
Dec 1st 2017 -
Jun 30th 2018
Dec 1st 2018 -
Jun 30th 2019
Dec 1st 2019 -
Jun 30th 2020
Dec 1st 2020 -
Jun 30th 2021
Dec 1st 2021 -
Jun 30th 2022
Dec 1st 2022 -
Jun 30th 2023
ear swabs positive to GAS %
Pathogens 2024, 13, 350 4 of 13
prompt consideration of a local suppurative complication, such as a peritonsillar or retro-
pharyngeal abscess [29].
In children under 3 years of age, streptococcal pharyngitis rarely presents with
exudative pharyngitis. Instead, manifestations may include coryza, excoriated nares, and
generalized adenopathy. While specific treatment can expedite recovery, in most cases, fe-
ver resolves within 3 to 5 days, and throat pain typically improves within a week, even
without specific intervention [27].
3.2. Scarlet Fever
Scarlet fever is most common in children 5 to 15 years of age and is found rarely in
children under 3. A disease caused by erythrogenic toxins produced by GAS, scarlet fever
manifests as a finely papular (1 to 2 mm), blanching erythematous rash that gives a “sand-
paper” texture to the skin [30]. The rash generally spares the face, palms, and soles and is
often more pronounced in intertriginous areas, followed by a period of desquamation dur-
ing recovery. In the antecubital fossa and axillary folds, the rash frequently has a linear,
petechial quality, known as Pastia’s lines [30]. Circumoral pallor and oral mucositis in the
form of a white or, at later stages, red strawberry tongue are frequent findings. Scarlet fever
is often associated with streptococcal pharyngitis. Due to significant similarity in symptoms
and age ranges affected, SARS-CoV-2 multisystem inflammatory syndrome (MIS-C) should
be included within the differential diagnosis.
3.3. Rheumatic Fever
ARF is an inflammatory condition that arises as a consequence of inadequately treated
or untreated GAS infections, particularly pharyngitis. The disease primarily targets the con-
nective tissues of the heart, joints, skin, and subcutaneous tissues [26]. The hallmark of ARF
is its propensity to involve the heart, resulting in rheumatic carditis. Patients may present
with a variety of cardiac symptoms, ranging from mild to severe. Common cardiac mani-
festations include pancarditis (involvement of the pericardium, epicardium, myocardium,
and endocardium) and valvulitis, particularly affecting the mitral and aortic valves. Cardiac
involvement is generally apparent within 3 weeks of GAS infection [31]. Rheumatic fever
can also affect large joints such as the knees, ankles, elbows, and wrists. Typically migratory
in nature, arthritis may shift from one joint to another over a short period. Pain, swelling,
and increased temperature are typical, and while the symptoms are usually self-limiting,
their recurrence can contribute to chronic joint damage [2]. Dermatological manifestations
of ARF include erythema marginatum and subcutaneous nodules. Erythema marginatum
presents as pink, non-pruritic, serpiginous lesions with a clear center and well-demarcated
borders, typically affecting the trunk and proximal extremities. Subcutaneous nodules, on
the other hand, are firm, painless, and may be found over extensor surfaces and joints.
Lastly, acute rheumatic fever can result in Sydenham’s chorea, characterized by rapid, un-
coordinated movements [31]. Diagnosis is aided by use the of the modified Jones criteria,
demonstrating improved accuracy in clinical diagnosis [32].
3.4. Post-Streptococcal Glomerulonephritis
APSGN is an immune-mediated inflammatory response affecting the glomeruli of the
kidneys, typically occurring after an episode of pharyngitis or impetigo caused by nephri-
togenic strains of GAS. The onset of APSGN generally occurs 1 to 3 weeks following a strep-
tococcal infection. The hallmark of APSGN is its impact on renal function, characterized by
hematuria, proteinuria, and edema. Hematuria is often the initial presenting symptom. Pro-
teinuria is typically mild to moderate, and edema may manifest as localized facial edema or
generalized swelling, reflecting the underlying renal pathology. Hypertension is a common
accompaniment to APSGN and may contribute to the progression of renal damage. APSGN
is characterized histologically by diffuse proliferative glomerulonephritis with hypercellu-
larity, “lumpy–bumpy” immunofluorescence deposits, and subepithelial humps on
Pathogens 2024, 13, 350 5 of 13
electron microscopy, indicative of immune complex deposition involving both streptococcal
antigens and components of the glomerular basement membrane [26,33].
3.5. Impetigo
Impetigo is a common skin infection in children ages 2 to 5 years old. Non-bullous
impetigo is more frequently caused by Staphylococcus aureus (80% of cases), but in a minority
of cases (10%) it is caused by Streptococcus pyogenes [34]. The initial lesion is a vesicle on an
erythematous base, easily ruptured, leading to superficial ulceration covered by purulent
discharge that forms an adhering, honey-colored crust, most commonly on the face and ex-
tremities. Lesions typically measure 1 to 2 cm in diameter, growing centrifugally. Satellite
lesions caused by self-inoculation are common. Impetigo may be a primary infection of the
skin or may secondarily infect atopic dermatitis, contact dermatitis insect bites, pediculosis,
herpetic lesions, or scabies. Regional lymphadenopathy is frequent, and severe cases may
exhibit fever. Malnutrition and poor hygiene are predisposing factors [35]. Non-bullous im-
petigo typically resolves within two to three weeks without scarring.
3.6. Cellulitis and Erysipelas
Cellulitis is an infection of the dermis and subcutaneous tissues, presenting as localized
inflammation, characterized by warmth, erythema, pain, and lymphangitis. The disease can
progress to systemic involvement, marked by fever and an elevated white blood cell count.
Erysipelas, categorized as a type of cellulitis, is distinguished by pronounced superficial in-
flammation, with the term commonly employed when facial involvement is noted. While
cellulitis and erysipelas predominantly target the lower limbs, the ears, trunk, fingers, and
toes are also involved to a less frequent extent [36].
4. Invasive Group A Streptococcal Infections
Although GAS infections in the great majority of cases are localized infections of the
oropharynx or soft tissues, invasive systemic infections from GAS occur via direct extension
into a normally sterile site, such as blood, cerebrospinal fluid, deep muscle, or pleural fluid,
as is the case of necrotizing fasciitis, streptococcal bacteremia, and the endotoxin-mediated,
fulminant Streptococcal toxic shock syndrome (STSS) [3]. Other forms of iGAS infections
include GAS meningitis and septic arthritis.
4.1. Necrotizing fasciitis
Necrotizing fasciitis, an infrequent soft-tissue infection, manifests as swift inflamma-
tion leading to necrosis of the epidermis, dermis, subcutaneous tissue, and muscle fascia.
The course of necrotizing fasciitis typically adheres to a defined sequence. Initial signs and
symptoms include diffuse erythema and swelling, accompanied by intense tenderness and
pain. Subsequently, clear, fluid-filled bullae emerge, which turn maroon or violet in color.
This progression is succeeded by cutaneous gangrene, evolving rapidly alongside an exten-
sion of inflammation. Lymphangitis and lymphadenitis are infrequent. Necrotizing infec-
tion typically presents acutely with progression over hours. Rarely, cases of subacute pro-
gression over days have been documented [37]. Necrotizing infection most commonly in-
volves the extremities. Whether the upper or lower extremities are more commonly in-
volved is unclear, as observations vary between studies, and this aspect may change over
time [38,39]. Risk factors include diabetes and/or peripheral vascular disease. Rapid pro-
gression can occur, leading to systemic involvement, limb loss, or death. While often trig-
gered by penetrating or blunt trauma, instances of infection may occur without evident pre-
ceding injury. Predisposing factors encompass varicella, chronic skin conditions (such as
decubitus or ischemic ulcers and psoriasis), and prior surgical procedures [37].
4.2. Streptococcal Toxic Shock Syndrome
Pathogens 2024, 13, 350 6 of 13
Streptococcal toxic shock syndrome (STSS) is a rare exotoxin-induced complication of
streptococcal pharyngitis. STSS often presents with an abrupt onset of high fever, hypoten-
sion, and multiorgan dysfunction. Patients may exhibit signs of shock, including altered
mental status, tachycardia, and hypoperfusion of vital organs. Soft-tissue infections, such as
cellulitis or necrotizing fasciitis, frequently precede STSS, serving as a portal of entry for the
pathogen. Classically, the rash presents as a diffuse, blanching, macular erythroderma. Ini-
tially, it may manifest as a fleeting macular rash, primarily on the chest. The rash undergoes
desquamation one to two weeks later, followed by complete peeling. Mucosal involvement
may include a strawberry tongue and ulceration of the vaginal mucosa or conjunctival ery-
thema. Patients may display disorientation or altered mental status without focal deficits
[40]. Laboratory investigations in STSS often reveal hematological abnormalities, including
leukocytosis, thrombocytopenia, and disseminated intravascular coagulation (DIC). These
findings reflect the systemic inflammatory response and the potential for widespread mi-
crovascular thrombosis. Hypotension is present by definition, as are signs of multiple organ
failure in at least two systems, including signs of acute renal or hepatic failure, signs of acute
coagulopathy, and acute respiratory distress syndrome [41].
5. Diagnosis of GAS Infections
Diagnosis of GAS infections involves a comprehensive approach, including clinical
evaluation, laboratory tests, and, in certain cases, imaging. The diagnosis of acute Strepto-
coccus pyogenes infection is based on culturing bacteria from clinical specimens, while that
of post-streptococcal disease is based on the detection of specific antibodies. Patients pre-
senting with symptoms suggestive of GAS pharyngitis, without typical signs of viral infec-
tion, are eligible for microbiologic testing, including a rapid antigen detection test (RADT)
or throat culture. Clinical features alone cannot reliably distinguish between GAS and viral
pharyngitis, except in cases with viral symptoms of rhinorrhea, cough, or oral ulcers [27].
An RADT’s positive result obviates the need for throat culture due to the high specificity of
the test. False-positive antigen results can be seen for patients previously diagnosed and/or
treated for Group A Streptococcus or for patients colonized with non-pyogenes streptococcal
species that carry the Lancefield group A antigen. The sensitivity of RADT for GAS is com-
parable to that of conventional throat culture. A negative RADT should be followed by a
throat culture if a diagnosis of GAS infection cannot be ruled out. Although RADTs provide
rapid results to allow early treatment decisions, culturing throat swabs for Streptococcus py-
ogenes remains the gold standard. Anti-streptococcal antibody titers are not recommended
for the diagnosis of GAS pharyngitis because the test reflects previous infections. Following
treatment, throat cultures or RADTs are not recommended routinely but may be considered
in special circumstances. For the other acute infections, including those of the skin and the
invasive ones, the culture of specimens is indicated in order to identify the bacteria in clinical
samples. Imaging studies, such as radiography, ultrasound, and computed tomography
(CT), may be performed to assess the extent of tissue involvement in cases of severe infec-
tions, such as necrotizing fasciitis. The diagnosis of post-streptococcal diseases is based on
clinical history and findings compatible with the specific illness associated with the evidence
of a preceding group A strep infection, including the isolation of GAS from the throat/skin
or the detection of certain streptococcal antibodies (anti-streptolysin O and anti-DNase B).
A four-fold increase in titer is considered the proof of antecedent streptococcal infection
[27,29,33,42–44].
6. Treatment
The management of GAS pharyngitis remains disputed given the presence of multiple,
varying guidelines. As a recent review highlights, these guidelines can be divided into three
groups [43]. The first group recommends identifying GAS pharyngitis, treating it properly,
and preventing possible sequelae. The second group considers GAS pharyngitis as a benign
and self-limiting disease requiring treatment only in select cases. Finally, the third group,
which includes guidelines from Australia and New Zealand, identifies two groups of
Pathogens 2024, 13, 350 7 of 13
patients at higher risk: patients of Maori or Aboriginal ethnicity, especially people living in
rural areas, characterized by overcrowding and low socioeconomic status, and those with a
previous history of acute rheumatic fever aged 3–40 years old. Once a diagnosis of GAS
pharyngitis is confirmed, antimicrobial therapy should be promptly initiated to prevent
both suppurative and non-suppurative complications, in particular, ARF, in which case the
treatment should be initiated within 9 days of symptom onset [44,45].
Generally, given that GAS resistance to penicillin has not been detected to date, all
guidelines agree on considering penicillin V as the drug of choice for the treatment of GAS
pharyngitis [46]. Alternatively, if penicillin V is not available, Amoxicillin may be pre-
scribed, also for better palatability [42]. Both Penicillin V and Amoxicillin are inexpensive,
narrow-spectrum, and have a low rate of side effects. In cases with low compliance to these
treatments, Penicillin G benzathine can be administered in a single intramuscular dose. For
those patients who have a documented allergy to penicillins, a first-generation cephalo-
sporin such as Cephalexin can be prescribed, particularly in non-anaphylactic forms of pen-
icillin allergy, while clindamycin and azithromycin can be used in other cases [46]. It should
be underlined that in recent years there has been an increase in the resistance of GAS to
macrolides in Western countries [47]. Hence, if a macrolide is necessary, it is recommended
to consider local resistance patterns and ensure bacterial susceptibility to this class of anti-
biotics [43]. Table 1 summarizes the antibiotic options for the treatment of GAS pharyngitis
in children. Post-treatment throat culture to confirm the cure is not necessary unless symp-
toms persist for days following treatment [48]. Repeated positive tests for GAS without signs
and symptoms of local inflammation are defined as a chronic GAS carrier state. These chil-
dren are at low risk of immune-mediated complications and generally should not be treated
[49]. Furthermore, they are unlikely to transmit the infection [50]. Eradication for the GAS
carrier state must be taken into account in the following risk conditions: a local outbreak of
GAS sequelae, including ARF, APSGN, or iGAS disease; an outbreak of GAS pharyngitis in
a closed or semiclosed community; family or personal history of acute rheumatic fever; and
multiple episodes of GAS pharyngitis occurring in a family for many weeks despite appro-
priate treatment [42–45,49]. Antibiotic options for eradication include clindamycin, penicil-
lin, rifampin, and amoxicillin–clavulanic acid [46]. During the last few years, increased rates
of invasive GAS infections in children have been reported in many countries [50,51]. Inva-
sive GAS infections may be non-specific at the onset and may rapidly progress. Conse-
quently, a high index of suspicion is essential to diagnose and treat the disease appropriately
[20]. Antibiotic therapy remains the cornerstone of treatment in invasive infections, with the
recommendation to initiate with a broad-spectrum antibiotic, subsequently modifiable once
culture results are available. If GAS infection is confirmed, β-lactam antibiotics should be
considered in susceptible cases. In case of penicillin allergy, macrolides are not recom-
mended, and vancomycin is the preferred choice. The addition of an antitoxin antibiotic
such as clindamycin or linezolid is recommended, especially in cases of necrotizing fasciitis
and streptococcal toxic shock syndrome [20].
Table 1. Suggested antibiotic treatments for GAS acute pharyngitis in children.
Antibiotic Dose Duration Considerations
Penicillin V (oral)
≤27 kg of body weight: 250 mg 2–3
times a day
>27 kg: 500 mg 2–3 times a day
10 days Preferred treatment
Amoxicillin (oral) 50 mg/kg once a day (max dose: 1 g)
10 days
(in low-risk patients, a 5-
day course of treatment
should be considered)
Preferred treatment
Penicillin G benzathine
(intramuscular)
≤27 kg of body weight: 600,000 U
>27 kg: 1,200,000 U 1 dose To be considered in case of poor
treatment adherence
Pathogens 2024, 13, 350 8 of 13
Cephalexin 40 mg/kg/day 2 times a day (max
dose: 500 mg) 10 days In children with non-anaphylac-
tic penicillin allergy
Azithromycin 12 mg/kg on day 1 and 6 mg/kg on
days 2–5 (max dose: 500 mg) 5 days
In children with anaphylactic
penicillin allergy;
consider macrolide resistance
Clindamycin 20 mg/kg/day 3 times a day (max
dose: 300 mg) 10 days
In children with anaphylactic
penicillin allergy;
consider clindamycin resistance
7. Antimicrobial Resistance
Even though GAS infections have historically responded well to β-lactam antibiotics,
recent years have seen increasing reports of treatment failures in eradicating GAS from the
throat in patients with GAS tonsillitis, with a rate of penicillin failure reported near 40% [52].
Studies have identified the gene encoding penicillin-binding protein 2X (pbp2x) in GAS
strains with reduced β-lactam susceptibility; the lack of diffusion of this particular PBP2x
polymorphism is probably related to the small evolutionary advantage conferred by this
variant [53].
Multiple hypotheses exist regarding the possible mechanisms of GAS penicillin re-
duced susceptibility. According to one, the internalization of GAS in epithelial cells effec-
tively makes eradication more difficult due to the poor penetration of penicillins into the
tonsillar tissues. A second hypothesis posits a synergistic relationship between GAS and
bacteria colonizing the oral cavity (e.g., Moraxella catarrhalis), facilitating the adhesion and
persistence of GAS, or, alternatively, protection induced by other β-lactamase-producing
commensal bacterial species such as Staphylococcus aureus [52,54,55]. Since 1990, there has
been a notable increase in macrolide resistance among GAS strains, with resistance rates
varying widely across geographic regions. Some European countries report resistance rates
below 4%, while rates exceed 40% in some Asian countries. Mechanisms of resistance in-
clude target site modification or drug efflux, particularly affecting erythromycin. Fortu-
nately, a decrease in resistance rates has been described in some countries under antimicro-
bial stewardship programs [47,56,57]. The prevalence of resistance to fluoroquinolones
ranges from infrequent occurrences at low levels to sporadic instances at high levels. Con-
versely, resistance to tetracycline is characterized by its low occurrence and is typically as-
sociated with mutations in genes encoding efflux pumps, which are relatively rare in strep-
tococci. Notably, the genes of macrolide resistance are collocated on mobile elements near
those responsible for tetracycline resistance.
8. The Current Status of GAS Vaccines
A GAS vaccine is not yet available, but the urgency of developing one is supported by
the fact that GAS still ranks among the top ten infectious diseases causing mortality world-
wide and remains one of the most frequent pathogens responsible for upper respiratory
tract infections (pharyngitis and tonsillitis). The GAS global disease burden may be under-
estimated given the lack of epidemiological data from underdeveloped countries [58]. A
GAS vaccine should be affordable at all income levels and should be allocated across all
countries, regardless of their economic status. A worldwide distribution could prevent
many cases of superficial diseases and deaths, reduce throat colonization, and decrease in-
fections transmitted from asymptomatic carriers. Indirect benefits would include a reduc-
tion in antibiotic use and consequently a mitigation of antimicrobial resistance.
Several obstacles hinder the development of a GAS vaccine. Firstly, healthcare inter-
ventions in high-income countries, focusing on the prompt diagnosis and early treatment of
sore throats, have reduced mortality and complications related to GAS infections, thus di-
minishing the demand for vaccines in these regions. Secondly, the shortage of funding for
the development of a vaccine is consequent to the disproportionate need in low-income
countries, where there is often insufficient return on investment. Certainly, the vast majority
Pathogens 2024, 13, 350 9 of 13
of cases of ARF, RHD, APSGN, and iGAS occur in developing countries, which are charac-
terized by health inequities, poverty, and social disadvantage, suggesting that social deter-
minants of health (SDHs) are a major driver of GAS infection persistence [59,60]. The GAS
distribution is very different between developed countries, where circulating strains are
few, and low-income settings, where the rate of circulating strains is higher. Social and en-
vironmental factors (such as overcrowding or comorbidities) contribute to bacterial growth
and transmission, resulting in greater genetic diversity. This differential distribution, in ad-
dition to the extensive emm-type diversity (more than 250 types of Streptococcus pyogenes), is
a great challenge for the development of a GAS vaccine, which should be able to cover mul-
tiple serotypes, leading to cross-serotype protection [8]. Another impediment to progress is
the paucity of suitable animal models susceptible to GAS infection—indeed, mice do not
have tonsils, while non-human primates are expensive and complex to use, requiring spe-
cialized facilities and personnel. Moreover, a delay in development is related to the fact that
trials should be conducted first in healthy adults and after many years reach those phases
in which the real target vaccine population is tested (specifically children and adolescents
who are subject to the major burden of GAS infection) [61]. Another obstacle to vaccine de-
velopment is the limited knowledge of the molecular mechanisms associated with compli-
cations caused by Group A Streptococcus infection. When developing a GAS vaccine, it is
necessary to avoid the risk of autoimmune complications due to passive immunization. One
of the reasons behind the discontinuation of trials is the onset of rheumatic fever in some
patients immunized with a candidate vaccine. Since the beginning of the 20th century, many
studies about vaccines able to prevent scarlet fever were conducted, leading to the first trial
in 1923. Between 1923 and the late 1960s, different vaccine products were tested. In 1968, a
candidate vaccine based on the M protein caused acute rheumatic fever in at least two chil-
dren enrolled in a trial; this event led to the discontinuation of trials for decades. In Decem-
ber 2005, the regulation was revoked by the Food and Drug Administration (FDA), and
since 2006, many initiatives for vaccine research have been supported by the World Health
Organization (WHO) to ensure the development of a safe, effective, and affordable GAS
vaccine [60].
Two types of GAS vaccine are available: those focused on the major cell surface protein
(M-protein-based vaccines) and those targeting different GAS factors, including toxins, pro-
teins, and capsule constituents (non-M-protein-based vaccines) (see Tables 2 and 3) [58,62].
Currently, among the M-protein-based vaccines, three candidates have completed or
begun a phase 1 clinical trial. Specifically, Streptanova, a 30-valent vaccine, has completed a
phase 1 clinical trial and was found to be effective against 72 GAS emm-types; StreptIncor, a
polypeptide vaccine with B and T cell epitopes, has begun a phase 1 trial and seems to pre-
vent infection against M1, M5, M12, M22, and M87 GAS strains; MJ8Vax is still in the pre-
clinical research stage, and, if successful, it will be the first nasally administered GAS vac-
cine. The 26-valent M-protein-based vaccine completed a phase 2 trial, being well-tolerated
and immunogenic in healthy adults [62,63]. The non-M-protein-based vaccines include
many candidates in the preclinical stage: carbohydrate vaccines (GAC), Combo4 and
Combo5, TeeVax, Vax-A1, 5CP, Spy7, and SPy-2191. The Combo vaccine is a multiple anti-
gen composed of SLO (a pore-forming toxin), SpyAD (a surface-exposed adhesin), SpyCEP
(a protease), and Group A carbohydrate (GAC) and should soon enter clinical development
[62]. At present, considering the ongoing development of vaccine candidates, the prevention
strategies for GAS infections include early diagnosis and treatment of GAS tonsillitis,
screening of asymptomatic cases in hospital and care facilities, post-exposure prophylaxis
of vulnerable groups, improved hand hygiene practices, improvements in the quality of
housing, and reductions in overcrowding. Lastly, improved surveillance and epidemiolog-
ical investigation should be emphasized, especially in low-resource settings, as essential
practices in the prevention and control of the spread of GAS diseases [64]. Many authors
have reported that a cost-effective Streptococcus pyogenes vaccine could lower the morbidity
and mortality burden in all income settings [65]. A static cohort model has been developed
to estimate the projected health impact of GAS vaccination using country-specific
Pathogens 2024, 13, 350 10 of 13
demographic data (high- and low-income countries). In this model, available online, the
vaccination impact is estimated in terms of reduction in the burden of several major GAS
disease states (both throat and skin infections, but also post-streptococcal complications),
sequelae, and deaths due to severe GAS diseases. The app shows the predicted lifetime
health benefits if a GAS vaccine were to be distributed, underlining the direct reduction in
disease burden on the bases of vaccine efficacy, coverage, and vaccine-derived immunity
[66].
Table 2. GAS vaccines and their stages of development, M-protein-based vaccines.
Vaccine Name Target Antigen Stage of Development Characteristics
M-Protein 26-valent
vaccine M-Protein Phase II
Effective against 26 different serotypes
of GAS; safe and effective in 26 healthy adult volunteers;
no occurrence of cross reaction with human tissue
M-Protein 30-valent
vaccine (Streptanova) M-Protein Phase I
Four recombinant proteins; covers 30 GAS serotypes;
safe in healthy adults without causing autoimmunity
M-Protein C repente
epitope (StreptInCor) M-Protein Phase I
A 55-amino acid peptide from the C-terminal region of
the M-protein (highly conserved among GAS serotypes).
Animal immunization
studies have shown high levels of specific antibodies
with no cross-reactivity to cardiac proteins
MJ8Vax M-Protein Phase I
J8 is the smallest epitope in the C region of the M protein
binding to CRM (an inactive and non-toxic form of DT);
it is conjugated with K4S2-CRM. It will be the first
nasally administered GAS vaccine
PMA-P-J8 M-Protein Preclinical
J8 B-cell epitope of M protein, PADRE, and PMA expres-
sion of IgG and mucosal IgA after a single immunization
PADRE: pan HLA-DR-binding epitope; PMA: poly methyl acetate.
Table 3. GAS vaccines and their stages of development, non-M-protein-based vaccines.
Target Antigen Stage of Development
P*17/K4S2 M-Protein Preclinical
BP-p*17-S2 M-Protein Preclinical
GAC GAC Preclinical
Combo4 SpyCEP, SLO SpyAD, GAC Preclinical
Combo5 SLO, SpyCEP, SCPA, ADI, TF Preclinical
TeeVax T antigen Preclinical
VAX-A1 GACprSpyAD, SLO, SPCA Preclinical
SCP SrtA, SCPA, SpyAD, SpyCEP, SLO Preclinical
Spy7 SCAPA, OppA, PulA, SpyAD, Apy1228, Spy1037,
Apy0843 Preclinical
Spy_2191 Spy_2191 Preclinical
ADI: argininedeiminase; SCPA: Streptococcus C5a peptidase; TF: trigger factor; SMQ: squalene-in-wa-
ter emulsion containing a Toll-like receptor 4 agonist and QS21; GAC: group A carbohydrate; SLO:
streptolysin O; CpG: CpG-oligodeoxynucleotide; CFA: complete Freund’s adjuvant.
9. Conclusions and Future Directions
Although GAS is responsible for trivial infections such as pharyngitis, it is increasingly
evident that the suppurative and non-suppurative complications should not be underesti-
mated given that this pathogen is one of the most significant causes of global morbidity and
mortality. In the last few years, a progressive increase in emm-type numbers has been iden-
tified along with the emergence of the first forms exhibiting reduced susceptibility to
Pathogens 2024, 13, 350 11 of 13
penicillins. There is therefore an urgent need for vaccine development against Group A
Streptococcus, especially in low-resource settings where the diagnosis and treatment of phar-
yngitis is not always feasible and where the complications of GAS infections occur most
frequently. Continued monitoring of the incidence of GAS infections, especially in low-re-
source settings, is important in order to assess the impact of preventive measures and the
effectiveness of future vaccination strategies.
Author Contributions: Conceptualization, G.M.D.P.; Writing—original draft preparation, G.M.D.P.,
P.B., M.L.C. and P.L.; Writing—review and supervision, G.M.D.P., P.L. and P.M. All authors have read
and agreed to the published version of the manuscript.
Funding: This work was (partially) funded by Italian Ministry of Health—Current research IRCCS Cà
Granda Ospedale Maggiore Policlinico di Milano.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.
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