Group A Streptococcal Infections

Etiology

GAS is a gram-positive, nonspore-forming, catalase- and oxidase-negative bacterium that grows in pairs and chains (see Image. S pyogenes Bacterium).[14] When cultured on blood agar at 35 °C and 37 °C in a 10 percent carbon dioxide environment, GAS produces smooth, moist, grayish-white colonies with clear margins measuring over 0.5 mm. These colonies are surrounded by a zone of complete hemolysis (beta-hemolysis) (see Image. Comparisons of Hemolytic Activity of Groups A, B, G, and F Streptococci).

The Lancefield classification categorizes streptococci into serologic groups, labeled A to O, based on the reactions of antisera with carbohydrate antigens on the streptococcal cell wall.[15] At least 20 serological groups have been identified, including groups A, B, and C; GAS belongs to Lancefield group A.[16][17] Other streptococci from different Lancefield groups can cause syndromes similar to those caused by GAS. Notably, group B Streptococcus (GBS; Streptococcus agalactiae) colonizes the human gastrointestinal and genital mucosa and can lead to conditions such as puerperal sepsis, neonatal infections, pneumonia, bacteremia, and meningitis.[18] 

GAS has also been subdivided based on the serotypes of the M- and T-antigens expressed on its surface.[15] Traditional serotyping methods to detect T- and M antigens have largely been replaced by sequence typing of the N-terminal part of the M-protein gene (emm), which is now primarily used for genotyping GAS, mainly for epidemiological purposes.[15][19] Whole genome sequencing (WGS) is increasingly utilized to identify epidemic strains of GAS. Over 220 emm types have been classified based on the M-protein gene sequence.[20][15] The streptococcal M-protein, a key virulence factor used for epidemiological typing, also serves as a potential vaccine antigen.[19]

Numerous virulence determinants in GAS have been identified, aiding in adhesion, colonization, evasion of the innate immune system, invasion, and dissemination within the host.[21] Key virulence factors include the M-protein, hyaluronic acid, streptokinase, and deoxyribonuclease B (DNase-B). Among its notable toxins are the pyrogenic toxins (also known as scarlatina or erythrogenic toxins), which cause the rash in scarlet fever. These toxins also stimulate mononuclear cells to produce tumor necrosis factor (TNF)-alpha and interleukins (IL-1 and IL-6), thereby contributing to fever and shock in patients with STSS.[1][22]

Certain bacterial superantigenic exotoxins, associated with syndromes such as STSS, trigger an atypical polyclonal activation of lymphocytes. This leads to rapid-onset shock and multiorgan failure, contributing to high mortality. The primary superantigenic exotoxins identified are toxic shock syndrome toxin-1 (TSST-1) and enterotoxins.[22]

GAS is uniquely adapted to humans, with mucous membranes and skin serving as its only known reservoirs. GAS commonly causes a wide spectrum of infections in the upper respiratory tract and skin, ranging from mild, superficial infections to severe iGAS.[1][2] iGAS infections generally occur in normally sterile sites, such as the bloodstream, cerebrospinal fluid, or pleura. 

Epidemiology

GAS exclusively infects humans[14], spreading through respiratory secretions, fomites, and direct contact with infected skin, such as in cases of impetigo. Although GAS infections can occur at any age, children, older adults, and immunocompromised individuals are at higher risk of becoming infected.[23] Environmental factors and time spent in communal settings, such as schools, households, and nursing homes, significantly increase the risk of transmission.[24] GAS can also cause disease in young, healthy individuals, with one study reporting its occurrence in 25 percent of people without identifiable risk factors.[24]

Pharyngitis

GAS can be found in the pharynx either as an asymptomatic carrier state or as a pathogen, causing pharyngitis. Approximately 5 to 15 percent of individuals in the general population are estimated to be GAS carriers. The World Health Organization (WHO) estimates that 600 million cases of GAS pharyngitis occur globally every year, with 80 percent in children and 20 percent in adults.[25] GAS pharyngitis most commonly occurs in children aged 5 to 15 years and is the leading bacterial cause of acute pharyngitis in this age group. It accounts for 5 to 15 percent of ambulatory care visits for acute pharyngitis in adults and 20 to 30 percent in children.[4][5][6] GAS pharyngitis usually occurs most frequently in the Winter and early Spring.[5] Pharyngitis caused by GAS typically results from person-to-person transmission through oropharyngeal secretions and respiratory droplets from infected individuals.[21][26]

Impetigo

Impetigo is a skin infection caused by Staphylococcus aureus, S pyogenes, or both bacteria. According to the WHO, an estimated 100 million cases of impetigo occur globally every year.[25] In the United States (US), more than 3 million cases of impetigo are estimated to occur each year. It is highly contagious and most frequently affects children between the ages of 2 and 5 years old. Risk factors include spending time in communal settings (eg, daycare centers, schools, correctional facilities, and homeless shelters) and poor personal hygiene. While impetigo can occur year-round, it is more common in areas with hot, humid summers and mild winters. 

Scarlet Fever

It is estimated that fewer than 10 percent of persons with GAS pharyngitis will develop scarlet fever, which most commonly presents with exudative pharyngitis, fever, and the characteristic bright-red rash. Scarlet fever is caused by streptococcal pyrogenic exotoxins (SPEs) produced by GAS. A new emm1 sublineage, coined M1_UK, was identified in 2008 in the United Kingdom (UK) and exhibited increased expression of the scarlet fever toxin and streptococcal pyrogenic exotoxin A (speA), leading to a rise in scarlet fever and invasive infections in the UK between 2014 and 2018. As a result, it became the dominant type in the country.[27][28][29] Following the COVID-19 pandemic, 3 emerging M1_UK clades rapidly expanded across the UK, resulting in severe outcomes in children.[30] All globally sequenced M1_UK isolates (speA) can be traced back to the UK, where they caused an epidemic and have since spread across Europe and internationally.[30] Although declining immunity may contribute to streptococcal outbreaks, the genetic characteristics of M1_UK suggest a fitness advantage in pathogenicity and a remarkable ability to endure population bottlenecks. M1_UK is now the dominant strain in England. In addition, 2 other lineages—M113SNPs and M123SNPs—were also identified.[30][31]

Cellulitis and Erysipelas

Cellulitis and erysipelas are skin infections commonly caused by S aureus and GAS. It is estimated that there were 43 million cases of cellulitis globally in 2019, resulting in over 18,000 deaths.[32] Approximately 10 percent of the cases are caused by GAS alone.[33] Risk factors for cellulitis include, among others, leg ulcers, lymphedema, congestive heart failure, venous insufficiency, diabetes mellitus, and lower socioeconomic status.[34] 

iGAS

Globally, it is estimated that over 600,000 cases of iGAS occur every year, accounting for over 160,000 deaths.[25] In the US, the Centers for Disease Control and Prevention (CDC) estimates there are between 20,000 and 27,000 cases annually, accounting for around 2,000 deaths. In a population-based study covering nearly 35 million people in ten US states, there were over 21,000 cases of iGAS diagnosed from 2013 through 2022, accounting for almost 2000 deaths. Incidence rose from 3.6 infections per 100,000 persons in 2013 to 8.2 infections per 100,000 persons in 2022. Risk factors included persons experiencing homelessness, people who inject drugs, and residents of long-term care facilities.[35]  

Severe illness and iGAS infections exhibit a bimodal distribution, occurring most commonly in individuals aged 2 years or younger and 50 years or older.[26][36] Risk factors associated with increased mortality include advanced age, male sex, nursing home residency, chronic underlying conditions, immunosuppression, recent surgery, septic shock, necrotizing fasciitis, concurrent viral infections, isolated bacteremia, and infection with emm type 1 or 3.[24][36] 

Epidemiological surveillance is crucial for tracking epidemics, particularly given the increasing incidence and burden of GAS infections, especially iGAS, worldwide. Whole genome sequencing (WGS) plays an important role in this effort.[2][15][20][36][25] Since 2000, the dominant emm types in Europe and North America have been emm1 and emm3, with emm1 being the most prevalent among invasive infections in high-income countries.[30] The 7 emm types responsible for 50 to 70 percent of iGAS infections include emm1, emm28, emm89, emm3, emm12, emm4, and emm6 [15][37], which are collectively referred to as M1_global.

RHD

It is estimated that over 15 million people are living with RHD, with an estimated 280,000 new cases of ARF occurring globally every year. The prevalence is highest in Sub-Saharan Africa, with an estimated 80 percent of RHD occurring in low and middle-income countries.[25] The single most important risk factor for RHD is failing to treat GAS pharyngitis with appropriate antibiotics, with other risk factors including living in overcrowded settings, poor personal hygiene, and limited access to healthcare.[38]

PSGN

An estimated 470,000 people develop acute PSGN globally every year, accounting for an estimated 5000 deaths.[25] As with RHD, the single most important risk factor for PSGN is failure to treat GAS pharyngitis with appropriate antibiotics. The same risk factors for GAS pharyngitis and impetigo also apply to PSGN. 

Pathophysiology

GAS infections result from a complex interplay between host and bacterial factors that facilitate the establishment of infection. GAS utilizes various virulence factors, including toxins and other substances, to evade the host immune system and infect humans.[1] The hyaluronic acid capsule of GAS acts as a camouflage mechanism by resembling human hyaluronic acid, allowing the bacterium to evade immune detection. The surface-associated protein (S-protein) protects the bacterium from phagocytic destruction. Additionally, GAS produces proteases that degrade host immune signaling molecules and extracellular DNases to neutralize host immune defenses.[1]

Various surface substances, such as lipoteichoic acid and F-protein, enable GAS to adhere to host cells and facilitate colonization.[1] Cytolytic toxins, including streptolysins and hyaluronidase, contribute to tissue destruction, allowing GAS to invade the host.[1][39] Additionally, GAS has several factors, including its capsule, G protein, C5a peptidase, and M protein, that help it evade host immune defenses. Among these, M-protein is particularly significant for GAS virulence, as it inhibits the phagocytosis of host immune cells.[40]

Histopathology

Histopathological findings in GAS infections are typically characterized by acute inflammation and tissue destruction. Impetigo manifests as subcorneal pustules containing neutrophils and Gram-positive cocci. Deeper skin and soft tissue infections, such as cellulitis, will reveal diffuse edema and a neutrophil-rich infiltrate within the dermis and subcutaneous fat.

The hallmark of necrotizing fasciitis (NF) is extensive necrosis of the fascia and subcutaneous fat, often accompanied by vascular thrombosis and a lack of polymorphonuclear (PMN) leukocytes in the necrotic zones. 

On light microscopy, PSGN will show diffuse endocapillary hypercellularity and exudative changes with neutrophils in the glomerular tufts. On electron microscopy, subepithelial "humps" (electron-dense deposits) can often be visualized. On immunofluorescence, a "starry sky" or "garland" pattern of C3 and IgG deposits along the capillary walls can be seen. 

History and Physical

Obtaining a thorough history of the present illness and medical history is crucial for individuals presenting with GAS symptoms. GAS infections can present in diverse ways, influenced by factors such as the site of infection, toxin production, the invasiveness of the GAS strain, the patient's immune status, and whether the infection is superficial or deep. Clinicians must remain vigilant, as even mild-appearing infections can rapidly progress.

Pharyngitis

The most common symptoms of GAS pharyngitis are the sudden onset of fever and sore throat. Individuals with GAS pharyngitis, especially children, may also report headaches, nausea, vomiting, and abdominal pain.[8] When obtaining a patient history, it is common to identify exposure to a GAS infection, particularly among school-age children or individuals in communal living environments, such as nursing homes, where prevalence is higher due to close living conditions. 

Physical exam findings in GAS pharyngitis commonly include generalized inflammation of the tonsils and pharynx, variable tonsillar exudates, a red, swollen uvula, and palatal petechiae. Tender cervical lymphadenopathy is frequently noted during palpation.[8] Symptoms such as conjunctivitis, cough, coryza, or diarrhea are uncommon and, when present, are more suggestive of a viral etiology.[41] Physical examination of the posterior oropharynx alone is insufficient to differentiate GAS from other causes of acute pharyngitis, such as viral pharyngitis, which is the most common cause of pharyngitis. 

Impetigo

Impetigo typically occurs in school-aged children and is characterized by distinct cutaneous lesions described as discrete to confluent "honey-crusted" areas, most commonly on the face and extremities (see Image, Streptococcal impetigo). Usually, vital sign abnormalities are not associated with the clinical presentation, and the individual will have no additional physical examination findings apart from the characteristic lesions.[42]

Scarlet Fever

The diffuse erythematous rash characteristic of scarlet fever is usually associated with pharyngitis, petechiae on the soft palate, and tender cervical lymph nodes. A thorough skin examination will reveal the presence of a fine maculopapular erythematous "sandpaper" rash (see Image, scarlet fever rash on the forearm), along with a "strawberry tongue," which strongly suggests scarlet fever. The rash usually starts in the groin and axilla, expands to cover the trunk and extremities, and then desquamates. The palms and soles are usually spared. While scarlet fever is commonly associated with GAS streptococcal pharyngitis, it can also occur with iGAS infections.[43] 

Cellulitis and Erysipelas

Cellulitis and erysipelas manifest as areas of redness, edema, and warmth on the skin. Fever may be present. They are typically unilateral and involve the lower extremities. While erysipelas involves the upper dermis and superficial lymphatic system, cellulitis involves the deeper dermis and subcutaneous fat. Erysipelas is well-demarcated, with sharp, raised borders, and is nonpurulent (see Image, Streptococcal erysipelas). Cellulitis tends to be less well demarcated, but when caused by GAS, it is typically nonpurulent. 

iGAS

iGAS infections include NF and TSST-1 and are severe infections requiring prompt diagnosis and management, as affected individuals can deteriorate rapidly. NF is a critical, life-threatening soft tissue infection that involves the skin, subcutaneous tissue, and fascia. This can resemble cellulitis, making it easy to misdiagnose. One key finding in NF is that the pain is disproportionate to physical exam findings.[44] Clinicians must maintain a high level of suspicion, as misdiagnosis or treatment delays can lead to poor outcomes. Prompt intervention with aggressive surgical debridement and antibiotic therapy is critical.[45]

STSS is a severe and life-threatening condition caused by GAS. This condition results from an iGAS infection where bacterial enterotoxins are released, leading to severe systemic symptoms. STSS often develops following a primary GAS infection, particularly in deep wound infections. Clinically, individuals typically present with symptoms of severe sepsis, including tachycardia, hypotension, poor tissue perfusion, and signs of end-organ dysfunction.[46]

RHD

ARF typically presents 2 to 3 weeks after pharyngitis and characteristically causes rheumatic carditis, inflammation of the cardiac valves, most commonly the mitral and aortic valves. Valvular regurgitation results, which typically do not cause symptoms until they become severe, include symptomatic dyspnea and exercise intolerance. On exam, regurgitant murmurs can be detected on auscultation of the chest. Classically, mitral regurgitation presents with a holosystolic murmur. 

PSGN

Acute PSGN may be asymptomatic, characterized only by microscopic hematuria and reduced serum complement, or may be symptomatic with acute nephritic syndrome, characterized by hematuria, edema, oliguria, and hypertension. In one prospective study, asymptomatic PSGN occurred four times as frequently as symptomatic PSGN.[47]

Evaluation

Pharyngitis

In an individual with symptoms of GAS pharyngitis and no symptoms of a viral infection, such as rhinorrhea, cough, hoarseness, oral ulcers, or conjunctivitis, it is prudent to proceed with GAS testing. GAS pharyngitis testing is recommended in:

• Symptomatic children less than 3 years of age who have risk factors for GAS infection, such as an older sibling with GAS infection
• Children 3 years and older and adolescents with symptoms of GAS infection
• Adults with symptoms compatible with GAS pharyngitis who lack symptoms of viral pharyngitis

Testing can include a rapid antigen detection test for GAS, molecular assays, or throat culture. In a systematic review, the rapid antigen test had a sensitivity of 86% and a specificity of 95%, although performance varied substantially across studies.[48] One major advantage of the rapid antigen test is that results are made available more quickly than with molecular testing and culture. Molecular assays such as polymerase chain reaction (PCR) and nucleic acid amplification tests (NAATs) are highly sensitive and specific for diagnosing GAS as well, but have a longer turnaround time than point-of-care tests. For both rapid antigen and NAAT tests, it is reasonable to forego a throat culture if the results are positive. If the results are negative, a throat culture should be performed. Throat culture has long been the gold standard for diagnosing GAS pharyngitis, although the turnaround time limits its usefulness. 

The Centor criteria are used to estimate the probability of GAS pharyngitis using a clinical scoring system. A 2011 meta-analysis found that the Centor criteria had a sensitivity of 49 percent, meaning that around half of persons with GAS pharyngitis were missed. The specificity was higher at 82 percent, making it more helpful for ruling in people with likely GAS pharyngitis[49]

Impetigo

A diagnosis of impetigo is typically made clinically based on consistent physical exam findings. A Gram stain and culture can be performed to confirm the diagnosis, but they are typically not needed.

Scarlet Fever

As with impetigo, a diagnosis is made clinically in an individual with GAS pharyngitis and a characteristic erythematous rash and a strawberry tongue. 

Cellulitis and Erysipelas

Cellulitis and erysipelas are typically made clinically. Imaging is not needed unless there are concerns for an underlying abscess, in which ultrasound can be helpful. 

iGAS

If there is a clinical concern for an iGAS infection, such as NF, this is a surgical emergency, and a diagnosis is made in the operating room during exploration of the infected tissue. Although radiographic imaging, such as a computed tomography (CT) scan, can support the diagnosis, surgery should not be delayed while waiting for additional diagnostic studies. A diagnosis of STSS is made based on compatible clinical findings and isolation of GAS from a normally sterile site. 

RHD

A diagnosis of RHD can be made when there is a history of acute rheumatic fever and a valvular abnormality on a transthoracic echocardiogram, as defined by the World Heart Federation criteria for RHD.[50] If there is no history of acute rheumatic fever, a diagnosis of RHD can be made if there are morphologic features of RHD of either the aortic valve or mitral valve.  

PSGN

PSGN is typically diagnosed when there is a history of recent GAS infection and clinical findings of acute nephritis, such as hematuria, proteinuria, oliguria, edema, and hypertension. 

Treatment / Management

Pharyngitis

GAS is among the few causes of pharyngitis for which antibiotics are recommended. Symptoms may resolve without treatment, but antibiotic therapy is important for reducing the risk of post-infectious complications. Antibiotics are not recommended for asymptomatic GAS carriers. Penicillin remains the treatment of choice for GAS pharyngitis. Oral penicillin V can be used in children, although amoxicillin is often preferred as the taste of amoxicillin in suspension is more palatable than that of penicillin, and oral penicillin V requires more frequent dosing. In adults, oral penicillin V is the preferred treatment, although oral amoxicillin can be used instead. A single intramuscular dose of penicillin G benzathine can also be used, particularly for individuals who are unlikely to complete the full course of oral antibiotics. For individuals with a penicillin allergy or who cannot take it, cephalosporins (such as cephalexin), clindamycin, and macrolides (such as azithromycin) can be used. A test of cure is typically not indicated for individuals whose symptoms resolve after completing antibiotics. 

Impetigo

For individuals with limited impetigo, topical mupirocin or fusidic acid (if available) is usually effective. Both agents have activity against both S aureus and GAS. For individuals with systemic symptoms, such as fever, or who are at risk for complications (eg, immunosuppression), oral agents should be considered. An agent with a spectrum of activity against both S aureus and GAS, such as dicloxacillin or cephalexin, should be used. If impetigo is known to be caused by GAS only, oral penicillin V or amoxicillin should be used, with amoxicillin preferred, given the unpleasant taste of oral penicillin V and the more frequent dosing. Macrolides or clindamycin can alternatively be used to treat GAS-only impetigo. 

Scarlet Fever

The treatment of scarlet fever is the same as for GAS pharyngitis. Either oral penicillin V or amoxicillin is preferred; cephalosporins, macrolides, or clindamycin can be used alternatively. 

Cellulitis and Erysipelas

It is not always easy to differentiate between erysipelas and cellulitis, so typically infections are treated as cellulitis unless the diagnosis is clearly erysipelas. Treatment should always cover GAS as well as methicillin-sensitive S aureus (MSSA), and coverage should include methicillin-resistant S aureus (MRSA) if there are risk factors for MRSA (eg, known MRSA colonization or injection drug use), systemic symptoms, or purulence.

GAS causes most cases of erysipelas and can be managed as an outpatient with oral antibiotics, including penicillin V, amoxicillin, or cephalexin. 

For individuals with cellulitis who are not severely ill, do not require parenteral antibiotics, and do not require MRSA coverage, empiric coverage for GAS and MSSA is indicated. Oral dicloxacillin or cephalexin is a good choice. If there is a severe beta-lactam allergy, trimethoprim-sulfamethoxazole, linezolid, or clindamycin can be used instead. If empiric coverage for MRSA is indicated, trimethoprim-sulfamethoxazole, amoxicillin plus doxycycline, linezolid, or clindamycin can be used. For individuals who require parenteral antibiotics, if MRSA coverage is not indicated, empiric coverage of GAS and MSSA with intravenous cefazolin, nafcillin, or oxacillin can be used. For GAS and MRSA coverage, intravenous vancomycin or daptomycin can be used. For severely ill individuals, broad-spectrum coverage is indicated with vancomycin or daptomycin plus cefepime or meropenem. 

iGAS

The cornerstone of management for NF is prompt surgical exploration and debridement of necrotic tissue plus empiric broad-spectrum antibiotics. Empiric antibiotics should cover gram-positive, gram-negative, and anaerobic organisms and should be initiated immediately after blood cultures are obtained. Options include a carbapenem (eg, imipenem, meropenem, or ertapenem) or piperacillin-tazobactam plus vancomycin or daptomycin (to cover for MRSA) plus clindamycin. If NF is determined to be caused by GAS only, antibiotics can be narrowed to penicillin G plus clindamycin. The management of STSS includes treatment of septic shock and its associated complications, surgical debridement of infected tissue (if needed), and administration of intravenous immune globulin. Antibiotic therapy should empirically cover both GAS and MRSA, and both empiric and targeted antimicrobial therapy are the same as that for NF. 

RHD

The management of RHD includes periodic echocardiographic evaluation of valvular abnormalities, prophylaxis against endocarditis for individuals undergoing invasive dental procedures, and valve repair or replacement if cardiac function deteriorates or symptoms of congestive heart failure become severe. 

PSGN

If a GAS infection is present at the time of diagnosis, treatment of the underlying infection with penicillin or amoxicillin is indicated. Otherwise, management should focus on treating the clinical manifestations of PSGN, such as volume overload and hypertension. For individuals with severe PSGN, a kidney biopsy may be indicated if there is significant deterioration in renal function and/pr progression towards hemodialysis. 

Antimicrobial Resistance 

Although GAS remains susceptible to beta-lactams (eg, penicillin and amoxicillin), there is increasing resistance to alternative antibiotics such as macrolides and clindamycin. Reports from China indicate macrolide resistance rates as high as 90%, with resistance in some European countries ranging from 20% to 40% and lincosamide (eg, clindamycin) resistance reaching up to 19%. In other parts of Europe, these rates can be as low as 2%.[51][52] This resistance is attributed to multiple factors, including macrolide resistance mechanisms involving the MLSb phenotype.[51][52][53] There are rare reports of reduced susceptibility of GAS to beta-lactams[10][54][55], although no fully resistant GAS strains have been confirmed, and GAS remains uniformly susceptible to beta-lactams.(A1)

Differential Diagnosis

Pharyngitis

• Viral pharyngitis (eg, adenovirus, rhinovirus, Sars-CoV-2 and other coronaviruses, enteroviruses, influenza, parainfluenza, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, respiratory syncytial virus)
• Acute HIV infection 
• Groups C and G Streptococcus
• Neisseria gonorrhoeae
• Fusobacterium necrophorum
• Arcanobacterium haemolyticum
• Corynebcterium diptheriae
• Mycoplasma pneumoniae
• Tularemia 
• Treponema pallidum 
• Peritonsillar abscess, retropharyngeal abscess, Lemierre syndrome
• Non-infectious causes (eg, allergic rhinitis, gastroesophageal reflux disease, irritants such as smoke, trauma)
• Systemic diseases (eg, Kawasaki disease, Behcet syndrome)

Impetigo

• Herpes simplex virus
• Contact dermatitis
• Tinea infection
• Eczema
• Scabies
• Ecthyma
• Drug eruption 
• Burns
• Arthropod bites
• Varicella
• Pyoderma gangrenosum 
• Pemphigus vulgaris or bullous pemphigoid
• Erythema multiforme 

Scarlet Fever

• Viral exanthems (eg, rubeola/measles, rubella, Fifth disease)
• Other bacterial infections (eg, non-GAS Streptococcal species, A haemolyticum
• Drug eruption 
• Staphylococcal scaled skin syndrome
• Toxic shock syndrome
• Kawasaki disease

Cellulitis and Erysipelas

• Necrotizing fasciitis 
• Toxic shock syndrome
• Clostridial myonecrosis/gas gangrene
• Erythema migrans
• Herpes zoster
• Septic bursitis
• Non-infectious causes (eg, contact dermatitis, gout, drug reaction, arthropod bite, deep vein thrombosis, panniculitis, vaccine site reaction, statis dermatitis [although this is usually bilateral], lymphadema)

iGAS

• Cellulitis or erysipelas
• Abscess
• Toxic shock syndrome
• Pyoderma gangrenosum
• Clostridial myonecrosis/gas gangrene
• Pyomyositis
• Deep vein thrombosis 
• Acute compartment syndrome
• Vasculitis

RHD

• Mitral valve prolapse
• Infective endocarditis
• Congenital heart disease
• Viral myocarditis/carditis
• Degenerative valve disease

PSGN

• Non-PSGN causes of acute nephritis (eg, membranoproliferative glomerulonephritis, IgA nephropathy, lupus nephritis)
• C3 glomerulopathy
• Anti-GBM disease
• Hemolytic-uremic syndrome (HUS)
• Alport syndrome
• Thin basement membrane disease

Pertinent Studies and Ongoing Trials

As of March 2026, the following clinical trials of GAS were ongoing:

Prevention

• NCT07085702 is a multicenter, phase I, randomized, blinded study evaluating the safety and immunogenicity of three doses of two new formulations of a low-dose, medium-dose, and high-dose GAS vaccine. 
• NCT07078357 is a single-center, phase I/IIa, randomized, double-blind, placebo-controlled, dose-escalation study evaluating the safety and immunogenicity of a GAS vaccine candidate (StreptInCor).
• NCT06370208 is a single-center, randomized, double-blind trial evaluating whether prophylactic use of S. salivarius eK12 can reduce the frequency and severity of GAS pharyngitis episodes in children. 

Prognosis

The prognosis for most GAS infections is generally excellent, with the caveat that GAS can cause long-term sequelae, as previously discussed (eg, RHD and PSGN). 

For GAS pharyngitis, symptoms typically resolve within a few days of starting antibiotics and will often resolve on their own, even without antibiotic treatment (although antibiotics are important for preventing long-term complications). Similarly, scarlet fever symptoms typically resolve within a couple of days of antibiotic treatment. Impetigo has an excellent prognosis, with most infections becoming noncontagious within 24 to 48 hours after treatment initiation. Symptoms usually start improving within 3 days of treatment initiation, with complete healing after a week or so. 

Individuals with cellulitis or erysipelas typically experience symptom improvement within 24 to 48 hours after antibiotic initiation. If symptoms are not improving or are worsening, the differential diagnosis should be reevaluated. 

NF carries a high mortality rate, even with appropriate management, with mortality rates ranging from 12 to 20 percent.[56][57][58][59] STSS carries an even poorer prognosis. In a systematic review and meta-analysis, STSS was associated with a mortality rate as high as 50 percent.[60][57]

The prognosis for RHD varies with the timeliness of detection, access to penicillin prophylaxis, and timely surgical intervention. In a prospective observational study from 24 low- and middle-income countries, nearly 15 percent of individuals with RHD died within 3 years, most commonly due to heart failure or sudden death.[61]

PSGN generally has a favorable prognosis. Over 90 percent of children recover completely within weeks to months, with only a small minority progressing to acute renal failure or persistent proteinuria and hematuria.[62] Adults who develop PSGN are more likely to have a worse outcome due to underlying renal dysfunction. 

Complications

GAS is associated with significant morbidity and mortality if infections are not properly and promptly treated. In addition to causing infections, GAS can trigger immune-mediated sequelae, such as ARF and PSGN, as well as long-term sequelae such as RHD.[3] The valvular damage caused by ARF can be permanent and, in severe cases, may necessitate surgical intervention, including valve repair or replacement.[63]