Streptococcal pharyngitis, commonly known as strep throat, is a bacterial infection of the throat and tonsils caused by Streptococcus pyogenes, also referred to as group A streptococcus (GAS) [1]. It is one of the most common bacterial causes of sore throat, particularly in children aged 5 to 15 years, and is distinct from viral pharyngitis, which does not require antibiotic treatment [2]. The infection spreads through respiratory droplets, direct contact with infected secretions, or contaminated surfaces, and is highly contagious during the acute phase [3]. Classic symptoms include sudden-onset sore throat, fever, tonsillar exudates, tender cervical lymphadenopathy, and absence of cough, which help differentiate it from viral causes [1]. Diagnosis is confirmed using rapid antigen detection tests (RADT) or throat culture, with RADT offering quick results and high specificity, while throat culture remains the gold standard for sensitivity [5]. First-line treatment involves a 10-day course of penicillin or amoxicillin, which effectively eradicates the bacteria, reduces transmission, and prevents serious complications such as acute rheumatic fever, post-streptococcal glomerulonephritis, peritonsillar abscess, and scarlet fever [6]. Despite global susceptibility to penicillin, rising resistance to macrolides like azithromycin necessitates careful antibiotic selection, especially in penicillin-allergic patients [7]. Public health strategies emphasize accurate diagnosis, antibiotic stewardship, and hygiene practices such as handwashing and respiratory etiquette to curb transmission [8]. While no vaccine is currently available, research into Group A streptococcus vaccine development offers future promise for primary prevention, particularly in low-resource settings where the burden of rheumatic heart disease remains high [9].

Etiology and Microbiology

Streptococcal pharyngitis is caused exclusively by Streptococcus pyogenes, a Gram-positive bacterium also known as group A streptococcus (GAS) [1]. This pathogen is the sole bacterial agent responsible for streptococcal sore throat and is distinguished from other causes of pharyngitis by its specific virulence mechanisms and immune interactions. GAS is a member of the Streptococcaceae family and is classified based on the antigenic properties of its M protein, a critical surface protein that contributes to both pathogenicity and immune evasion [11].

Bacterial Pathogen and Transmission

Streptococcus pyogenes is highly contagious and spreads primarily through respiratory droplets when an infected individual coughs, sneezes, or talks [12]. Transmission can also occur via direct contact with saliva, nasal secretions, or mucus, as well as through fomites—contaminated surfaces or objects such as utensils, toothbrushes, or drinking glasses [13]. Asymptomatic carriers, who harbor the bacteria in their pharynx without clinical symptoms, can also serve as reservoirs for transmission, particularly in close-contact settings such as households, schools, and daycare centers [14].

After exposure, the incubation period typically ranges from 2 to 5 days, after which symptoms manifest abruptly [15]. An infected person is most contagious during the acute phase of illness but can remain infectious for up to 2 to 3 weeks if left untreated. However, appropriate antibiotic therapy significantly reduces contagiousness, with individuals usually no longer transmitting the bacteria after 24 hours of treatment [1].

Virulence Factors and Pathogenesis

The ability of S. pyogenes to cause pharyngitis is mediated by a complex array of virulence factors that facilitate adherence, immune evasion, and tissue invasion. These mechanisms enable the bacterium to colonize the pharyngeal mucosa and initiate an inflammatory response.

Adherence to Pharyngeal Mucosa

Colonization begins with bacterial adherence to epithelial cells, a process mediated by several surface structures:

  • M protein: This major surface protein binds to host extracellular matrix components such as fibronectin and collagen, enhancing attachment to pharyngeal epithelial cells. It also interacts with CD44, a receptor on human keratinocytes, promoting tight adherence [11].
  • Hyaluronic acid capsule: Although primarily involved in immune evasion, this capsule also acts as a ligand for CD44, further supporting bacterial attachment [18].
  • Pili (fimbriae): Long, hair-like structures composed of pilin subunits that mediate firm adhesion to epithelial cells by binding to host matrix proteins [19].
  • Fibronectin-binding proteins: Surface molecules such as SfbI and PrtF1/2 that bind fibronectin in the host basement membrane, reinforcing bacterial attachment [20].

Immune Evasion Mechanisms

To survive in the hostile host environment, GAS employs multiple strategies to avoid immune detection and destruction:

  • M protein-mediated antiphagocytosis: The M protein inhibits opsonization by binding host proteins like fibrinogen and C4b-binding protein (C4BP), which block complement activation via the classical and lectin pathways, thereby preventing phagocytosis by neutrophils [21].
  • Molecular mimicry via hyaluronic acid capsule: The capsule is chemically identical to human hyaluronic acid, making it poorly immunogenic and allowing the bacterium to evade immune recognition. It also forms a physical barrier that limits complement deposition and phagocyte access [22].
  • Secreted complement inhibitors: GAS produces C5a peptidase (ScpA), which cleaves the chemotactic fragment C5a, reducing neutrophil recruitment to the infection site [23].

Tissue Invasion and Inflammatory Damage

Once adhered, GAS induces tissue damage and inflammation through the action of secreted toxins and enzymes:

  • Streptolysins:
    • Streptolysin O (SLO) is a cholesterol-dependent cytolysin that lyses epithelial cells, erythrocytes, and immune cells by forming pores in host membranes. SLO also facilitates intracellular survival by enabling escape from phagosomes [24].
    • Streptolysin S (SLS) contributes to epithelial damage and inflammation, though its mechanism is less well understood.
  • Streptococcal pyrogenic exotoxins (SPEs): Superantigens such as SpeA, SpeC, and SSA bind directly to MHC class II molecules and T-cell receptors, triggering massive polyclonal T-cell activation and a cytokine storm (e.g., TNF-α, IL-1, IL-6), leading to fever, systemic inflammation, and the rash seen in scarlet fever [25].
  • Proteases and DNases: Enzymes such as streptokinase, DNase (e.g., Sda1), and hyaluronidase degrade host macromolecules, facilitating bacterial spread. DNases also degrade neutrophil extracellular traps (NETs), helping GAS evade neutrophil-mediated killing [23].

Strain Variation and Tissue Tropism

GAS strains exhibit significant genetic diversity, particularly in the M protein, which is used to classify over 200 serotypes. Pharyngitis-causing strains often express specific M types (e.g., M1, M3, M12) and carry genes encoding superantigens like speA, which are less common in skin-tropic strains associated with impetigo. This variation reflects adaptation to specific host niches through differential expression of adhesins, toxins, and immune modulators [27].

Asymptomatic Carriage

A significant challenge in the microbiology of GAS is the phenomenon of asymptomatic carriage, where individuals harbor the organism in the pharynx without symptoms of infection. Carriage rates range from 5% to 20% in school-aged children and contribute to community transmission [28]. Because diagnostic tests such as rapid antigen detection tests (RADTs) and throat cultures cannot distinguish between active infection and colonization, clinical judgment guided by symptom assessment and scoring systems like the Centor criteria is essential to avoid overdiagnosis and unnecessary antibiotic use [29].

Clinical Presentation and Differential Diagnosis

Streptococcal pharyngitis, caused by Streptococcus pyogenes (Group A Streptococcus, GAS), presents with a distinct constellation of signs and symptoms that help differentiate it from viral causes of sore throat. The clinical presentation is typically abrupt, with prominent pharyngeal inflammation and systemic features. Accurate recognition of these manifestations is essential for guiding appropriate diagnostic testing and avoiding unnecessary antibiotic use. Differentiation from viral pharyngitis relies on a combination of symptom assessment, physical examination findings, and, when indicated, laboratory confirmation.

Key Clinical Features of Streptococcal Pharyngitis

The hallmark symptoms of streptococcal pharyngitis include a sudden-onset, severe sore throat and pain with swallowing (odynophagia) [1]. Fever is common, often exceeding 101°F (38.3°C), and may be accompanied by headache, body aches, and malaise [31]. In children, additional symptoms such as nausea, vomiting, and abdominal pain may be prominent, sometimes mimicking gastroenteritis [32].

Physical examination typically reveals erythema and significant swelling of the tonsils, often with visible tonsillar exudates—white or yellow patches of pus on the tonsillar surface [1]. Cervical lymphadenopathy is a key finding, with tender, enlarged anterior cervical lymph nodes palpable on the front of the neck [34]. Another characteristic but less common sign is the presence of palatal petechiae, which are tiny red spots on the soft palate [31]. These clinical features collectively increase the likelihood of a bacterial etiology.

In some cases, streptococcal infection can manifest as scarlet fever, a complication caused by toxin-producing strains of GAS. Scarlet fever is characterized by a diffuse, erythematous, sandpaper-like rash that begins on the trunk and spreads peripherally, often accompanied by a "strawberry tongue" and circumoral pallor [36]. The presence of this rash should prompt evaluation for GAS infection even in the absence of severe pharyngitis.

Distinguishing Features from Viral Pharyngitis

Differentiating streptococcal pharyngitis from viral causes is critical, as viral infections do not benefit from antibiotic therapy. Viral pharyngitis, which accounts for the majority of sore throats, typically presents with a more gradual onset and is associated with upper respiratory tract symptoms that are uncommon in GAS infection. The presence of cough, rhinorrhea (runny nose), hoarseness, conjunctivitis, and diarrhea strongly suggests a viral etiology [15]. These symptoms are rarely seen in uncomplicated streptococcal pharyngitis and serve as important negative predictors.

In contrast, the absence of cough is one of the most reliable clinical indicators of bacterial pharyngitis. The Centor criteria, a widely used clinical scoring system, incorporate this and other features to estimate the probability of GAS infection. The four components of the Centor score are: absence of cough, presence of tonsillar exudates, history of fever, and tender anterior cervical lymphadenopathy [38]. A higher score correlates with increased likelihood of GAS, with a score of 4 indicating a 30–60% probability in adults [39]. In pediatric populations, the modified McIsaac score adds an age adjustment, assigning an additional point to children aged 3–14 years, reflecting their higher risk [40].

Age-Related Variations in Presentation

The clinical presentation of streptococcal pharyngitis varies significantly by age. Children aged 5 to 15 years are at the highest risk and typically present with the classic triad of sore throat, fever, and tonsillar exudates [1]. In contrast, the disease is uncommon in children under 3 years of age, and routine testing is not recommended in this group due to the low incidence of GAS pharyngitis and the rare occurrence of complications such as acute rheumatic fever [42]. When it does occur in toddlers, symptoms may be atypical, including fever of unknown origin, irritability, anorexia, and rhinitis, making clinical diagnosis challenging [43].

Adults are less frequently affected, accounting for only 10–15% of sore throat cases, and may present with milder symptoms [44]. However, when classic features such as exudative tonsillitis and tender lymphadenopathy are present in the absence of viral symptoms, the possibility of GAS infection should still be considered.

Challenges of Asymptomatic Carriage

A significant challenge in diagnosis is the phenomenon of asymptomatic carriage, where individuals harbor GAS in the oropharynx without signs of active infection. Carriage rates can range from 5% to 20% in school-aged children, particularly in winter months [29]. Because diagnostic tests such as rapid antigen detection tests (RADTs) and throat cultures cannot distinguish between active infection and colonization, a positive test in a symptomatic patient with clear viral features may represent coincidental carriage rather than true disease [46]. This can lead to overdiagnosis and unnecessary antibiotic prescriptions, contributing to antimicrobial resistance.

To mitigate this, clinical judgment should guide testing decisions. Patients with a low pretest probability—such as those with cough, coryza, or other viral symptoms—should not be tested, as the likelihood of a positive result reflecting true infection is low [47]. In uncertain cases, serologic testing for rising titers of antistreptolysin O (ASO) or anti-DNase B antibodies can help confirm recent infection, as carriers typically do not mount a significant immune response [46].

In summary, the clinical presentation of streptococcal pharyngitis is characterized by abrupt onset of sore throat, fever, tonsillar exudates, and tender cervical lymphadenopathy, with the absence of cough being a key differentiator from viral causes. Age-specific variations and the challenge of asymptomatic carriage necessitate careful clinical assessment, often aided by scoring systems like the Centor or McIsaac criteria, to guide appropriate diagnostic testing and prevent misdiagnosis.

Diagnostic Methods and Testing Algorithms

Accurate diagnosis of streptococcal pharyngitis relies on a combination of clinical evaluation and laboratory confirmation to distinguish bacterial infection from viral causes and guide appropriate antibiotic use. Because clinical symptoms alone cannot reliably differentiate between viral and group A streptococcal (GAS) pharyngitis, laboratory testing is essential for definitive diagnosis. The primary diagnostic tools include rapid antigen detection tests (RADTs), throat cultures, and increasingly, molecular assays such as nucleic acid amplification tests (NAATs). Each method varies in sensitivity, specificity, turnaround time, and clinical utility, necessitating a stratified approach based on patient age, risk factors, and available resources.

Rapid Antigen Detection Tests (RADTs)

Rapid antigen detection tests are point-of-care diagnostics that detect GAS antigens directly from throat swab specimens, providing results within minutes. These tests are widely used in primary care, urgent care, and pediatric settings due to their speed and ease of use. RADTs have high specificity, typically ≥95%, meaning false-positive results are rare [49]. A positive RADT is considered sufficient to confirm GAS infection and initiate antibiotic therapy without the need for confirmatory testing in most cases [6].

However, RADTs have moderate sensitivity, ranging from 79% to 95.5%, with most studies reporting values around 80–90% [51]. This means that approximately 10–20% of true GAS infections may be missed, resulting in false-negative results. Therefore, when clinical suspicion remains high despite a negative RADT—especially in children—a confirmatory test is recommended. The use of RADTs aligns with antibiotic stewardship principles by reducing unnecessary prescriptions while ensuring timely treatment for confirmed cases [5].

Throat Culture

Throat culture remains the gold standard for diagnosing GAS pharyngitis due to its superior sensitivity and specificity under optimal laboratory conditions. The procedure involves collecting a throat swab from the tonsillar areas and posterior pharynx, which is then inoculated onto selective media to isolate and identify GAS. Sensitivity ranges from 78% to 97%, and specificity approaches 99%, minimizing false diagnoses [53].

Despite its diagnostic accuracy, throat culture has a major limitation: results take 24 to 48 hours, delaying clinical decision-making. This makes it unsuitable for immediate treatment initiation but valuable for confirming negative RADT results, particularly in pediatric populations. Current guidelines from the Infectious Diseases Society of America (IDSA) and the Centers for Disease Control and Prevention (CDC) recommend that children and adolescents with a negative RADT undergo a backup throat culture due to their higher prevalence of GAS and increased risk of complications such as acute rheumatic fever [6]. In adults, routine backup cultures are generally not recommended because the pretest probability of GAS is lower and the risk of rheumatic fever is minimal.

Molecular Assays (NAATs/PCR)

Molecular methods, including nucleic acid amplification tests (NAATs) such as polymerase chain reaction (PCR), offer a highly sensitive and specific alternative to traditional diagnostics. These assays detect GAS DNA or RNA directly from throat swabs and deliver results in 30 minutes to 2 hours, bridging the gap between the speed of RADTs and the accuracy of culture [55].

NAATs demonstrate superior performance, with sensitivities exceeding 95% and often reaching 97.5%, surpassing both RADTs and standard throat cultures in some evaluations [56]. Specificity is also very high, generally ≥98%, making them highly reliable for confirming infection [57]. Point-of-care NAAT systems like the Xpert® Xpress Strep A are increasingly adopted in clinical settings where rapid, accurate diagnosis is critical, particularly in high-risk populations or regions with high rates of rheumatic fever.

While NAATs reduce the need for confirmatory testing and improve diagnostic confidence, their higher cost and requirement for specialized equipment may limit access in resource-limited settings [58]. Nonetheless, they represent a significant advancement in diagnostic precision and are recommended in situations where maximizing sensitivity is paramount.

Clinical Scoring Systems and Testing Indications

To guide appropriate use of diagnostic testing and avoid overdiagnosis, clinical scoring systems such as the Centor and McIsaac criteria are used to estimate the pretest probability of GAS infection. The Centor criteria assign one point each for the following features: absence of cough, presence of tonsillar exudates, history of fever, and tender anterior cervical lymphadenopathy [38]. In pediatric patients, the McIsaac modification adds an age adjustment: +1 point for ages 3–14 years and −1 point for ages ≥15 years, improving predictive accuracy in younger populations [40].

A higher score correlates with increased likelihood of GAS infection:

  • Score of 0–1: Low risk (1–2% probability); testing not indicated
  • Score of 2: Intermediate risk (5–10% probability); testing recommended
  • Score of 3: High risk (15–30% probability); testing recommended
  • Score of 4: Very high risk (30–60% probability); testing strongly indicated [39]

Testing is generally not recommended for children under 3 years of age, as GAS pharyngitis is rare in this group and the risk of rheumatic fever is exceedingly low [62]. Similarly, individuals with clear viral symptoms such as cough, rhinorrhea, or conjunctivitis are unlikely to have GAS and typically do not require testing.

Differentiating Infection from Asymptomatic Carriage

A significant challenge in diagnosis is distinguishing true GAS pharyngitis from asymptomatic carriage, where individuals harbor the organism without signs of acute infection. Asymptomatic carriers can test positive on RADTs or cultures, leading to potential misdiagnosis and unnecessary antibiotic use [29]. These individuals are less likely to transmit the bacteria and do not benefit from treatment, as antibiotics have limited efficacy in eradicating colonization [64].

Clinical judgment remains essential: a positive test in a symptomatic patient with classic features (e.g., fever, exudates, absence of cough) supports true infection, whereas a positive result in someone with viral-like symptoms likely reflects carriage. In uncertain cases, serologic testing for rising titers of antistreptolysin O (ASO) or anti-DNase B antibodies may help confirm recent or active infection [46]. Repeat cultures during asymptomatic periods can also identify chronic carriers.

Summary of Testing Algorithms by Clinical Context

Population Preferred Method Rationale
Children with suspected GAS Initial RADT; if negative, confirm with culture or NAAT High pretest probability and risk of complications justify confirmatory testing [6].
Adults with suspected GAS RADT alone; no routine backup culture Lower prevalence and complication risk make confirmatory testing unnecessary [6].
High-risk populations (e.g., rheumatic fever endemic areas) Molecular assay (NAAT) preferred Superior sensitivity reduces missed diagnoses and prevents sequelae [68].
Point-of-care settings with access to molecular testing NAAT (e.g., Xpert® Xpress Strep A) Enables accurate, rapid diagnosis without need for follow-up testing [69].
Resource-limited settings RADT with selective use of throat culture Balances cost, availability, and diagnostic accuracy [70].

In conclusion, the diagnosis of streptococcal pharyngitis requires a nuanced, evidence-based approach that integrates clinical assessment with laboratory testing. RADTs offer rapid, specific results ideal for immediate decision-making, while throat cultures remain the reference standard for sensitivity. Molecular assays provide the highest diagnostic accuracy and are increasingly favored in modern practice. Testing should be guided by clinical scoring systems and reserved for patients with intermediate to high pretest probability to support antibiotic stewardship and prevent complications such as post-streptococcal glomerulonephritis and scarlet fever [6].

Treatment and Antibiotic Management

The treatment of streptococcal pharyngitis focuses on eradicating Streptococcus pyogenes, alleviating symptoms, preventing transmission, and most critically, avoiding post-infectious complications such as acute rheumatic fever and post-streptococcal glomerulonephritis. Antibiotic therapy is the cornerstone of management, with treatment decisions guided by confirmed diagnosis and patient-specific factors, particularly allergy status.

First-Line Antibiotic Therapy

Penicillin and amoxicillin are the preferred first-line agents for treating confirmed group A streptococcal (GAS) pharyngitis. These beta-lactam antibiotics are recommended by major health organizations, including the Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA), due to their proven efficacy, narrow spectrum of activity, safety, low cost, and lack of documented resistance in S. pyogenes [6]. The recommended regimen is a 10-day course to ensure complete eradication of the bacteria and to minimize the risk of complications.

  • Oral penicillin V: 250 mg twice daily for children under 27 kg or 500 mg twice daily for those 27 kg or more.
  • Amoxicillin: Often preferred in pediatric populations due to better taste and ease of dosing; administered at 50 mg/kg/day (up to 1000 mg/day) once or twice daily for 10 days [5].
  • Benzathine penicillin G: A single intramuscular injection (600,000 units for children ≤27 kg; 1.2 million units for children >27 kg) is an effective alternative, particularly for patients with concerns about adherence to a 10-day oral regimen [6].

The 10-day duration is critical, as shorter courses have been associated with lower eradication rates and a higher risk of complications such as acute rheumatic fever [75].

Alternative Therapies for Penicillin-Allergic Patients

For patients with a documented penicillin allergy, alternative antibiotics are selected based on the severity and type of allergic reaction.

  • Non-immediate (non-IgE-mediated) allergy: Patients with mild reactions, such as a non-anaphylactic rash, can safely receive first-generation cephalosporins like cephalexin or cefadroxil. The risk of cross-reactivity between penicillin and first-generation cephalosporins is low (less than 10%), and high-quality evidence supports their use as effective alternatives [76].
  • Immediate (IgE-mediated or anaphylactic) allergy: In patients with a history of anaphylaxis, angioedema, or urticaria, cephalosporins should be avoided. Recommended alternatives include:
    • Clindamycin: 20 mg/kg/day in three divided doses (maximum 1800 mg/day) for 10 days. Clindamycin is effective and does not rely on active bacterial replication, making it particularly useful in stationary-phase organisms [77].
    • Azithromycin: 12 mg/kg once daily (maximum 500 mg/day) for 5 days. While convenient due to its short course, macrolide resistance in S. pyogenes is a growing concern globally [7].
    • Clarithromycin: 15 mg/kg/day in two divided doses (maximum 1000 mg/day) for 10 days [79].

Clinicians are encouraged to verify penicillin allergy histories, as many labeled allergies are not IgE-mediated and can be safely de-labeled through evaluation or testing, thereby preserving the use of beta-lactam antibiotics [80].

Considerations Regarding Antibiotic Resistance

While Streptococcus pyogenes remains universally susceptible to penicillin, significant and rising resistance has been documented for macrolide and lincosamide antibiotics. Surveillance data from the CDC indicate that erythromycin resistance in invasive GAS isolates nearly tripled from 8% in 2010 to 23% by 2017, with global rates reaching as high as 87% in certain regions [7]. Macrolide resistance is primarily mediated by erm genes (conferring high-level resistance) and mef genes (conferring efflux-mediated resistance), which are often carried on mobile genetic elements that facilitate horizontal gene transfer [82].

This rising resistance necessitates cautious use of macrolides and clindamycin, particularly in regions with known high resistance rates. The D-test (double-disk diffusion test) is recommended when clindamycin is considered for treatment of severe GAS infections to detect inducible clindamycin resistance in strains with the iMLSB phenotype [83].

Supportive Care and Public Health Measures

In addition to antibiotics, supportive care measures can help manage symptoms. These include over-the-counter analgesics such as acetaminophen or ibuprofen, throat lozenges, warm saltwater gargles, and adequate hydration and rest [84].

From a public health perspective, patients should remain home from school or work until they have been on antibiotics for at least 12 hours and are fever-free to prevent spreading the infection [6]. This practice, combined with antibiotic stewardship—such as avoiding empirical treatment and confirming diagnosis with rapid antigen detection tests (RADTs) or throat culture—helps reduce unnecessary antibiotic use and combat the global threat of antimicrobial resistance [86].

Complications and Sequelae

If left untreated or inadequately managed, streptococcal pharyngitis can lead to a range of complications, from localized infections to severe systemic and immune-mediated sequelae. These complications arise either from direct bacterial spread or from an aberrant host immune response to Group A Streptococcus (GAS) antigens. Prompt diagnosis and appropriate antibiotic therapy are essential to prevent these outcomes, particularly in pediatric populations where the risk of post-infectious complications is highest.

Acute Rheumatic Fever

Acute rheumatic fever (ARF) is a serious, immune-mediated, nonsuppurative complication that typically develops 2 to 4 weeks after an untreated episode of streptococcal pharyngitis [87]. It is triggered by molecular mimicry, where antibodies directed against GAS antigens cross-react with host tissues, particularly in the heart, joints, skin, and central nervous system. The clinical manifestations of ARF are diverse and include:

  • Migratory polyarthritis, affecting large joints such as the knees and elbows
  • Carditis, which may involve endocarditis, myocarditis, or pericarditis and can lead to permanent valvular damage
  • Sydenham’s chorea, characterized by involuntary, rapid, purposeless movements
  • Erythema marginatum, a transient, non-pruritic rash with serpiginous borders
  • Subcutaneous nodules, firm painless lumps over bony prominences

The most significant long-term consequence of ARF is the development of rheumatic heart disease (RHD), a chronic condition involving progressive valve dysfunction, particularly of the mitral and aortic valves. RHD remains a major cause of cardiovascular morbidity and mortality in low- and middle-income countries, where access to timely diagnosis and treatment of streptococcal pharyngitis is limited [88]. Early administration of penicillin or amoxicillin within 9 days of symptom onset can reduce the risk of ARF by up to 80%, underscoring the critical importance of prompt antibiotic therapy [6].

Post-Streptococcal Glomerulonephritis

Post-streptococcal glomerulonephritis (PSGN) is a kidney disorder that occurs following infection with nephritogenic strains of GAS, typically 1 to 3 weeks after pharyngitis or skin infection [90]. It results from the deposition of immune complexes in the glomeruli, leading to inflammation and impaired kidney function. Clinical features include:

  • Hematuria, often presenting as dark, cola-colored urine
  • Proteinuria
  • Edema, particularly in the face, periorbital area, and lower extremities
  • Hypertension
  • Oliguria (reduced urine output)
  • Fatigue and signs of anemia

While most cases of PSGN resolve spontaneously, especially in children, some may progress to chronic kidney disease or acute kidney injury requiring hospitalization [91]. Unlike ARF, the preventive effect of antibiotics on PSGN is less well-established, as the immune response may be initiated before clinical symptoms of pharyngitis appear. However, timely treatment helps reduce community transmission of nephritogenic strains and limits secondary cases [92].

Peritonsillar Abscess

A peritonsillar abscess, also known as quinsy, is a localized collection of pus that forms in the peritonsillar space, usually as a complication of severe or untreated tonsillitis [93]. It is more common in adolescents and young adults and presents with:

  • Severe unilateral throat pain
  • Trismus (difficulty opening the mouth)
  • Muffled or “hot potato” voice
  • Drooling
  • Fever
  • Deviation of the uvula toward the unaffected side

Diagnosis is typically clinical, supported by imaging such as computed tomography (CT) if uncertainty exists. Management involves drainage—either by needle aspiration or incision—and a course of antibiotics, often with clindamycin or amoxicillin-clavulanate to cover potential polymicrobial infection [94].

Scarlet Fever

Scarlet fever is a toxin-mediated illness caused by strains of GAS that produce erythrogenic exotoxins (streptococcal pyrogenic exotoxins A, B, or C) [95]. It often occurs in conjunction with streptococcal pharyngitis and is characterized by:

  • A diffuse, erythematous, sandpaper-like rash that begins on the trunk and spreads peripherally
  • Circumoral pallor
  • Strawberry tongue (initially white-coated, later red and bumpy)
  • Pastia’s lines (dark red streaks in skin folds)
  • Fever and sore throat

Treatment involves a 10-day course of penicillin or amoxicillin, which effectively eliminates the bacteria and halts toxin production. Without treatment, scarlet fever can predispose individuals to complications such as ARF or PSGN [96].

Suppurative and Invasive Complications

In rare cases, GAS can spread beyond the pharynx, leading to suppurative and invasive infections. These include:

  • Otitis media (middle ear infection)
  • Sinusitis
  • Mastoiditis, an infection of the mastoid bone behind the ear
  • Cellulitis and erysipelas
  • Necrotizing fasciitis, a rapidly progressive soft tissue infection often referred to as “flesh-eating disease”
  • Streptococcal toxic shock syndrome (STSS), a life-threatening condition characterized by fever, hypotension, multi-organ failure, and high mortality

These invasive infections require urgent medical intervention, often involving surgical debridement and intravenous antibiotics [97].

Other Post-Streptococcal Sequelae

Additional immune-mediated conditions linked to GAS infection include:

  • PANDAS, a controversial syndrome involving abrupt-onset obsessive-compulsive disorder or tics following streptococcal infection [98]
  • Post-streptococcal reactive arthritis, which presents with joint inflammation and may be difficult to distinguish from ARF

Prevention of Complications

The cornerstone of preventing complications is the timely and accurate diagnosis of streptococcal pharyngitis, followed by a full 10-day course of appropriate antibiotics, typically penicillin or amoxicillin [5]. In regions where ARF is endemic, public health strategies emphasize secondary prophylaxis with regular intramuscular injections of benzathine penicillin G for individuals with a history of ARF to prevent recurrence [100]. Global efforts to improve access to diagnostics, antibiotics, and future Group A streptococcus vaccine development are critical to reducing the burden of post-streptococcal complications worldwide [9].

Prevention and Public Health Strategies

Preventing the transmission of Group A Streptococcus (GAS), the causative agent of streptococcal pharyngitis, requires a multifaceted approach that combines individual hygiene practices, accurate diagnosis, appropriate antibiotic use, and broader public health interventions. As the infection spreads primarily through respiratory droplets and direct contact with infected secretions, effective prevention strategies are essential to reduce both the incidence of acute illness and the risk of serious post-infectious complications such as acute rheumatic fever and post-streptococcal glomerulonephritis [6].

Personal and Environmental Hygiene Measures

The cornerstone of prevention lies in interrupting the chain of transmission through consistent hygiene practices. Key measures include frequent handwashing with soap and water, especially after coughing, sneezing, or touching surfaces that may be contaminated [8]. Respiratory etiquette—such as covering the mouth and nose with a tissue or the elbow when coughing or sneezing—helps minimize the spread of infectious droplets [8]. Individuals should also avoid sharing personal items like utensils, drinking glasses, towels, and toothbrushes to prevent direct transmission of the bacteria [8].

Regular disinfection of frequently touched surfaces, particularly in homes, schools, and healthcare settings, further reduces the risk of indirect transmission [8]. In educational environments, promoting hand hygiene and respiratory etiquette among children has been shown to significantly decrease illness-related absences and respiratory infections, including streptococcal pharyngitis [107]. The Centers for Disease Control and Prevention (CDC) has reinforced these measures as core components of infection control in K–12 schools [108].

Prompt Diagnosis and Antibiotic Treatment

Prompt diagnosis and appropriate antibiotic therapy are critical public health tools for preventing complications and limiting community spread. Antibiotics reduce the duration of contagiousness; individuals are typically no longer infectious after 24 hours of effective treatment [1]. Therefore, patients should stay home from school or work until they have been on antibiotics for at least 12 hours and are fever-free [6].

Accurate diagnosis is essential to avoid unnecessary antibiotic use, which contributes to antimicrobial resistance. Clinical scoring systems such as the Centor criteria and its pediatric adaptation, the McIsaac score, help stratify the likelihood of GAS infection based on symptoms like fever, tonsillar exudates, tender lymphadenopathy, and absence of cough [38]. However, laboratory confirmation using a rapid antigen detection test (RADT) or throat culture is required before initiating antibiotics [5]. A positive RADT is sufficient to confirm infection, while a negative result in children should be followed by a throat culture due to the higher risk of complications [6].

Antibiotic Stewardship and Resistance Management

Antibiotic stewardship is a key public health strategy to preserve the efficacy of first-line treatments. Penicillin and amoxicillin remain the preferred agents due to their narrow spectrum, safety, and lack of documented resistance in GAS [6]. Despite decades of use, no confirmed cases of penicillin-resistant GAS have been reported worldwide, underscoring the importance of reserving broader-spectrum antibiotics for specific indications [6].

In contrast, macrolide resistance—particularly to erythromycin and azithromycin—has risen significantly, with global rates increasing from 18.1% to 19.3% post-pandemic and exceeding 80% in some regions [116]. This resistance is mediated by genetic mechanisms such as erm and mef genes, which are often carried on mobile genetic elements that facilitate horizontal gene transfer [82]. Therefore, macrolides should be used cautiously, especially in areas with high resistance, and only when alternatives are contraindicated [79].

For patients with penicillin allergy, first-generation cephalosporins like cephalexin are safe and effective for non-anaphylactic reactions, while clindamycin or macrolides may be used in severe allergy cases, guided by local resistance patterns [119]. Verifying allergy histories and de-labeling non-true allergies can help preserve the use of beta-lactams [80].

Management of Close Contacts and Outbreaks

Routine testing or prophylactic treatment of asymptomatic close contacts, including siblings, is not recommended in most cases [6]. Asymptomatic individuals should monitor for symptoms such as sore throat, fever, or vomiting and seek medical evaluation if they develop illness [122]. However, in high-risk situations—such as household contacts of individuals with invasive GAS infection or outbreaks in closed settings—targeted antibiotic prophylaxis may be considered [123].

Public health authorities may implement enhanced surveillance, education campaigns, and temporary exclusion policies during outbreaks in schools or childcare centers [124]. The UK Health Security Agency (UKHSA) and other national bodies provide guidance on risk assessment and contact management to prevent secondary cases [123].

Global Surveillance and Seasonal Preparedness

GAS infections exhibit seasonal variation, with peaks in winter and early spring in temperate climates due to increased indoor crowding and reduced ventilation [126]. Surveillance systems such as the CDC’s Active Bacterial Core surveillance (ABCs) and national reporting protocols enable real-time tracking of trends and early detection of unusual increases in disease activity [127]. These systems are critical for anticipating seasonal peaks and guiding public health responses.

In low- and middle-income countries (LMICs), where the burden of rheumatic heart disease is highest, surveillance is often limited. The World Health Organization (WHO) recommends strengthening diagnostic capacity and implementing clinical algorithms to improve access to care [128]. School-based screening and treatment programs, such as those in New Zealand, have demonstrated up to a 60% reduction in acute rheumatic fever incidence among high-risk populations [129].

Vaccine Development and Future Prospects

While no vaccine is currently available, research into a Group A streptococcus vaccine is advancing rapidly. Challenges include antigenic variability of the M-protein and historical safety concerns, but recent candidates targeting conserved epitopes have shown promise in early trials [130]. A successful vaccine could prevent millions of cases of pharyngitis and its complications, reduce antibiotic use, and generate substantial herd immunity [131].

The WHO has published a technology roadmap to accelerate development, emphasizing the need for global partnerships, equitable access, and integration into existing immunization programs [132]. If deployed widely, a vaccine could avert an estimated 500,000 deaths annually from GAS-related diseases [133]. Such a development would represent a transformative shift in public health policy, reducing reliance on antibiotics and reshaping transmission dynamics worldwide [134].

Special Populations and Age-Related Considerations

The diagnosis and management of streptococcal pharyngitis vary significantly across different age groups and special populations due to differences in disease prevalence, clinical presentation, risk of complications, and diagnostic considerations. Understanding these variations is essential for accurate diagnosis, appropriate antibiotic use, and effective prevention of post-infectious sequelae.

Children Under 3 Years

Streptococcal pharyngitis is uncommon in children under 3 years of age, and routine diagnostic testing is generally not recommended in this group [135]. The risk of complications such as acute rheumatic fever is exceedingly low in this age group, further supporting a conservative approach to testing and treatment [62]. When Group A Streptococcus (GAS) infection does occur, it may present atypically with nonspecific symptoms such as fever of unknown origin, irritability, anorexia, abdominal pain, nausea, vomiting, or rhinitis, which can mimic viral illness [137]. The classic signs of exudative tonsillitis and severe sore throat are less prominent, making clinical diagnosis challenging. Testing may be considered if there is a known household exposure to GAS or if symptoms persist or worsen.

Children Aged 3 to 15 Years

This age group has the highest incidence of streptococcal pharyngitis, with peak occurrence between 5 and 15 years [1]. Children in this range typically present with the classic triad of severe sore throat, fever (>38°C), and tonsillar exudates [44]. The absence of cough and coryza is a key differentiator from viral pharyngitis. The modified Centor (McIsaac) score, which incorporates age as a variable, is widely used to assess pretest probability in pediatric patients [140]. A score of 3 or higher supports diagnostic testing with a rapid antigen detection test (RADT). Due to the higher risk of complications such as acute rheumatic fever, a negative RADT in children and adolescents should be confirmed with a throat culture to rule out false-negative results [6].

Adolescents and Adults

While adolescents may present similarly to younger children, adults are less likely to have streptococcal pharyngitis, accounting for only 10–15% of adult sore throats [44]. Adult presentations may be milder or atypical, and the risk of acute rheumatic fever is significantly lower than in children. As a result, routine backup throat culture after a negative RADT is not recommended in adults, as the likelihood of GAS infection and the risk of complications are both reduced [5]. Clinical decision-making in adults relies more heavily on symptom assessment and pretest probability, with testing reserved for patients exhibiting classic features of bacterial pharyngitis.

Asymptomatic Carriers and Diagnostic Challenges

Asymptomatic carriage of GAS complicates the diagnosis of streptococcal pharyngitis, particularly in pediatric populations. Carriage rates can range from 5% to 20% in school-aged children, and carriers may test positive on RADT or throat culture without having active infection [29]. This increases the risk of overdiagnosis and unnecessary antibiotic prescriptions. Differentiating true infection from colonization relies on clinical judgment, with emphasis on the presence of symptoms such as sudden-onset sore throat, fever, tonsillar exudates, and tender cervical lymphadenopathy. Repeat testing during asymptomatic periods or serologic testing for rising titers of antistreptolysin O (ASO) or anti-DNase B antibodies may help identify chronic carriers in uncertain cases [46].

Management in High-Risk and Institutional Settings

In closed or institutional settings such as schools, daycare centers, or long-term care facilities, the risk of GAS transmission is elevated due to close contact and crowded conditions [146]. Outbreaks may require enhanced surveillance, prompt diagnosis, and exclusion of symptomatic individuals until they have been on antibiotics for at least 12 hours [8]. In high-risk populations, such as those in regions with high rates of rheumatic heart disease, public health strategies may include school-based screening programs and targeted antibiotic use to prevent complications [129]. During outbreaks, prophylactic antibiotics may be considered for close contacts in specific high-risk scenarios, particularly in households with immunocompromised individuals or during invasive GAS infections [123].

Considerations for Penicillin-Allergic Patients

Antibiotic selection in penicillin-allergic patients must be guided by the severity of the allergy and local resistance patterns. For non-anaphylactic allergies, first-generation cephalosporins such as cephalexin are safe and effective alternatives due to low cross-reactivity [119]. For IgE-mediated (anaphylactic) allergies, alternatives include clindamycin or macrolides such as azithromycin. However, rising global resistance to macrolides, with erythromycin resistance rates exceeding 20% in some regions, limits the utility of these agents [7]. Clinicians are encouraged to verify penicillin allergy histories, as many labeled allergies are not true IgE-mediated reactions, and allergy de-labeling can preserve the use of first-line beta-lactam therapy [80].

Global Epidemiology and Disease Burden

Streptococcal pharyngitis, caused by Streptococcus pyogenes (Group A Streptococcus, GAS), represents a substantial global health burden, with over 616 million incident cases annually worldwide [153]. The disease disproportionately affects children, with an estimated 288.6 million episodes occurring in children aged 5–14 years each year [154]. GAS accounts for approximately 20–25% of sore throat cases in children globally, although this proportion varies significantly by region and healthcare infrastructure [155]. The global incidence of GAS infections, including pharyngitis and invasive forms, has shown a notable increase in recent years, particularly following the post-pandemic resurgence observed in 2023 and 2024 across regions such as the United States, Europe, and Japan [156]. This resurgence has been linked to disruptions in population immunity, increased viral circulation, and changes in social behavior after the relaxation of public health measures during the COVID-19 pandemic [157].

Regional and Resource-Based Disparities

A marked disparity exists in the epidemiology of streptococcal pharyngitis between high-income and low- and middle-income countries (LMICs). In high-resource settings, the prevalence of GAS among children presenting with sore throat is relatively low, averaging around 10%, due to widespread access to diagnostics such as rapid antigen detection tests (RADTs) and throat cultures, prompt antibiotic treatment, and effective infection control measures [158]. In contrast, low-resource settings report significantly higher prevalence rates, with some studies indicating that over 24% of sore throat cases in children are attributable to GAS, and rates exceeding 30% in certain areas [155]. Factors contributing to this disparity include overcrowding, poor sanitation, limited healthcare access, and the common practice of over-the-counter antibiotic use without proper diagnosis, which can exacerbate antimicrobial resistance pressures [155].

Disease Burden and Post-Infectious Sequelae

While acute streptococcal pharyngitis is typically self-limiting or easily treatable, its most significant public health consequences arise from post-infectious immune-mediated complications. The most severe of these are acute rheumatic fever (ARF) and rheumatic heart disease (RHD), which remain leading causes of cardiovascular morbidity and mortality among children and young adults in endemic regions. The global incidence of ARF is estimated at 8 to 51 cases per 100,000 population, with the highest rates observed in LMICs and marginalized populations in high-income countries [161]. RHD affects an estimated 40 to 55 million people globally and causes approximately 300,000 to 360,000 deaths annually [162]. Over 90% of these deaths occur in resource-limited settings, particularly in sub-Saharan Africa, South Asia, and Indigenous populations in Australia and New Zealand [155]. Age-standardized death rates from RHD can exceed 10 per 100,000 in parts of Oceania and Central Sub-Saharan Africa, compared to less than 0.1 per 100,000 in high-income Western nations [164].

Other post-streptococcal sequelae include post-streptococcal glomerulonephritis (PSGN), which results from immune complex deposition in the kidneys and can lead to acute kidney injury, particularly in children [90]. Additionally, conditions such as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and post-streptococcal reactive arthritis contribute to the broader disease burden, though they are less common and more controversial in diagnosis [98]. Collectively, severe GAS diseases—including invasive infections, ARF, RHD, and PSGN—account for at least 517,000 deaths annually and affect over 18 million people worldwide [167].

Seasonal and Geographic Patterns

Streptococcal pharyngitis exhibits a consistent seasonal pattern, with peak incidence occurring during winter and early spring in temperate climates [168]. In the United States, GAS activity typically rises from December through April, coinciding with school attendance cycles and increased indoor crowding [169]. Surveillance systems such as the CDC’s Active Bacterial Core surveillance (ABCs) and Public Health Scotland’s quarterly reports enable real-time tracking of these trends and facilitate early warning of outbreaks [127]. In tropical regions, transmission may occur year-round, though data are often limited. Regional variations also exist; for example, within the United States, the highest rates of GAS pharyngitis are reported in the South, possibly due to climatic and socioeconomic factors [171].

Public Health Implications and Global Response

The divergent epidemiological profiles of streptococcal pharyngitis across global settings underscore the need for context-specific public health strategies. In high-income countries, robust surveillance, diagnostic accuracy, and antibiotic stewardship have effectively minimized both transmission and complications [5]. In contrast, low-resource settings face systemic gaps in healthcare infrastructure, leading to underreporting, delayed diagnosis, and uncontrolled progression to ARF and RHD [155]. The World Health Organization (WHO) has emphasized the importance of strengthening primary healthcare systems, improving access to penicillin, and implementing secondary prophylaxis programs for individuals with a history of ARF [9]. The 2023 World Heart Federation guidelines further refine diagnostic criteria for RHD using echocardiography, enabling earlier detection and intervention [175].

Efforts to develop a Group A streptococcus vaccine represent a critical opportunity to reduce the global burden of disease. Modeling studies suggest that a moderately effective vaccine could prevent millions of cases of pharyngitis and skin infections, significantly reduce ARF and RHD incidence, and avert substantial morbidity and mortality [131]. Such a vaccine would also support global antibiotic stewardship by reducing the need for diagnostic testing and antibiotic prescriptions, thereby mitigating antimicrobial resistance [86]. Proactive planning, equitable pricing, and integration with existing immunization programs will be essential to ensure that high-burden countries benefit equitably from vaccine deployment [134].

References