Scarlet Fever

Etiology

GAS is a gram-positive, non-sporeforming, and catalase- and oxidase-negative bacterium that grows in pairs and chains.[2] GAS thrives on blood agar when incubated at 35 °C to 37°C, with optimal growth in a 10% carbon dioxide environment. The bacterium forms smooth, moist, greyish-white colonies with clear margins, measuring over 0.5 mm.[6] The colonies are surrοunded by a zone of complete hemolysis (β-hemolysis).[6] GAS is found ubiquitously in nature and is adapted to humans. The only known reservoirs in humans are the mucous membranes and skin. GAS commonly causes a wide range of infections in the upper respiratory tract and skin, such as pharyngitis, scarlet fever, impetigo, cellulitis, and erysipelas. These infections can vary in severity, ranging from mild and superficial to severe and invasive GAS (iGAS).[6][9]

Invasive infections typically occur in normally sterile sites, such as the bloodstream, cerebrospinal fluid, or pleura. Both GAS and iGAS infections are increasing globally, with high morbidity and mortality rates.[6][9] In addition to acute infections, GAS infections can trigger immune-mediated sequelae, such as acute rheumatic fever (ARF), PSGN, and complications such as RHD. Recent data suggest that in the United States, 1% to 3% of patients with untreated GAS infections, usually GAS pharyngitis, will develop ARF, and 60% of these cases will progress to chronic RHD.[10] 

The Lancefield classification categorizes streptococci according to serological groups, designated from A to O, which are based on the reactions between antisera and carbohydrate antigens on the streptococcal cell wall.[11] At least 20 serological groups have been identified, including groups A, B, and C. GAS belongs to Lancefield group A.[12][13] Other streptococci in different Lancefield groups can cause similar syndromes to those caused by GAS. Notably, group B Streptococcus (GBS; S agalactiae) colonizes the human gastrointestinal and genital mucosa and can cause puerperal sepsis and neonatal infections, such as pneumonia, bacteremia, and meningitis.[14] 

Many virulence determinants have been identified in GAS, enabling it to perform key processes such as adhesion, colonization, immune evasion, invasion, and dissemination within the host.[15] Prominent virulence factors include the M-protein, hyaluronic acid, streptokinase, and DNase B. Notable toxins, such as pyrogenic toxins (also known as scarlatina toxins or erythrogenic toxins), are responsible for the rash in scarlet fever. These toxins also induce mononuclear cells to produce tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, which may contribute to fever and shock in patients with streptococcal toxic shock syndrome (STSS).[6][16]

GAS is further classified based on the serotypes of M- and T antigens expressed on its surface.[11] Traditional serotyping methods for detecting these antigens have largely been replaced by sequence typing of the N-terminal region of the M-protein (emm) gene, which is now widely used for genotyping GAS, particularly for epidemiological studies.[11][17] Whole genome sequencing (WGS) is increasingly used to identify epidemic strains. To date, over 250 emm types have been identified based on the M-protein gene sequence. Over 250 emm types have been identified based on the gene sequence of the M-protein.[18][11] The streptococcal M-protein, encoded by the emm gene and used for epidemiological typing, serves as a virulence factor and holds potential as a vaccine antigen.[17] 

Emm1 strains are particularly virulent and are frequently associated with invasive infections.[19] Specific emm types, such as M1, M2, M3, M4, M6, M12, and M22, have been linked to scarlet fever outbreaks. A global resurgence of scarlet fever has been reported in regions including the United Kingdom, Hong Kong, mainland China, and Korea, often associated with the emergence of novel emm clones.[20][21] 

GAS is one of the few bacteria capable of producing superantigen exotoxins, which are among the most potent activators of T cells. These superantigens, also referred to as erythrogenic or scarlet fever toxins, are responsible for the erythematous sandpaper-like rash and strawberry tongue characteristic of scarlet fever.[5] In conditions such as STSS, certain superantigenic exotoxins trigger atypical polyclonal activation of lymphocytes, leading to a rapid onset of shock and multiorgan failure with high mortality rates. Key identified superantigenic exotoxins include toxic shock syndrome toxin-1 (TSST-1) and enterotoxins.[16]

Epidemiology

Epidemic scarlet fever, also known as scarlatina, is a cutaneous eruption caused by SPEs produced during GAS infections in humans and is most commonly associated with GAS pharyngitis. However, it can also arise from other GAS infections. Scarlet fever is a toxin-mediated disease that tends to occur in epidemics approximately every 5 to 6 years, likely due to type-specific herd immunity. Historically, it caused significant morbidity and mortality during the 19th and early 20th centuries.[22] The prevalence of scarlet fever declined significantly in the latter half of the 20th century, likely due to the introduction of antibiotics, reducing its public health impact.[20][1] Characteristic symptoms of scarlet fever include a coarse, papular erythematous rash, a strawberry tongue, and exudative pharyngitis.[1]

GAS exclusively infects humans and can affect many areas of the body.[2] Globally, GAS infections are increasing, contributing to significant morbidity and mortality rates.[6][9] Transmission of GAS occurs through respiratory secretions, fomites, and contact with infected skin, such as in impetigo. While GAS infections can affect individuals of any age, children, older adults, and immunocompromised individuals are at higher risk.[23][3] The incubation period for GAS ranges from 1 to 5 days, during which patients remain infectious and can transmit the bacteria to others.[3] Environmental factors and crowded settings, such as schools, households, and nursing homes, facilitate increased GAS transmission.[3][4] GAS commonly causes a variety of infections in the upper respiratory tract and skin, ranging from mild to severe and from superficial to iGAS.[6][9] Heavy shedding of GAS in classrooms or other crowded spaces, even in asymptomatic individuals, can lead to outbreaks.[3]

GAS has been reported to cause disease in young, healthy individuals, with a study noting its occurrence in 25% of those without risk factors.[4] GAS may exist as an asymptomatic carrier in the pharynx or act as a pathogen causing GAS pharyngitis. Within populations, an estimated 5% to 15% of individuals are asymptomatic carriers. Pharyngitis results from person-to-person transmission through oropharyngeal secretions and droplets from infected individuals.[15][24] GAS infections can be categorized based on their location and depth, including pharyngitis, scarlet fever, impetigo (superficial keratin layer), cellulitis (subcutaneous tissue), erysipelas (superficial epidermis), STTS, myositis and myonecrosis (muscle), and necrotizing fasciitis (fascia).[25] In addition to these infections, GAS can trigger immune-mediated sequelae, such as ARF and PSGN, as well as direct sequelae of immune-mediated processes, such as RHD.[26]

The epidemiology of GAS-related infections varies by infection type. GAS pharyngitis is most common in children aged 5 to 15 and is the most common bacterial cause of acute bacterial pharyngitis in this age group. This is commonly associated with contact with sick or asymptomatic children at school.[3][27] GAS is the most common bacterial cause of acute pharyngitis and is responsible for 5% to 15% of visits for sore throat in adults and 20% to 30% in children who complain of pharyngitis.[27][28][29]

Pharyngitis caused by GAS typically occurs in the winter and early spring.[27] Severe illness and invasive infections exhibit a bimodal distribution, which is more common in individuals aged 2 or younger and 50 or older.[24][30] Risk factors for increased mortality include advancing age, male gender, residence in a nursing home, chronic underlying illnesses, immunosuppression, recent surgery, septic shock, necrotizing fasciitis, concurrent viral infection, isolated bacteremia, and the presence of emm type 1 or 3 strains.[4][30]

The global prevalence of severe GAS infections is estimated at 18.1 million cases, with 1.78 million new cases of GAS and 616 million cases of GAS pharyngitis reported annually.[31] Severe GAS infections are responsible for approximately 500,000 deaths globally each year, with most attributed to RHD and invasive infections.[31] The burden of iGAS is significant, accounting for approximately 663,000 new cases and 163,000 deaths annually.[31] Skin and soft tissue are the most common sites of infection, with 32% of patients presenting with cellulitis and 8% developing necrotizing fasciitis.[4]

GAS emm1 strains are highly virulent, and the M-protein, encoded by the emm gene, serves as a key virulence factor in GAS.[32] The resurgence of GAS infections in the 1980s was attributed to the emergence of emm1 as the predominant cause of iGAS infections following genetic changes.[33] GAS emm1 strains are highly virulent and associated with invasive infections.[34] Specific strains, including M1, M2, M3, M4, M6, M12, and M22, have been linked to scarlet fever outbreaks. A global reemergence of scarlet fever has been reported in countries such as the United Kingdom, Hong Kong, mainland China, and Korea and is often associated with novel emm clones.[20][21] 

Epidemiological surveillance is crucial to monitor epidemics, particularly due to the increasing incidence and burden of GAS infections, especially iGAS, worldwide. WGS has a key role in this monitoring.[9][11][18][30][31] Since 2000, the dominant emm types in Europe and North America have been emm1 and emm3, with emm1 being the dominant type associated with invasive infections in high-income countries.[32] The 7 emm types responsible for 50% to 70% of iGAS infections were emm1, emm28, emm89, emm3, emm12, emm4, and emm6.[11][35] These emm types are collectively referred to as M1_global.

In 2011, a scarlet fever outbreak in Hong Kong documented a 10-fold increase in cases compared to the baseline and was associated with GAS types emm12 and emm1. Among the isolates cultured during that year, emm12 was the dominant clone.[36] GAS strains harboring these emm types had acquired mutations that enhanced their virulence and transmissibility.[36] Surveillance for emm types in Hong Kong revealed that these new strains exhibited increased resistance to macrolides and clindamycin due to the internalization of resistance genes from bacteria found in the human urogenital and gastrointestinal tracts.[37] 

Following the Hong Kong outbreak, WGS revealed an increase in scarlet fever cases in mainland China, with the expansion of emm12 clones contributing to the rise in infections.[21] Furthermore, the analysis revealed that the mobile genetic elements involved in the spread were the streptococcal toxin-encoding prophages φHKU.vir and φHKU.ssa, as well as the macrolide and tetracycline-resistant ICE-emm12 and ICE-HKU397. This indicated that multiclonal emm12 isolates had a significant role in expanding scarlet fever lineages both in China and globally.[21]

A new emm1 sublineage, termed "M1_UK," was identified in 2008 in the United Kingdom and was associated with increased expression of the scarlet fever toxin and SPE-A (speA). Epidemiological surveillance during the scarlet fever outbreak in 2014 in the United Kingdom revealed that regional outbreaks were caused by multiple emm types, including emm3, emm12, emm1, and emm4, as well as various phylogenetic lineages. A significant increase in the prevalence of the ssa gene was associated with scarlet fever cases.[14] The M1_UK lineage was responsible for the rising number of cases, outbreaks, and invasive infections in the United Kingdom from 2014 to 2018, eventually becoming the dominant strain in the country.[34][38][39] By 2020, the M1_UK lineage accounted for 91% of invasive emm1 isolates in England.[34] The incidence of scarlet fever declined during the COVID-19 pandemic.

Following the COVID-19 pandemic, 3 emerging M1_UK clades rapidly expanded across the United Kingdom, resulting in severe outcomes in children. The emergence of a new dominant clone within the emm1 genetic lineage, referred to as "M1_UK," was first reported in the United Kingdom in 2019. This clone was associated with seasonal outbreaks of scarlet fever and an increase in invasive infections, likely driven by a 10-fold overproduction of speA superantigen, also known as erythrogenic toxin A or scarlet fever toxin.[39] The genomic structure of the M1_UK lineage differed from the classic M1T1 strain, having accumulated an additional 27 single-nucleotide polymorphisms that resulted in enhanced production of the speA superantigen compared to M1T1 isolates.[19] 

The M1_UK lineage appears to have outcompeted the globally dominant emm1 M1_global strain, which had been widespread since the 1980s. M1_UK strains were found to produce higher levels of the superantigenic scarlet fever toxin speA compared to contemporary M1_global strains.[34] Although declining immunity may contribute to streptococcal outbreaks, the genetic characteristics of M1_UK suggest a fitness advantage in pathogenicity and an exceptional ability to endure population bottlenecks. M1_UK is now the dominant strain in England. Two other lineages, M113SNPs and M123SNPs, were also identified.[32][40] GAS emm1 strains are responsible for more than 50% of invasive infections in children in the United Kingdom during the 2022-23 season.[32][34] All globally sequenced M1_UK isolates (speA) can be traced back to the United Kingdom, where they caused an epidemic and have since spread into Europe and internationally.[32] 

Pathophysiology

Many GAS virulence determinants facilitate key processes, including adhesion, colonization, evasion of the innate immune system, invasion, and dissemination within the host.[15] Key virulence factors include the M-protein, hyaluronic acid, streptokinase, and DNase B. Notable toxins include the pyrogenic toxins (also called scarlatina or erythrogenic toxins), which are responsible for the rash seen in scarlet fever. These toxins also induce mononuclear cells to produce TNF-α, IL-1, and IL-6, potentially contributing to fever and shock in patients with STTS.[6][16] 

The streptococcal M-protein, encoded by the emm gene and used for epidemiological typing, serves as a critical virulence factor and potential vaccine antigen.[17] Strains classified as emm1 are particularly virulent and frequently implicated in invasive infections. Specific emm types, including M1, M2, M3, M4, M6, M12, and M22, have been associated with scarlet fever outbreaks. A global resurgence of scarlet fever has been reported in countries such as the United Kingdom, Hong Kong, mainland China, and Korea, and it is often linked to the emergence of novel emm clones.[20][21] 

GAS is one of the few bacteria that produce superantigen exotoxins, which are among the most potent activators of T cells. GAS superantigens, also known as erythrogenic or scarlet fever toxins, are responsible for the erythematous sandpaper rash and strawberry tongue characteristic of scarlet fever.[5] In syndromes such as STTS, certain bacterial superantigenic exotoxins cause atypical polyclonal lymphocyte activation, leading to rapid-onset shock, multiorgan failure, and high mortality. The primary superantigenic exotoxins implicated include TSST-1 and enterotoxins.[16]

The scarlet fever rash was once believed to result from primary toxicity caused by GAS. However, it is now understood to stem from a delayed host-acquired hypersensitivity reaction to streptococcal superantigens. Furthermore, the rash typically appears in individuals who have been previously exposed to GAS and is thus pre-sensitized, while it is absent in those with no prior GAS infection. The skin reactivity is likely due to rapid cytokine release and leukocyte presence, triggered by the amplified response to GAS superantigens during secondary antigen exposure.[41][42]

Histopathology

Scarlet fever does not exhibit specific histological changes. Histological findings may include neutrophilic infiltrate, spongiosis, and parakeratosis in the epidermis.

History and Physical

A comprehensive history of the present illness and past medical history is essential for evaluating patients with symptoms of infection. Patients may seek medical attention for complaints such as pharyngitis or cellulitis without initially noticing the rash. Scarlet fever is most commonly associated with acute pharyngitis caused by GAS but may also result from other GAS infections, such as erysipelas or wound infections.[41] The incubation period for GAS ranges from 1 to 5 days. The characteristic rash of scarlet fever typically appears 24 to 48 hours after the onset of initial symptoms, most commonly GAS pharyngitis.

The most common symptoms of GAS pharyngitis include a sudden onset of fever and sore throat. Additional complaints may include headache, nausea, chills, vomiting, and abdominal pain.[43] When taking a patient’s history, it is common to note exposure to close contact with a GAS infection, particularly if the individual is a school-age child or someone residing in a community setting, such as a nursing home, where close living conditions can increase the risk of transmission. On examination, physical findings of GAS pharyngitis typically include generalized inflammation of the tonsils and pharynx, variable tonsillar exudates, a red and swollen uvula, and palatal petechiae. Tender cervical lymphadenopathy is also commonly noted on palpation.[43] 

Conjunctivitis, cough, coryza, emesis, or diarrhea may be present, and their presence typically suggests a viral etiology rather than GAS.[44] Physical examination of the posterior oropharynx alone is generally insufficient to differentiate GAS from other causes of acute pharyngitis, such as viral pharyngitis, which is the most common type. While the Centor Criteria were developed to aid in diagnosing GAS pharyngitis based on clinical findings, they are not reliable as a standalone tool and should be supplemented with microbiological testing for accurate diagnosis.[43][45] 

A thorough skin examination is essential, as a fine, blanching, maculopapular erythematous rash accompanied by a strawberry tongue strongly suggests scarlet fever.[46] The rash associated with scarlet fever typically appears 2 to 3 days after the onset of infection but can be delayed for up to 7 days. The rashes generally begin on the trunk, underarms, and groin, spreading to the extremities while sparing the palms and soles.[46] The area around the mouth remains pale, creating a distinctive "circumoral pallor." A characteristic strawberry tongue develops, initially presenting with a white membrane on the tongue and enlarged, protruding papillae, referred to as a "white strawberry tongue." As the membrane sloughs off, the papillae persist, giving the tongue a red, strawberry-like appearance.[46] Pastia lines are linear clusters of papules observed in skin folds or pressure points, such as the neck, antecubital fossa, and groin. After the initial rash subsides, a phase of skin desquamation may occur, sometimes lasting up to 2 weeks.[46]

Evaluation

When evaluating a patient suspected of having scarlet fever due to a blanching, maculopapular, sandpaper-like rash, or other compatible physical findings, it is essential to identify the source of their GAS infection. As scarlet fever is most commonly associated with GAS pharyngitis, the use of the CENTOR criteria, combined with laboratory testing when necessary, can help confirm or rule out this diagnosis.[47][48][49] If pharyngitis is excluded, other potential sites of primary GAS infection should be investigated, necessitating a thorough physical examination.

Laboratory testing for GAS pharyngitis involves a throat swab and culture, which remain the gold standard for identifying GAS. GAS is easily cultured on sheep blood agar and is both catalase- and oxidase-negative. Confirmatory identification can be performed using Lancefield grouping or more advanced methods such as the matrix-assisted laser desorption ionization-time of flight (MALDI-TOF). [2][50] However, culture results typically take 24 hours or longer, which may delay critical decisions related to treatment, isolation, and epidemiological considerations.

A rapid antigen detection test (RADT) can also be used to diagnose GAS pharyngitis. The RADT has a sensitivity of approximately 85% in children, although there is some variability, and its specificity is stable at 95%.[51] Due to the RADT's high specificity in children, antibiotic therapy is recommended without the need for a follow-up throat culture to distinguish between infection and carriage. If the RADT result is negative, treatment decisions should follow national guidelines.[51] However, in the United States, adults typically have a lower general rate of GAS pharyngitis, resulting in a low pretest probability. Therefore, when a negative RADT is obtained, confirmatory culture is generally not necessary, as a negative rapid swab strongly reduces the likelihood of GAS infection.[44][44] To culture GAS from other body sites, whether superficial or deep (eg, skin, blood, wound, or lung), it is recommended to perform a Gram stain and culture to make a definitive diagnosis. A polymerase chain reaction (PCR) can also identify specific GAS strains, particularly in complicated cases.[52]

Treatment / Management

Timely and accurate recognition of GAS infections, particularly in patients with a scarlatiniform rash, can be challenging due to the wide range of conditions that may present with similar clinical features. The presence of a scarlatiniform rash accompanied by pharyngitis symptoms should strongly indicate scarlet fever as a leading diagnostic consideration. Diagnostic tests should be promptly performed, and treatment should be initiated without delay. GAS infections are associated with increased morbidity due to the potential for invasive disease and are among the top 10 infectious causes with the highest mortality rates.[8] Culture results are crucial for tailoring antibiotic therapy and ensuring that the initial empirical antibiotic regimen covers GAS, especially in light of reports of penicillin resistance and the increasing resistance of GAS to macrolides and clindamycin.[43](A1)

β-lactam antibiotics remain consistently effective against GAS and scarlet fever and are the preferred treatment for both noninvasive and iGAS infections. While there have been reports of penicillin resistance and increased minimum inhibitory concentrations to penicillin and cephalosporins, these are primarily attributed to mutations in the peptidoglycan-synthetic enzyme pbp2x gene. However, resistance rates remain low,[43][53] and penicillin continues to be the gold standard for treatment.[43][54] For patients allergic to penicillin, the most notable alternative antibiotics are macrolides (eg, erythromycin) and lincosamides (eg, clindamycin). However, resistance to these antibiotics has increased over the past decade, with variable prevalence of resistant GAS strains observed globally.[55] (A1)

Reports from China indicate macrolide resistance rates as high as 90%, while some European countries report resistance rates of 20% to 40% for macrolides and up to 19% for lincosamides. In other parts of Europe, resistance rates may be as low as 2%.[55][56] These variations are attributed to macrolide resistance mechanisms, including those encoding the MLSb phenotype.[55][56][57] If these antibiotics are resistant, alternative antibiotics for penicillin-allergic patients can be considered. The choice of therapy should be based on the location and severity of infection, local antibiotic resistance patterns associated with GAS, and the allergy profile of the patient.[43] (A1)

More specifically, when treating GAS pharyngitis and scarlet fever, a 10-day course of oral antibiotics is typically recommended. Recommended regimens include penicillin V or amoxicillin for 10 days, which is administered by mouth.[43] An alternative treatment for GAS pharyngitis is a single intramuscular dose of penicillin G benzathine, particularly for patients who may not complete the full course of oral antibiotics.[43][44] Macrolides or clindamycin can be used for patients allergic to penicillin, although local resistance patterns should be considered.[43](A1)

Broad-spectrum antibiotics should be initiated for severe infections caused by GAS, such as necrotizing fasciitis and TSS, to ensure adequate coverage while awaiting final culture results.[58] For severe infections, such as TSST-1 and necrotizing fasciitis, clindamycin is often added to the antibiotic regimen, such as penicillin, as it may inhibit superantigen production and facilitate phagocytosis of S pyogenes by blocking M-protein production.[59] In addition to antibiotics, supportive measures—such as fluid resuscitation and blood pressure management with vasopressors—should also be implemented for these severe or systemic infections.[60][61](B3)

Differential Diagnosis

The differential diagnosis for fever and rash is broad. When a sandpaper-like rash is observed, additional clinical findings, signs, and symptoms should be evaluated to confirm scarlet fever and distinguish it from other potential causes. Key supporting features for scarlet fever include the presence of a strawberry tongue and Pastia lines, which strongly suggest the diagnosis. When scarlet fever is suspected, it is important to identify the source of the GAS infection, such as GAS pharyngitis, impetigo, or erysipelas.

Other conditions to consider in the differential diagnosis of a rash include rubella, rubeola, mononucleosis (caused by Epstein-Barr virus or Cytomegalovirus), parvovirus B19, varicella, enteroviruses (eg, Coxsackie virus causing hand, foot, and mouth disease), Arcanobacterium haemolyticum, Kawasaki disease, TSS, staphylococcal scalded skin syndrome (SSSS), other viral exanthems, and drug reactions.

Prognosis

The prognosis for scarlet fever today is excellent, a significant improvement from the early 20th century. This progress is primarily attributed to the introduction of antibiotics and advances in rapid diagnosis. Once treatment begins, patients can usually resume regular activities 24 hours after their fever resolves. However, if left untreated, the condition may worsen, increasing the risk of complications related to GAS infection.

For most patients who receive prompt treatment, the prognosis is excellent. Recovery typically occurs within 3 to 6 days, although skin symptoms may persist for 14 to 21 days. In some cases, the infection can recur. With the advent of antibiotics, the mortality rate for scarlet fever is now less than 1%. Morbidity is primarily associated with complications such as glomerulonephritis, rheumatic fever, sinusitis, and other infections, although these complications are rare.[62][63] 

Complications

Historically, scarlet fever had a high complication rate and significant mortality among children. However, with the introduction of antibiotics, scarlet fever is now considered a relatively mild disease. Notably, delayed or untreated GAS infections can still lead to severe complications, which are categorized as either suppurative or non-suppurative.

Suppurative complications typically arise from the worsening or spread of the original infection site. For instance, bacterial pharyngitis may extend to the ear, leading to otitis media, to the sinuses, causing sinusitis, or to the meninges, resulting in bacterial meningitis. In contrast, non-suppurative complications are usually immune-mediated and occur after the initial infection has resolved. Rheumatic fever, which affects the heart valves, is a notable non-suppurative complication of GAS infections and can result in significant long-term morbidity.

Although scarlet fever does not directly cause complications, GAS infections can lead to the issues mentioned below.

Suppurative Complications 

• Peritonsillar or pharyngeal abscess
• Otitis media
• Sinusitis
• Necrotizing fasciitis
• Streptococcal bacteremia
• Meningitis or brain abscess
• Jugular vein septic thrombophlebitis 

Non-Suppurative Complications

• Acute rheumatic fever
• Poststreptococcal reactive arthritis
• Streptococcal toxic shock syndrome
• Acute glomerulonephritis
• Pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infections