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Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes : Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016-.
Pharyngitis, or sore throat, is the most common manifestation of infection with Streptococcus pyogenes. Sore throat is a frequently presenting complaint for outpatient medical visits; as a result, infection with S. pyogenes is diagnosed in 20 to 40% of pharyngitis cases in children, and in 5 to 15% in adults. Scarlet fever denotes a clinical syndrome that is characterized by the presence of a rash along with an S. pyogenes infection, usually pharyngitis. In this chapter, the topics covered include pathogenesis of pharyngitis, animal models of S. pyogenes pharyngitis, adherence of S. pyogenes to epithelial cells, intracellular survival and persistence in the pharynx, regulation of capsule production, S. pyogenes survival in the pharynx, and immunity to pharyngitis. Finally, there is an overview and discussion of clinical features, complications, diagnosis, and treatment of these diseases.
Pharyngitis, or sore throat, is the most common manifestation of infection with Streptococcus pyogenes. Sore throat is a frequent presenting complaint for outpatient medical visits, and infection with S. pyogenes is diagnosed in 20 to 40% of pharyngitis cases in children and in 5 to 15% in adults (Ebell, Smith, Barry, Ives, & Carey, 2000; Shaikh, Leonard, & Martin, 2010). The peak incidence of S. pyogenes pharyngitis occurs in children 5 to 15 years of age (Danchin, et al., 2007). Infection is more common during winter and spring in temperate climates. Outbreaks may occur in households, schools, military facilities, and other settings in which there is close human-to-human contact. There is no known environmental reservoir or natural animal host of S. pyogenes, apart from human beings; and as a result, direct or indirect contact with an infected person is the source of human infection. Transmission is thought to occur primarily by large droplets from respiratory secretions, although spread through contaminated objects and food are well-described alternate routes of transmission. Unpasteurized milk and contaminated food have also been sources of several well-documented S. pyogenes outbreaks (Dublin, Rogers, Perkins, & Graves, 1943; Kemble, et al., 2013).
Scarlet fever, or streptococcal pharyngitis associated with a characteristic rash, has been recognized for centuries. “Scarlatina” was clearly distinguished from other febrile rash illnesses (such as measles, in particular) by Sydenham in the 17th century. Epidemics of scarlet fever with high mortality occurred in cities in Europe and North America as late as the latter part of the 19th century (Rolleston, 1928). The historical aspects of scarlet fever are described in detail in Chapter 1. Since the advent of penicillin treatment, scarlet fever has become less common and fatal cases are extremely rare. However, some large outbreaks have been reported in the 21st century, most notably in China and Hong Kong (Yang, et al., 2013).
Todd and Lancefield observed that S. pyogenes freshly isolated from patients with tonsillitis or scarlet fever grew as “matt” colonies (those that are large, with an irregular surface), a characteristic that was associated with production of “M substance;” that is, the M protein (Todd & Lancefield, 1928). The matt (or matte) colony type was subsequently shown to be a later stage of the mucoid colony morphology, which occurs due to abundant production of the hyaluronic acid capsular polysaccharide (Wilson, 1959). In contrast to strains associated with symptomatic infection, isolates from individuals undergoing tonsillectomy for enlarged tonsils yielded a mixture of matte and glossy (small, smooth) colonies. In vitro passage of matte isolates often resulted in their conversion to the glossy morphology, with the latter colony type being deficient in both the M protein and capsule. These observations suggested that expression of the M protein and capsule were associated with symptomatic S. pyogenes pharyngitis, although not necessarily with asymptomatic pharyngeal carriage. More recent studies on clinical isolates and in experimental infection in non-human primates have supported these early insights (see below).
Human beings are the only known natural hosts for S. pyogenes infection, and for pharyngitis in particular, it has been difficult to mimic human infection in animal models. Studies in mice have demonstrated colonization of the upper airway after intranasal challenges, but either the organisms are cleared over a few days, or the animals develop rapidly progressive pneumonia and systemic infections (Husmann, Dillehay, Jennings, & Scott, 1996; Wessels & Bronze, 1994). A study in rats showed the persistence of low numbers of S. pyogenes in throat cultures for several weeks in approximately 50% of animals (Hollingshead, Simecka, & Michalek, 1993). Models in non-human primates are thought to most closely resemble the features of human infection. A high rate of colonization has been demonstrated in rhesus and cynomolgous macaques and in baboons after intranasal inoculation or direct introduction of S. pyogenes into the oropharynx (Ashbaugh, et al., 2000; Skinner, et al., 2011; Virtaneva, et al., 2005; Watson, Rothbard, & Swift, 1946). Although one study in cynomolgous macaques reported pharyngeal erythema and swelling during infection, other studies have observed only minimal erythema or no clinical signs of infection, despite persistent colonization. In a baboon model, an M-type 3 invasive clinical isolate colonized the pharynx of all six animals after oral inoculation and persisted for at least 42 days (Ashbaugh, et al., 2000). In marked contrast, in the same study, an isogenic M protein-deficient mutant colonized only 2 of 6 animals after inoculation and was cleared from both after 14 days. A mutant that produced wild-type amounts of M protein but lacked the hyaluronic acid capsule colonized 5 of 6 animals, but was cleared by 28 days. These results suggest that M protein is required both for initial colonization of the pharynx and for persistence. The capsule appears to be unnecessary for colonization, but its presence enhanced persistence in this model.
In vitro studies have attempted to identify the molecular basis for the adherence of S. pyogenes to the oropharyngeal epithelium. Experiments that tested the attachment of S. pyogenes to various cell lines in vitro have identified multiple bacterial surface molecules that appear to mediate or modulate adherence. A two-step model of adhesion has been proposed, in which an initial weak interaction involves lipoteichoic acid, and a second phase of more avid binding is mediated by S. pyogenes surface proteins (Hasty, Ofek, Courtney, & Doyle, 1992). The participation and relative importance of particular adhesins varies widely and depends on bacterial strain, growth phase, target cell type, and the presence or absence of potential bridging molecules, such as fibronectin or fibrinogen. Certain M proteins contribute to S. pyogenes adherence to human cells, either directly or through binding with an intermediary integrin-binding protein, such as fibronectin. Types 6 and 24 M proteins mediated attachment to oropharyngeal keratinocytes in vitro, but type 18 did not (Schrager, Albertí, Cywes, Dougherty, & Wessels, 1998). On the other hand, type 1 M protein appears to inhibit adherence to oropharyngeal keratinocytes (Anderson, et al., 2014). The hyaluronic acid capsule can inhibit M protein-mediated adherence. However, the capsule itself mediates S. pyogenes attachment to CD44, a hyaluronic acid-binding glycoprotein that is expressed on many cell types, including oropharyngeal cells (Schrager, Albertí, Cywes, Dougherty, & Wessels, 1998). Eleven or more fibronectin-binding proteins are expressed by various strains of S. pyogenes. Binding of fibronectin can link surface proteins on the bacterial cell to fibronectin-binding α5β1 integrins on human epithelial cells (Yamaguchi, Terao, & Kawabata, 2013). The level of expression of α5β1 integrins on keratinocytes may be lower than on other cell types (Edwards, Potter, Meenan, Potts, & Massey, 2011), and the expression of fibronectin-binding protein F1 by S. pyogenes has been reported to direct bacterial binding to Langerhans cells in human skin tissue sections in vitro (Okada, Pentland, Falk, & Caparon, 1994).
Although S. pyogenes is considered an extracellular pathogen, multiple studies have demonstrated the internalization of the organism by human epithelial cells, including oropharyngeal keratinocytes, in vitro (LaPenta, Rubens, Chi, & Cleary, 1994; Molinari, et al., 1987; Ozeri, Rosenshine, Mosher, Fässler, & Hanski, 1998; Schrager, Rheinwald, & Wessels, 1996). Clinical isolates associated with pharyngitis or asymptomatic carriage appear to be internalized more efficiently than isolates associated with invasive infection, and it has been suggested that entry into epithelial cells may enhance persistent colonization by protecting intracellular bacteria from immune effectors and antibiotics (Molinari & Chhatwal, 1998). Conversely, strains that are associated with invasive infection tend to be internalized inefficiently, perhaps because they produce larger amounts of hyaluronic acid capsule and streptolysin O (SLO), both of which reduce S. pyogenes internalization by epithelial cells in vitro (Schrager, Rheinwald, & Wessels, 1996; Håkansson, Bentley, Shakhnovic, & Wessels, 2005). The production of SLO also influences the intracellular survival of S. pyogenes within epithelial cells. As they are both pore-forming toxins, SLO and streptolysin S (SLS) induce the formation of autophagosome-like compartments in epithelial cells (Nakagawa, et al., 2004; O'Seaghdha & Wessels, 2013). Streptococci are internalized into an early endosome; however, the production of SLO results in damage to the endosomal membrane and exposure of S. pyogenes to the cytosol, where they bind ubiquitin. Ubiquitination of the bacteria results in targeting of the autophagy pathway. In the absence of SLO, production of SLS can sufficiently damage the endosomal membrane to recruit galectin 8, a cytosolic lectin that binds to galactosides that are normally found on the interior surface of vacuolar compartments, but which become exposed upon SLS-mediated membrane injury (O'Seaghdha & Wessels, 2013). Galectin 8 binding to the endosome provides an additional means to traffic S. pyogenes to autophagosomes. Many S. pyogenes strains also produce NAD-glycohydrolase (NADase), an enzyme that is translocated into the cytosol of epithelial cells in an SLO-dependent fashion. NADase inhibits the fusion of lysosomes with S. pyogenes-containing autophagosomes, preventing their maturation into degradative autolysosomes and prolonging intracellular survival. In this way, SLO and NADase enhance the survival of S. pyogenes within epithelial cells and may contribute to its overall persistence in the pharynx.
The global two-component regulatory system CsrRS (or CovRS) appears to play a critical role in the adaptation of S. pyogenes for survival and persistence in the pharynx. Inactivating mutations are present in csrS or, less often, in csrR in approximately 40% of clinical isolates from patients with necrotizing fasciitis or streptococcal toxic shock. By contrast, such mutations are rarely observed among pharyngitis isolates—an observation that suggests CsrRS contributes to the survival of S. pyogenes in this host environment (Ikebe, et al., 2010; Shea, et al., 2011). Further support for this view comes from studies that show a competitive advantage of wild-type S. pyogenes, as compared to CsrRS mutants during growth in human saliva (Treviño, et al., 2009). Experiments using a mouse model of upper airway colonization also showed reduced colonization with CsrRS mutants (Alam, Turner, Smith, Wiles, & Sriskandan, 2013). Along with several other virulence factors, synthesis of the hyaluronic acid capsule is regulated by CsrRS (Levin & Wessels, 1998). The overproduction of capsule by CsrRS mutants favors resistance to phagocytosis and survival in blood or deep tissues, but may impair persistence in the pharynx. A study of serial throat isolates from monkeys with experimental S. pyogenes pharyngeal infection showed an accumulation of mutations over time that resulted in reduced capsule expression, which is consistent with this hypothesis (Shea, et al., 2011). In addition, clinical isolates from patients with pharyngitis revealed a similar pattern of mutations that reduced capsule production. These observations seem inconsistent with the finding discussed above, in which an acapsular mutant strain was more rapidly cleared from the pharynx in a non-human primate model. These apparently contradictory results may be explained by the fact that the capsule not only impairs adherence to the pharyngeal mucosa and internalization by epithelial cells (thereby impairing colonization), but also helps to defend the bacteria against opsonophagocytic killing in the non-immune host (thereby resisting clearance). Highly encapsulated or mucoid strains of S. pyogenes have certainly been associated with outbreaks of pharyngitis and acute rheumatic fever (Marcon, et al., 1988; Veasy, et al., 1987; Westlake, Graham, & Edwards, 1990); however, the downregulation of capsule production may favor asymptomatic pharyngeal carriage.
Early studies in mice by Lancefield and others established that protective immunity to systemic S. pyogenes infection was conferred by opsonic serum antibodies against the M protein (Lancefield, 1962). Protective antibodies were type-specific, recognizing the antigenically variable amino terminal domain of M protein. Antibodies elicited from immunization with killed S. pyogenes bacteria protected against challenges by strains of the same, but not different, M types. Studies in non-human primates suggest that immunity to pharyngeal infection also is type-specific. Pharyngeal colonization of baboons with an M type 3 strain resulted in complete protection against subsequent rechallenge with the same strain, but no protection against infection with a type 1 strain (Ashbaugh, et al., 2000). The type-specificity of immunity in human pharyngitis is less well-defined. A prospective natural history study of the spread of several strains of S. pyogenes among families suggested that pre-existing type-specific serum antibodies did not prevent pharyngeal acquisition nor influence the duration of carriage (Guirguis, Fraser, Facklam, El Kholy, & Wannamaker, 1982). Fox et al. found that immunization with type 1 M protein had only a modest and statistically insignificant effect on pharyngeal colonization in volunteers after challenge with a type 1 strain, but that immunized subjects had a significantly lower rate of symptomatic infection, as compared to subjects in the control group (5% vs 47%) (Fox, Waldman, Wittner, Mauceri, & Dorfman, 1973). When taken together, these studies indicate that type-specific antibodies to M protein play an important role in protection against symptomatic infection. There is some evidence for type-specific immunity to pharyngeal colonization, although it is less clear whether such protection is mediated primarily or exclusively by type-specific serum antibodies. Local mucosal immunity induced by prior exposure or by a mucosal vaccine may also play a role in overall immunity to colonization.
The classical presentation of streptococcal pharyngitis begins with an abrupt onset of fever, malaise, and sore throat. Pain with swallowing and the presence of swollen, tender anterior cervical lymph nodes are typical features. Abdominal pain and vomiting is common, especially in younger children. Cough, rhinorrhea, hoarseness, conjunctival irritation, and diarrhea are notably absent in streptococcal pharyngitis, and the presence of these symptoms should suggest a non-streptococcal (usually viral) etiology. Physical findings include fever (often greater than 39 °C), erythema, and edema of the tonsils and posterior pharynx, which may be covered with a patchy white or yellowish exudate (Figure 1). Petechiae may be present on the soft palate. Anterior cervical lymph nodes typically are enlarged, firm, and tender. The presence of most or all of these characteristic clinical features is suggestive of, but not specific to, S. pyogenes pharyngitis. Without treatment, sore throat usually resolves in 3 to 6 days, and fever abates within 1 week. Despite the resolution of symptoms, throat cultures often remain positive for several weeks in the absence of antibiotic treatment (Catanzaro, et al., 1954). Infectious mononucleosis from the Epstein-Barr virus can have a similar presentation, as can infection with adenovirus or other respiratory viruses. Less commonly, a similar syndrome can be caused by various bacterial or viral pathogens. Conversely, culture-proven S. pyogenes pharyngeal infection may be associated with milder signs and symptoms than those described above. For these reasons, a diagnosis on clinical grounds alone is unreliable. Exudative pharyngitis is uncommon in children younger than 3 years of age, although S. pyogenes infection can occur in this age group and may be manifested through fever, lymphadenopathy, and mucopurulent rhinitis.
A 15-year-old girl with fever and exudative streptococcal pharyngitis (from (Block, 2014)).
Suppurative complications of streptococcal pharyngitis can arise from direct extension of pharyngeal infection to adjacent structures, or by hematogenous or lymphatic spread to more remote sites. Such complications include peritonsillar or retropharyngeal abscess, sinusitis, otitis media, cervical lymphadenitis, bacteremia, endocarditis, pneumonia, and meningitis. Local complications, such as peritonsillar or retropharyngeal abscess formation, should be considered in a patient with unusually severe or prolonged symptoms or localized pain associated with high fever and a toxic appearance. Non-infectious autoinflammatory complications can include acute rheumatic fever and post-streptococcal glomerulonephritis, both of which are thought to result from immune responses to streptococcal infection (see the chapters on PANDAS and poststreptococcal glomerulonephritis). Treatment of streptococcal pharyngitis with penicillin has been shown to reduce the likelihood of acute rheumatic fever, but not to reduce the likelihood of post-streptococcal glomerulonephritis.
Scarlet fever denotes a clinical syndrome characterized by the presence of a rash along with an S. pyogenes infection, usually pharyngitis. The rash typically begins on the first or second day of illness, initially on the trunk, and spreads to involve the extremities, sparing the palms and soles of the feet. The rash is often accentuated in flexural creases, such as in the antecubital fossae and axillae (Pastia’s lines). The cheeks are flushed, with sparing of the area around the mouth (circumoral pallor) (Figure 2). The rash is made up of minute papules, giving a characteristic “sandpaper” feel to the skin. Enlarged papillae may be seen on a coated tongue (strawberry tongue), which later may become denuded. The rash generally fades in 6–9 days, and is followed by desquamation of the palms and soles after several days, which typically begins on the fingertips at the free margin of the fingernails. The differential diagnosis of scarlet fever includes viral exanthems, Kawasaki disease, staphylococcal toxic shock syndrome, and allergic reactions.
A 7-year-old boy with streptococcal pharyngitis and scarlet fever. Note the accentuation of the rash in skin folds and circumoral pallor (from (Block, 2014)).
The pathogenesis of scarlet fever is not completely understood. Studies in the 1920s by George and Gladys Dick and others implicated one or more secreted S. pyogenes proteins, which was previously called erythrogenic toxin, and which are now classified as pyrogenic exotoxins (Birkhaug, 1925; Dick & Dick, 1924; Dick & Dick, 1983). Injection of culture filtrates of scarlet fever-associated S. pyogenes evoked a rash in some naïve subjects, but not in those who had recovered from scarlet fever. Intradermal injection of antiserum to the scarlet fever strain caused blanching of the rash. Together, these observations suggested that the rash-associated illness was at least partially due to the effects of S. pyogenes products present in the culture supernatant. Subsequent research has identified erythrogenic toxin as a group of related streptococcal pyrogenic exotoxins (SPEs). Eleven such toxins have been identified, and an individual strain typically produces 4 to 6 of them (Spaulding, et al., 2013). No single toxin has been consistently implicated in scarlet fever, although SpeA, SpeC, and SSA, often in combination, have been associated with several outbreaks (Davies, et al., 2015; Silva-Costa, Carriço, Ramirez, & Melo-Cristino, 2014; Tyler, et al., 1992; Yu & Ferretti, 1989). The SPEs also appear to play an important role in the severe, systemic manifestations of streptococcal toxic shock syndrome through their activity as superantigens that are capable of stimulating cytokine secretion from a large population of T cells in an antigen-independent fashion (see the chapter on streptococcal superantigens).
Scoring systems have been devised to improve the accuracy of clinical diagnoses of S. pyogenes pharyngitis. These systems assign points based on the presence or absence of suggestive clinical features, such as fever, absence of cough, presence of tonsillar exudates, and swollen, tender anterior cervical lymph nodes. The best-known clinical assessment tools are the Centor score and the very similar McIsaac score, which includes patient age as an additional criterion (Centor, Witherspoon, Dalton, Brody, & Link, 1981; McIsaac, White, Tannenbaum, & Low, 1998). A study analyzing data collected from more than 200,000 patients that were 3 years of age or older and were seen at a U.S. retail health chain found that the likelihood of a positive throat culture for S. pyogenes was 8% in individuals with a McIsaac score of 0, and rose to 55% in those with scores of 4 or 5 (Fine, Nizet, & Mandl, 2012). Algorithms based on such scoring systems have been used to limit the use of throat culture or rapid antigen detection tests in those patients in whom the probability of S. pyogenes infection is very low (McIsaac, Kellner, Aufricht, Vanjaka, & Low, 2004). For example, the clinical guidelines of the American College of Physicians-American Society of Internal Medicine and the U.S. Centers for Disease Control and Prevention recommend not testing for S. pyogenes in adults with a Centor score of 0 or 1 in the absence of special risk factors (Cooper, et al., 2001).
The “gold standard” for diagnosis of S. pyogenes pharyngitis is a positive culture from a properly collected throat swab specimen, i.e., a swab rubbed on both tonsillar pillars, avoiding the lips and tongue. Faster and more convenient rapid antigen tests are widely used in many clinical settings. These tests are highly specific, generally 95% or higher, so a positive result provides an immediate diagnosis and obviates the need for culture. In children and adolescents, a negative rapid test should be confirmed with a throat culture, as the sensitivity of the culture method is higher than that of the rapid antigen tests. Most clinical guidelines do not recommend the routine confirmation of a negative antigen test in adults, since the risk of rheumatic fever is extremely low in adults without a prior episode. Serologic assays for antibodies to S. pyogenes antigens, such as SLO or DNase B, are useful for retrospective diagnosis of an antecedent S. pyogenes infection in cases of suspected acute rheumatic fever or post-streptococcal glomerulonephritis, but these tests are not useful for the acute diagnosis of S. pyogenes pharyngitis, as a rise in specific antibodies only begins 7 to 14 days after the onset of infection, reaching maximum levels at 3 to 4 weeks.
Streptococcal pharyngitis is almost always a self-limited illness, and many have questioned whether antibiotic treatment is warranted. However, such treatment can be justified for three reasons:
Treatment shortens the duration and severity of illness. Several studies suggest that specific therapy reduces the duration of fever and sore throat by approximately 1 day, on average.
Treatment prevents rheumatic fever. Acute rheumatic fever is a potential complication of S. pyogenes pharyngitis, and studies conducted primarily on the U.S. military in the mid-twentieth century demonstrated that penicillin treatment reduced the risk of subsequent rheumatic fever. While this rationale for treatment remains compelling in many resource-poor countries where the incidence of acute rheumatic fever is high, in industrialized countries, the relative risks and benefits no longer clearly support this treatment goal in routine cases.
Treatment prevents the suppurative complications of pharyngitis. Antibiotic treatment has been shown to reduce the incidence of secondary infectious complications, such as otitis media and sinusitis (Spinks, Glasziou, & Del Mar, 2013). An additional benefit of treatment is that it reduces the spread of infection to others—an important consideration for outbreak control. Clinical practice guidelines in the U.S. recommend treatment for children and adults with proven S. pyogenes pharyngitis (Gerber, et al., 2009; Shulman, et al., 2012). Guidelines from some European countries are similar, while other countries do not recommend specific diagnostic testing or treatment, since treatment has a small impact on the natural history of pharyngitis, and the incidence of suppurative and non-suppurative complications is low in these populations (Van Brusselen, et al., 2014).
Penicillin has been the mainstay of treatment for S. pyogenes pharyngitis for many years. Clinical isolates remain universally susceptible to penicillin and to many other beta-lactam antibiotics. Amoxicillin is similarly effective and is often preferred for its longer half-life, especially in children. Once-daily dosing of amoxicillin appears to have similar efficacy to a twice-daily dosing regimen (Clegg, et al., 2006; Lennon, Farrell, Martin, & Stewart, 2008). A cephalosporin may be used in patients with a history of allergy to penicillin or amoxicillin that is not of the immediate hypersensitivity type. Macrolide antibiotics are an additional alternative, but resistance to these is relatively common (Liu, et al., 2009; Tamayo, Pérez-Trallero, Gómez-Garcés, Alós, & Spanish Group for the Study of Infection, 2005; Tanz, et al., 2004). Table 1 summarizes antibiotic regimens recommended in guidelines from the Infectious Diseases Society of America.
Antibiotic Regimens Recommended for Streptococcal Pharyngitis (adapted from (Shulman, et al., 2012))
Some have argued that clinical and/or bacteriological cure rates are lower with penicillin (or amoxicillin) than with alternate agents, including cephalosporins (Casey & Pichichero, 2004; Pichichero, et al., 2000). The counter-argument has been that studies showing superiority of alternative agents have inadvertently included S. pyogenes carriers, and that penicillin is inferior for the eradication of carriage, but is comparable to other agents for treatment of true infection (Bisno, 2004; Shulman & Gerber, 2004). Penicillin continues to be recommended as a first line treatment in clinical practice guidelines because of its well-established record of safety and efficacy, narrow spectrum, and low cost.
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