Group A Streptococcal Infection 

Streptococcus pyogenes (group A Streptococcus) is one of the most important pathogens encountered in clinical practice. An understanding of the diverse nature of infectious disease complications attributable to this organism is an important cornerstone of pediatric medicine. In addition to infections of the upper respiratory tract and the skin, S pyogenes can cause a wide variety of invasive systemic infections, and infection with this pathogen is also causally linked to 2 potentially serious nonsuppurative complications: acute rheumatic fever and acute glomerulonephritis. Recently, infection with S pyogenes has reemerged as an important cause of toxic shock syndrome (TSS), as well as life-threatening skin and soft tissue infections, especially necrotizing fasciitis.

Clinical syndromes compatible with S pyogenes infection have been documented in humans for many centuries. S pyogenes was likely responsible for the apparent scarlet fever epidemic described by Hippocrates in the fifth century BC. The first modern description of streptococcal infection was based on the demonstration of the organism in cases of erysipelas and wound infection by Billroth in 1874. In 1884, Pasteur was the first to report isolation of this organism from the bloodstream in a woman with puerperal sepsis. The organism was designated S pyogenes by Rosenbach in the late 19th century. Another important historical milestone was the description of the classic differential patterns of alpha, beta, and gamma hemolysis on blood agar plates, which was described by Brown in 1919. This observation allowed differentiation of pathogenic streptococci.

Perhaps the major historic turning point in the classification of streptococcal infections occurred in the early 1930s by Rebecca Lancefield with her pioneering work in the identification and description of distinct streptococcal serogroups. The work of Lancefield was instrumental in leading to the important classification of beta-hemolytic strains into distinct serogroups. This insight, in turn, led to the recognition that serogroup A isolates (S pyogenes) were the streptococcal strains responsible for pharyngitis, pyoderma, and nonsuppurative sequelae.

Description and identification of the organism

Streptococci are gram-positive cocci that tend to grow as pairs and short chains in clinical specimens. When cultured on blood agar plates, the production of a characteristic zone of complete hemolysis (beta-hemolysis) is an important clue to classification. S pyogenes produces beta-hemolysis, in contrast to the zone of partial hemolysis (alpha-hemolysis) generated by Streptococcus pneumoniae.

As originally described by Lancefield, beta-hemolytic streptococci can be divided into many groups based on the antigenic differences in group-specific polysaccharides located in the bacterial cell wall. More than 20 serologic groups have been identified and designated by letters (eg, A, B, C). Of the non–group A streptococci, the group B strain is the most important human pathogen (the most common cause of neonatal sepsis and bacteremia), although other groups (particularly group G) have occasionally been implicated as causes of pharyngitis.

Although serologic grouping by the Lancefield method is the criterion standard for differentiation of pathogenic streptococcal species, group A organisms can be identified more cost effectively by numerous latex agglutination, coagglutination, or enzyme immunoassay procedures.

Group A strains can also be distinguished from other groups by their sensitivity to bacitracin. A disc that contains 0.04 U of bacitracin inhibits the growth of more than 95% of group A strains, whereas 80-90% of non–group A strains are resistant to this antibiotic. The bacitracin disc test is simple to perform and interpret in an office-based laboratory and is sufficiently accurate for presumptive identification of group A streptococci.

Presumptive identification of a strain as group A streptococci can also be made on the basis of production of the enzyme L-pyrrolidonyl-beta-naphthylamide (PYRase). Among the beta-hemolytic streptococci isolated from throat culture, only group A isolates produce PYRase, which can be identified on the basis of the characteristic color change (red) after inoculation of a disk on an agar plate followed by overnight incubation.

Cellular constituents and virulence factors

The somatic cellular constituents as well as the extracellular enzymes and toxins of S pyogenes are responsible for many of the pathogenic effects observed in vivo. These are summarized as follows:

• Intrinsic (somatic) constituents

  • M protein
  • Hyaluronic acid
  • Lipoteichoic acid
  • Protein F
  • Serum opacity factor (OF)
  • T protein
• Extracellular streptococcal proteins

  • Streptococcal pyogenic exotoxins (SPEs)
  • Streptolysin O
  • Streptolysin S
  • Deoxyribonucleases (DNAses)
  • Hyaluronidase
  • Streptokinase
  • Nicotinamide adenine dinucleotidase (NADase)

The major virulence factor of the organism is the M protein. This protein, a stable dimer, is anchored to the cell membrane and traverses and penetrates the cell wall. The proximal portion of the molecule is highly conserved among group A isolates, whereas the distal portions contain type-specific epitopes localized on the tips of fibrils (fimbriae) that protrude from the cell surface. The ability of group A streptococci to initiate disease is highly depends on M protein.^[1] Strains lacking M protein are essentially nonpathogenic. Interestingly, streptococci isolated from chronic pharyngeal carriers (individuals asymptomatically colonized with S pyogenes) contain little or no M protein and are also relatively avirulent.

Molecular mechanisms by which M protein mediates pathogenesis are complex. In the nonimmune host, M protein mediates an antiphagocytic effect by inhibition of activation of the alternate complement pathway. Acquired immunity to streptococcal infection is based on the development of opsonic antibodies directed against the antiphagocytic epitopes of M protein. Although such antibodies protect from infection against a homologous M protein type, they unfortunately confer no immunity against other M types. This observation is one of the factors that represent a major theoretical obstacle to the S pyogenes vaccine design because more than 80 M serotypes have been described to date. Community-based outbreaks of particular streptococcal diseases tend to be associated with certain M types; therefore, M serotyping has been very valuable for epidemiologic studies.

Other streptococcal cell wall antigens are important in pathogenesis and epidemiologic typing of S pyogenes. Most strains are enveloped in a hyaluronic acid capsule that serves as an accessory virulence factor by inhibiting phagocytosis. Lipoteichoic acid and protein F are cell wall constituents that play roles in the adherence of S pyogenes to fibronectin on the surface of human epithelial cells, an important event in the initiation of the infectious process. Serum OF is a lipoproteinase associated with M protein that serves in classifying strains not identifiable by M typing. Another streptococcal protein, T protein, does not appear to be a virulence factor but shows significant antigenic variation among clinical isolates. Therefore, T typing is a useful adjunct to M typing for epidemiologic studies of group A streptococcal outbreaks.

Another typing schemes that has been used to characterize and measure the genetic diversity among isolates of S pyogenes is emm typing, which is based on sequence at the 5' end of a locus (emm) that is present in all isolates. The targeted region of emm displays the highest level of sequence polymorphism known for a S pyogenes gene; more than 150 emm types have been described to date.^[2] Theemm gene encodes the M protein, which forms the basis of a serological typing scheme described above. There are 4 major subfamilies of emm genes, which are defined by sequence differences within the 3' end, encoding the peptidoglycan-spanning domain. The chromosomal arrangement of emm subfamily genes reveals 5 major emm patterns, designated as emm patterns A through E. An example of the usefulness of emm typing is described by McGregor et al.^[3]

In addition to somatic constituents, group A streptococci produce a wide variety of extracellular enzymes and toxins important in pathogenesis. The family of SPEs includes SPEs A, B, C, and F. These toxins are responsible for the rash of scarlet fever. These toxins are further responsible for other pathogenic effects on the host, including pyrogenicity, cytotoxicity, and enhancement of susceptibility to endotoxin. SPE B is a precursor for a cysteine protease, another determinant of virulence.

Group A streptococcal isolates associated with streptococcal TSS encode certain SPEs (ie, A, C, F) capable of functioning as superantigens. These antigens induce a marked febrile response, induce proliferation of T lymphocytes, and induce synthesis and release of multiple cytokines, including tumor necrosis factor, interleukin-1 beta, and interleukin-6. This activity is attributed to the ability of the superantigen to simultaneously bind to the V-beta region of the T-cell receptor and to class II major histocompatibility antigens of antigen-presenting mononuclear cells, resulting in widespread nonspecific T-cell proliferation and increased production of interleukin-2.

S pyogenes also elaborates 2 distinct hemolysins. These proteins are responsible for the zone of hemolysis observed on blood agar plates and are also important in the pathogenesis of tissue damage in the infected host. Streptolysin O is toxic to a wide variety of cell types, including myocardium. Streptolysin O is highly immunogenic, and determination of the antibody responses engendered to this protein (ASO titer) is often useful in the serodiagnosis of recent infection. Streptolysin S is another virulence factor capable of damaging polymorphonuclear leukocytes and subcellular organelles; however, in contrast to streptolysin O, it does not appear to be immunogenic.

Other extracellular products are elaborated by S pyogenes that may play a role in tissue damage and spread of organisms through tissue planes. These products include a family of DNAses (ie, DNAses A-D), hyaluronidase, and streptokinase. Other virulence factors of streptococci include NADase, proteinase, C5a-peptidase, amylase, and esterase, although the role of these proteins in pathogenesis is less well understood.

A characteristic of S pyogenes studied in greater detail is the ability of the organism to invade epithelial cells. Failure of penicillin to eradicate S pyogenes from the throats of patients, especially those who are carriers of S pyogenes, has been increasingly reported. The viability of ingested, intracellular S pyogenes after epithelial cell exposure to antibiotics commonly recommended for therapy was recently studied in a human laryngeal epithelial cell line (HEp-2) using bacteriologic and electron microscopic evaluation.^[4]S pyogenes survived intracellularly despite exposure of the streptococci-containing epithelial cells to penicillin. In contrast, ingested S pyogenes was killed after exposure of epithelial cells to either erythromycin or azithromycin.

These observations strongly suggest that if the carrier state results from intraepithelial cell streptococci survival, the failure of penicillin to kill ingested S pyogenes may be related to a lack of effective penicillin entry into epithelial cells. These observations may have clinical implications for understanding carriers and managing S pyogenes infection.

Frequency

United States

Upper respiratory tract infection is most common in the northern regions of the United States, especially during winter and early spring. By contrast, streptococcal skin infections occur most frequently during the summer (or year-round in warm climates), when the skin is exposed and abrasions and insect bites are more likely to occur. Interestingly, unique strains characterized by Erdem and colleagues appear to predominant in Hawaii,^[5] and novel emm types are associated with invasive disease and streptococcal-related sequelae.

Disease in neonates is uncommon, probably in part because of the effect of protective transplacentally acquired antibody. Prevalence of pharyngeal infection is highest in children older than 3 years. Indeed, group A streptococcal pharyngitis has been described as hazard in school-aged children.^[6]S pyogenes also has the potential to produce outbreaks of disease in younger children in daycare.

Evidence suggests that the frequency of severe, invasive group A streptococcal infections is increasing and that strains of streptococci with increased pathogenic potential are appearing. An increasing number of patients are being identified who have various unusually severe soft tissue infections associated with marked systemic toxicity, bacteremia, and shock. Factors responsible for the emergence of these more virulent strains of S pyogenes are not clearly defined, although many of these outbreaks appear to be clonal in nature.

International

Infections with group A Streptococcus are observed worldwide. Prevalence of streptococcal pyoderma is higher in regions near the tropics. Aside from this observation, no geographic barriers to infection with this ubiquitous organism are recognized.

Rheumatic fever is most frequently observed in the age group most susceptible to group A streptococcal infections (ie, children aged 5-15 y). The attack rate following upper respiratory tract infection is approximately 3% in individuals with untreated or inadequately treated infection.

Mortality/Morbidity

Infection with group A streptococci leads to various clinical manifestations responsible for considerable morbidity and, with increasing frequency, mortality.^[7] In addition, infection with this organism leads to postsuppurative sequelae, particularly acute rheumatic fever and poststreptococcal glomerulonephritis (PSGN). These disease manifestations are considered in Medical Care.

Race

Group A streptococcal infections are observed worldwide. Streptococcal pyoderma is a more common complication closer to tropical regions of the world. Otherwise, no racial or ethnic predispositions to infection with this organism are recognized.

Sex

In general, no sex-based differences are observed with this pathogen.

Age

Group A streptococcal infections may be observed in people of any age, although the prevalence of infection is higher in children, presumably because of the combination of multiple exposures (in school or daycare) and little immunity. Group A streptococcal pharyngitis is particularly common in school-aged children.