Streptococcus Group A Infections 

Streptococcus pyogenes is beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as group A streptococci (GAS). GAS, a ubiquitous organism, causes a wide variety of diseases in humans and is the most common bacterial cause of acute pharyngitis, accounting for 15-30% of cases in children and 5-10% of cases in adults.^[1] During the winter and spring in temperate climates, up to 20% of asymptomatic school-aged children may be GAS carriers.^[2]

GAS usually causes pharyngitis or impetigo but, in rare cases, can also cause invasive diseases such as cellulitis, bacteremia, necrotizing fasciitis, and toxic shock syndrome (TSS). Along with Staphylococcus aureus, GAS is one of the most common pathogens responsible for cellulitis .

Historical perspectives

S pyogenes was first described by Billroth in 1874 in patients with wound infections. In 1883, Fehleisen isolated chain-forming organisms in pure culture from perierysipelas lesions. Rosebach named the organism S pyogenes in 1884. Studies by Schottmueller in 1903 and J.H. Brown in 1919 led to knowledge of different patterns of hemolysis described as alpha, beta, and gamma hemolysis.

A later development in this field was the Lancefield classification of beta-hemolytic streptococci by serotyping based on M-protein precipitin reactions. Lancefield established the critical role of M protein in disease causation. In the early 1900s, Dochez, George, and Dick identified hemolytic streptococcal infection as the cause of scarlet fever. The epidemiological studies of the mid 1900s helped establish the link between GAS infection and acute rheumatic fever (ARF) and acute glomerulonephritis.^[3]

The traditional Lancefield M-protein classification system, which is based on serotyping, has been replaced by emm typing. This gene-typing system is based on sequence analysis of the emm gene, which encodes the cell surface M protein. Approximately 200 emm types have been identified by the Centers for Disease Control and Prevention (CDC) thus far.

Spectrum of diseases due to group A streptococcal infections

In the preantibiotic era, streptococci frequently caused significant morbidity and were associated with significant mortality rates. However, in the postantibiotic period, diseases due to streptococcal infections are well-controlled and uncommonly cause death. GAS can cause a diverse variety of both suppurative diseases and nonsuppurative postinfectious sequelae.

The suppurative spectrum of GAS diseases includes the following:

• Pharyngitis with or without tonsillopharyngeal cellulitis or abscess
• Impetigo (purulent honey-colored crusted skin lesions)
• Pneumonia
• Necrotizing fasciitis
• Cellulitis
• Streptococcal bacteremia
• Osteomyelitis
• Otitis media
• Sinusitis
• Meningitis or brain abscess (a rare complication resulting from direct extension of an ear or sinus infection, or from hematogenous spread)

The nonsuppurative sequelae of GAS infections include the following:

• Acute rheumatic fever (ARF; defined by Jones criteria)
• Rheumatic heart disease (chronic valvular damage, predominantly mitral valve)
• Acute glomerulonephritis

Superantigen-mediated immune response may result in the following entities:

• Streptococcal TSS (STSS): This is characterized by systemic shock with multiorgan failure, with manifestations of respiratory failure, acute renal failure, hepatic failure, neurological symptoms, hematological abnormalities, and skin findings, among others. This is predominantly associated with M types 1 and 3 that produce pyrogenic exotoxin A, exotoxin B, or both.^[4]
• Scarlet fever: This is characterized by upper-body rash, generally following pharyngitis.

Streptococci are a large group of gram-positive, nonmotile, non–spore-forming cocci about 0.5-1.2 µm in size. They often grow in pairs or chains and are oxidase- and catalase-negative.

S pyogenes tends to colonize the upper respiratory tract and is highly virulent as it overcomes the host defense system. The most common forms of S pyogenes disease include respiratory and skin infections, with different strains usually responsible for each form.

The cell wall of S pyogenes is very complex and chemically diverse. The antigenic components of the cell are the virulence factors. The extracellular components responsible for the disease process include invasins and exotoxins. The outermost capsule is composed of hyaluronic acid, which has a chemical structure resembling host connective tissue, allowing the bacterium to escape recognition by the host as an offending agent. Thus, the bacterium escapes phagocytosis by neutrophils or macrophages, allowing it to colonize. Lipoteichoic acid and M proteins located on the cell membrane traverse through the cell wall and project outside the capsule.

Bacterial virulence factors

The cell wall antigens include capsular polysaccharide (C-substance), peptidoglycan and lipoteichoic acid (LTA), R and T proteins, and various surface proteins, including M protein, fimbrial proteins, fibronectin-binding proteins (eg, protein F), and cell-bound streptokinase.

The C-substance is composed of a branched polymer of L-rhamnose and N -acetyl-D-glucosamine. It may have a role in increased invasive capacity. The R and T proteins are used as epidemiologic markers and have no known role in virulence.^[5]

M protein, the major virulence factor, is a macromolecule incorporated in fimbriae present on the cell membrane projecting on the bacterial cell wall. More than 50 types of S pyogenes M proteins have been identified based on antigenic specificity, and the M protein is the major cause of antigenic shift and antigenic drift among GAS.^[6] The M protein binds the host fibrinogen and blocks the binding of complement to the underlying peptidoglycan. This allows survival of the organism by inhibiting phagocytosis. Strains that contain an abundance of M protein resist phagocytosis, multiply rapidly in human tissues, and initiate disease process. After an acute infection, type-specific antibodies develop against M protein activity in some cases.

In addition to M protein, S pyogenes possesses additional virulence factors, such as C5A peptidase, which destroys the chemotactic signals by cleaving the complement component of C5A. See the image below.

Bacterial adherence factors

At least 11 different surface components of GAS have been suggested to play a role in adhesion. In 1997, Hasty and Courtney proposed that GAS express different arrays of adhesins in various environmental niches. Based on their review, M protein mediates adhesion to HEp-2 cells in humans, but not buccal cells, whereas FBP54 mediates adhesion to buccal cells, but not to HEp-2 cells. Protein F mediates adhesion to Langerhans cells, but not keratinocytes.

The most recent theory proposed in the process of adhesion is a two-step model. The initial step of overcoming the electrostatic repulsion of the bacteria from the host is mediated by LTA rendering weak reversible adhesion. The second step is firm irreversible adhesion mediated by tissue-specific M protein, protein F, or FBP54, among others. Once adherence has occurred, the streptococci resist phagocytosis, proliferate, and begin to invade the local tissues.^[7] GAS show enormous and evolving molecular diversity, driven by horizontal transmission among various strains. This is also true when compared with other streptococci. Acquisition of prophages accounts for much of the diversity, conferring not only virulence via phage-associated virulence factors but also increased bacterial survival against host defenses.

Extracellular products and toxins

Various extracellular growth products and toxins produced by GAS are responsible for host cell damage and inflammatory response. Streptolysin S, a 28 residue peptide, is an oxygen-stable leukocidin toxic to polymorphonuclear leukocytes, RBCs, and platelets. Streptolysin S is responsible for RBC lysis observed on sheep blood agar. Streptolysin O is an oxygen-labile leukocidin that is toxic to neutrophils and induces a brisk antibody response. Measurement of antistreptolysin O (ASO) antibody titer in humans is used as an indicator of recent streptococcal infection. Other extracellular products include NADase (leukotoxic), hyaluronidase (which digests host connective tissue, hyaluronic acid, and the organism's own capsule), streptokinases (proteolytic), and streptodornase A-D (deoxyribonuclease activity).^[8]

Pyrogenic exotoxins

GAS produce 3 different types of exotoxins (A, B, C).^[6] These toxins act as superantigens and are responsible for inciting systemic immune response and acute disease caused by the sudden and massive release of T-cell cytokines into the blood stream. The superantigens bypass processing by antigen presenting cells and cause T-cell activation by binding class II MHC molecules directly and nonspecifically.

The streptococcal pyrogenic exotoxins (SPEs) are responsible for causing scarlet fever, pyrogenicity, and STSS. The mechanism is similar to that of staphylococcal TSS.^[9]

Nucleases

Four antigenically distinct nucleases (A, B, C, D) assist in the liquefaction of pus and help to generate substrate for growth.

Other enzymes

In addition, streptococci produce proteinase, nicotinamide adenine dinucleotidase, adenosine triphosphatase, neuraminidase, lipoproteinase, and cardiohepatic toxin.

Streptococcal pharyngitis

S pyogenes causes up to 15-30% of cases of acute pharyngitis.^[10] Frank disease occurs based on degree of bacterial virulence after colonization of the upper respiratory tract. Accurate diagnosis is essential for appropriate antibiotic selection.

Impetigo

The bacterial toxins cause proteolysis of epidermal and subepidermal layers, allowing the bacteria to spread quickly along the skin layers, thereby causing blisters or purulent lesions. The other common cause of impetigo is S aureus.

Pneumonia

Invasive GAS can cause pulmonary infection, often with rapid progression to necrotizing pneumonia.

Necrotizing fasciitis

Necrotizing fasciitis is caused by bacterial invasion into the subcutaneous tissue, with subsequent spread through superficial and deep fascial planes. The spread of organisms is aided by bacterial toxins and enzymes (eg, lipase, hyaluronidase, collagenase, streptokinase), interactions among organisms (synergistic infections), local tissue factors (eg, decreased blood and oxygen supply), and general host factors (eg, immunocompromised state, chronic illness, surgery). As the infection spreads deep along the fascial planes, vascular occlusion, tissue ischemia, and necrosis occur.^[11] Although GAS is often isolated in cases of necrotizing fasciitis, this disease state is frequently polymicrobial.

Otitis media and sinusitis

These are common suppurative complications of streptococcal tonsillopharyngitis. They are caused by spread of organisms via the eustachian tube (otitis media) and direct spread to sinuses (sinusitis).

Acute rheumatic fever

Certain M types are considered rheumatogenic, as they contain antigenic epitopes related to heart muscle, and therefore may lead to autoimmune rheumatic carditis (rheumatic fever) following acute infection. CD4⁺ T cells are probably the ultimate effectors of chronic valve lesions in rheumatic heart disease. T cells can recognize streptococcal M5 protein peptides and produce various inflammatory cytokines (eg, tumor necrosis factor [TNF]–alpha, interferon [IFN]–gamma, interleukin [IL]–10, IL-4), which could be responsible for progressive fibrotic valvular lesions. Cardiac myosin has been defined as a putative autoantigen recognized by autoantibodies in patients with rheumatic fever. Cross-reactivity between cardiac myosin and group A beta-hemolytic streptococcal M protein has been adequately demonstrated and may contribute to pathogenesis.^[12]

Poststreptococcal glomerulonephritis

Poststreptococcal glomerulonephritis (PSGN) is caused by infection with specific nephritogenic strains of GAS (types 12 and 49) and may occur in sporadic cases or during an epidemic. PSGN results from deposition of antigen-antibody-complement complexes on the basement membrane of renal glomeruli. Subepithelial deposits of immunoglobulin can be observed with immunofluorescent staining.

Streptococcal toxic shock syndrome

Severe GAS infections associated with shock and organ failure have been reported with increasing frequency, predominantly in North America and Europe. STSS is a severe systemic immune response mediated by superantigens, as described above (see Pyrogenic exotoxins).

The primary evidence for poststreptococcal autoimmune CNS disease is provided by studies of Sydenham chorea, the neurologic manifestation of rheumatic fever. Reports of obsessive-compulsive disorder (OCD), tic disorders, and other neuropsychiatric symptoms that occur in association with group A beta-hemolytic streptococcal infections suggest that various CNS sequelae may be triggered by poststreptococcal autoimmunity.^[13]

Frequency

United States

According to a CDC report dated April 3, 2008, approximately 9,000-11,500 cases of invasive GAS disease (3.2-3.9 per 100,000 population) occur each year in the United States. STSS and necrotizing fasciitis each accounted for approximately 6-7% of cases. More than 10 million noninvasive GAS infections (primarily throat and superficial skin infections) occur annually.^[14]

In a recent study, the incidence of streptococcal disease reportedly increased in postpartum women compared with nonpregnant women, (group B streptococci: 0.49 cases per 1000 woman-years [range, 0.36-0.64 cases per 1000 woman-years] vs 0.018 [range, 0.016-0.020 cases per 1000 woman-years]).^[15]

International

The resurgence of GAS as a cause of serious human infections in the United States, Europe, and elsewhere in the 1980s and into the 1990s was thoroughly documented and has heightened public awareness about this organism. Disease resurgence coupled with the lack of a licensed GAS vaccine and ongoing concern about acquisition of penicillin resistance remain a major concern.

In Denmark, the incidence of rheumatic fever decreased from 250 cases per 100,000 population to 100 cases per 100,000 population from 1862-1962. By 1980, the incidence ranged from 0.23-1.88 cases per 100,000 population.

The incidence of PSGN ranges from 9.5-28.5 new cases per 100,000 individuals per year. PSGN accounted for 2.6% to 3.7% of all primary glomerulopathies from 1987-1992, but only 9 cases were reported between 1992 and 1994. In China and Singapore, the incidence of PSGN has decreased in the past 40 years. In Chile, the disease has virtually disappeared since 1999, and, in Maracaibo, Venezuela, the incidence of sporadic PSGN decreased from 90-110 cases per year from 1980-1985 to 15 cases per year from 2001-2005. In Guadalajara, Mexico, the combined data from two hospitals showed a reduction in cases of PSGN from 27 in 1992 to only 6 in 2003.^[16]

The Strep-EURO program, which analyzed data gathered in 11 participating countries, reported the epidemiology of severe S pyogenes disease in Europe during the 2000s. A crude rate of 2.46 cases per 100,000 population was reported in Finland, 2.58 in Denmark, 3.1 in Sweden, and 3.31 in the United Kingdom. In contrast, the rates of reports in the more central and southern countries, the Czech Republic, Romania, Cyprus, and Italy, were substantially lower (0.3-1.5 per 100,000 population), attributed to poor diagnostic microbiological investigative methods in these countries.

Mortality/Morbidity

As reported by the CDC in April 2008, invasive GAS infections carry a mortality rate of 10-15%, with STSS and necrotizing fasciitis carrying fatality rates of over 35% and approximately 25%, respectively. STSS may also result in organ system failure, while necrotizing fasciitis may result in amputation.^[14]

Race

GAS infections have no racial predilection.

Sex

GAS infections have no sexual predilection, although rheumatic mitral stenosis is more common in females.

Age

• Strep throat is more common in school-aged children and teens.
• PSGN is more common in persons older than 60 years and in children younger than 15 years.
• ARF is commonly seen in young adults or children aged 4-9 years.