Group A Streptococcus

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Chapter 176 Group A Streptococcus

Group A streptococcus (GAS), also known as Streptococcus pyogenes, is a common cause of infections of the upper respiratory tract (pharyngitis) and the skin (impetigo, pyoderma) in children and is a less common cause of perianal cellulitis, vaginitis, septicemia, pneumonia, endocarditis, pericarditis, osteomyelitis, suppurative arthritis, myositis, cellulitis, and omphalitis. These microorganisms also cause distinct clinical entities (scarlet fever and erysipelas), as well as a toxic shock syndrome and necrotizing fasciitis. GAS is also the cause of 2 potentially serious nonsuppurative complications: rheumatic fever (Chapters 176.1 and 432) and acute glomerulonephritis (Chapter 505.1).

Etiology

Group A streptococci are gram-positive coccoid-shaped bacteria that tend to grow in chains. They are broadly classified by their reactions on mammalian red blood cells. The zone of complete hemolysis that surrounds colonies grown on blood agar distinguishes β-hemolytic (complete hemolysis) from α-hemolytic (green or partial hemolysis) and γ (nonhemolytic) species. The β-hemolytic streptococci can be divided into groups by a group-specific polysaccharide (Lancefield carbohydrate C) located in the cell wall. More than 20 serologic groups are identified, designated by the letters A through V. Serologic grouping by the Lancefield method is precise, but group A organisms can be identified more readily by any one of a number of latex agglutination, coagglutination, or enzyme immunoassay procedures. Group A strains can also be distinguished from other groups by differences in sensitivity to bacitracin. A disk containing 0.04 U of bacitracin inhibits the growth of most group A strains, whereas other groups are generally resistant to this antibiotic. GAS can be subdivided into >100 serotypes on the basis of the M protein antigen, which is located on the cell surface and in fimbriae that project from the outer edge of the cell. M typing has traditionally relied primarily on the serologic typing of the surface M protein using available polyclonal sera. However, it is frequently difficult to detect M proteins in this way; a molecular approach to M typing GAS isolates using the polymerase chain reaction is based on sequencing the emm gene of GAS that encodes the M protein. More than 180 distinct M types have been identified using emm typing, and there has been a good correlation between the known serotypes and the emm types.

M serotyping has been valuable for epidemiologic studies; particular GAS diseases tend to be associated with certain M types. Types 1, 12, 28, 4, 3, and 2 (in that order) are the most common causes of uncomplicated streptococcal pharyngitis in the USA. The M types commonly associated with pharyngitis rarely cause skin infections, and the M types commonly associated with skin infections rarely cause pharyngitis. A few of the pharyngeal strains (M type 12) have been associated with glomerulonephritis, but far more of the skin strains (M types 49, 55, 57, and 60) have been considered nephritogenic. A few of the pharyngeal serotypes, but none of the skin strains, have been associated with acute rheumatic fever. Rheumatogenic potential is not solely dependent on the serotype but is a characteristic of specific strains within several serotypes.

Epidemiology

Humans are the natural reservoir for GAS. These bacteria are highly communicable and can cause disease in normal individuals of all ages who do not have type-specific immunity against the particular serotype involved. Disease in neonates is uncommon, probably because of maternally acquired antibody. The incidence of pharyngeal infections is highest in children 5-15 yr of age, especially in young school-aged children. These infections are most common in the northern regions of the USA, especially during winter and early spring. Children with untreated acute pharyngitis spread GAS by airborne salivary droplets and nasal discharge. Transmission is favored by close proximity; therefore, schools, military barracks, and homes are important environments for spread. The incubation period for pharyngitis is usually 2-5 days. GAS has the potential to be an important upper respiratory tract pathogen and to produce outbreaks of disease in the daycare setting. Foods containing GAS occasionally cause explosive outbreaks of pharyngotonsillitis. Children are usually not infectious 24 hr after appropriate antibiotic therapy has been started. Chronic pharyngeal carriers of GAS rarely transmit this organism to others.

Streptococcal pyoderma (impetigo, pyoderma) occurs most frequently during the summer in temperate climates, or year round in warmer climates, when the skin is exposed and abrasions and insect bites are more likely to occur (Chapter 657). Colonization of healthy skin by GAS usually precedes the development of impetigo. Because GAS cannot penetrate intact skin, impetigo usually occurs at the site of open lesions (insect bites, traumatic wounds, burns). Although impetigo serotypes may colonize the throat, spread is usually from skin to skin, not via the respiratory tract. Fingernails and the perianal region can harbor GAS and play a role in disseminating impetigo. Multiple cases of impetigo in the same family are common. Both impetigo and pharyngitis are more likely to occur among children living in crowded homes and in poor hygienic circumstances.

The incidence of severe invasive GAS infections, including bacteremia, streptococcal toxic shock syndrome, and necrotizing fasciitis, has increased in recent years. The incidence appears to be highest in the very young and in older persons. Prior to the routine use of varicella vaccine, varicella was the most commonly identified risk factor in children. Other risk factors include diabetes mellitus, HIV infection, intravenous drug use, and chronic pulmonary or chronic cardiac disease. The portal of entry is unknown in almost 50% of the cases of severe invasive GAS infection; in most cases, it is believed to be skin or mucous membrane. Severe invasive disease rarely follows GAS pharyngitis.

Pathogenesis

Virulence of GAS depends primarily on the M protein, and strains rich in M protein resist phagocytosis in fresh human blood, whereas M-negative strains do not. GAS isolated from chronic pharyngeal carriers contains little or no M protein and are relatively avirulent. The M protein antigen stimulates the production of protective antibodies. These antibodies are type specific. They protect against infection with a homologous M type but confer no immunity against other M types. Therefore, multiple GAS infections attributable to different M types are common during childhood and adolescence. By adult life, individuals are probably immune to many of the common M types in the environment, but because of the large number of serotypes it is doubtful that total immunity is ever achieved.

GAS produces a large variety of enzymes and toxins, including erythrogenic toxins (known as streptococcal pyrogenic exotoxins). Streptococcal pyrogenic exotoxins A, B, and C are responsible for the rash of scarlet fever and are elaborated by streptococci that are infected with a particular bacteriophage. These exotoxins stimulate the formation of specific antitoxin antibodies that provide immunity against the scarlatiniform rash but not against other streptococcal infections. Because GAS can produce 3 different rash-producing pyrogenic exotoxins (A, B, or C), a 2nd attack of scarlet fever may sometimes occur. Streptococcal pyrogenic exotoxins A, B, and C, as well as several newly discovered exotoxins, appear to be involved in the pathogenesis of invasive GAS disease, including the streptococcal toxic shock syndrome.

The roles of most of the other streptococcal toxins and enzymes in human disease have yet to be established. Many of these extracellular substances are antigenic and stimulate antibody production after an infection. However, these antibodies bear no relationship to immunity. Their measurement is useful for evidence of a recent streptococcal infection. The test for antibodies against streptolysin O (antistreptolysin O) is the most commonly used antibody determination. Because the immune response to extracellular antigens varies among individuals as well as with the site of infection, it is sometimes necessary to measure other streptococcal antibodies, such as anti-deoxyribonuclease (anti-DNase).

Clinical Manifestations

The most common infections caused by GAS involve the respiratory tract and the skin and soft tissues.

Respiratory Tract Infections

GAS is an important cause of acute pharyngitis (Chapter 373) and pneumonia (Chapter 392).

Scarlet Fever

Scarlet fever is an upper respiratory tract infection associated with a characteristic rash, which is caused by an infection with pyrogenic exotoxin (erythrogenic toxin)-producing GAS in individuals who do not have antitoxin antibodies. It is now encountered less commonly and is less virulent than in the past, but the incidence is cyclic, depending on the prevalence of toxin-producing strains and the immune status of the population. The modes of transmission, age distribution, and other epidemiologic features are otherwise similar to those for GAS pharyngitis.

The rash appears within 24-48 hours after onset of symptoms, although it may appear with the first signs of illness (Fig. 176-1A). It often begins around the neck and spreads over the trunk and extremities. It is a diffuse, finely papular, erythematous eruption producing a bright red discoloration of the skin, which blanches on pressure. It is often more intense along the creases of the elbows, axillae, and groin. The skin has a goose-pimple appearance and feels rough. The face is usually spared, although the cheeks may be erythematous with pallor around the mouth. After 3-4 days, the rash begins to fade and is followed by desquamation, 1st on the face, progressing downward, and often resembling a mild sunburn. Occasionally, sheetlike desquamation may occur around the free margins of the fingernails, the palms, and the soles. Examination of the pharynx of a patient with scarlet fever reveals essentially the same findings as with GAS pharyngitis. In addition, the tongue is usually coated and the papillae are swollen (Fig. 176-1B). After desquamation, the reddened papillae are prominent, giving the tongue a strawberry appearance (Fig. 176-1C).

Figure 176-1 Scarlet fever. A, Punctate, erythematous rash (2nd day). B, White strawberry tongue (1st day). C, Red strawberry tongue (3rd day).

(Courtesy Dr. Franklin H. Top, Professor and Head of the Department of Hygiene and Preventive Medicine, State University of Iowa, College of Medicine, Iowa City, IA; and Parke, Davis & Company’s Therapeutic Notes. From Gershon AA, Hotez PJ, Katz SL: Krugman’s infectious diseases of children, ed 11, Philadelphia, 2004, Mosby, plate 53.)

Typical scarlet fever is not difficult to diagnose; the milder form with equivocal pharyngeal findings can be confused with viral exanthems, Kawasaki disease, and drug eruptions. Staphylococcal infections are occasionally associated with a scarlatiniform rash. A history of recent exposure to a GAS infection is helpful. Identification of GAS in the pharynx confirms the diagnosis, if uncertain.

Impetigo

Impetigo (or pyoderma) has traditionally been classified into 2 clinical forms: bullous and nonbullous (Chapter 657). Nonbullous impetigo is the more common form and is a superficial infection of the skin that appears first as a discrete papulovesicular lesion surrounded by a localized area of redness. The vesicles rapidly become purulent and covered with a thick, confluent, amber-colored crust that gives the appearance of having been stuck on the skin. The lesions may occur anywhere but are more common on the face and extremities. If untreated, nonbullous impetigo is a mild but chronic illness, often spreading to other parts of the body, but occasionally is self-limited. Regional lymphadenitis is common. Nonbullous impetigo is generally not accompanied by fever or other systemic signs or symptoms. Impetiginized excoriations around the nares are seen with active GAS infections of the nasopharynx particularly in young children. However, impetigo is not usually associated with an overt streptococcal infection of the upper respiratory tract.

Bullous impetigo is less common and occurs most often in neonates and young infants. It is characterized by flaccid, transparent bullae usually <3 cm in diameter on previously untraumatized skin. The usual distribution involves the face, buttocks, trunk, and perineum. Although Staphylococcus aureus has traditionally been accepted as the sole pathogen responsible for bullous impetigo, there has been confusion about the organisms responsible for nonbullous impetigo. In most episodes of nonbullous impetigo, either GAS or S. aureus, or a combination of these 2 organisms, is isolated. Earlier investigations suggested that GAS was the causative agent in most cases of nonbullous impetigo and that S. aureus was only a secondary invader. However, studies have demonstrated the recent emergence of S. aureus as the causative agent in most cases of nonbullous impetigo. Culture of the lesions is the only way to distinguish nonbullous impetigo caused by S. aureus from that caused by GAS.

Erysipelas

Erysipelas is a relatively rare acute GAS infection involving the deeper layers of the skin and the underlying connective tissue. The skin in the affected area is swollen, red, and very tender. Superficial blebs may be present. The most characteristic finding is the sharply defined, slightly elevated border. At times, reddish streaks of lymphangitis project out from the margins of the lesion. The onset is abrupt, and signs and symptoms of a systemic infection, such as high fever, are often present. Cultures obtained by needle aspirate of the inflamed area often reveal the causative agent.

Perianal Dermatitis

Perianal dermatitis, also called perianal streptococcal disease, is a distinct clinical entity characterized by well-demarcated, perianal erythema associated with anal pruritus, painful defecation, and blood-streaked stools. Physical examination reveals flat, pink to beefy-red perianal erythema with sharp margins extending as far as 2 cm from the anus. Erythema may involve the vulva and vagina. Lesions may be very tender and, particularly when chronic, may fissure and bleed. Systemic symptoms and fever are unusual.

Vaginitis

GAS is a common cause of vaginitis in prepubertal girls (Chapter 543). Patients usually have a serous discharge with marked erythema and irritation of the vulvar area, accompanied by discomfort in walking and in urination.

Severe Invasive Disease

Invasive GAS infection is defined by isolation of GAS from a normally sterile body site and includes 3 overlapping clinical syndromes. The 1st is GAS toxic shock syndrome, which is differentiated from other types of invasive GAS infections by the presence of shock and multiorgan system failure early in the course of the infection (Table 176-1). The second is GAS necrotizing fasciitis characterized by extensive local necrosis of subcutaneous soft tissues and skin. The third is the group of focal and systemic infections that do not meet the criteria for toxic shock syndrome or necrotizing fasciitis and includes bacteremia with no identified focus, meningitis, pneumonia, peritonitis, puerperal sepsis, osteomyelitis, suppurative arthritis, myositis, and surgical wound infections.

Table 176-1 DEFINITION OF STREPTOCOCCAL TOXIC SHOCK SYNDROME

Clinical criteria

Hypotension plus 2 or more of the following:

Renal impairment

Coagulopathy

Hepatic involvement

Adult respiratory distress syndrome

Generalized erythematous macular rash

Soft tissue necrosis

Definite case

Clinical criteria plus group A streptococcus from a normally sterile site

Probable case

Clinical criteria plus group A streptococcus from a nonsterile site

The pathogenic mechanisms responsible for severe, invasive GAS infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, have yet to be defined completely, but an association with streptococcal pyrogenic exotoxins has been suggested. The three original streptococcal pyrogenic exotoxins (A, B, C), the newly discovered streptococcal pyrogenic exotoxins, and potentially other, as yet unidentified toxins produced by GAS act as superantigens, which stimulate an intense activation and proliferation of T lymphocytes and macrophages resulting in the production of large quantities of cytokines. These cytokines are capable of producing shock and tissue injury, and are believed to be responsible for many of the clinical manifestations of severe, invasive GAS infections.

Diagnosis

When attempting to decide whether to perform a microbiologic test on a patient presenting with acute pharyngitis, consideration of the clinical and epidemiologic findings should take place before the test is performed. A history of close contact with a well-documented case of GAS pharyngitis is helpful, as is an awareness of a high prevalence of GAS infections in the community. The signs and symptoms of streptococcal and nonstreptococcal pharyngitis overlap too broadly to allow the requisite diagnostic precision on clinical grounds alone. The clinical diagnosis of GAS pharyngitis cannot be made with certainty even by the most experienced physicians, and bacteriologic confirmation is required.

Culture of a throat swab on a sheep blood agar plate remains the standard for the documentation of the presence of GAS in the upper respiratory tract and for the confirmation of the clinical diagnosis of acute GAS pharyngitis. If performed correctly, a single throat swab cultured on a blood-agar plate has a sensitivity of 90-95% for detecting the presence of GAS in the pharynx.

A disadvantage of culturing a throat swab on a blood-agar plate is the delay (overnight or longer) in obtaining the culture result. Rapid antigen detection tests have been developed for the identification of GAS directly from throat swabs. Although these rapid tests are more expensive than the blood-agar culture, the advantage they offer over the traditional procedure is the speed with which they can provide results. Rapid identification and treatment of patients with streptococcal pharyngitis can reduce the risk for the spread of GAS, allowing the patient to return to school or work sooner, and can reduce the acute morbidity of this illness.

The great majority of the rapid antigen detection tests that are currently available have an excellent specificity of >95% when compared with blood-agar plate cultures. False-positive test results are unusual, and, therefore, therapeutic decisions can be made on the basis of a positive test result with confidence. Unfortunately, the sensitivity of most of these tests is 80-90%, possibly lower, when compared with the blood-agar plate culture. Therefore, a negative test does not exclude the presence of GAS, and a confirmatory throat culture should be performed. Newer tests may be more sensitive than other rapid antigen detection tests and perhaps may even be as sensitive as blood-agar plate cultures. However, the definitive studies to determine whether some rapid antigen detection tests are significantly more sensitive than others, and, whether any of these tests are sensitive enough to be used routinely without throat culture confirmation of negative test results, have not been performed. Some experts believe that physicians who use a rapid antigen detection test without culture backup should compare the results with that specific test to those of throat cultures to confirm adequate sensitivity in their practice.

GAS infection can also be diagnosed retrospectively on the basis of an elevated or increasing streptococcal antibody titer. The antistreptolysin O assay is the streptococcal antibody test most commonly used. Because streptolysin O also is produced by group C and G streptococcus, the test is not specific for group A infection. The antistreptolysin O response can be feeble in patients with streptococcal impetigo, and its usefulness for this condition is limited. In contrast, the anti-DNase B responses are present after both skin and throat infections. A significant antibody increase is usually defined as an increase in titer of 2 or more dilution increments between the acute phase and convalescent phase specimens, regardless of the actual height of the antibody titer. Physicians frequently misinterpret streptococcal antibody titers because of a failure to appreciate that the normal levels of these antibodies are higher among school-aged children compared to adults. Both the traditional ASO and anti-DNase B tests are neutralization assays. Newer tests use latex agglutination or nephelometric assays. Unfortunately, these newer tests have not been well-standardized against the traditional neutralization assays. Physicians need to be aware of these potential problems when interpreting the results of streptococcal serologic testing performed on their patients.

A commercially available slide agglutination test for the detection of antibodies to several streptococcal antigens is the Streptozyme test (Wampole Laboratories, Stamford, CT). This test is less well standardized and less reproducible than other antibody tests, and it should not be used as a test for evidence of a preceding GAS infection.

Differential Diagnosis

Viruses are the most common cause of acute pharyngitis in children. Respiratory viruses such as influenza virus, parainfluenza virus, rhinovirus, coronavirus, adenovirus, and respiratory syncytial virus are frequent causes of acute pharyngitis. Other viral causes of acute pharyngitis include enteroviruses and herpes simplex virus (HSV). Epstein-Barr virus (EBV) is a frequent cause of acute pharyngitis that is often accompanied by other clinical findings of infectious mononucleosis (e.g., splenomegaly, generalized lymphadenopathy). Systemic infections with other viral agents including cytomegalovirus, rubella virus, measles virus, and HIV may be associated with acute pharyngitis.

GAS is the most common cause of bacterial pharyngitis, accounting for 15-30% of the cases of acute pharyngitis in children. Groups C and G β-hemolytic streptococcus (Chapter 178) also produce acute pharyngitis in children. Arcanobacterium haemolyticum and Fusobacterium necrophorum are additional less common causes. Neisseria gonorrhoeae can occasionally cause acute pharyngitis in sexually active adolescents. Other bacteria such as Francisella tularensis and Yersinia enterocolitica as well as mixed infections with anaerobic bacteria (Vincent angina) are rare causes of acute pharyngitis. Chlamydia pneumoniae and Mycoplasma pneumoniae have been implicated as causes of acute pharyngitis, particularly in adults. Corynebacterium diphtheriae (Chapter 180) can cause pharyngitis but is rare because of universal immunization. Although other bacteria such as Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae are frequently cultured from the throats of children with acute pharyngitis, their etiologic role in pharyngitis has not been established.