Infection with Streptococcus pyogenes, a beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as the group A streptococci (GAS), causes a wide variety of diseases in humans. A ubiquitous organism, S pyogenes 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 group A streptococcus carriers. (See Pathophysiology, Etiology, and Epidemiology.)[2, 3]
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. Along with Staphylococcus aureus, group A streptococcus is one of the most common pathogens responsible for cellulitis. Infection with this pathogen is also causally linked to 2 potentially serious nonsuppurative complications: acute rheumatic fever (ARF) and acute glomerulonephritis. In addition, infection with S pyogenes has reemerged as an important cause of toxic shock syndrome (TSS) and of life-threatening skin and soft-tissue infections, especially necrotizing fasciitis (see the image below). (See Pathophysiology, Etiology, Presentation, Workup, Treatment, and Medication.)
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Invasive soft tissue infection due to Streptococcus pyogenes. This child developed fever and soft-tissue swelling on the fifth day of a varicella-zost....
Lancefield classification scheme
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, group B 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. (See Pathophysiology.)
The emm classification scheme
The traditional Lancefield classification system, which is based on serotyping, has been replaced by emm typing, which has been used to characterize and measure the genetic diversity among isolates of S pyogenes. This system is based on a 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 an S pyogenes gene; more than 150 emm types have been described to date.[4] The emm gene encodes the M protein.
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.[5]
Identification of GAS
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. (See Workup.)
Group A strains can also be distinguished from other groups by their sensitivity to bacitracin. A disc that contains 0.04U 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 GAS.
Presumptive identification of a strain as a group A streptococcus 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.
When cultured on blood agar plates, the production of a characteristic zone of complete hemolysis (beta hemolysis) is another important clue to the classification of S pyogenes (see the image below). (For example, Streptococcus pneumoniae generates a zone of only partial hemolysis [alpha hemolysis].)
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Streptococcus group A infections. Beta hemolysis is demonstrated on blood agar media.
Spectrum of diseases caused by 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 suppurative diseases and nonsuppurative postinfectious sequelae. (See Pathophysiology, Etiology, Prognosis, and Treatment.)
The suppurative spectrum of GAS diseases includes the following:
Pharyngitis - With or without tonsillopharyngeal cellulitis or abscess
A superantigen-mediated immune response may result in the development of scarlet fever or streptococcal TSS. Scarlet fever is characterized by an upper-body rash, generally following pharyngitis.
Streptococcal TSS is characterized by systemic shock with multiorgan failure, with manifestations that include respiratory failure, acute renal failure, hepatic failure, neurologic symptoms, hematologic 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.[6]
Streptococci are a large group of gram-positive, nonmotile, non–spore-forming cocci about 0.5-1.2µm in size. They often grow in pairs or chains and are negative for oxidase and catalase.
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.
Epithelial cell invasion
A characteristic of S pyogenes is the organism’s ability 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 results of one study strongly suggested 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.[7] These observations may have clinical implications for understanding carriers and managing S pyogenes infection.
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.[8]
Another virulence factor, C5A peptidase, destroys the chemotactic signals by cleaving the complement component of C5A.
M protein, the major virulence factor, is a macromolecule incorporated in fimbriae present on the cell membrane projecting on the bacterial cell wall. It is the primary cause of antigenic shift and antigenic drift among GAS. (See the image below.)[9, 10]
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Streptococcus group A infections. M protein.
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 the disease process. After an acute infection, type-specific antibodies develop against M protein activity in some cases.
However, although such antibodies protect against infection by a homologous M protein type, they confer no immunity against other M types. This observation is one of the factors representing 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.
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, but not to buccal cells, in humans, whereas FBP54 mediates adhesion to buccal cells, but not to HEp-2 cells. Protein F mediates adhesion to Langerhans cells, but not to keratinocytes.
One of the theories proposed with regard to the process of adhesion is a 2-step model. The initial step in overcoming the electrostatic repulsion of the bacteria from the host is mediated by LTA, which provides weak, reversible adhesion. The second step takes the form of 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.[11]
GAS show enormous and evolving molecular diversity, driven by horizontal transmission among various strains. This is also true when they are 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.
Hemolysins
S pyogenes 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, and is highly immunogenic. The determination of the antibody responses to this protein (antistreptolysin O [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.
Pyrogenic exotoxins
The family of streptococcal pyrogenic exotoxins (SPEs) includes SPEs A, B, C, and F. These toxins are responsible for the rash of scarlet fever. Other pathogenic effects caused by these substances include pyrogenicity, cytotoxicity, and enhancement of susceptibility to endotoxin. SPE B is a precursor of a cysteine protease, another determinant of virulence.[12]
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.
Nucleases
Four antigenically distinct nucleases (A, B, C, D) assist in the liquefaction of pus and help to generate substrate for growth.
Other products
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).[13]
Proteinase, amylase, and esterase are additional streptococcal virulence factors, although the role of these proteins in pathogenesis is not fully understood.
Suppurative disease spectrum
Streptococcal pharyngitis
S pyogenes causes up to 15-30% of cases of acute pharyngitis.[14] Frank disease occurs based on the degree of bacterial virulence after colonization of the upper respiratory tract. Accurate diagnosis is essential for appropriate antibiotic selection.
Impetigo
Pyoderma is the most common form of skin infection caused by GAS. Also referred to as streptococcal impetigo or impetigo contagiosa, it occurs most commonly in tropical climates but can be highly prevalent in northern climates as well, particularly in the summer months. Risk factors that predispose to this infection include low socioeconomic status; low level of overall hygiene; and local injury to skin caused by insect bites, scabies, atopic dermatitis, and minor trauma. Colonization of unbroken skin precedes the development of pyoderma by approximately 10 days.
Streptococcal pyoderma may occur in children belonging to certain population groups and in overcrowded institutions. The modes of transmission are direct contact, environmental contamination, and houseflies. The strains of streptococci that cause pyoderma differ from those that cause exudative tonsillitis.
The bacterial toxins cause proteolysis of epidermal and subepidermal layers, allowing the bacteria to spread quickly along the skin layers and thereby cause blisters or purulent lesions. The other common cause of impetigo is Staphylococcus 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 GAS 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.[15] 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 the spread of organisms via the eustachian tube (otitis media) or by direct spread to the sinuses (sinusitis).
Nonsuppurative disease spectrum
Acute rheumatic fever
ARF is a delayed, nonsuppurative sequela of GAS tonsillopharyngitis. Following the pharyngitis, a latent period of 2-3 weeks passes before the signs or symptoms of ARF appear. The disease presents with various clinical manifestations, including arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum.
Rheumatic fever may be the result of host genetic predisposition. The disease gene may be transmitted either in an autosomal-dominant fashion or in an autosomal-recessive fashion, with limited penetrance. However, the disease gene has not yet been identified.
Considerable evidence supports the link between group A streptococcal infections of the upper respiratory tract and ARF, although only certain M-group serotypes (ie, 1, 3, 5, 6, 18, 24) are associated with this complication. Very mucoid strains, particularly strains of M type 18, have appeared in numerous communities prior to the appearance of rheumatic fever. Rheumatic fever is most frequently observed in children aged 5-15 years (the age group most susceptible to GAS infections).
The attack rate following upper respiratory tract infection is approximately 3% for individuals with untreated or inadequately treated infection. The latent period between the GAS infection and the onset of rheumatic fever varies from 2-4 weeks. In contrast to poststreptococcal glomerulonephritis (PSGN), which may follow either pharyngitis or streptococcal pyoderma, rheumatic fever can occur only after an infection of the upper respiratory tract.
Despite the depth of knowledge that has been accumulated about the molecular microbiology of Streptococcus pyogenes, the pathogenesis of ARF remains unknown. A direct effect of a streptococcal extracellular toxin, in particular streptolysin O, may be responsible for the pathogenesis of ARF, according to some hypotheses. Observations that streptolysin O is cardiotoxic in animal models support this hypothesis, but linking this toxicity to the valvular damage observed in ARF has been difficult.
A more popular hypothesis is that an abnormal host immune response to some component of the group A Streptococcus is responsible. The M protein of GAS shares certain amino acid sequences with some human tissues, and this has been proposed as a source of cross-reactivity between the organism and human host that could lead to an immunopathologic immune response. Also, antigenic similarity between the group-specific polysaccharide of S pyogenes and glycoproteins found in human and bovine cardiac valves has been recognized, and patients with ARF have prolonged persistence of these antibodies compared with controls with uncomplicated pharyngitis. Other GAS antigens appear to cross-react with cardiac sarcolemma membranes.[16]
During the course of the host's immune response to the GAS, the host's antigens may, as a result of this molecular mimicry, be mistaken as foreign; this leads to an inflammatory cascade with resultant tissue damage. In patients with ARF with Sydenham chorea, common antibodies to antigens found in the S pyogenes cell membrane and the caudate nucleus of the brain are present, further supporting the concept of an aberrant autoimmune response in the development of ARF.
Interest in whether such autoimmune responses play a role in the pathogenesis of the syndrome known as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) has been considerable, although further work is necessary to establish the link between streptococcal infections and these syndromes.
Poststreptococcal glomerulonephritis
Glomerulonephritis can follow group A streptococcal infections of either the pharynx or the skin, and incidence varies with the prevalence of so-called nephritogenic strains of group A streptococci in the community. Type 12 is the most frequent M serotype that causes PSGN after pharyngitis, and M type 49 is the serotype most commonly related to pyoderma-associated nephritis. The latent period between GAS infection and the onset of glomerulonephritis varies from 1-2 weeks.
Pathogenesis appears to be immunologically mediated. Immunoglobulins, complement components, and antigens that react with streptococcal antisera are present in the glomerulus early in the course of the disease, and antibodies elicited by nephritogenic streptococci are postulated to react with renal tissue in such a way as to promote glomerular injury. In contrast to acute rheumatic fever, recurrences of PSGN are rare. Diagnosis of PSGN is based on clinical history, physical examination findings, and confirmatory evidence of recent streptococcal infection.
Toxic shock syndrome
Severe GAS infections associated with shock and organ failure have been reported with increasing frequency, predominantly in North America and Europe.
Considerable overlap occurs between streptococcal TSS and streptococcal necrotizing fasciitis, insofar as most cases occur in association with soft-tissue infections. However, streptococcal TSS may also occur in association with other focal streptococcal infections, including pharyngeal infection.
The pathogenesis of streptococcal TSS appears to be related in part to the ability of certain (ie, A, C, F) streptococcal pyogenic exotoxins (SPEs) to function as superantigens.
Scarlet fever
When a fine, diffuse, erythematous rash is present in the setting of acute streptococcal pharyngitis, the illness is called scarlet fever. The rash of scarlet fever is caused by the pyrogenic exotoxins (ie, SPE A, B, C, and F). The rash highly depends on toxin expression; preexisting humoral immunity to the specific SPE toxin prevents the clinical manifestations of scarlet fever.
Scarlet fever has apparently become less common and less virulent than in past decades; however, incidence is cyclic, depending on the prevalence of toxin-producing strains and the immune status of the population. Modes of transmission, age distribution of cases, and other epidemiologic features are similar to those for streptococcal pharyngitis.
Central nervous system diseases
The primary evidence for poststreptococcal autoimmune central nervous system (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 occurring in association with group A beta-hemolytic streptococcal infections suggest that various CNS sequelae may be triggered by poststreptococcal autoimmunity.[17]
S pyogenes is highly communicable and can cause disease in healthy people of all ages who do not have type-specific immunity against the specific serotype responsible for infection. The streptococcus can be present on healthy skin for at least a week before lesions appear.
S pyogenes is primarily spread through person-to-person transmission, although foodborne and waterborne outbreaks have been documented. Neither spread of organisms by fomites nor transmission from animals (eg, family pets) appears to play a significant role in contagion.
Respiratory droplet spread is the major route for transmission of strains associated with upper respiratory tract infection, although skin-to-skin spread is known to occur with strains associated with streptococcal pyoderma. Impetigo serotypes may colonize the throat.
Children with untreated acute infections spread organisms by airborne salivary droplet and nasal discharge. The incubation period for pharyngitis is 2-5 days. Children are usually not infectious within 24 hours after appropriate antibiotic therapy has been started, an observation that has important implications for return to the daycare or school environment.
Individuals who are streptococcal carriers (chronic asymptomatic pharyngeal and nasopharyngeal colonization) are not usually at risk of spreading disease to others because of the generally small reservoir of often-avirulent organisms.
Fingernails and the perianal region can harbor streptococci and can play a role in disseminating impetigo.
Multiple streptococcal infections in the same family are common. Impetigo and pharyngitis are more likely to occur among children living in crowded homes and in suboptimal hygienic conditions.
According to a report from the Centers for Disease Control and Prevention (CDC), 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. Streptococcal TSS 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.[18, 19]
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 be predominant in Hawaii,[20] and novel emm types are associated with invasive disease and streptococcal-related sequelae.
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 soft-tissue infections that are unusually severe and that are 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.
Acute rheumatic fever
During the 1960s and 1970s, ARF nearly disappeared in the United States, although it continued unabated in developing countries. This decline in disease was largely attributed to careful disease surveillance and initiation of prompt aggressive antibiotic therapy in primary care practice. However, in 1985, several multifocal outbreaks of rheumatic fever occurred in several parts of the United States.
In contrast with earlier outbreaks in this country, most of the patients were white, middle-class children from rural and suburban communities who had good access to health care. This unexplained resurgence in acute rheumatic fever underscores the point that a great deal remains to be learned about the pathogenesis of this disease.
International occurrence
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 heightened public awareness about this organism. Disease resurgence, coupled with the lack of a licensed GAS vaccine and ongoing concern about the acquisition of penicillin resistance, remains 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 had virtually disappeared by 1999, while 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 2 hospitals showed a reduction in cases of PSGN from 27 in 1992 to only 6 in 2003.[21]
The Strep-EURO program, which analyzed data gathered from 11 participating countries, investigated 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 per 100,000 population, in Denmark; 3.1 per 100,000 population, in Sweden; and 3.31 per 100,000 population in the United Kingdom.
In contrast, the rates reported in more central and southern countries―the Czech Republic, Romania, Cyprus, and Italy―were substantially lower (0.3-1.5 per 100,000 population), although this was attributed to poor microbiologic investigative methods in these countries.
The 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.
Race- and sex-related demographics
GAS 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.
GAS infections have no sex predilection, although rheumatic mitral stenosis is more common in females.
Age-related demographics
GAS 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. Strep throat is more common in school-aged children and teens.
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 a hazard in school-aged children.[22] S pyogenes also has the potential to produce outbreaks of disease in younger children in daycare.
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.
ARF is commonly seen in young adults or children aged 4-9 years, while PSGN is more common in persons older than 60 years and in children younger than 15 years.
Acute proliferative PSGN carries a good prognosis, as more than 95% of patients recover spontaneously within 3-4 weeks with no long-term sequelae. With appropriate treatment, pharyngitis and skin infections also have a good prognosis.
As reported by the CDC in April 2008, invasive GAS infections carry an overall mortality rate of 10-15%, with streptococcal TSS and necrotizing fasciitis carrying fatality rates of over 35% and approximately 25%, respectively.
Suppurative complications from the spread of streptococci to adjacent structures were very common in the preantibiotic era. Cervical adenitis, peritonsillar abscess, retropharyngeal abscess, otitis media, mastoiditis, and sinusitis still occur in children in whom the primary illness has gone unnoticed or in whom treatment of the pharyngitis has been inadequate because of noncompliance.[23]
Acute hematogenous osteomyelitis is an important complication of streptococcal infection. Isolated bacteremia, meningitis, and endocarditis are described but appear to be rare manifestations of acute infection.[24]
Streptococcal TSS may cause organ system failure (including renal impairment in approximately 80% of patients, and hepatic dysfunction in 65% of patients), while necrotizing fasciitis may result in amputation.[18]
Puerperal sepsis follows abortion or delivery when streptococci that colonize the genital tract invade the endometrium and enter the bloodstream. Pelvic cellulitis, septic pelvic thrombophlebitis, pelvic abscess, and septicemia can occur. Peripartum genital tract infections with group B streptococci are relatively more common, but fatal peripartum GAS infections have been reported.[25]
Empyema develops in 30-40% of pneumonia cases. Other complications of pneumonia include mediastinitis, pericarditis, pneumothorax, and bronchiectasis.
The nonsuppurative complications of GAS tonsillopharyngitis include ARF, rheumatic heart disease, and acute glomerulonephritis.
For patient education resources, see the Infections Center, the Women's Health Center, and the Ear, Nose, and Throat Center, as well as Sore Throat, Toxic Shock Syndrome, and Strep Throat.
Group A streptococci (GAS) can cause various diseases, including strep throat, skin and soft-tissue infections (eg, pyoderma, erysipelas, cellulitis, necrotizing fasciitis, myositis, osteomyelitis, pneumonia, abscess), severe systemic disease, and long-term nonsuppurative complications (eg, rheumatic fever, acute glomerulonephritis).
Head and neck infections
Streptococcal pharyngitis is strongly suggested by the presence of fever; tonsillar exudate; tender, enlarged, anterior cervical lymph nodes; and absence of cough (Centor criteria).[14] Strep throat has an incubation period of 2-4 days and is characterized by sudden onset of sore throat, cervical lymphadenopathy, malaise, fever, and headache. Younger patients may also develop nausea, vomiting, and abdominal pain. Acute sinusitis manifests as persistent coryza, postnasal drip, headache, and fever.
The most important historic information to obtain in the evaluation of a sore throat is whether other symptoms of upper respiratory tract infection are present or not. Children with streptococcal pharyngitis do not have cough, rhinorrhea, or symptoms of viral upper respiratory tract infection. Indeed, the diagnosis of streptococcal pharyngitis can effectively be ruled out on the basis of the clinical findings of marked coryza, hoarseness, cough, or conjunctivitis.
However, although these are important exclusionary criteria, the pediatrician must be aware that signs and symptoms of streptococcal pharyngitis may otherwise be nonspecific and that they vary widely depending on patient age, severity of the infection, and timing of the illness.
Relatively few localizing or constitutional symptoms may be present, such that the illness may be unrecognized (subclinical infection). Young infants do not present with classic pharyngitis. Streptococcal upper respiratory tract infections in infants and toddlers instead may be characterized by low-grade fever, anorexia, and a thick, purulent nasal discharge (so-called streptococcosis). Conversely, some patients may be toxic, with high fever, malaise, headache, and severe pain upon swallowing.
Streptococcal toxic shock can be associated with pharyngitis; however, this is rare. Vomiting and abdominal pain may be prominent early symptoms simulating gastroenteritis or even acute appendicitis. Hence, streptococcal pharyngitis should be considered in a child with acute onset of abdominal pain. Because streptococcal pharyngitis is chiefly a disease of winter and spring and primarily affects children older than 3 years, fewer throat cultures should be completed in the summer and in children younger than 3 years.
Skin and soft-tissue infections
Scarlet fever
Scarlet fever results from pyrogenic exotoxin released by GAS and is characterized by a scarlatiniform rash that blanches with pressure. The rash usually appears on the second day of illness and fades within a week, followed by extensive desquamation that lasts for several weeks.
A history of recent exposure to another individual (eg, classroom or household contact) with streptococcal infection is a helpful clue. Isolation of S pyogenes from the pharynx confirms the diagnosis in uncertain cases, and serologic evidence of recent GAS infection may be present (ASO or anti-deoxyribonuclease B [anti-DNase B] antibody response).
Erysipelas
Erysipelas is an acute infection of the skin. In the past, the face was the most commonly involved site of infection; however, it now accounts for 20% or less of cases. Lower extremities are commonly affected. The symptoms of erysipelas include erythematous, warm, painful skin lesions with raised borders that are commonly associated with fever. With appropriate antibiotics, the lesions resolve in days to weeks, with possible peeling. The condition usually occurs in children or elderly people. (See the image below.)
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Streptococcus group A infections. Erysipelas is a group A streptococcal infection of skin and subcutaneous tissue.
Cellulitis
Cellulitis is characterized by inflammation of the skin and subcutaneous tissues and is associated with local pain, tenderness, swelling, and erythema. Patients also develop fever, chills, and malaise and may become bacteremic. Intravenous (IV) drug abuse, abnormal lymphatic drainage, and breaks in skin integrity (eg, dry, cracked skin; tenia pedis) predispose the patient to streptococcal cellulitis. (See the image below.)
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Erythema secondary to group A streptococcal cellulitis.
Perianal cellulitis and vaginitis should be considered in children who report perineal discomfort or vaginal discharge.
Impetigo
This form of streptococcal infection is usually painless, and the patient is usually afebrile. Streptococcal impetigo usually has the highest prevalence in young children (aged 2-5y). Infection spreads readily to other individuals from the skin lesions, and multiple occurrences within families are common.
Necrotizing fasciitis
Necrotizing fasciitis caused by S pyogenes (so-called streptococcal gangrene) is an acute, rapidly progressive, severe, deep-seated infection of the subcutaneous tissue that is associated with extensive destruction of superficial and deep fascia. It may arise following minor trauma or from hematogenous spread of GAS from the throat to a site of blunt trauma or muscle strain. Although any part of the body may be affected, streptococcal fasciitis usually begins on an extremity.
Unexplained and rapidly progressing pain may be the first indication of necrotizing fasciitis. Pain may be disproportional to the physical findings; indeed, exquisite pain occurs at the affected site, so a finding of severe, excruciating pain that seems inconsistent with the observed clinical findings should strongly suggest the possibility of this diagnosis.
Erythema may be diffused or localized or may be absent. Fever, malaise, myalgias, diarrhea, and anorexia may also be present. Hypotension may develop initially or over time. Surgical exploration is critical for establishing the diagnosis and directing management.
A major risk factor for the development of streptococcal necrotizing fasciitis is a history of recent varicella-zoster virus (VZV) infection. The risk of varicella-associated necrotizing fasciitis should decrease with the implementation of routine childhood immunization against VZV.
Bacteremia
The risk factors for GAS bacteremia vary with age. Among children younger than 2 years, risk factors include burns, varicella virus infection, malignant neoplasm, and immunosuppression. Among individuals aged 40-60 years, the risk factors for GAS bacteremia include burns, cuts, surgical incisions, childbirth, IV drug abuse, and nonpenetrating trauma. Predisposing factors for GAS bacteremia in elderly people include diabetes mellitus, peripheral vascular disease, malignancy, and corticosteroid use.
GAS bacteremia usually results from invasive GAS infection. TSS is characterized by early onset of shock and multiorgan failure. Blood cultures results are positive in approximately 60% of STSS cases. These patients usually develop renal failure, acute respiratory distress syndrome, hepatic dysfunction, hematologic abnormalities, confusion, skin lesions, and diffuse capillary leak syndrome.
Acute rheumatic fever
The Jones criteria are used to diagnose rheumatic fever. The 5 major criteria consist of the following:
Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
The minor criteria include the following:
Fever
Arthralgia
Elevated erythrocyte sedimentation rate or C-reactive protein level
Prolonged PR interval on electrocardiogram (ECG)
The presence of 2 major manifestations or of 1 major and 2 minor manifestations, supported by evidence of a preceding GAS infection by positive throat swab or culture results or by high serum ASO titers, strongly suggests ARF.
Following the initial pharyngitis, a latent period of 2-3 weeks occurs before the first signs or symptoms of ARF appear.
Rheumatic heart disease is a sequela of ARF that manifests as valvular heart disease 10-20 years after the causative episode of ARF.
Poststreptococcal glomerulonephritis
This manifestation occurs rapidly within days after streptococcal pharyngitis and is characterized by acute renal failure with hematuria and nephrotic-range proteinuria.
Physical findings of pharyngitis include erythema, edema, and swelling of the pharynx. The tonsils are enlarged, and a grayish white exudate may be present. Submandibular and periauricular lymph nodes are usually enlarged and tender to palpation.
Scarlet fever, characterized by diffuse erythematous eruption, fever, sore throat, and a bright red tongue, can accompany pharyngitis in patients who have had prior exposure to the organism. The rash of scarlet fever requires the presence of pyrogenic exotoxin and delayed type skin reactivity to streptococcal toxins.
Upon physical examination, children with classic group A streptococcal pharyngitis are more likely to demonstrate tonsillopharyngeal erythema, a red edematous uvula, palatal petechiae, and tender anterior cervical adenopathy than are children with pharyngitis arising from other etiologies.
Typically, tonsils are enlarged and erythematous, with patchy exudate on the surface, although the presence of exudate is not pathognomonic for streptococcal pharyngitis and may be observed in the context of other bacterial and viral etiologies of pharyngitis, particularly Epstein-Barr virus. Patients with pharyngitis may also develop chills and fever.
The papillae of the tongue may be red and swollen (so-called strawberry tongue). Cutaneous petechiae are not uncommon, and a scarlatiniform rash may be present. When the characteristic rash of scarlet fever exists, a clinical diagnosis can be made with increased confidence. However, consistently making the diagnosis of streptococcal pharyngitis on clinical grounds alone is difficult. (See the image below.)
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Streptococcus group A infections. White strawberry tongue observed in streptococcal pharyngitis. Image courtesy of J. Bashera.
A study from the University of Pittsburgh School of Medicine established a patient-reported outcome measure (Strep-PRO) for assessing symptoms of group A Streptococcus pharyngitis from the child's point of view.[26] Preliminary data suggest that the scale effectively measures pain and overall functional status and support the use of Strep-PRO as a measure of outcome in future clinical trials.
Impetigo
Patients usually do not have systemic symptoms. Streptococcal impetigo begins with the appearance of a small papule that evolves into a vesicle surrounded by erythema. The vesicle turns into a pustule and then breaks down over 4-6 days to form a thick, confluent, honey-colored crust. The characteristics of streptococcal impetigo lesions thus contrast with the classic bullous appearance of lesions that arise from impetigo due to phage group II Staphylococcus aureus.
However, evidence now indicates that many cases of nonbullous impetigo are, in fact, mixed infections containing both S aureus and S pyogenes. Therefore, conclusions about etiology based on the clinical appearance of impetigo should be drawn with caution.
Lesions are most commonly encountered on the face and extremities. If untreated, streptococcal impetigo is a mild, but chronic, illness, often spreading to other parts of the body. Regional lymphadenitis is common. The M types that give rise to streptococcal tonsillitis (ie, types 1, 3, 5, 6, 12, 18, 19, 24) are rarely found in streptococcal impetigo. One of the streptococcal pyoderma-associated strains, the M49 strain, is very strongly associated with PSGN.
Deeper soft-tissue infections may occur following colonization of the skin with S pyogenes. A deeply ulcerated form of streptococcal impetigo, ecthyma, may complicate streptococcal impetigo. Ecthyma tends to be a more deep-seated and chronic form of streptococcal impetigo and is encountered mainly in the tropics.
Cellulitis and erysipelas
Streptococcal cellulitis is an acute, rapidly spreading infection of the skin and subcutaneous tissue that can follow the occurrence of burns, wounds, surgical incisions, varicella infection, or mild trauma. Pain, tenderness, swelling and erythema, and systemic toxicity are common, and patients may have associated bacteremia. Careful serial examination is crucial because cellulitis may progress to necrotizing fasciitis. (See the image below).
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Invasive soft tissue infection due to Streptococcus pyogenes. This child developed fever and soft-tissue swelling on the fifth day of a varicella-zost....
Perianal cellulitis and vaginitis should be considered in children who report perineal discomfort or vaginal discharge.
Today, erysipelas is a relatively rare acute streptococcal infection involving the deeper layers of the skin and the underlying connective tissue. Skin over the affected area tends to be swollen, red, and exquisitely tender, unlike in streptococcal impetigo, which is usually painless. Superficial blebs may be present. The most characteristic finding in erysipelas, the sharply defined and slightly elevated border, helps to differentiate this entity from cellulitis, which has an indistinct border.
At times, reddish streaks of lymphangeitis may project out from the margins of the lesion. Systemic toxicity is common. For both erysipelas and cellulitis, cultures obtained by leading edge needle aspirate of the inflamed area are warranted.
Pneumonia
In patients with pneumonia, crackles may be found on physical examination. In patients with empyema or pleural effusion, decreased breath sounds and dullness on percussion are observed.
Necrotizing fasciitis
Necrotizing fasciitis is an extensive and rapidly spreading infection of the subcutaneous tissue and fascia that is accompanied by necrosis and gangrene of the skin and underlying structures. Differentiation between streptococcal cellulitis and necrotizing fasciitis can be difficult, and careful serial physical examination is crucial.
Initially, the involved area in necrotizing fasciitis appears erythematous, but it progresses rapidly within 24-48 hours, becoming purplish and then often evolving into blisters or bullae that contain hemorrhagic fluid. Frank gangrene and extensive tissue necrosis follow. (See the images below.)
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Streptococcus group A infections. Necrotizing fasciitis rapidly progresses from erythema to bullae formation and necrosis of skin and subcutaneous tis....
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Streptococcus group A infections. Necrotizing fasciitis of the left hand in a patient who had severe pain in the affected area.
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Streptococcus group A infections. Patient who had had necrotizing fasciitis of the left hand and severe pain in the affected area (from Image 8). This....
Scarlet fever
Scarlet fever rash usually appears within 24-48 hours after onset of symptoms, although it may appear with the first signs of illness. It is often initially noticed on the neck and upper chest as a diffuse, finely papular, erythematous eruption producing a bright red discoloration of the skin that blanches on pressure. The texture is that of fine sandpaper.
The flexor skin creases, particularly in the antecubital fossae, may be unusually prominent (ie, Pastia lines). The area around the mouth is pale, creating the appearance of circumoral pallor. In severe cases, small vesicular lesions (ie, miliary sudamina) may appear on the abdomen, hands, and feet.
Toward the end of the first week of illness, the rash begins to fade and is followed by a desquamation over the trunk, which progresses to the hands and feet. Typical scarlet fever is not generally difficult to diagnose, but it may be confused with roseola, Kawasaki syndrome, drug eruptions, and toxigenic S aureus infections.
Poststreptococcal glomerulonephritis
In a patient with acute glomerulonephritis, even in the absence of bacteriologic confirmation of S pyogenes, the presence of skin lesions compatible with streptococcal impetigo is highly suggestive of PSGN.
Sepsis
Signs of sepsis (eg, fever, tachycardia, tachypnea, hypotension) may be present in invasive infections.
Streptococcal toxic shock syndrome
Criteria proposed by the Working Group on Severe Streptococcal Infections for the diagnosis of streptococcal toxic shock are outlined as follows[27] :
Isolation of group A Streptococcus - From a sterile site or from a nonsterile body site
Clinical signs of severity (2 or more of the following clinical and laboratory abnormalities are required) - Renal impairment, coagulopathy, liver abnormalities, acute respiratory distress, extensive tissue necrosis (necrotizing fasciitis), erythematous rash
Definite case - Isolation of group A Streptococcus from a sterile site plus compatible clinical signs
Probable case - Isolation of group A Streptococcus from a nonsterile body site plus compatible clinical signs
Depending on disease manifestations, cultures of pharyngeal secretions, blood, cerebrospinal fluid, joint aspirate, leading edge aspirate of cellulitis, skin biopsy specimen, epiglottic secretions, bronchoalveolar lavage fluid, thoracocentesis fluid, or abscess fluid may be sources for locating the organism. In cases of suspected necrotizing fasciitis, a frozen section biopsy obtained in the operating room may be of great value in confirming the diagnosis and may aid in defining how much surgical débridement of devitalized tissue is necessary.
Serologic assays (antistreptococcal antibodies) are a potentially useful adjunct for diagnosis. Other ancillary laboratory tests—eg, complete blood count (CBC), white blood cell (WBC) count, erythrocyte sedimentation rate, and C-reactive protein—may also be useful, depending on the manifestations of disease under consideration.
Other tests, depending on disease syndrome, can be very diverse in nature. For example, a histopathologic analysis of skin biopsy specimens, which may need to be analyzed intraoperatively, is warranted in cases of suspected necrotizing fasciitis. Calculation of creatinine clearance may be valuable in assessing the extent of renal dysfunction for nephritis.
Throat culture
Because pharyngitis and tonsillitis may result from various infectious etiologies other than S pyogenes infection, the diagnosis should be confirmed. Throat culture remains the criterion standard diagnostic test for streptococcal pharyngitis.
If performed correctly, culture of a single throat swab on a blood agar plate yields a sensitivity of 90-95% for the detection of group A streptococci (GAS) in the pharynx.[2, 28]
Although some throat culture results are false-positive (eg, they do not reflect acute infection but, rather, symptomatic carriage), all patients with positive culture results are treated with antibiotics.
Culture technique
GAS grow readily on routine media, but they can be isolated more easily using selective media that inhibit the growth of normal pharyngeal flora. Most laboratories inoculate throat swabs on 5% sheep blood agar containing trimethoprim-sulfamethoxazole. A bacitracin disk that contains 0.04U of bacitracin is also placed at the initial inoculation of the swab.
After overnight incubation at a temperature of 35-37°C, beta-hemolytic colonies that grow despite inhibition of the antibiotic disk are presumed to be composed of GAS.
Cultures that are negative for GAS after 24 hours are held for another overnight incubation and reexamined.
Blood culture, ASO titer, sputum culture, and tissue culture
These studies should be performed in patients with systemic infections. In patients with acute pharyngitis, group A beta-hemolytic streptococcal infection should be ruled out. With appropriate antibiotic treatment, the duration of illness is decreased, suppurative complications are prevented, infectivity is decreased, and serious nonsuppurative sequelae (eg, ARF, PSGN) can be prevented. Interestingly, delaying antimicrobial therapy for a short period does not diminish its efficacy in preventing rheumatic fever.[29]
Elevated streptococcal antibody titers in the setting of hypocomplementemic nephritis are essentially diagnostic of PSGN.
With rare exceptions, neither posttreatment throat cultures in asymptomatic patients nor routine cultures in asymptomatic family contacts are necessary.[30]
Rapid antigen detection test
When the diagnosis of streptococcal pharyngitis seems particularly likely based on examination findings or when social factors necessitate an immediate decision about antibiotic therapy, the use of rapid antigen detection tests capable within minutes of identifying GAS directly from the throat swab is a reasonable option in most practice settings.
Most kits use antibodies for the detection of group A carbohydrate antigen. The indicator systems used are latex agglutination or enzyme immunoassay. Tests can be completed in a matter of minutes.
Numerous studies have demonstrated that the currently available rapid streptococcal tests have a sensitivity of 70-90% compared with standard throat cultures. In contrast to their relatively low sensitivity, the specificity of these rapid tests has consistently been 90-100%. Therefore, if a rapid streptococcal test result is positive, a culture is not necessary, and appropriate antibiotic therapy can be immediately initiated. However, when a negative rapid test result is encountered, a standard throat culture should always be obtained.
Acute pharyngitis represents one of the most common reasons children are seen by a pediatrician. Yet, despite the common nature of the problem, few subjects engender more controversy than that of the diagnostic and therapeutic approach to the child with a sore throat. Many questions provoke disagreement on this topic, but some of the major points debated among clinicians include the following:
Which children should be tested for streptococcal pharyngitis
How should children be tested for streptococcal pharyngitis
What treatment approach should be used for suspected streptococcal pharyngitis
In general, make decisions about laboratory testing and antibiotic therapy only after careful consideration of epidemiologic factors and clinical findings.
Various clinical scoring systems have been devised to attempt to predict the results of subsequent throat cultures or antigen detection tests. At best, however, these scoring systems have no more than an 80% predictive value. Therefore, even the most experienced clinician should rely on bacteriologic confirmation of the diagnosis.
Some clinicians express a reluctance to obtain diagnostic studies in children with sore throats, rationalizing this approach with the mistaken assumption that all febrile respiratory tract ailments require a course of antibiotic therapy. The ongoing crisis in antibiotic resistance and the urgent need to use a more judicious approach in antimicrobial prescribing practice should, it is hoped, herald a return to appropriate diagnostic testing for group A streptococcal pharyngitis.
The appropriate bacteriologic confirmation of the tentative diagnosis of streptococcal pharyngitis is disputed. Fifteen years after their introduction into clinical practice, controversy persists regarding the relative merits of antigen detection systems for S pyogenes compared with traditional throat culture. Despite technologic improvements in rapid streptococcal testing, the throat culture remains the criterion standard for the diagnosis of streptococcal pharyngitis.
Throat culture
If performed correctly, a throat swab cultured on a blood agar plate has a sensitivity rate of 90-95% in detecting the presence of S pyogenes in the pharynx. This sensitivity depends on properly obtaining the specimen. When possible, a specimen should be obtained from the surface of both tonsils and from the posterior pharyngeal wall. Other areas of the oropharynx are not acceptable; in the uncooperative child, study of a culture that was obtained from areas of the mouth that are clearly known to be inadequate for culturing is difficult to justify. The culture should be examined at 24 hours postinoculation and again at 48 hours postinoculation.
Although a negative throat culture finding essentially rules out the diagnosis of streptococcal pharyngitis, a positive culture finding unfortunately cannot be used to differentiate between acute infection and asymptomatic carriage. Some studies have reported that the degree of positivity of the culture may, by quantifying the load of organisms, assist in making this differentiation. In practice, however, assuming that all positive results in appropriately cultured patients represent streptococcal infection and accepting that some degree of overtreatment is inevitable is probably best.
The video below demonstrates a throat culture.
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Throat swab. Video courtesy of Therese Canares, MD; Marleny Franco, MD; and Jonathan Valente, MD (Rhode Island Hospital, Brown University).
Contraindications
When considering the approach to bacteriologic diagnosis, emphasizing those patients who should not undergo throat culture is important. Cultures should not be obtained from children with nasal congestion, injected conjunctiva, and cough, because these features indicate the presence of acute viral pharyngitis. A positive culture finding in this context only reflects chronic colonization (streptococcal carrier state). Although identifying and treating the streptococcal carrier may occasionally have merit, routinely obtaining cultures in children with symptoms suggestive of viral pharyngitis is not warranted and leads to unwarranted courses of antibiotic therapy.
ARF is largely a clinical diagnosis that is best established by careful physical examination. Few patients with ARF have positive throat culture or rapid streptococcal antigen test findings at the time of presentation.
Because the isolation and identification of GAS from a throat swab does not distinguish between a person with acute streptococcal infection and a person who is a streptococcal carrier, the best evidence of an antecedent streptococcal infection is a serologic response to the organism. An elevated streptococcal antibody titer can be used as serologic evidence of a recent GAS infection. Serial samples should be obtained because identification of a rising titer is particularly helpful.
The most commonly used streptococcal antibody test is the ASO titer, although anti-DNase B and antihyaluronidase assays, which can be measured as a part of a panel of streptococcal antibodies (referred to as the streptozyme panel), are also helpful. When 2 or more different streptococcal antibody tests are performed, an increased titer is found within the first few months of onset in most instances of ARF.
Imaging Studies
Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are helpful in the diagnosis of cellulitis, myositis, abscess, and necrotizing fasciitis. Chest radiography and CT scanning of the thorax can aid in the diagnosis of pneumonia.
Possible imaging studies include plain radiography, CT scanning, ultrasonography, echocardiography, and radioisotope renal scanning.
For CNS manifestations, such as chorea and PANDAS syndrome, modalities such as MRI or positron emission tomography (PET)/single-photon emission CT (PET/SPECT) scanning may be valuable.
Histologic Findings
Gram stain of tissue shows gram-positive cocci in chains or clusters. Tissue removed for diagnostic or therapeutic measures may show inflammation with polymorph neutrophil infiltration, cytotoxic effects, and/or extensive necrosis. In case of PSGN, immune complex deposition is observed on glomerular basement membrane. (See the image below.)
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Group A Streptococcus on Gram stain of blood isolated from a patient who developed toxic shock syndrome.
As noted earlier, histologic analysis of skin biopsies may be an important tool in the diagnosis of streptococcal necrotizing fasciitis. In this setting, one of the hallmarks of the histologic findings is the absence of inflammatory cells, which suggests the necrotic, avascular nature of the affected tissue.
Physicians must be aware and concerned about the potential for life-threatening complications presented by infection with group A streptococci (GAS). Even seemingly minor infections (eg, pharyngitis, impetigo) may lead to fatal TSS.
Necessary procedures for the management of the diverse nature of GAS infections may include the following:
Endotracheal intubation
Thoracocentesis
Lumbar puncture
Abscess or skin aspiration
Prompt surgical drainage
Surgical débridement of devitalized tissue, fasciotomy, or amputation
In cases of shock, a central venous catheter or a wide-bore peripheral line may be needed immediately for fluid resuscitation.
Some children with recurrent streptococcal pharyngitis (7 culture-proven episodes in the preceding year) may benefit from tonsillectomy.
Children with GAS infection who appear unusually ill require aggressive inpatient evaluation and treatment. Streptococcal infections superimposed on varicella infection (chicken pox) represent a particularly high-risk situation. Aggressive treatment of such infections and close follow-up care are essential.
Debridement in necrotizing fasciitis
As the lesion in necrotizing fasciitis progresses (approximately 48-72 h), the skin becomes bluish and dusky, and bullae containing yellow or hemorrhagic fluid appear. By the fourth to fifth day, frank gangrene is present, and extensive sloughing of skin occurs. Surgical débridement of necrotic tissue is a crucial adjunct to management. Consultation with a surgeon early in the course of infection is essential because débridement is often lifesaving.
Rehabilitation
Further inpatient care may be necessary in patients with group A streptococcal infections for rehabilitative reasons (eg, in cases of chorea or neuropsychiatric manifestations of infection) or for debilitating arthritis. Consultation with a physical medicine and rehabilitation (PMR) physician, neurologist, or rheumatologist may be useful in these situations.
Therapy for streptococcal pharyngitis is aimed primarily at preventing nonsuppurative and suppurative complications and decreasing infectivity. A 10-day course of penicillin V 250 mg twice daily in children and 500 mg twice daily or 250 mg 4 times daily in adults is very effective. A single intramuscular injection of 1.2 million units of penicillin G benzathine can be administered in patients who weigh more than 27 kg; 600,000 units is used in patients who weigh less than 27 kg. Amoxicillin is equally effective and may be better tolerated in children.
Timing of treatment
Sometimes families express concern regarding the delay of 24-48 hours that is required to obtain throat culture findings. Therefore, clinicians feel pressure to immediately initiate therapy, prior to obtaining the result of the culture. However, because starting treatment of GAS sore throat as long as 9 days after the onset of symptoms still effectively prevents rheumatic fever, initiation of antibiotics is seldom of urgent importance.
Early antibiotic therapy may have beneficial effects in relieving symptoms and allowing an earlier return to school or daycare, but early treatment may have disadvantages as well. Several controlled studies have shown that children receiving immediate antibiotic therapy are more likely to have symptomatic recurrences in the months following treatment than are children who delay the initiation of therapy by 48 hours.
Antibiotic considerations
In patients who are allergic to penicillin, erythromycin or the newer macrolides (eg, azithromycin, clarithromycin) appear to be effective. Oral cephalosporins are also highly effective in the treatment of streptococcal pharyngitis. Although eradication rates associated with cephalosporins may be superior to those achieved with penicillin, the latter is the recommended drug of choice by the American Heart Association and the Infectious Diseases Society of America.[2]
A meta-analysis comparing bacterial and clinical cure rates in patients with GAS tonsillopharyngitis found that short-course cephalosporin treatment was superior to 10 days of penicillin for bacterial cure rate, that short-course penicillin therapy was inferior to 10 days of penicillin, and that clinical cure rates were similar to bacterial cure rates.[31]
Treatment failure
Treatment failures are uncommon but may occur. If symptoms recur, the throat should be recultured and another course of treatment should be prescribed, preferably with an oral cephalosporin. An asymptomatic carrier state, as evidenced by positive throat culture results obtained on a weekly basis, is not treated with antibiotics.
The most common reason for oral antibiotic failure for streptococcal pharyngitis is noncompliance. Use of the drug is often discontinued before the 10-day course is completed, because individuals usually appear to have recovered in 3-4 days. When oral treatment is prescribed, the necessity of completing a full course of therapy must be emphasized.
Even in compliant patients, reports suggest that penicillin fails to eradicate S pyogenes in about 15% of treated patients. Many theories have been proposed to explain these apparent penicillin failures. The presence of beta-lactamase–producing normal flora (particularly organisms such as mouth anaerobes) is proposed as a potential mechanism by which penicillin may become inactivated. However, the clinical significance of this theory has never been conclusively demonstrated.
Many of the failures of penicillin therapy are more likely to occur in studies in which streptococcal pharyngitis has not been defined rigorously enough, and some of the studies' patients may, in fact, be streptococcal carriers who had viral pharyngitis at the onset of these trials.
Strains of GAS resistant to macrolides have been highly prevalent in some areas of the world and have resulted in treatment failures. The IDSA 2012 guidelines state macrolide resistance rates among pharyngeal isolates in most areas of the United States have been around 5-8%.[2]
Impetigo
Streptococcal pyoderma is treated with oral antibiotics (eg, penicillin or erythromycin) for 10 days. However, because concomitant Staphylococcus aureus infection may occur, therapy with cephalexin or cefaclor is suggested. Treatment of pyoderma may not prevent nephritis if the patient is infected with a nephritogenic strain.
Toxic shock syndrome
IV polyspecific immunoglobulin G (IVIG) has been reported to be efficacious as an adjunctive therapy in patients with GAS TSS.
Necrotizing fasciitis
Treatment of necrotizing fasciitis consists of antibiotic therapy, supportive therapy for associated shock, and prompt surgical intervention.
Early and extensive surgical intervention is currently advocated for necrotizing fasciitis. However, a medical regimen, which includes IVIG, may allow an initial nonoperative or minimally invasive management approach, thus limiting the need for extensive débridement and amputation.[32]
GAS remain susceptible to beta-lactam antibiotics. Clinical failures of penicillin therapy for streptococcal infections may occur. The failure rates in patients with invasive infections are higher because of the larger number of organisms.
Clindamycin may be more effective in invasive infections. Unlike with penicillin, the efficacy of clindamycin is unaffected by the size of the inoculum and the stage of bacterial growth. In addition, clindamycin inhibits the production of toxin by streptococci.
Routine throat culture is unnecessary in asymptomatic patients who have completed a course of antibiotic therapy, except in special circumstances. Symptoms that persist after a treatment course may have several explanations, including the following:
Persistent carriage in the face of intercurrent viral infection
Noncompliance with the prescribed antimicrobial regimen
A new GAS infection acquired from family, the classroom, or community contacts
A recurrent episode of pharyngitis caused by the original infecting strain of GAS (ie, treatment failure)
Streptococcus carriers are unlikely to spread the organism to their close contacts and are at very low risk, if any, of developing suppurative complications or nonsuppurative complications (eg, ARF). Continuous antimicrobial prophylaxis is not recommended except to prevent the recurrence of rheumatic fever in patients who have experienced a previous episode of this disease.
Follow-up culturing of throat swabs is not routinely indicated in asymptomatic patients who have received a complete course of therapy for GAS pharyngitis (A-II), except in those with a history of rheumatic fever. Follow-up throat culturing should also be considered in patients who develop acute pharyngitis during outbreaks of ARF or acute PSGN, during outbreaks of GAS pharyngitis in closed or partially closed communities, or when a "ping-pong" spread of GAS infection has been occurring within a family (B-III).[2]
Long-term antibiotic therapy to prevent streptococcal infection is indicated for patients with a history of acute rheumatic fever or rheumatic heart disease. The recommended regimen is 1.2 million international units of benzathine penicillin G injected every 3-4 weeks, 250 mg of oral penicillin V twice daily, or 0.5-1 g of sulfadiazine daily.
Household contacts
The role of prophylaxis for household contacts of individuals with either acute streptococcal disease or nonsuppurative complications is uncertain. The currently available evidence does not justify routine chemoprophylaxis in close contacts. Some authorities recommend that cultures be obtained from all contacts if a family history of rheumatic fever is noted or when a patient with acute glomerulonephritis is identified.
All household contacts of a patient with invasive GAS disease should be informed of the clinical manifestations of invasive disease and counseled to seek immediate medical attention upon development of such symptoms.
An alternative approach to prophylaxis is to treat all household contacts in the setting of acute PSGN in an effort to eradicate household transmission of nephritogenic strains. For invasive GAS infections (eg, necrotizing fasciitis, TSS), no data are available on which to base assessment of risk to household contacts. However, because of the devastating nature of these infections and the observation that invasive disease may be due to clonal outbreaks of more virulent strains, empiric antibiotic therapy of household contacts seems warranted.
Prospects for streptococcal vaccines
Apart from rheumatic fever prophylaxis and the prevention of intrafamily spread, few strategies are available to prevent streptococcal infection.[33]
A streptococcal vaccine could be a promising tool for disease prevention, but an effective vaccine would have to provide protection from multiple serotypes. Furthermore, theoretical concern that vaccine-induced antibodies could injure host tissue and precipitate rheumatic fever is recognized.
Multivalent vaccines that contain multiple M-protein peptide epitopes have been engineered and show efficacy in animal models but have not yet entered clinical trials.[34] However, several vaccine candidates against GAS infection are in varying stages of preclinical and clinical development, and the hope is that one of these vaccines will reach licensure within the next decade.[35] Only the multivalent N-terminal vaccine has entered clinical trials over the last 30 years.
The Infectious Disease Society of America updated its guidelines for the management of group A streptococcal (GAS) pharyngitis in 2012. The key recommendations for diagnosis and treatment are outlined below.[2]
Diagnosis
Diagnostic guidelines are as follows:
Rapid antigen detection test (RADT) and/or culture should be performed to distinguish between GAS and viral pharyngitis, except when overt viral features such as rhinorrhea, cough, oral ulcers, and/or hoarseness are present.
In children and adolescents, negative RADT results should be confirmed with a throat culture.
Because of the low incidence of GAS pharyngitis in adults and the exceptionally low risk of subsequent acute rheumatic fever, throat culture after a negative RADT result is unnecessary.
Treatment
Treatment guidelines are as follows:
Penicillin or amoxicillin is the recommended drug of choice.
For penicillin-allergic patients, first-generation cephalosporin (for those not anaphylactically sensitive), clindamycin, clarithromycin, or azithromycin
As an adjunct to antibiotic therapy, acetaminophen or an NSAID should be considered for treatment of moderate to severe symptoms or control of high fever
Aspirin should be avoided in children
Corticosteroids are not recommended as adjunctive therapy
Tonsillectomy solely to reduce the frequency of GAS pharyngitis is not recommended
To date, S pyogenes has remained universally susceptible to penicillin. Therefore, penicillin remains the first-line drug of choice for pharyngeal infections, as well as for complicated or invasive infections.
European surveillance in Italy found that 32% of group A streptococcal isolates exhibited resistance to macrolides. France has reported a steady escalation of erythromycin resistance in group A streptococci (GAS), reaching 23% to date. Portugal identified 11% of GAS isolates as resistant to macrolides. Resistance in other European countries during the 1990s fell between 1% and 7%.[36]
Invasive GAS isolates were tested for fluoroquinolone susceptibility from 1992-1993 and in 2003 in Ontario, Canada. All isolates were susceptible to levofloxacin. Two of 153 (1.3%) in 1992-1993 and 7 of 160 (4.4%) in 2003 had a levofloxacin minimal inhibitory concentration (MIC) of 2 µg/mL; all 9 had parC mutations, and 8 were serotype M6.
Between October 2003 and September 2006, 482 GAS strains were collected from 45 medical institutions in various parts of Japan. Susceptibility of GAS strains to 8 beta-lactam agents was excellent, with MICs of 0.0005-0.063 µg/mL–1. Macrolide-resistant strains accounted for 16.2% of all strains. Although no strains with high resistance to levofloxacin were found, strains with an MIC of 2-4 µg/mL–1 (17.4%) with intermediate susceptibility were observed.[37]
In 2006, of 50 GAS isolates examined with antibiotic susceptibility tests, 100% were found to be susceptible to penicillin, ampicillin, cefotaxime, cefazolin, and vancomycin. Eight isolates (16%) exhibited some level of antibiotic resistance. Six were resistant to erythromycin alone, and 2 were resistant to erythromycin and clindamycin (the first clindamycin-resistant isolates reported since 1999).[38]
Clinical Context:
Penicillin VK is a drug of choice for GAS pharyngitis. It inhibits the biosynthesis of cell-wall mucopeptides. This agent elicits bactericidal effects against sensitive organisms when adequate concentrations are reached and is most effective during the stage of active multiplication.
Clinical Context:
Amoxicillin is a drug of choice for GAS pharyngitis. It is a derivative of ampicillin and has a similar antibacterial spectrum. With a bactericidal action comparable to penicillin, amoxicillin acts on susceptible bacteria during the multiplication stage by inhibiting cell-wall mucopeptide biosynthesis. It has superior bioavailability and stability to gastric acid and has a broader spectrum of activity than penicillin.
Clinical Context:
Penicillin G benzathine interferes with the synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. If noncompliance with oral therapy seems likely, parenteral therapy is indicated.
The formulation is painful when administered intramuscularly, and it is often combined with penicillin G procaine to minimize discomfort at the injection site. When this combination is used in a single injection, take care to ensure that an adequate amount of penicillin G benzathine is administered. The combination of 900,000U of penicillin G benzathine and 300,000 U of penicillin G procaine is satisfactory for most children.
Clinical Context:
Erythromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
In children, age, weight, and the severity of infection determine proper dosage. When twice-daily dosing is desired, the half-total daily dose may be taken every 12 hours. For more severe infections, double the dose.
Oral erythromycin is an acceptable alternative for patients who are allergic to penicillin or cephalosporin antibiotics and is effective in the treatment of streptococcal pharyngitis. Re-emerging macrolide resistance must be considered. Of 708 GAS isolates tested for susceptibility to erythromycin and clindamycin, performed for all pharyngeal GAS isolates recovered at the Children's Hospital of Pittsburgh and a local pediatric practice between September 2001 and May 2002, 68 (9.6%) were macrolide resistant, while all isolates were sensitive to clindamycin. Erythromycin is associated with substantially higher rates of GI side effects compared with other macrolides. Strains of GAS resistant to macrolides have been highly prevalent in some areas of the world and have resulted in treatment failures.
Clinical Context:
Clarithromycin inhibits bacterial growth, possibly by binding to 50S ribosomal unit, causing RNA-dependent protein synthesis to arrest. It has a similar susceptibility profile to erythromycin, but clarithromycin has fewer adverse effects.
Clinical Context:
Azithromycin has a similar susceptibility profile to erythromycin, but it has fewer adverse effects. This agent treats mild to moderate microbial infections. Binds to the 50S ribosomal subunit where it blocks transpeptidation.
Clinical Context:
Cephalexin, a first-generation cephalosporin, arrests bacterial growth by inhibiting bacterial cell wall synthesis. It has bactericidal activity against rapidly growing organisms. The drug's primary activity is against skin flora; cephalexin is used for skin infections and for prophylaxis in minor procedures. Oral cephalosporins are effective in the treatment of streptococcal pharyngitis.
Short-course regimens of oral cephalosporin therapy have been studied and offer obvious advantages from a compliance perspective. However, this must be balanced against the higher cost and unnecessarily broad spectrum of these agents.
Clinical Context:
Cefadroxil is a first-generation semi-synthetic cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. It may be considered for GAS pharyngitis in patients allergic to penicillin (without immediate-type hypersensitivity).
Clinical Context:
Clindamycin is a lincosamide for the treatment of serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. Patients with invasive GAS infections (eg, necrotizing fasciitis, TSS, sepsis) should be treated with IV penicillin in combination with clindamycin. Because the pathophysiology of invasive GAS infection is largely toxin mediated, the use of a protein synthesis inhibitor (eg, clindamycin) offers a theoretical advantage.
Furthermore, in vivo evidence of the lack of efficacy of penicillin in deep-tissue infections has been observed in animal models. This effect, first described by Eagle in 1952, appears to occur because of the high inoculum of organisms encountered in overwhelming infections (eg, necrotizing fasciitis, myositis, sepsis).
Large concentrations of organisms lead to the rapid attainment of the stationary growth phase, which is associated with decreased expression of cell wall penicillin-binding proteins (PBPs), the molecular targets of penicillin. Decreased expression of PBPs in deep-tissue infections with GAS appears to render penicillin less effective. In contrast, clindamycin retains efficacy. Vigorous supportive care, including fluids, pressors, and mechanical ventilation, is also a critical aspect of management of invasive streptococcal skin and soft-tissue infections. Prompt surgical drainage, débridement, fasciotomy, or amputation may be indicated.
Differentiating a streptococcal carrier with recurrent viral infection from a child with recurrent streptococcal pharyngitis may be difficult. Although most streptococcal carriers do not require medical intervention, situations arise in which eradication of the carrier state is desirable (eg, families in with an inordinate amount of anxiety about streptococci, families in which ping-pong spread has been occurring, situations in which tonsillectomy is considered only because of chronic carriage). A course of clindamycin has been shown to be highly effective in eradicating the carrier state and should be tried in patients with recurrent or frequent episodes of culture-proven pharyngitis.
Some children with recurrent streptococcal pharyngitis (7 culture-proven episodes in the preceding year) may benefit from tonsillectomy.
Clinical Context:
Vancomycin acts by inhibiting proper cell wall synthesis in gram-positive bacteria. It is indicated for the treatment of serious infections caused by beta-lactam–resistant organisms and in patients who have serious allergies to beta-lactam antimicrobials.
Clinical Context:
Oritavancin is lipoglycopeptide antibiotic that inhibits cell wall biosynthesis and disrupts bacterial membrane integrity that leads to cell death. It is indicated for treatment of acute bacterial skin and skin structure infections caused by gram-positive bacteria including S aureus (including methicillin-susceptible S aureus and MRSA), S pyogenes, S agalactiae, S dysgalactiae, S anginosus group (S anginosus, S intermedius, S constellatus) and E faecalis (vancomycin-susceptible isolates only).
Clinical Context:
Dalbavancin is lipoglycopeptide antibiotic that prevents cross-linking by interfering with cell wall synthesis. It is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations observed in humans at recommended doses. It is indicated for treatment of acute bacterial skin and skin structure infections caused by Gram-positive bacteria including Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S aureus [MRSA]), S pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S anginosus, S intermedius, S constellatus).
Clinical Context:
Tedizolid is an oxazolidinone antibiotic indicated for skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria including Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, S agalactiae, S anginosus Group (including S anginosus, S intermedius, and S constellatus), and Enterococcus faecalis. Its action is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis.
Therapy should cover all likely pathogens in the context of clinical settings. Antibiotic selection should be guided by blood culture sensitivity, whenever feasible.
Natural penicillins have good activity against S pyogenes. Various forms of natural penicillins are used for various diseases caused by GAS. The recommendation for S pyogenes pharyngitis in adults is a single intramuscular (IM) dose of benzathine penicillin G 1.2 million units or penicillin V 500 mg PO BID for 10 days. For S pyogenes necrotizing fasciitis in adults, IV penicillin G (up to 24 million units daily in divided doses q4-6h) is recommended.
What is group A Streptococcus (GAS)?Which disorders are caused by group A streptococcal (GAS) infection?How many serologic groups have been identified for beta-hemolytic streptococci (BHS)?What is the role of emm typing for the classification of group A streptococci (GAS)?What distinguishes group A streptococci (GAS) from other serologic groups?What is the basis for presumptive identification of a strain as a group A Streptococcus (GAS)?How has morbidity of group A streptococci (GAS) infection changed since the widespread use of antibiotics?Which disorders are included in the suppurative spectrum of group A streptococci (GAS) diseases?What are the nonsuppurative sequelae of group A streptococci (GAS) infections?How do group A streptococcal (GAS) infections cause scarlet fever and toxic shock syndrome (TSS)?What is group A streptococci (GAS)?What is the pathophysiology of group A streptococcal (GAS) infection?What is the clinical implication of the ability of group A streptococci (GAS) to invade epithelial cells?Which cell wall antigens are found in group A streptococcal (GAS) infection?What is the polysaccharide (C-substance) composed of and what is its role in the pathogenesis of group A streptococcal (GAS) infections?What is the role of C5A peptidase and M protein in the pathogenesis of group A streptococcal (GAS) infections?What allows the survival of group A streptococci (GAS) and initiation of the disease process?What is the role of M protein serotyping in epidemiologic studies of group A streptococcal (GAS) infections?What is the role of surface components of group A streptococci (GAS) in adhesion?What is the 2-step model of adhesion in group A streptococcal (GAS) infection?What drives the evolving molecular activity of group A streptococci (GAS)?What causes host cell damage and inflammatory response in group A streptococcal (GAS) infections?What role do hemolysins have in group A streptococcal (GAS) infections?What role do streptococcal pyrogenic exotoxins (SPEs) have in group A streptococcal (GAS) infections?What role do nucleases have in group A streptococcal (GAS) infections?Which extracellular products may have a role in group A streptococcal (GAS) infections?How often is acute pharyngitis caused by group A streptococci (GAS)?What is pyoderma (impetigo contagiosa) (nonbullous impetigo), and what are its risk factors as a manifestation of group A streptococcal (GAS) infection?How is pyoderma (impetigo contagiosa) (nonbullous impetigo) transmitted in group A streptococcal (GAS) infections?What is the pathogenesis of pyoderma (impetigo contagiosa) (nonbullous impetigo) in group A streptococcal (GAS) infections?Does group A Streptococcus (GAS) cause pneumonia?What is the pathogenesis of necrotizing fasciitis in group A streptococcal (GAS) infection?What are possible suppurative complications of tonsillopharyngitis caused by group A streptococci (GAS)?What are the symptoms of acute rheumatic fever (ARF) following group A streptococcal (GAS) tonsillopharyngitis?Does rheumatic fever (ARF) have a genetic predisposition?What is the link between group A streptococcal (GAS) infections of the upper respiratory tract and acute rheumatic fever (ARF)?What is the attack rate of acute rheumatic fever (ARF) following respiratory tract group A streptococcal (GAS) infections?What is the pathogenesis of acute rheumatic fever (ARF) in group A streptococcal (GAS) infections?Is there a link between a host's autoimmune response to group A streptococci (GAS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)?Does group A streptococcal (GAS) infection cause glomerulonephritis?What is the pathogenesis of poststreptococcal glomerulonephritis (PSGN) in group A streptococcal (GAS) infection?Does group A streptococcal (GAS) infection cause toxic shock syndrome (TSS)?What is the pathogenesis of toxic shock syndrome (TSS) in patients with group A streptococcal (GAS) infections?What is the pathogenesis of scarlet fever in patients with group A streptococcal (GAS) infection?How often does scarlet fever occur in patients with group A streptococcal (GAS) infections?Does group A streptococcal (GAS) infection cause central nervous system (CNS) disease?Who is at risk for infection by group A streptococci (GAS)?How is group A Streptococcus (GAS) transmitted?What is the major route for transmission of group A streptococci (GAS)?How do children with untreated acute infections spread group A streptococci (GAS)?Can asymptomatic carriers transmit group A Streptococcus (GAS)?Which body surfaces can harbor group A streptococci (GAS), potentially helping to disseminate impetigo?Which environmental factors increase the risk of group A streptococcal (GAS) impetigo and pharyngitis?What is the incidence of group A streptococcal (GAS) infections in the US?Are there regional differences in the incidence of skin and upper respiratory tract group A streptococcal (GAS) infections in the US?What factors are responsible for the emergence of more virulent strains of group A streptococci (GAS)?What is the prevalence of acute rheumatic fever (ARF) in the US?When was a global resurgence of group A streptococcal (GAS) infections seen?What is the incidence of rheumatic fever in Denmark?What is the international incidence of poststreptococcal glomerulonephritis (PSGN)?What is the global incidence of group A streptococcal (GAS) infections?Where is the prevalence of streptococcal pyoderma (impetigo contagiosa) (nonbullous impetigo) highest?Does group A streptococcal (GAS) infection have a sex or racial predilection?What are the age-related differences in the prevalence of group A streptococcal (GAS) infections?What age group is most at risk for acute rheumatic fever (ARF) following group A streptococcal (GAS) upper respiratory tract infection?What is the prognosis of acute proliferative poststreptococcal glomerulonephritis (PSGN) and group A streptococcal (GAS) pharyngitis and skin infections?What are the mortality rates of invasive group A streptococcal (GAS) infections, streptococcal toxic shock syndrome (TSS), and necrotizing fasciitis?How do suppurative complications occur in group A streptococcal (GAS) infections?Is acute hematogenous osteomyelitis a possible complication of group A streptococcal (GAS) infections?What are the possible complications of group A streptococcal (GAS) toxic shock syndrome (TSS) and necrotizing fasciitis?What are the possible complications of group A streptococci (GAS) that colonize the genital tract and enter the bloodstream during pregnancy and childbirth?How common is empyema in patients with group A streptococcal (GAS) pneumonia?What are the possible nonsuppurative complications of group A streptococcal (GAS) tonsillopharyngitis?What patient education resources are available for group A streptococcal (GAS) infections?What are the signs and symptoms of group A streptococcal (GAS) erysipelas?Which diseases are caused by group A streptococcal (GAS) infection?What are the symptoms of strep throat?Which symptoms are exclusionary in the diagnosis of streptococcal pharyngitis (strep throat)?What are the symptoms of streptococcal pharyngitis (strep throat) in infants and toddlers?What are the less common symptoms of streptococcal pharyngitis (strep throat) in children?What is the etiology of scarlet fever in patients with group A streptococcal (GAS) infections?What are the signs and symptoms of group A streptococcal (GAS) cellulitis?What is the presentation of group A streptococcal (GAS) impetigo (impetigo contagiosa) (nonbullous impetigo)?How does group A streptococcal (GAS) infection cause necrotizing fasciitis (streptococcal gangrene/fasciitis)?What are the signs and symptoms of group A streptococcal (GAS) necrotizing fasciitis (streptococcal gangrene/fasciitis)?What is a major risk factor for the development of group A streptococcal (GAS) necrotizing fasciitis (streptococcal gangrene/fasciitis)?Do the risk factors for group A streptococcal (GAS) bacteremia vary by age?What are the signs and symptoms of group A streptococcal (GAS) toxic shock syndrome (STSS)?What are the Jones criteria for diagnosis of acute rheumatic fever (ARF)?When do the first symptoms of acute rheumatic fever (ARF) appear, and when is rheumatic heart disease likely to occur?What are the signs and symptoms of poststreptococcal glomerulonephritis (PSGN)?When does scarlet fever rash typically appear in patients with group A streptococcal (GAS) infections and how is it identified?What are physical findings of streptococcal pharyngitis (strep throat)?What are the physical exam findings of scarlet fever, and how does the rash develop?Which physical findings differentiate streptococcal pharyngitis (strep throat) from pharyngitis of other etiologies?Which physical findings suggest streptococcal pharyngitis (strep throat)?Can a diagnosis of streptococcal pharyngitis (strep throat) be made clinically?What is Strep-PRO and is it effective as an outcome measure for streptococcal pharyngitis (strep throat)?What is the typical disease course of with group A streptococcal (GAS) impetigo (impetigo contagiosa) (nonbullous impetigo)?What happens if group A streptococcal (GAS) impetigo (impetigo contagiosa) (nonbullous impetigo) is left untreated?What are the possible complications of group A streptococcal (GAS) impetigo (impetigo contagiosa) (nonbullous impetigo)?What are the signs and symptoms of streptococcal cellulitis?When should perianal cellulitis and vaginitis be considered in children with group A streptococcal (GAS) infections?How is erysipelas differentiated from cellulitis in patients with group A streptococcal (GAS) infections?What test should be performed when erysipelas or cellulitis is suspected in patients with group A streptococcal (GAS) infections?What respiratory findings suggest group A streptococcal (GAS) infection?How is necrotizing fasciitis (streptococcal gangrene/fasciitis) differentiated from cellulitis in group A streptococcal (GAS) infections?What is the disease course of group A streptococcal (GAS) necrotizing fasciitis (streptococcal gangrene/fasciitis)?Which disorders should be included in the differential diagnoses of scarlet fever?Which symptoms suggest poststreptococcal glomerulonephritis (PSGN)?What are the signs of sepsis in patients with group A streptococcal (GAS) infections?What are the diagnostic criteria for streptococcal toxic shock syndrome (STSS)?Which disorders should be included in the differential diagnoses of group A streptococcal (GAS) infection?Which tests may be used in the workup of group A streptococcal (GAS) infection?Which ancillary lab tests may be useful in the diagnosis and management of group A streptococcal (GAS) infections?What is the criterion standard diagnostic test for streptococcal pharyngitis (strep throat)?Which culture techniques are used to identify group A streptococcal (GAS) infections?Which studies should be performed in the diagnosis of systemic group A streptococcal (GAS) infections?How is a diagnosis of poststreptococcal glomerulonephritis (PSGN) confirmed?Is posttreatment throat culture necessary in asymptomatic patients with group A streptococcal (GAS) infections or asymptomatic family contacts?When are rapid antigen detection tests used to confirm a diagnosis of streptococcal pharyngitis (strep throat)?Which indicator systems are used to detect group A carbohydrate antigens in the workup of group A streptococcal (GAS) infections?What is the sensitivity and specificity of rapid strep tests for the diagnosis of group A streptococcal (GAS) infections?Do clinicians agree on the approach to diagnose and manage suspected streptococcal pharyngitis (strep throat)?When are decisions made regarding lab testing for diagnosis of group A streptococcal (GAS) infections?Are there effective clinical scoring systems for predicting the results of subsequent lab tests for group A streptococcal (GAS) infections?What risks are associated with treating children based on a clinical diagnosis of streptococcal pharyngitis (strep throat)?Are antigen detection systems as valid as throat culture for the diagnosis of streptococcal pharyngitis (strep throat)?What is the sensitivity of a throat culture for the presence of group A streptococcal (GAS) infections?Does a negative throat culture result rule out a diagnosis of streptococcal pharyngitis (strep throat)?When is throat culture for group A streptococcal (GAS) infection contraindicated?What testing is required for a diagnosis of acute rheumatic fever (ARF)?Is throat culture or group A streptococcal (GAS) antibody testing preferred during workup of acute rheumatic fever (ARF)?What is the most commonly used group A streptococcal (GAS) antibody test for acute rheumatic fever (ARF)?What is the role of imaging studies in the workup of group A streptococcal (GAS) infection?Which imaging studies are helpful in the diagnosis of central nervous system (CNS) manifestations of group A streptococcal (GAS) infections?Which histologic findings suggest group A streptococcal (GAS) infection?Which complications should a physician be aware of in patients with group A streptococcal (GAS) infection?Which procedures may be necessary for the management of group A streptococcal (GAS) infections?What is the treatment for shock in patients with group A streptococcal (GAS) infection?When is tonsillectomy indicated in children with streptococcal pharyngitis (strep throat)?Which patients with group A streptococcal (GAS) infection should be hospitalized?How is necrotizing fasciitis (streptococcal gangrene/fasciitis) managed?When is rehabilitative care necessary in the treatment of group A streptococcal (GAS) infections?What is the goal of therapy for streptococcal pharyngitis (strep throat)?Does a delay in antibiotic therapy for streptococcal pharyngitis (strep throat) affect treatment efficacy?Which treatments are effective in patients with streptococcal pharyngitis (strep throat) who are allergic to penicillin?Is cephalosporin effective for the treatment of group A streptococcal (GAS) tonsillopharyngitis?How is streptococcal pharyngitis (strep throat) managed if treatment fails and symptoms recur?What is the most common reason for antibiotic failure in streptococcal pharyngitis (strep throat)?What are the possible causes of penicillin treatment failure in streptococcal pharyngitis (strep throat)?What is the rate of group A streptococci (GAS) macrolide resistance?What is the treatment for group A streptococcal (GAS) pyoderma (impetigo contagiosa) (nonbullous impetigo)?What is the role of polyspecific IVIG in the treatment of streptococcal toxic shock syndrome (STSS)?What is the treatment for group A streptococcal (GAS) necrotizing fasciitis (streptococcal gangrene/fasciitis?Which factors increase the risk of penicillin therapy failure in the treatment of group A streptococcal (GAS) infections?What is the role of clindamycin in the treatment of group A streptococcal (GAS) infections?Is posttreatment throat culture indicated in the treatment of group A streptococcal (GAS) infections?How likely are asymptomatic carriers to transmit group A streptococci (GAS) to close contacts?When are follow-up throat cultures indicated in group A streptococcal (GAS) infections?When is long-term antibiotic therapy indicated for prevention of group A streptococcal (GAS) infections?What is the role of prophylaxis for household contacts of patients with group A streptococcal (GAS) infections?What information should be given to close contacts of a patient with invasive group A streptococcal (GAS) infection?What is the approach to prophylaxis to eradicate household transmission of group A streptococcal (GAS) infections?How are group A streptococcal (GAS) infections prevented?Which specialists may be consulted in the treatment of group A streptococcal (GAS) infections?What are the IDSA guidelines for the diagnosis of group A streptococcal (GAS) infections?What are the IDSA guidelines for the treatment of group A streptococcal (GAS) infections?What is the first-line drug of choice for treatment of group A streptococcal (GAS) infections?Do group A streptococcal (GAS) isolates exhibit resistance to macrolides?Are group A streptococcal (GAS) isolates susceptible to levofloxacin?Are group A streptococcal (GAS) strains susceptible to 8 beta-lactam agents?What is the rate of antibiotic resistance among group A streptococcal (GAS) isolates?Which medications in the drug class Antibiotics are used in the treatment of Group A Streptococcal (GAS) Infections?
Zartash Zafar Khan, MD, FACP, Infectious Disease Consultant
Disclosure: Nothing to disclose.
Coauthor(s)
Michelle R Salvaggio, MD, FACP, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, Director, Clinical Trials Unit, Director, Ryan White Programs, Department of Medicine, University of Oklahoma Health Sciences Center; Attending Physician, Infectious Diseases Consultation Service, Infectious Diseases Institute, OU Medical Center
Disclosure: Received honoraria from Merck for speaking and teaching.
Chief Editor
Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Godfrey Harding, MD, FRCP(C) Program Director of Medical Microbiology, Professor, Department of Medicine, Section of Infectious Diseases and Microbiology, St Boniface Hospital, University of Manitoba, Canada
Godfrey Harding, MD, FRCP(C) is a member of the following medical societies: American College of Physicians, American Society for Microbiology, Canadian Infectious Disease Society, Canadian Medical Association, Infectious Diseases Society of America, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.
Larry I Lutwick, MD Professor of Medicine, State University of New York Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus
Larry I Lutwick, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.
José Rafael Romero, MD Director of Pediatric Infectious Diseases Fellowship Program, Associate Professor, Department of Pediatrics, Combined Division of Pediatric Infectious Diseases, Creighton University/University of Nebraska Medical Center
José Rafael Romero, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, New York Academy of Sciences, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.
Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School
Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association
Disclosure: Nothing to disclose.
Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Graziella O, Roberto N, Christina VH. Nevio Cimolai, ed. Laboratory Diagnosis of Bacterial Infections. Informa Healthcare; 2001. 258.
Beal B. Assigning emm Types and Subtypes. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncidod/biotech/strep/assigning.htm. Accessed: June 5, 2012.
National Center for Immunization and Respiratory Diseases: Division of Bacterial Diseases. Group A Streptococcal (GAS) Disease. April 3, 2008. Available at http://www.cdc.gov/ncidod/dbmd/diseaseinfo/Groupastreptococcal_g.htm
Invasive soft tissue infection due to Streptococcus pyogenes. This child developed fever and soft-tissue swelling on the fifth day of a varicella-zoster infection. Leading edge aspirate of cellulitis grew S pyogenes. Although the patient responded to intravenous penicillin and clindamycin, operative débridement was necessary because of clinical suspicion of early necrotizing fasciitis.
Streptococcus group A infections. Beta hemolysis is demonstrated on blood agar media.
Streptococcus group A infections. M protein.
Streptococcus group A infections. Erysipelas is a group A streptococcal infection of skin and subcutaneous tissue.
Erythema secondary to group A streptococcal cellulitis.
Streptococcus group A infections. White strawberry tongue observed in streptococcal pharyngitis. Image courtesy of J. Bashera.
Invasive soft tissue infection due to Streptococcus pyogenes. This child developed fever and soft-tissue swelling on the fifth day of a varicella-zoster infection. Leading edge aspirate of cellulitis grew S pyogenes. Although the patient responded to intravenous penicillin and clindamycin, operative débridement was necessary because of clinical suspicion of early necrotizing fasciitis.
Streptococcus group A infections. Necrotizing fasciitis rapidly progresses from erythema to bullae formation and necrosis of skin and subcutaneous tissue.
Streptococcus group A infections. Necrotizing fasciitis of the left hand in a patient who had severe pain in the affected area.
Streptococcus group A infections. Patient who had had necrotizing fasciitis of the left hand and severe pain in the affected area (from Image 8). This photo was taken at a later date, and the wound is healing. The patient required skin grafting.
Throat swab. Video courtesy of Therese Canares, MD; Marleny Franco, MD; and Jonathan Valente, MD (Rhode Island Hospital, Brown University).
Group A Streptococcus on Gram stain of blood isolated from a patient who developed toxic shock syndrome.
Invasive soft tissue infection due to Streptococcus pyogenes. This child developed fever and soft-tissue swelling on the fifth day of a varicella-zoster infection. Leading edge aspirate of cellulitis grew S pyogenes. Although the patient responded to intravenous penicillin and clindamycin, operative débridement was necessary because of clinical suspicion of early necrotizing fasciitis.
Streptococcus group A infections. Beta hemolysis is demonstrated on blood agar media.
Streptococcus group A infections. M protein.
Streptococcus group A infections. Erysipelas is a group A streptococcal infection of skin and subcutaneous tissue.
Streptococcus group A infections. White strawberry tongue observed in streptococcal pharyngitis. Image courtesy of J. Bashera.
Streptococcus group A infections. Streptococcal rash. Image courtesy of J. Bashera.
Group A Streptococcus on Gram stain of blood isolated from a patient who developed toxic shock syndrome.
Streptococcus group A infections. Necrotizing fasciitis of the left hand in a patient who had severe pain in the affected area.
Streptococcus group A infections. Patient who had had necrotizing fasciitis of the left hand and severe pain in the affected area (from Image 8). This photo was taken at a later date, and the wound is healing. The patient required skin grafting.
Streptococcus group A infections. Gangrenous streptococcal cellulitis in a patient with diabetes.
Erythema secondary to group A streptococcal cellulitis.
Invasive soft tissue infection due to Streptococcus pyogenes. This child developed fever and soft-tissue swelling on the fifth day of a varicella-zoster infection. Leading edge aspirate of cellulitis grew S pyogenes. Although the patient responded to intravenous penicillin and clindamycin, operative débridement was necessary because of clinical suspicion of early necrotizing fasciitis.
Streptococcus group A infections. Necrotizing fasciitis rapidly progresses from erythema to bullae formation and necrosis of skin and subcutaneous tissue.
Throat swab. Video courtesy of Therese Canares, MD; Marleny Franco, MD; and Jonathan Valente, MD (Rhode Island Hospital, Brown University).
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