Streptococcus Group A Infections Author: Zartash Zafar Khan, MD, Fellow in Infectious Diseases, University of Oklahoma Health Science

Center Coauthor(s): Michelle R Salvaggio, MD, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, University of Oklahoma Health Sciences Center; 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; 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 Contributor Information and Disclosures Updated: Sep 23, 2009

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Overview Differential Diagnoses & Workup Treatment & Medication Follow-up Multimedia References Keywords Further Reading Introduction

Background

Streptococcus pyogenes is beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as group A streptococci (GAS). GAS, a ubiquitous organism, causes a wide variety of diseases in humans and is the most common bacterial cause of acute pharyngitis, accounting for 15%-30% of cases in children and 5%-10% of cases in adults.1 During the winter and spring in temperate climates, up to 20% of asymptomatic school-aged children may be GAS carriers.2
GAS usually causes pharyngitis or impetigo but, in rare cases, can also cause invasive diseases such as cellulitis, bacteremia, necrotizing fasciitis, and toxic shock syndrome (TSS). Along with Staphylococcus aureus, GAS is one of the most common pathogens responsible for cellulitis . Historical perspectives

S pyogenes was first described by Billroth in 1874 in patients with wound infections. In 1883, Fehleisen isolated chain-forming organisms in pure culture from perierysipelas lesions. Rosebach named the organism S pyogenes in 1884. Studies by Schottmueller in 1903 and J.H. Brown in 1919 led to knowledge of different patterns of hemolysis described as alpha, beta, and gamma hemolysis.
A later development in this field was the Lancefield classification of beta-hemolytic streptococci by serotyping based on M-protein precipitin reactions. Lancefield established the critical role of M protein in disease causation. In the early 1900s, Dochez, George, and Dick identified hemolytic streptococcal infection as the cause of scarlet fever. The epidemiological studies of the mid 1900s helped establish the link between GAS infection and acute rheumatic fever (ARF) and acute glomerulonephritis.3

The traditional Lancefield M-protein classification system, which is based on serotyping, has been replaced by emm typing. This gene-typing system is based on sequence analysis of the emm gene, which encodes the cell surface M protein. Approximately 200 emm types have been identified by the Centers for Disease Control and Prevention (CDC) thus far. Spectrum of diseases due to group A streptococcal infections In the preantibiotic era, streptococci frequently caused significant morbidity and were associated with significant mortality rates. However, in the postantibiotic period, diseases due to streptococcal infections are well-controlled and uncommonly cause death. GAS can cause a diverse variety of both suppurative diseases and nonsuppurative postinfectious sequelae. The suppurative spectrum of GAS diseases includes the following:

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

The nonsuppurative sequelae of GAS infections include the following:

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

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

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

Pathophysiology Streptococci are a large group of gram-positive, nonmotile, nonspore-forming cocci about 0.51.2 m in size. They often grow in pairs or chains and are oxidase- and catalase-negative.

S pyogenes tends to colonize the upper respiratory tract and is highly virulent as it overcomes the host defense system. The most common forms of S pyogenes disease include respiratory and skin infections, with different strains usually responsible for each form.
The cell wall of S pyogenes is very complex and chemically diverse. The antigenic components of the cell are the virulence factors. The extracellular components responsible for the disease process include invasins and exotoxins. The outermost capsule is composed of hyaluronic acid, which has a chemical structure resembling host connective tissue, allowing the bacterium to escape recognition by the host as an offending agent. Thus, the bacterium escapes phagocytosis by neutrophils or macrophages, allowing it to colonize. Lipoteichoic acid and M

proteins located on the cell membrane traverse through the cell wall and project outside the capsule. Bacterial virulence factors The cell wall antigens include capsular polysaccharide (C-substance), peptidoglycan and lipoteichoic acid (LTA), R and T proteins, and various surface proteins, including M protein, fimbrial proteins, fibronectin-binding proteins (eg, protein F), and cell-bound streptokinase. The C-substance is composed of a branched polymer of L-rhamnose and N -acetyl-Dglucosamine. 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. M protein, the major virulence factor, is a macromolecule incorporated in fimbriae present on the cell membrane projecting on the bacterial cell wall. More than 50 types of S pyogenes M proteins have been identified based on antigenic specificity, and the M protein is the major cause of antigenic shift and antigenic drift among GAS.5 The M protein binds the host fibrinogen and blocks the binding of complement to the underlying peptidoglycan. This allows survival of the organism by inhibiting phagocytosis. Strains that contain an abundance of M protein resist phagocytosis, multiply rapidly in human tissues, and initiate disease process. After an acute infection, type-specific antibodies develop against M protein activity in some cases. In addition to M protein, S pyogenes possesses additional virulence factors, such as C5A peptidase, which destroys the chemotactic signals by cleaving the complement component of C5A.

Streptococcus group A infections. M protein. Bacterial adherence factors At least 11 different surface components of GAS have been suggested to play a role in adhesion. In 1997, Hasty and Courtney proposed that GAS express different arrays of adhesins in various environmental niches. Based on their review, M protein mediates adhesion to HEp-2 cells in humans, but not buccal cells, whereas FBP54 mediates adhesion to buccal cells, but not to HEp-2 cells. Protein F mediates adhesion to Langerhans cells, but not keratinocytes. The most recent theory proposed in the process of adhesion is a two-step model. The initial step of overcoming the electrostatic repulsion of the bacteria from the host is mediated by LTA rendering weak reversible adhesion. The second step is firm irreversible adhesion mediated by tissue-specific M protein, protein F, or FBP54, among others. Once adherence has occurred, the streptococci resist phagocytosis, proliferate, and begin to invade the local tissues.6 GAS show enormous and evolving molecular diversity, driven by horizontal transmission among various strains. This is also true when compared with other streptococci. Acquisition of prophages

accounts for much of the diversity, conferring not only virulence via phage-associated virulence factors but also increased bacterial survival against host defenses. Extracellular products and toxins Various extracellular growth products and toxins produced by GAS are responsible for host cell damage and inflammatory response. Streptolysin S, a 28 residue peptide, is an oxygen-stable leukocidin toxic to polymorphonuclear leukocytes, RBCs, and platelets. Streptolysin S is responsible for RBC lysis observed on sheep blood agar. Streptolysin O is an oxygen-labile leukocidin that is toxic to neutrophils and induces a brisk antibody response. Measurement of antistreptolysin O (ASO) antibody titer in humans is used as an indicator of recent streptococcal infection. Other extracellular products include NADase (leukotoxic), hyaluronidase (which digests host connective tissue, hyaluronic acid, and the organism's own capsule), streptokinases (proteolytic), and streptodornase A-D (deoxyribonuclease activity).7 Pyrogenic exotoxins GAS produce 3 different types of exotoxins (A, B, C).5 These toxins act as superantigens and are responsible for inciting systemic immune response and acute disease caused by the sudden and massive release of T-cell cytokines into the blood stream. The superantigens bypass processing by antigen presenting cells and cause T-cell activation by binding class II MHC molecules directly and nonspecifically. The streptococcal pyrogenic exotoxins (SPEs) are responsible for causing scarlet fever, pyrogenicity, and STSS. The mechanism is similar to that of staphylococcal TSS.8 Nucleases Four antigenically distinct nucleases (A, B, C, D) assist in the liquefaction of pus and help to generate substrate for growth. Other enzymes In addition, streptococci produce proteinase, nicotinamide adenine dinucleotidase, adenosine triphosphatase, neuraminidase, lipoproteinase, and cardiohepatic toxin. Suppurative Disease Spectrum Streptococcal pharyngitis

S pyogenes causes up to 15%-30% of cases of acute pharyngitis.9 Frank disease occurs based on degree of bacterial virulence after colonization of the upper respiratory tract. Accurate diagnosis is essential for appropriate antibiotic selection.
Impetigo The bacterial toxins cause proteolysis of epidermal and subepidermal layers, allowing the bacteria to spread quickly along the skin layers, thereby causing blisters or purulent lesions. The other common cause of impetigo is S aureus. Pneumonia Invasive GAS can cause pulmonary infection, often with rapid progression to necrotizing pneumonia. Necrotizing fasciitis

Necrotizing fasciitis is caused by bacterial invasion into the subcutaneous tissue, with subsequent spread through superficial and deep fascial planes. The spread of organisms is aided by bacterial toxins and enzymes (eg, lipase, hyaluronidase, collagenase, streptokinase), interactions among organisms (synergistic infections), local tissue factors (eg, decreased blood and oxygen supply), and general host factors (eg, immunocompromised state, chronic illness, surgery). As the infection spreads deep along the fascial planes, vascular occlusion, tissue ischemia, and necrosis occur.10 Although GAS is often isolated in cases of necrotizing fasciitis, this disease state is frequently polymicrobial. Otitis media and sinusitis These are common suppurative complications of streptococcal tonsillopharyngitis. They are caused by spread of organisms via the eustachian tube (otitis media) and direct spread to sinuses (sinusitis). Nonsuppurative Complications Acute rheumatic fever Certain M types are considered rheumatogenic, as they contain antigenic epitopes related to heart muscle, and therefore may lead to autoimmune rheumatic carditis (rheumatic fever) following acute infection. CD4+ T cells are probably the ultimate effectors of chronic valve lesions in rheumatic heart disease. T cells can recognize streptococcal M5 protein peptides and produce various inflammatory cytokines (eg, tumor necrosis factor [TNF]alpha, interferon [IFN]gamma, interleukin [IL]10, IL-4), which could be responsible for progressive fibrotic valvular lesions. Cardiac myosin has been defined as a putative autoantigen recognized by autoantibodies in patients with rheumatic fever. Cross-reactivity between cardiac myosin and group A beta-hemolytic streptococcal M protein has been adequately demonstrated and may contribute to pathogenesis.11 Poststreptococcal glomerulonephritis Poststreptococcal glomerulonephritis (PSGN) is caused by infection with specific nephritogenic strains of GAS (types 12 and 49) and may occur in sporadic cases or during an epidemic. PSGN results from deposition of antigen-antibody-complement complexes on the basement membrane of renal glomeruli. Subepithelial deposits of immunoglobulin can be observed with immunofluorescent staining. Streptococcal toxic shock syndrome Severe GAS infections associated with shock and organ failure have been reported with increasing frequency, predominantly in North America and Europe. STSS is a severe systemic immune response mediated by superantigens, as described above (see Pyrogenic exotoxins). Central Nervous System Diseases The primary evidence for poststreptococcal autoimmune CNS disease is provided by studies of Sydenham chorea, the neurologic manifestation of rheumatic fever. Reports of obsessivecompulsive disorder (OCD), tic disorders, and other neuropsychiatric symptoms that occur in association with group A beta-hemolytic streptococcal infections suggest that various CNS sequelae may be triggered by poststreptococcal autoimmunity.12 Frequency United States

According to a CDC report dated April 3, 2008, approximately 9,000-11,500 cases of invasive GAS disease (3.2-3.9 per 100,000 population) occur each year in the United States. STSS and necrotizing fasciitis each accounted for approximately 6%-7% of cases. More than 10 million noninvasive GAS infections (primarily throat and superficial skin infections) occur annually.13 International The resurgence of GAS as a cause of serious human infections in the United States, Europe, and elsewhere in the 1980s and into the 1990s was thoroughly documented and has heightened public awareness about this organism. Disease resurgence coupled with the lack of a licensed GAS vaccine and ongoing concern about acquisition of penicillin resistance remain a major concern. In Denmark, the incidence of rheumatic fever decreased from 250 cases per 100,000 population to 100 cases per 100,000 population from 1862-1962. By 1980, the incidence ranged from 0.23-1.88 cases per 100,000 population. The incidence of PSGN ranges from 9.5-28.5 new cases per 100,000 individuals per year. PSGN accounted for 2.6% to 3.7% of all primary glomerulopathies from 1987-1992, but only 9 cases were reported between 1992 and 1994. In China and Singapore, the incidence of PSGN has decreased in the past 40 years. In Chile, the disease has virtually disappeared since 1999, and, in Maracaibo, Venezuela, the incidence of sporadic PSGN decreased from 90-110 cases per year from 1980-1985 to 15 cases per year from 2001-2005. In Guadalajara, Mexico, the combined data from two hospitals showed a reduction in cases of PSGN from 27 in 1992 to only 6 in 2003.14 The Strep-EURO program, which analyzed data gathered in 11 participating countries, reported the epidemiology of severe S pyogenes disease in Europe during the 2000s. A crude rate of 2.46 cases per 100,000 population was reported in Finland, 2.58 in Denmark, 3.1 in Sweden, and 3.31 in the United Kingdom. In contrast, the rates of reports in the more central and southern countries, the Czech Republic, Romania, Cyprus, and Italy, were substantially lower (0.3-1.5 per 100,000 population), attributed to poor diagnostic microbiological investigative methods in these countries. Mortality/Morbidity As reported by the CDC in April 2008, invasive GAS infections carry a mortality rate of 10%15%, with STSS and necrotizing fasciitis carrying fatality rates of over 35% and approximately 25%, respectively. STSS may also result in organ system failure, while necrotizing fasciitis may result in amputation.13 Race GAS infections have no racial predilection. Sex GAS infections have no sexual predilection, although rheumatic mitral stenosis is more common in females. Age

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

Clinical History Group A streptococci (GAS) can cause various diseases, including strep throat, skin and softtissue 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 o Streptococcal pharyngitis is strongly suggested by the presence of fever, tonsillar exudate, tender enlarged anterior cervical lymph nodes, and absence of cough (Centor criteria).9 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. o Acute sinusitis manifests as persistent coryza, postnasal drip, headache, and fever. Skin and soft-tissue infections o Scarlet fever results from pyrogenic exotoxin released by GAS and is characterized by 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. o 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, 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.

Streptococcus group A infections. Erysipelas is a group A streptococcal infection of skin and subcutaneous tissue.
o

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 drug abuse, abnormal lymphatic drainage, and breaks in skin integrity (eg, dry cracked skin, tenia pedis) predispose to streptococcal cellulitis.

Erythema secondary to group A streptococcal cellulitis. Impetigo and pyoderma, also called impetigo or impetigo contagiosa, are outbreaks of streptococcal pyoderma that may occur in children of certain population groups and in overcrowded institutions. The mode of spread is via direct contact, environmental contamination, and houseflies. The strains of streptococci that cause pyoderma differ from those that cause exudative tonsillitis. o Necrotizing fasciitis is a rapidly invasive GAS infection that may arise following minor trauma or from hematogenous spread of GAS from the throat to a site of blunt trauma or muscle strain. Unexplained and rapidly progressing pain may be the first indication of necrotizing fasciitis. Pain may be disproportional to the physical findings. 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. Bacteremia o 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, intravenous drug abuse, and nonpenetrating trauma. Predisposing factors for GAS bacteremia in elderly people include diabetes mellitus, peripheral vascular disease, malignancy, and corticosteroid use. o 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, hematological abnormalities, confusion, skin lesions, and diffuse capillary leak syndrome. Acute rheumatic fever o The Jones criteria are used to diagnose rheumatic fever. The 5 major criteria include carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. The minor criteria include fever, arthralgia, elevated erythrocyte sedimentation rate or C-reactive protein level, and prolonged PR interval on ECG. The presence of two major manifestations or of one major and two minor manifestations, supported by evidence of a preceding GAS infection by positive throat swab or culture results or high serum ASO titers, strongly suggests acute rheumatic fever (ARF). o Following the initial pharyngitis, a latent period of 2-3 weeks occurs before the first signs or symptoms of ARF appear. o 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.
o

Physical

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. Patients with pharyngitis may develop chills and fever. 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.

Streptococcus group A infections. White strawberry tongue observed in streptococcal pharyngitis. Image courtesy of J. Bashera, eMedicine, Inc.

Pyoderma begins as a small papule and 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 crust. Patients usually do not have systemic symptoms. Local signs of skin erythema, warmth, tenderness and swelling are usually associated with cellulitis and erysipelas. Rash with honey-colored crust is observed with impetigo. 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 fascitis is an extensive and rapidly spreading infection of the subcutaneous tissue and fascia accompanied by necrosis and gangrene of the skin and underlying structures. Initially, the involved area appears erythematous but 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 follows.

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.

Signs of sepsis (eg, fever, tachycardia, tachypnea, hypotension) may be present in invasive infections.

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