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Nonpneumococcal Streptococcal Infections and Rheumatic Fever
Classification and Identification of Streptococci
Streptococci are gram-positive facultatively anaerobic, catalase-negative coccoid bacteria that grow in chains and colonize the skin and mucous membranes. When grown on blood agar plates, they may cause complete (β), incomplete (α), or no (γ) hemolysis. Using the Lancefield classification, hemolytic streptococci can be classified into types A through G based on acid-extractable carbohydrate antigens of cell wall material. Modern classification schemes categorize hemolytic and nonhemolytic streptococci using complex biochemical and genetic techniques.
The major pathogenic β-hemolytic streptococci are group A (Streptococcus pyogenes) and group B (Streptococcus agalactiae). Although most of this chapter is dedicated to discussing these two pathogens and the clinical diseases that they cause, the remainder of the chapter includes discussions of Streptococcus dysgalactiae subspecies equisimilis (groups C and G streptococcus), viridans group streptococcus (no Lancefield group), and zoonotic streptococci (various Lancefield groups).
Streptococcus Pyogenes (Group A Streptococcus) Infections
Acute Infections
Definition
S. pyogenes contains Lancefield group A antigen on the cell surface and thus is referred to as group A streptococcus. Group A streptococci are the most significant of the streptococcal human pathogens and cause an array of clinical infections ranging from pharyngitis, superficial skin infections, deep soft tissue infections, and toxic shock syndrome. Postinfectious sequelae include rheumatic fever, post-streptococcal glomerulonephritis, and reactive arthritis.
Epidemiology
Humans are the only known hosts for S. pyogenes . All group A streptococcal infections are more common in children younger than age 10 years. The asymptomatic prevalence of the group A streptococcus carrier state is also higher in children (15 to 20%) than in adults (<5%). In addition to age, group A streptococcus epidemics are also associated with crowded conditions, particularly in schools and military camps, during the winter months in temperate climates. The U.S. Centers for Disease Control and Prevention (CDC) estimates that the incidence of invasive S. pyogenes infections in the United States in 2019 was 7.5 cases per 100,000 population per year. Worldwide, an estimated 18 million annual infections cause about 500,000 deaths each year.
Pharyngeal and cutaneous group A streptococci are transmitted from person to person by aerosolized microdroplets or direct contact. Epidemics of pharyngitis and scarlet fever occur after the consumption of contaminated food or unpasteurized milk. Group A streptococcus infections are seen in hospitalized patients during childbirth (puerperal sepsis), after surgery or burns (wound infection), and in war settings (epidemic gangrene). Thus, most clinical streptococcal infections have a clear mode of transmission and portal of entry. In contrast, among patients with streptococcal toxic shock syndrome, the portal of entry is obvious in only 50% of cases.
Pathobiology
Mucous membranes and skin serve as the natural reservoirs for S. pyogenes . Group A streptococci adhere to host epithelium through complex interactions involving streptococcal factors such as M protein, lipoteichoic acid, fibronectin-binding protein, and fimbriae. Although streptococci must adhere to the epithelium to cause most infections, such adherence is not always sufficient to cause disease because many individuals may have prolonged asymptomatic carriage without clinical infection.
Streptococci evade opsonophagocytosis by expression of antiphagocytic M protein, by use of immunoglobulin-binding protein, by formation of a hyaluronic acid capsule, and/or by production of a C5a peptidase that destroys or inactivates complement-derived chemoattractants and opsonins. At the focus of infection, the exotoxin streptolysin O is cytotoxic and destroys approaching phagocytes. Distal to the infection, lower concentrations of streptolysin O stimulate hyperadhesion of polymorphonuclear leukocytes to endothelial cells (thereby effectively preventing a tissue inflammatory response and promoting vascular damage) and cause vascular occlusion with destruction of distal fascia and muscle. In a nonimmune host, streptolysin O, streptococcal pyrogenic exotoxins, and other streptococcal components drive the “cytokine storm” that causes hypotension and vascular leukostasis, thereby resulting in shock, microvascular injury, multiorgan failure, and even death.
M Proteins
More than 150 different M protein serotypes of group A streptococci have been described. The M protein is a coiled-coil structure that consists of four regions of repeating amino acids (A to D), a proline/glycine-rich region that intercalates the protein into the bacterial cell wall, and a hydrophobic membrane anchor. Region A, which is near the N terminus, is highly variable, and antibodies to this region confer type-specific protection by overcoming the antiphagocytic properties of the protein. The more conserved B to D regions bind complement regulatory proteins, sterically inhibiting antibody binding and complement-derived opsonin deposition and effectively camouflaging the organism against humoral immune surveillance. The quantity of M protein that is produced by an infecting strain progressively decreases during convalescence and during prolonged asymptomatic carriage.
Cell Wall, Lipoteichoic Acid, Fibronectin-Binding Protein (Protein F), and Fimbriae
Many different factors help group A streptococci adhere to host epithelial cells. Integral lipoteichoic acid components of the cell wall mediate hydrophobic interactions between pathogen and host cells. Fibronectin-binding protein (protein F) promotes binding to the host cell extracellular matrix. Fimbriae, flexible rods that protrude up to 3 µm from the bacterial cell surface, mediate adherence to epithelial cells and promote microcolony and biofilm formation.
Hyaluronic Acid Capsule
Some strains of S. pyogenes have hyaluronic acid capsules. These capsules, which bind to CD44 on epithelial cells and serve as antiphagocytic factors, are important in pharyngitis, soft tissue infection, and invasive disease.
Streptolysin O and S
Streptolysin O belongs to a family of highly homologous oxygen-labile, cholesterol-dependent cytolysins. These cytotoxins cause the broad zone of complete β-hemolysis that surrounds colonies of S. pyogenes grown on blood agar plates. As the name implies, cholesterol-dependent cytolysins bind to cholesterol on eukaryotic cell membranes, where they create toxin-cholesterol membrane pores that, at high doses, cause cell lysis by a colloid-osmotic mechanism. Sublytic doses stimulate cardiac cell dysfunction, leukocyte granule release, and intravascular leukostasis and blood flow occlusion. Anti-streptolysin O titers are used clinically to detect recent group A streptococcal infection and to aid in diagnosis of post-streptococcal syndromes such acute rheumatic fever and post-streptococcal glomerulonephritis. When the serum cholesterol level is high, as in the nephrotic syndrome, the anti-streptolysin O titer may be falsely elevated.
Streptolysin S is a cell-associated hemolysin that does not diffuse into the agar media. Purification and characterization of this protein have been difficult, and its only pathogenetic role may be in direct or contact cytotoxicity.
Deoxyribonucleases A, B, C, and D
The expression of deoxyribonucleases (DNases), especially the DNase B seen with group A streptococci, stimulates the production of anti-DNase antibody following both pharyngeal and skin infection. DNases may also contribute to the production of cytokines, but their importance in this setting is not essential.
Hyaluronidase and Nicotine Adenine Dinucleotidase
Hyaluronidase is an extracellular enzyme that hydrolyzes hyaluronic acid in deeper tissues, thereby facilitating the spread of infection along fascial planes. Antihyaluronidase titers rise after S. pyogenes infection, especially skin infections. The production of nicotine adenine dinucleotidase among group A streptococcus strains correlates with the epidemiologic emergence/reemergence of necrotizing fasciitis and streptococcal toxic shock syndrome. In neutrophils, nicotine adenine dinucleotidase impairs chemotaxis and changes the respiratory burst activity.
Pyrogenic Exotoxins
Streptococcal pyrogenic exotoxins types A, B, and C are also called scarlatina or erythrogenic toxins. These exotoxins act as superantigens that induce lymphocyte blastogenesis and fever, may potentiate endotoxin-induced shock, and may suppress antibody synthesis. Pyrogenic exotoxins and some M protein fragments are initially able to interact with certain V β regions of the T-cell receptor despite the absence of classic antigen processing by antigen-presenting cells ( E-Fig. 269-1 ). This interaction results in massive clonal proliferation of T-lymphocytes as well as stimulation of macrophages. Thus, streptococcal toxic shock syndrome causes watershed production of lymphokines (tumor necrosis factor-β [TNF-β], interferon-γ, and interleukin-2 [IL-2]) and monokines (TNF-α, IL-1, and IL-6) that results in the “cytokine storm,” which in turn mediates shock and organ dysfunction. Five other group A streptococcal superantigens, including streptococcal superantigen (SSA) and mitogenic factor, may also play a role in the pathogenesis. In addition, streptococcal pyrogenic exotoxins type B, which is a cysteine protease, may contribute to the pathogenesis of necrotizing fasciitis and shock by its ability to cleave pre–IL-1β into active IL-1β.
Clinical Manifestations and Diagnosis
Pharyngitis
Pharyngitis is the most common S. pyogenes infection, with peak incidence in children aged 5 to 15 years. Infection is characterized by an abrupt onset of fever, sore throat, and submandibular adenopathy. Chilliness is common, but frank rigors are unusual. Most patients report pain on swallowing, but cough and hoarseness are rare. On physical examination, the uvula is edematous, the tonsils are typically hypertrophied, the palate may have petechia, and the pharynx is usually erythematous with a punctate or confluent exudate ( Fig. 269-1 ).
Acute pharyngitis induces antibodies against M protein, streptolysin O, DNase, hyaluronidase, and, if present, pyrogenic exotoxins. Even without treatment, the pain, swelling, and fever of acute pharyngitis usually resolve spontaneously in 3 to 6 days. However, depending on the virulence of the infecting strain, pharyngitis also can progress to suppurative head and neck infections, scarlet fever, bacteremia, rheumatic fever, or post-streptococcal glomerulonephritis. Streptococcal toxic shock syndrome is an uncommon sequela of symptomatic pharyngitis.
Although S. pyogenes is the most common cause of acute pharyngitis (15 to 30% of pediatric cases and 5 to 15% of adult cases), definitive diagnosis is difficult on purely clinical parameters. Even in older children or adolescents who have all the typical physical findings of streptococcal pharyngitis, the clinical diagnosis is correct in only about 75% of patients. The modified Centor score was designed to assist with diagnosis and to help reduce unnecessary use of antibiotics and streptococcal testing ( Tables 269-1 and 397-2 ). If any one of the classic signs is absent, the likelihood of streptococcal pharyngitis is greatly reduced. Several societies suggest avoiding streptococcal testing and antibiotics if the modified Centor score is 0 or 1. Providers can generally avoid testing in children younger than age 3 years because of low rates of streptococcal infection complications in this age group.
TABLE 269-1
MODIFIED CENTOR CLINICAL DECISION RULE FOR DIAGNOSING GROUP A STREPTOCOCCAL PHARYNGITIS IN CHILDREN AND ADULTS
Adapted from: McIsaac WJ, Kellner JD, Aufricht P, Vanjaka A, Low DE. Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA . 2004;291(13):1587-1595.
| STEP 1—CALCULATE MODIFIED CENTOR SCORE |
| DIAGNOSTIC CRITERIA | POINTS |
|---|---|
| Temperature >38° C Absence of cough Swollen, tender anterior cervical lymph nodes Tonsillar swelling or exudate Age 3-14 years Age >44 years |
+1 +1 +1 +1 +1 −1 |
| STEP 2—DETERMINE SUGGESTED MANAGEMENT | |
| SCORE | RISK FOR STREPTOCOCCAL INFECTION | RAPID ANTIGEN TESTING AND/OR CULTURE | ANTIBIOTICS |
|---|---|---|---|
| ≤0 1 2 3 ≥4 |
1-2.5% 5-10% 11-17% 28-35% 51-53% |
No
Yes No |
No
If testing positive Yes, empirical |
Throat swabs for culture of S. pyogenes remain the diagnostic “gold standard.” Rapid site-of-care nucleic acid testing (sensitivity 97.5% and specificity 95%) is preferred over antigen tests, which have a sensitivity of only about 85%. , A popular approach, which is supported by professional guidelines, is to obtain two throat swabs from the posterior pharynx or tonsillar surface. If a rapid streptococcal test is positive on the first swab, the patient should be treated with antibiotics, and the second swab can be discarded. If the rapid test is negative in children and adolescents, the second sample should be sent for culture and treatment should be withheld unless the result is a positive culture. In adults, the second sample usually need not be sent for culture because of the low incidence of group A streptococcal pharyngitis in adults and the low risk for subsequent acute rheumatic fever even if group A streptococcus pharyngitis is present. The delay in antibiotics for confirmed cases of group A streptococcus pharyngitis is reasonable because acute antibiotic treatment has limited effect on improving acute symptoms. Delaying treatment by several days, however, reduces unnecessary antibiotic use while still achieving the goals of preventing rheumatic fever and reducing spread of disease. Antibiotics, regardless of the timing, do not reduce the likelihood of post-streptococcal glomerulonephritis.
Scarlet Fever
Scarlet fever is the syndrome defined as streptococcal infection (most commonly pharyngitis) with fever and a characteristic rash. Ninety percent of cases of scarlet fever occur in children ages 2 to 8 years. Scarlet fever is most common during the winter months in temperate regions. The rash usually begins as small, flat, erythematous macules on the trunk 1 to 2 days after the illness begins. The rash then transforms into minute papules, giving a “sandpaper” feel to the skin as it spreads to the limbs, sparing the palms and soles. The rash can be accentuated in the skin folds and flexure creases as of the elbow (Pastia lines). Other features include flushed cheeks with circumoral pallor and enlargement of the papillae of the tongue (strawberry tongue). As the rash resolves over the course of 6 to 9 days, there is often desquamation beginning at the palms and soles. Since the advent of penicillin treatment, scarlet fever has become uncommon, but recent outbreaks have been reported in several countries.
Impetigo and Ecthyma
Impetigo ( Chapter 408 ) most commonly occurs in children ages 2 to 5 years. It may occur year-round in tropical areas but occurs predominantly in the summer in temperate climates. Risk factors for impetigo include poor hygiene and malnutrition. Unbroken skin is colonized, and then minor abrasions or other traumas lead to infection of the superficial keratin layer of the skin. Within 10 to 14 days, single or multiple thick-crusted, golden-yellow lesions appear. Ecthyma is an ulcerative form of impetigo characterized by erosions into the dermis. In the past, nonbullous impetigo as described here could be confidently diagnosed as streptococcal and differentiated from bullous impetigo caused by Staphylococcus aureus ( Chapter 268 ). More recently, however, S. aureus has been isolated with increasing frequency from nonbullous impetigo when treatment with penicillin fails to cure the infection. Gram stain and culture of exudates from the skin lesions can help determine whether group A streptococcus or S. aureus is the cause.
Erysipelas
Erysipelas ( Chapter 408 ), which is caused exclusively by S. pyogenes, is characterized by an abrupt onset of fiery red swelling of the face or extremities. The infection is most commonly seen in infants and elderly adults. Infection is confined to the upper dermis with prominent lymphatic involvement leading to well-defined margins raised above the level of the surrounding skin, particularly along the nasolabial fold, without the crusty lesions seen in impetigo with its involvement of the superficial keratin layer of skin. Other distinctive features of erysipelas include scarlet or salmon-red rash, intense pain, and rapid progression. Flaccid bullae may develop on the second to third day, but the infection rarely extends into deeper soft tissues.
Cellulitis
Cellulitis ( Chapter 408 ) is infection of the subcutaneous tissues resulting in a pink hue to the skin and less defined borders than with erysipelas. Group A streptococcal cellulitis is usually nonpurulent. Purulent cellulitis is most commonly caused by staphylococcal species. Risk factors for streptococcal cellulitis include impaired lymphatic drainage, venous insufficiency, edema, obesity, and disruption of the cutaneous barrier as from wounds or dermatophyte infection (e.g., tinea pedis).
Severe Group A Streptococcal Infections
Bacteremia
Group A streptococcal bacteremia is relatively uncommon in the antibiotic era, and endocarditis is even less common. Endocarditis is more common with Streptococcus viridans, mitis/oralis , and gallolyticus species. In contrast to pharyngitis, scarlet fever, and impetigo, bacteremia occurs more often in the elderly and in neonates. The exceptions to these extremes of age are individuals with parenteral injection of illicit drugs and otherwise healthy middle-aged adults who develop bacteremia as part of a necrotizing soft tissue infection or streptococcal toxic shock syndrome.
Puerperal Sepsis
Patients with S. pyogenes puerperal sepsis typically present with fever, abdominal pain, and hypotension without tachycardia or leukocytosis. Maternal mortality is highest when infection occurs within 4 days of delivery or during the late third trimester. The incidence varies from about 6 to 80 cases per 100,000 live births, and the case-fatality rate is about 3.5%. Women who undergo cesarean section (and routinely receive prophylactic antibiotics) or are primiparous are at lower risk. Nosocomial transmission can occur, but because women are discharged home after 48 hours, acquisition may be from the home environment, particularly if young children at home have had recent streptococcal pharyngitis or are carriers of group A streptococcus.
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