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PART III Etiologic Agents of Infectious Diseases SECTION A 118 pyogenes (Group A Streptococcus) Victor Nizet and John C. Arnold

Group A streptococcus (GAS) is synonymous with Streptococcus disease, including M1, M3, M6, M12, M18, and M28. A globally pyogenes, the only within this group of β-hemolytic strep- disseminated clone of the M1 serotype has been the leading cause tococci. GAS is one of the leading that infects of severe invasive GAS such as and children and adolescents, and is associated with a wide spectrum over the past three decades.7 of infections and disease states. Worldwide, there are estimated to The GAS cell is a complex structure. In rapidly dividing strains be >600 million cases of GAS (“strep throat”) and (e.g., young cultures, epidemic strains), the cell is covered with a >100 million cases of GAS pyoderma annually.1 Although uni- capsule that gives the colonies a mucoid or water formly susceptible to and still exquisitely susceptible drop appearance. Protruding from the cell surface and into the to many other antimicrobial agents, GAS infections continue to hyaluronic capsular layer are microscopic hairlike fimbriae, which present formidable clinical and public health challenges. The promote adherence of GAS to epithelial cells and extracellular vast majority of GAS infections are of short duration and are rela- matrix proteins. The fimbriae are composed of a surface-anchored tively benign; however, invasive disease can be fulminant and M protein adopting a coiled-coil structure, closely associated with life-threatening. In addition, GAS differs from other pyogenic polymers.8,9 GAS recently has been recognized to bacteria in their potential to produce delayed, nonsuppurative express surface pili, which correspond to the classical “T ” sequelae (e.g., poststreptococcal acute in earlier serologic typing schemes.10 Roughly half of GAS strains (PSAGN) and acute (ARF)) following uncompli- display the capacity to opacify mammalian serum, through the cated infections. The importance of GAS infections in the activity of the surface-anchored serum opacity factor (SOF) United States was reinforced­ at the close of the 20th century by a protein, which binds to apolipoproteins to displace high-density resurgence of ARF2 as well as by the appearance of severe invasive lipoprotein (HDL) to form lipid droplets.11 Serologic diversity GAS infections (e.g., streptococcal toxic shock syndrome (STSS) among various T and SOF proteins can be helpful and necrotizing fasciitis) with high morbidity and mortality.3 On supplemental tools to emm typing in epidemiologic characteriza- the global scale, GAS is an important cause of morbidity and tion of GAS strains.12 mortality primarily in developing countries, with >500,000 deaths The group A carbohydrate, comprising 40% to 50% of the dry annually.1 weight of the GAS cell wall, is a polymer of rhamnose units with side chains of N-acetyl-glucosamine and is responsible for its DESCRIPTION OF PATHOGEN group (e.g., A) specificity.13 Like other gram-positive species, a peptidoglycan polymer provides thickness and rigidity for the cell Microbiology wall, consisting of glycan strands cross-linked by peptide bridges. M protein, pilus antigen, SOF, and other surface proteins are cova- GAS is a gram-positive coccoid-shaped bacterium that grows in lently attached to the GAS cell wall by recognition sequences on chains. GAS produces small white to grey colonies with a clear their C-terminal regions that interact with an anchoring enzyme zone of β- on blood agar. Rare strains of GAS are not called sortase.14 hemolytic.4 GAS is distinguished from other groups of β-hemolytic GAS produce and release into the surrounding medium a large streptococci by a group-specific polysaccharide (Lancefield carbo- number of biologically active extracellular products. Some of these hydrate C) located in the cell wall. Serologic grouping by the are toxic for human and other mammalian cells. S Lancefield method is precise, but group A organisms can be identi- (SLS) is a small oxygen-stabile responsible for β-hemolysis fied more readily by any one of a number of latex agglutination, of GAS on blood agar, while streptolysin O (SLO) is an oxygen- co-agglutination, or enzyme immunoassay procedures. labile, cholesterol-dependent toxin related to staphylococcal GAS can be subdivided into >100 serotypes by the M-protein α-hemolysin. Both SLS and SLO injure cell membranes, not antigen that is located on the cell surface and by fimbriae (hairlike only lysing red blood cells, but also damaging other eukaryotic fuzz) that project from the outer edge of the cell. Classically, cells and membranous subcellular organelles.15 Streptolysin O typing of the surface M protein relied upon available polyclonal is antigenic; streptolysin S is not. Streptococcal pyrogenic exotox- antisera. This largely has been supplanted by a contemporary ins (SPEs) are secreted factors with the capacity to act as super­ molecular approach that applies the polymerase chain reaction antigens and trigger T-cell proliferation and cytokine release.16 and DNA sequencing of the emm gene encoding the M protein. GAS elab­orates a broad-spectrum cysteine with multiple More than 130 distinct M genotypes have been identified using host targets, a variety of specific peptidases that cleave host emm typing, and there has been a good correlation between and complement factors, and several nucleases. known serotypes and emm types.5,6 Finally, GAS produces bacteriocins, low-molecular-weight pro- M serotyping or genotyping has been valuable for epidemio- teins that can kill a variety of other gram-positive bacteria, and logic studies; particular GAS diseases tend to be associated with thus may play a role in promoting or even persistence certain M types. The M types commonly associated with pharyn- of colonization.17 gitis rarely cause skin infections, and the M types commonly asso- The expression of GAS genes is controlled by the ciated with skin infections rarely cause pharyngitis. A few of the interplay of several transcriptional regulatory systems.18,19 These “pharyngeal” strains (e.g., M type 12) have been associated with include the two-component “control of virulence” system (CovR/S) PSAGN, but far more of the “skin” strains (e.g., M types 49, 55, that regulates 10% to 15% of the GAS genome including its 57, and 60) have been considered nephritogenic. A few of the hyaluronic acid capsule synthesis operon, and the stand-alone “pharyngeal” serotypes, but none of the “skin” strains, have been Mga regulator controlling expression of M protein and nearby associated with ARF. However, recent evidence suggests that rheu- genes. Genome sequencing has shown that bac­ matogenic potential is not solely dependent on the serotype, but teriophages have played an important role in the evolutionary rather is a characteristic of specific strains within several serotypes. genetics of GAS, including the transfer of genes encoding anti­ Certain GAS M types are more strongly associated with invasive biotic resistance, SPEs and other virulence determinants.20

698 Streptococcus pyogenes (Group A Streptococcus) 118

PATHOGENESIS AND VIRULENCE leukocyte antigen (HLA) haplotypes.35 The SPEs share homology with staphylococcal but not with staphylococcal toxic GAS induces serious human disease by at least three mechanisms: shock syndrome toxin-1.33 SpeA and SpeC are responsible for the suppuration, as in pharyngitis and pyoderma; toxin elaboration, rash of , stimulating the formation of specific antitoxin as in STSS; and immune-mediated inflammation, as in ARF and that provide immunity against future scarlatiniform PSAGN.21 No complete explanation is available for the predilec- rashes, but not against other GAS infections. tion of certain body sites for infection by GAS, nor for the ability of strains of certain M types to produce pharyngitis and of other M types to produce pyoderma. IMMUNOLOGIC RESPONSE The first step in GAS disease pathogenesis involves successful Although many GAS constituents and extracellular products colonization of the upper respiratory mucosa or skin of human are antigenic, protective immunity is type-specific, mediated by host. A large number of adherence factors for epithelial cells and opsonic anti-M-protein antibodies. These antibodies protect extracellular GAS have been described, including lipoteichoic acid, against infection with a homologous M type but confer no immu- M protein, pili, and fibronectin-binding proteins including Sfb1 nity against other M types.36 Therefore, multiple GAS infections and SOF.22 GAS biofilm formation facilitates persistence within attributable to different M types are common during childhood the human host.23 Both M protein and fibronectin-binding pro- and adolescence. Anti-M antibodies persist for years, perhaps for teins are important for subsequent endocytotic uptake of GAS into life, protecting against invasive infection but not against pharyn- respiratory epithelial cells.22 This process of intracellular invasion geal carriage.37 Type-specific may be transferred across the allows GAS access to a privileged intracellular niche, and repre- placenta from mother to fetus.38 Type-specific antibody against M sents a proximal step in the pathogenesis of systemic infection.24 protein is not usually detectable until 6 to 8 weeks after infection.39 The propensity of GAS to produce serious infection in otherwise Therefore, its primary role may not be in the limitation or termina- healthy children and adults defines a capacity of the pathogen to tion of active infection, but rather in the prevention of reinfection resist host innate clearance mechanisms that normally function to by the same serologic type. Opsonic type-specific antibodies do not prevent microbial dissemination.25 For example, when GAS gains appear after early and effective antimicrobial therapy.40 access to deeper tissues through cellular invasion or a break in Humoral antibodies to specific streptococcal extracellular prod- epithelial integrity, it deploys specific peptidases that cleave and ucts such as antistreptolysin O (ASO) and anti-DNAse B can be inactivate the chemoattractants interleukin-8 and com- demonstrated readily by neutralization assays. They have been plement factor 5a. Likewise, the broad-spectrum secreted cysteine particularly useful in allowing a more precise method of defining protease, streptococcal pyrogenic (Spe) B, can degrade GAS infection in clinical and epidemiologic studies and in docu- host immunoglobulins and cationic antimicrobial peptides. menting the occurrence of a preceding GAS infection in patients M protein is a multifaceted immune resistance factor that pro- with a suspected nonsuppurative . The ASO assay is motes GAS resistance to opsonophagocytosis through multiple the most commonly used streptococcal antibody test. Since SLO mechanisms, including the binding of , complement is also produced by group C or G streptococci, the test is not inhibitory , and the Fc region of immunoglobulins.26 M specific for GAS infections, and the response can be feeble in protein is essential to virulence in animal models, and immuniza- patients with streptococcal .41 In contrast, the anti-DNAse tion with M protein provides strong protection against infection B response is demonstrable after both skin and throat infections. with a type-specific GAS strain. During invasive infection, signifi- Neutralizing antibody titers to SLO peak at 3 to 6 weeks and to cant quantities of M protein are released from the cell surface by DNAse B at 6 to 8 weeks. Antibody titers against GAS extracellular proteolysis, whereupon they can form a proinflammatory clot-like antigens reported by clinical immunology laboratories may vary. complex with human fibrinogen, leading to uncontrolled neu- Upper limits of normal are higher for children than for adults and trophil activation, vascular leakage, and toxic shock symptomatol- these values, even for the same age group, are higher in some ogy.27,28 M protein also collaborates with the GAS virulence factor populations than in others.42 to bind host plasminogen to the GAS surface, where- upon activity is generated, effectively coating the bacterial surface with a powerful protease to facilitate tissue spread.29 SUPPURATIVE INFECTIONS The pore-forming SLS and SLO are toxic to multiple host cell types including macrophages and , and thus Epidemiology promote GAS tissue damage and resistance to phagocytic clear- ance.15 SLO in particular can induce the accelerated apoptosis of GAS have a narrow host range, identified almost exclusively in immune cells.30 The GAS hyaluronic acid capsule is nonimmuno- humans and only rarely in other species.43 GAS is highly com- genic, mimicking a common human matrix component, and municable and can cause disease in individuals of all ages who cloaks opsonic targets on the bacterial surface from do not have type-specific immunity. Disease in neonates is uncom- recognition.31 In the case of the highly invasive globally dissemi- mon, probably because of placental transfer of maternal antibody. nated M1T1 GAS clone, hyperinvasive forms bearing mutations in Significant differences exist between epidemiology of throat and the covR/S two-component regulator gene arise in vivo under skin infections due to GAS44 (see Chapter 27, Pharyngitis, and innate immune selection, leading to upregulation of capsule and Chapter 70, Superficial Bacterial Skin Infections and ). other key virulence determinants.32 Specific virulence determi- Severe invasive GAS infections had become uncommon in the nants present in the hyperinvasive M1T1 clone include the phage- U.S. and western Europe during the second half of the 20th encoded DNAse Sda1, which allows GAS to escape killing within century.45 However, since the late 1980s, there has been a world- DNA-based neutrophil extracellular traps, and the serum inhibitor wide increase in severe invasive GAS infections.46 The incidence of of complement (SIC), which binds and inactivates terminal com- severe invasive GAS disease in industrialized societies (2 to 3 per plement components and host defense peptides. 100,000 population) is similar in the geographically distinct The SPEs are a family of >15 bacterial , including regions of Europe, North America, and Australia.47,48 This rate the bacteriophage-encoded SPE A and SPE C.33 These superanti- translates to ~10,000 cases of invasive GAS disease annually in the gens induce antigen-nonspecific T-lymphocyte activation, suppress U.S.49 However, rates of invasive disease in indigenous popula- antibody synthesis, potentiate endotoxic shock, induce fever, tions in Africa, the Asian subcontinent, and the Pacific Islands promote release of proinflammatory cytokines, produce reticu- typically are much higher,1 with rates as high as 82.5/100,000 loendothelial blockade, and may contribute to multiorgan failure reported in North Queensland, Australia.50 Globally, it has been characteristic of STSS.34 In the U.S., STSS commonly is associated estimated that at least 663,000 cases of invasive GAS disease occur with infections with SpeA-producing strains.34 Susceptibility to each year, resulting in 163,000 deaths.1 STSS appears to be related to the absence of antibodies to both M The stratified squamous epithelium of the oropharynx and skin protein and superantigens as well as the presence of specific human is the principal barrier against invasive GAS disease. GAS can gain

699 All references are available online at www.expertconsult.com PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria

access to sterile sites via direct inoculation following an injury that breaches the mucous membranes or skin;49 however, a substantial number of invasive streptococcal infections have no known site of entry.51 Epidemiologic data suggest that the oropharynx is the primary site of origin for systemic GAS isolates; thus invasive disease is likely to occur as a result of transient bloodstream infec- tion (BSI) originating from the oropharynx, possibly as a result of direct tissue penetration by GAS.51 Varicella is a particularly impor- tant risk factor for severe invasive GAS infections in previously healthy children.52 Other risk factors more common in adults include diabetes mellitus, human immunodeficiency virus infec- tion, intravenous drug use, and chronic pulmonary or cardiac disease. Clinical Manifestations or Clinical Syndromes GAS is a common cause of acute pharyngitis (see Chapter 27, Pharyngitis) (Figure 118-1) and pyoderma (impetigo) (see Chapter A 70, Superficial Bacterial Skin Infections and Cellulitis) in children and adolescents. GAS also produces a variety of other infections of the respiratory tract, including otitis media, retropharyngeal abscess, peritonsillar abscess, sinusitis, and mastoiditis; of the skin and soft tissues (Figures 118-2, 118-3, and 118-4), including cel- lulitis, , perianal cellulitis, vaginitis, and blistering distal dactylitis (see Chapter 70, Superficial Bacterial Skin Infections and Cellulitis; Chapter 76, Subcutaneous Tissue Infections and Abscesses; and Chapter 77, Myositis, Pyomyositis, and Necrotizing Fasciitis); and invasive disease, including STSS (see Chapter 13, Mucocutaneous Symptom Complexes), necrotizing fasciitis, sep- ticemia, meningitis, pneumonia, empyema, peritonitis, puerperal , neonatal sepsis, , suppurative arthritis, myosi- tis, and surgical wound infections. GAS also is the proven cause of two potentially serious nonsuppurative complications, acute rheumatic fever (ARF) and acute postreptococcal glomerulone- phritis (PSAGN), and the possible cause of two other potential nonsuppurative complications, poststreptococcal reactive arthritis B (PSRA) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) (see below). Figure 118-2. (A, B) Young girl with bullous, invasive local infection without Severe invasive GAS infection is defined as the of GAS trauma or foreign body due to group A streptococcus. (Courtesy of J.H. from a normally sterile body site and includes three overlapping Brien©.) clinical syndromes. Cellulitis and BSI are the most common GAS invasive diseases, each accounting for ~20% to 40% of invasive GAS disease in published epidemiologic reports.47,48 Clinically, commonly appreciated as preludes to the more serious invasive cellulitis is characterized by acute onset of redness and inflamma- disease complications of necrotizing fasciitis and STSS. tion of the skin, with associated fever, pain, and swelling. GAS BSI The GAS “flesh-eating disease” necrotizing fasciitis is a devastat- often triggers a rapid and robust proinflammatory cytokine ing bacterial infection involving the skin, subcutaneous and deep response that results in high fever, nausea, and vomiting. While a soft tissue, and muscle. Necrotizing fasciitis involves rapid bac­ serious health concern in their own right, cellulitis and BSI are terial growth and spread along the fascial sheaths that separate adjacent muscle groups. As the infection progresses, the fascial sheaths are breached, resulting in necrosis of adjacent tissues.53 Pathogenesis of necrotizing fasciitis is complex and incompletely understood at the molecular level. However, rapid tissue destruc- tion and bacterial spread are thought to involve host and bacterial (plasmin, SpeB), GAS pore-forming cytotoxins such as SLO and SLS, and tissue-damaging enzymes released by host neutrophils in response to GAS cell wall components and superantigens.53 A major risk factor for the development of necro- tizing fasciitis is prior blunt trauma, which is suggested to result in increased vimentin expression which tethers circulating GAS to the injured muscle.54 Primary varicella () in unimmu- nized children also is a well-documented predisposing condition to GAS necrotizing fasciitis.52,55 Invasive GAS diseases also can result in STSS, a “cytokine storm,” produced in response to GAS superantigens that substan- tially increases the risk of death.47,48 GAS superantigens simultane- ously engage MHC class II molecules and TCR β-chain variable regions, a molecular “bridging” that results in antigen-independent activation of large numbers of T lymphocytes. The resulting cytokine response by T lymphocytes (lymphotoxin α, interleukin Figure 118-1. Typical group A streptococcal pharyngitis showing (IL)-2, interferon (IFN)-γ) and antigen-presenting cells tumor erythematous soft palate, uvula, and tonsils, with tonsillar exudate. necrosis factor (TNF)-α, IL-1β, IL-6) causes widespread organ dys- (Courtesy of J.H. Brien©.) function, disseminated intravascular thrombosis, and tissue injury.

700 Streptococcus pyogenes (Group A Streptococcus) 118

BOX 118-1. Definition of Streptococcal Toxic Shock Syndrome

CLINICAL CRITERIA • Hypotension plus two or more of the following: – Renal impairment – Coagulopathy – Hepatic involvement – Adult respiratory distress syndrome – Generalized erythematous macular rash – Soft-tissue necrosis DEFINITE CASE • Clinical criteria plus isolation of group A streptococcus from a normally sterile site PROBABLE CASE • Clinical criteria plus isolation of group A streptococcus from a nonsterile site A

The result is an acute, rapidly progressive illness typified by high fever, rapid-onset hypotension and accelerated multisystem failure.56 The magnitude of the STSS inflammatory response is closely linked to disease severity. As the sites at which superanti- gens bind to HLA class II are polymorphic, there is strong epide- miologic and genetic evidence that host MHC class II haplotype influences susceptibility to STSS.35,57 Specific criteria for diagnosis of STSS have been established (Box 118-1).58 Laboratory Findings and Diagnosis The clinical course of severe invasive GAS infections often is pre- cipitous, requiring rapid diagnosis and initiation of appropriate therapy. Although the initial clinical findings of STSS are nonspe- cific, a high index of suspicion is needed for this syndrome, par- ticularly in patients at increased risk (e.g., those with varicella). B Pain out of proportion to superficial signs of infection can be a clue to underlying necrotizing fasciitis. Hyper- or hypoesthesia, pallor, tenseness, duskiness or blistering (often hemorrhagic) at Figure 118-3. Toddler with aureus and group A the site also are clues. Cultures of focal lesions are helpful in streptococcal infection complicating chickenpox (A). Necrotizing group A patients with skin or soft-tissue involvement. Results of blood streptococcal cellulitis complicating chickenpox (B). (Courtesy of S.S. Long©.) cultures from patients with sepsis without an apparent focus of infection can also show GAS; a relatively normal total leukocyte count with a marked “left shift” of immature forms often is dem- onstrated on complete blood count. Blood pressure should be monitored frequently and carefully. Streptococcal toxic shock can be associated with multiorgan thromboses and multiorgan failure before or out of proportion to hypotension. If necrotizing fasciitis is suspected, magnetic resonance imaging may be helpful in con- firming the diagnosis and determining degree of involvement of fascia and muscle.39 Histologic examination of excised muscle/ fascia tissue shows extensive necrosis, inflammation, and hemor- rhage, with thrombosis of small vessels. Treatment Treatment of oropharyngeal, respiratory tract, and simple skin and soft-tissue infections is addressed by chapters specific to these clinical syndromes. Initial management of a child or adolescent with a severe invasive GAS infection includes hemodynamic sta- bilization and specific antimicrobial therapy to eradicate the GAS. When necrotizing fasciitis is suspected, prompt surgical drainage, debridement, fasciotomy, or amputation is often required. Patients with necrotizing fasciitis also need careful fluid and nutritional support and may require extensive skin grafting or other recon- structive surgery and physical therapy. Fluid resuscitation should be initiated as soon as possible for patients who are hypotensive, and frequently multiple boluses of fluid are required because of Figure 118-4. Toddler with erysipelas due to group A streptococcus. severe volume depletion and ongoing capillary leak. When fluid (Courtesy of J.H. Brien©.) resuscitation alone is insufficient to maintain adequate tissue

701 All references are available online at www.expertconsult.com PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria

perfusion, inotropic agents (e.g., dobutamine, dopamine, nore- fibronectin-binding proteins have been explored as potential uni- pinephrine) should be considered. versal GAS vaccine candidates.63 Two approaches have been taken Parenteral antimicrobial therapy should include coverage for to utilize the protective immunity of M protein without incurring both GAS and until the results of bacterio- the risks of molecular mimicry and autoimmune disease. One logic studies are available. Once GAS has been identified, intra­ has used a conserved, noncross-reactive, C-repeat region of the M venously administered penicillin G (200,000 to 400,000 U/kg per protein, found in the carboxy-terminal of the M protein proximal day) in four to six divided doses is the drug of choice. However, to the cell wall. In the other approach, molecular techniques have a mouse model of streptococcal myositis suggests that clindamy- been used to genetically engineer highly complex multivalent cin may be more effective than penicillin in eradicating GAS in M protein-based vaccines that appear to be free of potentially severe, invasive infections.41 In addition, inhibits harmful tissue cross-reactive epitopes. A 26-valent vaccine has protein synthesis and the production of important virulence been shown to be well tolerated and immunogenic in adult vol- factors (e.g., M protein, SPEs). Therefore, many experts recom- unteers and is now being considered for pediatric trials, which is mend intravenously administered clindamycin (25 to 40 mg/kg the primary target group for the vaccine.64 per day in three or four divided doses) in addition to penicillin. Fewer than 2% of GAS are resistant to clindamycin. Complications Several case reports have described the use of immune globulin intravenous (IGIV) therapy in patients with severe invasive GAS Suppurative complications from the spread of GAS to adjacent infections. An observational cohort study conducted in Canada structures were common before antibiotics were available. Cervical reported significantly reduced mortality among patients treated lymphadenitis, peritonsillar abscess, retropharyngeal abscess, with IGIV compared with those who were not treated.59 However, otitis media, mastoiditis, and sinusitis still occur in children in this study had confounding factors that potentially affected mor- whom the primary illness has gone unnoticed or in whom treat- tality data, including use of historical controls and increased use ment of pharyngitis has been inadequate. GAS pneumonia occurs of clindamycin among IGIV-treated patients. A European, multi- occasionally. Nonsuppurative complications are considered below. center, placebo-controlled trial was designed to evaluate the effi- cacy and safety of IGIV provided for 3 consecutive days (1 g/kg on ACUTE RHEUMATIC FEVER day 1 and 0.5 g/kg on days 2 and 3) in the treatment of STSS, showing a slight trend (not statistically significant) toward a ARF is an inflammatory disorder commonly involving joints and reduced mortality rate among the patients treated with IGIV.60 heart, and less commonly the brain and skin, which can develop as Currently, IGIV should be reserved for those patients who do not a complication of untreated GAS upper respiratory tract infection. respond to other therapeutic measures. The association of GAS and ARF was first postulated based on parallels in peak age (5 to 15 years) and seasonal (winter/spring) Prevention incidence, coupled with the observance that outbreaks of GAS phar- yngitis in closed communities, such as boarding schools and mili- The only specific indication for long-term use of antibiotics to tary bases, could be followed by outbreaks of acute ARF. Subsequent prevent GAS infection is for patients with a history of ARF or serologic studies documenting anti-GAS antibodies in ARF patients rheumatic heart disease (RHD). Mass prophylaxis generally is not provided further evidence. Finally, clinical studies showed that anti- feasible except to reduce the number of infections during epidem- microbial therapy that eliminates GAS from the pharynx also pre- ics of impetigo and to control epidemics of pharyngitis in military vents initial attacks of ARF, and long-term, continuous prophylaxis populations and in schools. that prevents GAS pharyngitis also prevents recurrences of ARF. Measures to prevent spread of GAS infections have variable effectiveness. Spread of throat or within a family Epidemiology unit often occurs before the index case is identified and isolated or treated. In epidemic situations, especially when there are cases While the incidence of ARF has declined substantially over the of ARF or PSAGN, a culture survey with treatment of all individu- past eight decades in the U.S. and other developed countries (a als with positive cultures (mass prophylaxis) may be indicated. In decline that began even before the advent of penicillin), it still families in which persistence or recurrence of streptococcal infec- remains a major public health burden in much of the developing tion is a problem, simultaneous and/or culture of world. There are currently at least 15.6 million people worldwide skin lesions of all members and treatment of all with positive with RHD, with 282,000 new cases and 233,000 deaths annually results has been successful in eradicating the organism. directly attributable to ARF or RHD.1 Clusters of invasive GAS infections have been reported within The incidence of ARF in some developing countries exceeds 50 a chronic care facility or among members of a single household.61 per 100,000 children. Some of the highest incidence rates reported However, given the infrequency of these infections and the lack of are in school-aged Pacific Islander children in New Zealand (80 a clearly effective chemoprophylactic regimen, available data cur- to 100 per 100,000) and in aboriginal children in central and rently do not support a recommendation for routine testing for northern Australia (245 to 351 per 100,000). In contrast, the most GAS colonization or for routine administration of chemoprophy- recent ARF incidence data for an industrialized country come from laxis to otherwise healthy household contacts of persons with the nonindigenous population of New Zealand (<100 per 100,000 invasive GAS disease. The Centers for Disease Control and Preven- children). The prevalence of RHD in children aged 5 to 14 years tion recommend that healthcare providers inform household con- is highest in sub-Saharan Africa (570 per 100,000), the Pacific tacts of persons with invasive GAS about the clinical manifestation Islander and indigenous populations of New Zealand and Aus- of pharyngeal and invasive GAS infections and emphasize the tralia (350 per 100,000), and south central Asia (220 per 100,000). importance of seeking immediate medical attention if contacts In contrast, the prevalence in developed countries usually is develop such symptoms.62 around 50 per 100,000.65 A dramatic outbreak of acute ARF Unfortunately, an effective vaccine to prevent GAS infection has occurred in the Salt Lake City, Utah area beginning in 1985, with yet to be developed. One major challenge derives from the great >200 cases in the first 4 years.66 Other smaller U.S. outbreaks have diversity of unique epitopes (>100) presented across GAS strains been reported in various communities as well as among recruits by the hypervariable N termini of the immunodominant surface in military training centers, but these resurgences have remained M proteins. A second challenge is presented by data that suggests localized, not leading to a nationwide increase in cases. GAS components including the coiled-coil of the M protein or the The observation that only a small proportion of patients with GlcNac side chain on the cell wall group A carbohydrate antigen GAS pharyngitis subsequently experience ARF suggests that specific could elicit antibodies that cross-react with host muscle or neural characteristics of the organisms, the host, and the environment tissues, thereby triggering ARF. Conserved, surface-associated GAS contribute to this complication. Although all risk factors have yet protein antigens such as pilus components, C5a peptidase, and to be identified, certain potential factors have been described.

702 Streptococcus pyogenes (Group A Streptococcus) 118

It has long been suspected, for example, that various strains of GAS differ in their ability to produce ARF, and a limited number BOX 118-2. Jones Criteria for Diagnosis of First Episode of Acute of M serotypes have been linked epidemiologically with outbreaks Rheumatic Fever (ARF) of ARF. Strains of certain rheumatogenic serotypes (e.g., types 1, 3, 5, 6, and 18), which were isolated infrequently during the 1970s DIAGNOSIS and early 1980s, reappeared dramatically as causes of pharyngitis Diagnosis of ARF requires two major criteria or one major and 61 during the localized outbreaks of ARF in the mid-1980s. Addi- two minor criteria, with supporting evidence of antecedent tionally, mucoid strains of GAS had only rarely been isolated from group A streptococcal infection throat cultures during the 1970s and early 1980s. However, during the focal outbreaks of ARF in the mid-1980s, mucoid strains of MAJOR CRITERIA GAS (i.e., with high capsule expression) were commonly isolated Carditis from patients, family members, and residents in surrounding Polyarthritis communities. 67 Chorea There appear to be genetic predispositions to ARF. Studies in Erythema marginatum twins have shown a higher concordance rate of ARF in monozy- Subcutaneous nodules gotic than in dizygotic twin pairs. Associations between HLA class II alleles and the B-lymphocyte alloantigen D8/17 and susceptibil- MINOR CRITERIA ity to ARF are under investigation; however, the association has Clinical findings: fever; arthralgia not been consistent in various populations. In one highly defined Laboratory finding: elevated acute-phase reactants (erythrocyte group with mitral valve disease, collective data suggested that DRB1*0701, DR6, and DQB1*0201 confer susceptibility to ARF.68 sedimentation rate or C-reactive protein); prolonged PR interval SUPPORTING EVIDENCE OF ANTECEDENT GROUP A Pathogenesis STREPTOCOCCAL INFECTION The pathogenic link between a GAS infection of the upper respira- Positive throat culture or rapid antigen test for GAS tory tract and an episode of ARF still is not established definitively. or Most attention has focused on the concept of based Elevated or rising streptococcal antibody titer (ASO, anti-DNase on molecular mimicry. This theory is supported by the latent B, etc.) period between GAS infection and ARF as well as by the observa- tions of antigenic similarity between molecular constituents of GAS and several human tissues, including the heart, synovium, red, swollen and exquisitely tender; pain can precede and can and basal ganglia. Sera of patients with ARF contain heart-reactive appear disproportionate to other findings. The migratory nature is or myosin-reactive antibodies, frequently in high titers.67 Studies most characteristic; a severely involved joint can become normal of anti-GAS/anti-heart monoclonal antibodies from RHD have within 1 to 3 days without treatment as one or more other large revealed that cardiac myosin, and GlcNac (the immunodominant joints become similarly inflamed for up to 2 to 6 weeks. Another epitope of the group A carbohydrate antigen), likely are cross- characteristic feature is a dramatic response to even small doses of reactive antigens involved in antibody deposition on the valve.68 nonsteroidal anti-inflammatory drugs (NSAIDs); lack of clear Early work had demonstrated the persistence of increased levels response should suggest an alternative diagnosis. Rheumatic arthri- of anti-group A carbohydrate antibody in RHD and their associa- tis almost never is deforming or associated with chronic changes. tion with a poor prognosis.69 More recently, human T-lymphocyte clones also have confirmed cross-reactivity between cardiac Carditis myosin sequences and GAS M proteins.70 Strikingly, immuniza- tion of rats with recombinant GAS M6 protein induces auto­ Carditis occurs in about 50% to 60% of ARF cases. Carditis and immune valvular heart disease.71 resultant chronic RHD are the most serious manifestations of ARF, accounting for essentially all associated morbidity and mortality. Clinical Features Rheumatic carditis is a pancarditis, with inflammation of myocar- dium, pericardium, and endocardium. Endocarditis (valvulitis), Because no single clinical or laboratory finding is pathognomonic manifesting as one or more cardiac murmurs, is the hallmark for ARF, T. Duckett Jones proposed guidelines in 1944 to aid in feature of rheumatic carditis; myocarditis or pericarditis without diagnosis and to limit overdiagnosis. The Jones criteria, as revised evidence of endocarditis rarely is due to ARF or RHD. The vast in 1992 by the American Heart Association (Box 118-2),72 provide majority of cases consist of isolated mitral valvular or aortic and five major criteria and four minor criteria as well as the require- mitral valvular disease. Valvular insufficiency is characteristic of ment for evidence (microbiologic or serologic) of recent GAS acute and convalescent stages of ARF, whereas valvular stenosis infection. The diagnosis of ARF is established according to the develops over years or decades. In developing countries, systematic Jones criteria when a case fulfills two major criteria or one major echocardiographic screening suggests the prevalence of chronic plus two minor criteria and meets the absolute requirement for RHD may be as high as 2% to 3%, 10 times that previously esti- proof of antecedent GAS infection. ARF can be overdiagnosed mated by clinical screening.73 even with strict application of the Jones criteria. Acute rheumatic carditis usually presents as tachycardia and There are three circumstances in which the diagnosis of ARF can cardiac murmurs with or without transient rhythm disturbances be made without strict adherence to the Jones criteria. Chorea can (reflecting myocardial involvement) or a friction rub (reflecting occur as the only clinical manifestation of ARF. Similarly, indolent pericarditis). The characteristic murmur of mitral regurgitation is carditis may be the only manifestation in patients who first come a high-pitched apical holosystolic murmur radiating to the axilla. to medical attention months after onset. Moderate to severe rheumatic carditis can result in cardiomegaly and congestive heart failure with hepatomegaly and peripheral Major Manifestations and pulmonary edema. Currently, echocardiographic evidence of carditis without clinical support (i.e., auscultation of a new Migratory Polyarthritis murmur) is neither a major nor minor Jones criterion. Arthritis occurs in about 75% of patients with ARF and classically Chorea involves larger joints, particularly the knees, ankles, wrists, elbows, or hips. Rarely, the spine or small joints of the fingers or toes can be Sydenham chorea (St. Vitus dance) is a neurologic disorder that affected. Inflamed joints and periarticular tissues generally are hot, occurs in 10% to 15% of patients with ARF, often occurring much

703 All references are available online at www.expertconsult.com PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria

later (up to 6 months) than other manifestations. A frequently TABLE 118-1. Differential Diagnosis of Acute Rheumatic Fever subtle disorder of behavior and movement, Sydenham chorea is characterized by emotional lability, incoordination, poor school performance, uncontrollable movements, and facial grimacing; Arthritis Carditis Chorea symptoms are often exacerbated by stress and disappear during Juvenile idiopathic Kawasaki disease Huntington chorea sleep. Onset can be insidious, with symptoms present for several arthritis Viral myocarditis Wilson disease months before recognition. Diagnosis of Sydenham chorea is Systemic lupus Viral pericarditis Systemic lupus based on clinical findings, with or without supportive evidence erythematosus erythematosus such as high serum levels of antistreptococcal antibodies. Although Serum sickness Mitral valve prolapse Cerebral palsy the acute illness is highly distressing, chorea rarely, if ever, has Sickle-cell disease Tics permanent neurologic sequelae. Congenital heart disease Malignancy Innocent murmur Hyperactivity Gonococcal infection Encephalitis Erythema Marginatum Reactive arthritis (e.g., Shigella, Salmonella, Erythema marginatum is a rare but distinctive rash of ARF Yersinia) manifest by erythematous, serpiginous, macular lesions with pale centers that are not pruritic. It occurs primarily on the trunk and Lyme arthritis extremities, typically sparing the face, and is seen in fewer than 3% of patients with ARF. Echocardiography can discriminate functional murmurs and Subcutaneous Nodules murmurs caused by congenital heart defects. Patients with infec- tive endocarditis can manifest both joint and cardiac manifesta- Seen in less than 1% of ARF patients, firm nonpainful subcutane- tions; these patients usually can be distinguished on the basis of ous nodules approximately 1 cm in diameter can be palpated positive blood culture results or associated findings (e.g., hematu- along the extensor surfaces of tendons near bony prominences. ria, splenomegaly, splinter hemorrhages). Subcutaneous nodules are often correlated with significant RHD. Treatment Minor Manifestations Management of ARF involves antibiotic and anti-inflammatory The two clinical minor manifestations included in the 1992 therapy, symptomatic treatment, and interventions to prevent revised Jones criteria are: (1) arthralgia in the absence of the future GAS infections. Once the diagnosis of ARF has been estab- major criterion polyarthritis; and (2) fever, typically ≥38.9°C and lished, the patient should receive either a single intramuscular occurring early in the course of illness. Two minor laboratory injection of benzathine penicillin or 10 days of orally administered manifestations are: (1) elevations of acute-phase reactants, such penicillin or amoxicillin (or a if penicillin allergic) to as C-reactive protein and/or erythrocyte sedimentation rate (which eradicate GAS from the upper respiratory tract, regardless of throat is usually >50 mm/hour); and (2) demonstration of prolonged culture results. For patients who have definite arthritis and those PR interval on electrocardiogram (first-degree heart block). Pro- who have carditis without cardiomegaly or congestive heart failure, spective studies have demonstrated that a prolonged PR interval salicylate therapy (50 to 75 mg/kg/day) should be initiated for 2 to alone does not constitute evidence of carditis nor predict long- 4 weeks, then tapered over the next 4 to 6 weeks. The response of term cardiac sequelae. the arthritis of ARF to salicylates is characteristically dramatic, and there is no evidence that other NSAIDs are superior. Patients with Recent Streptococcal Infection carditis and cardiomegaly or congestive heart failure should receive corticosteroid therapy (2 mg/kg/day) for 2 weeks with a slow taper Supporting evidence of a recent GAS infection is an absolute over 4 to 6 weeks. Supportive therapies for patients with moderate requirement for the diagnosis of ARF, except in isolated Sydenham to severe carditis include oxygen, fluid and salt restriction, diuret- chorea. Since ARF develops 2 to 4 weeks after acute GAS pharyn- ics, angiotensin-converting enzyme inhibitors, or digoxin. Bed rest gitis, clinical signs of pharyngitis are no longer present and throat for 2 weeks to 4 months, depending on the degree of carditis, is culture or rapid GAS antigen test are positive in only 10% to 20% usually recommended. Because Sydenham chorea often occurs as of cases; one-third of patients recall no history of antecedent an isolated manifestation after resolution of the acute phase of pharyngitis. Elevated or rising serum antistreptococcal antibody the disease, anti-inflammatory agents usually are not indicated. titers thus provide the most reliable basis for diagnosis. If only Patients may benefit from rest, limitation of external stimuli, and ASO is measured, elevated titers (>500 Todd units) are found in therapy with phenobarbital, haloperidol, or chlorpromazine as 80% to 85% of patients who have ARF; 95% to 100% of such guided by a pediatric neurologist. patients are identified if two additional antibody levels (e.g., anti- DNAse B, antistreptokinase or antihyaluronidase) are measured. Secondary Prevention Differential Diagnosis Because ARF frequently recurs with subsequent GAS infections, secondary prevention is required to avoid recurrences that The differential diagnosis of ARF includes many infectious as well increase the likelihood and severity of RHD. Secondary prevention as noninfectious conditions associated with mono- or polyarticu- requires continuous antibiotic prophylaxis, which should begin lar arthritis (Table 118-1). Children with juvenile idiopathic arthri- immediately after the full course of antibiotic therapy has been tis (JIA) tend to be younger and usually have less joint pain relative completed. Patients who have had carditis with the initial episode to their clinical findings than those with ARF. Spiking fevers, lym- of ARF should receive antibiotic prophylaxis well into adulthood phadenopathy, and splenomegaly are more suggestive of JIA than and perhaps for life. Other patients have a relatively low risk of ARF. Response to salicylate therapy is much less dramatic with JIA carditis with recurrences, and antibiotic prophylaxis can be dis- than with ARF. Systemic lupus erythematosus (SLE) usually can continued in these patients after 5 years or when they reach the be distinguished on the basis of the presence of antinuclear anti- age of 21 years (whichever comes later). The decision to discon- bodies with SLE. tinue antibiotic prophylaxis should only be made after careful When carditis is the sole major manifestation of ARF, viral consideration of the potential risks and benefits and of epidemio- myocarditis, viral pericarditis, Kawasaki disease, and infective logic factors, such as the risk of exposure to GAS infections. endocarditis should be considered. In general, the absence of Regimens for secondary prevention of ARF are shown in Table a significant cardiac murmur excludes the diagnosis of ARF. 118-2. A single injection of 1.2 million units of benzathine

704 Streptococcus pyogenes (Group A Streptococcus) 118

complexes is a GAS antigen or a host-derived antigen that cross- TABLE 118-2. Secondary Prevention of Rheumatic Fever reacts with antistreptococcal antibodies is not clear. Candidate (Prevention of Recurrent Attacks) GAS antigens for this process include glyceraldehyde-3-phosphate- dehydrogenase (GAPDH; also known as “nephritis-associated” Agent Dose streptococcal plasmin receptor) and the cysteine protease SpeB or Benzathine penicillin G 1,200,000 units IM every 4 weeksa its zymogen precursor.75 Because these proteins are present in Penicillin V 250 mg PO twice daily virtually all strains of GAS, additional host factors are suspected to influence susceptibility, but studies of HLA antigen distribution Sulfadiazine 0.5 g PO once daily for patients ≤27 kg; 1.0 g have failed to identify a specific association with PSAGN.76 PO once daily for patients >27 kg Although renal biopsy is rarely indicated for patients with Erythromycinb 250 mg PO twice daily PSAGN, biopsy can be helpful if hypertension, hypocomplemen- IM, intramuscularly; PO, by mouth. temia, heavy proteinuria, or renal insufficiency persists. The glomerular lesions of PSAGN can be proliferative, exudative, or a In high-risk situations, administration every 3 weeks is justified and both; typically, all glomeruli are diffusely involved in the process. recommended. Electron microscopy reveals deposits consisting of immunoglobu- bFor individuals allergic to penicillin and sulfadiazine. lin G and complement component C3, which usually are found Adapted from Dajani A, Taubert Y, Ferrieri P, et al. Treatment of acute in a subepithelial location during the first 3 to 6 weeks of the streptococcal pharyngitis and prevention of rheumatic fever: a statement disease; the glomerular basement membrane usually appears for health professionals. Committee on Rheumatic Fever, Endocarditis, and normal. Kawasaki Disease of the Council on in the Young, the American Heart Association. Pediatrics 1995;96:758. Clinical Features PSAGN typically occurs about 10 days after onset of acute GAS penicillin G every 4 weeks is the regimen of choice. Continuous pharyngitis or 3 weeks after onset of GAS pyoderma. Edema (often oral antimicrobial prophylaxis can be used in patients likely to periorbital) and hematuria most frequently bring patients with adhere to the regimen. Penicillin given twice daily and sulfadi- PSAGN to medical attention (Box 118-3). Approximately 30% to azine given once daily are equally effective when used in such 50% of children with PSAGN have gross hematuria, which typi- patients. Although erythromycin resistance generally is ≤5%, fre- cally is described as “cola-colored” urine. Gross hematuria can quency varies geographically, and clusters of cases with close persist for as little as a few hours or for as long as 2 weeks. contact can show higher resistance rates. Approximately 50% to 90% of children with PSAGN have hypertension. The severity of hypertension is highly variable, but Prognosis systolic pressures >200 mmHg and diastolic pressures >120 mmHg are not unusual. Most children with PSAGN also have evidence The prognosis for patients with ARF depends on the number and of circulatory congestion from the expansion of the intravascular severity of clinical manifestations during the initial episode and fluid volume. Dyspnea, orthopnea, cough, or pulmonary rales whether recurrences were allowed to develop. In the absence of may be present. Children with PSAGN also can have systemic recurrent GAS infections, rheumatic fever does not reappear more symptoms such as lethargy, anorexia, fever, and abdominal pain, than 8 weeks after the withdrawal of anti-inflammatory therapy. but they seldom appear extremely ill. Occasionally, a child with Approximately 70% of the patients with carditis during the initial PSAGN can have a fulminant course, including severe oliguria episode of ARF recover with no residual heart disease if they are congestive heart failure, or hypertensive encephalopathy. PSAGN adherent to prophylaxis. typically is self-limited, however, with spontaneous diuresis, loss of edema, and improvement in hypertension occurring within ACUTE GLOMERULONEPHRITIS 1 week. Epidemiology Laboratory Findings PSAGN was described by Richard Bright in 1836 as hematuria after Virtually all children with PSAGN have microscopic hematuria, scarlet fever. Unlike ARF, PSAGN occurs as a consequence of either and 30% to 50% have gross hematuria. Pyuria and urinary hyaline, GAS pharyngitis or pyoderma. PSAGN is primarily a disease of granular, or casts also can be present. Most children preschool and school-aged children; approximately 60% of with PSAGN also have proteinuria; approximately 30% have patients are between 2 and 12 years of age. Although the actual incidence of PSAGN is difficult to determine because many of cases are asymptomatic, PSAGN is by far the most common form of BOX 118-3. Signs and Symptoms of Poststreptococcal Acute glomerulonephritis and acute renal insufficiency in children. Certain M types of GAS associated with pharyngitis, such as M1, Glomerulonephritis (PSAGN) M2, M3, M4, M12, and M15, as well as certain M types associated with pyoderma, such as M49, M52, M55, M59, M60, and M61, are COMMON FINDINGS commonly associated with PSAGN and, therefore, are considered Hematuria (microscopic or macroscopic) nephritogenic.74 However, not all strains of a given M type are Edema nephritogenic. Although PSAGN is most often a sporadic disease, Hypertension it also can occur in epidemic forms. Concomitant presence of ARF Oliguria and PSAGN in a population is unusual and in a patient is rare. VARIABLE FINDINGS Pathogenesis and Pathology Systemic symptoms (fever, nausea, anorexia, lethargy, abdominal pain) Although the pathogenic link between GAS infections and PSAGN is established clearly, the mechanisms of renal injury have not UNCOMMON FINDINGS been defined clearly. There is considerable evidence, however, that Hypertensive encephalopathy (vomiting, headache, confusion, PSAGN occurs when soluble immunoglobulin G immune com- somnolence, seizures) plexes are deposited at the glomerular basement membrane, acti- Anuria and renal failure vating complement, with release of chemotactic factors leading to Congestive heart failure infiltration by inflammatory cells. Whether the antigen in these

705 All references are available online at www.expertconsult.com PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria

proteinuria in the nephrotic range, with protein loss >2 g/m2 per suggested these could arise as a result of a poststreptococcal 24 hours. autoimmune process.79 The investigators coined the acronym During the initial 2 weeks of PSAGN, total hemolytic comple- PANDAS to denote pediatric autoimmune neuropsychiatric disor- ment activity and C3 levels are depressed in almost all children. ders associated with streptococcal infections. It was proposed that About one-third of patients have modest elevations of blood urea in response to GAS infection, this subset of patients with OCD and nitrogen and creatinine. During the first week of PSAGN, eleva- tic disorder produce autoimmune antibodies that cross-react with tions of circulating immune complexes are seen in most patients, neuronal tissues in the basal ganglia and associated structures, and the quantity of these immune complexes correlates with the reminiscent of the autoimmune response implicated in similar severity of the PSAGN. Patients with moderate to severe impair- clinical manifestations of certain patients with ARF and Sydenham ment of renal function can demonstrate metabolic acidosis, hyper- chorea. It was proposed that these patients could benefit from kalemia, hyperchloremia, hyponatremia, hypoalbuminemia, or secondary antibiotic prophylaxis to prevent GAS infection and dilutional anemia. In PSAGN, the best evidence of an antecedent disease exacerbation, or in severe cases, immunoregulatory inter- streptococcal infection is a serologic response to GAS; 90% to 95% ventions such as plasma exchange or intravenous immunoglobu- of patients have elevations of ASO and/or anti-DNAse B. lin therapy. Recently, two prospective blinded multicenter cohort studies of matched pairs have found no evidence for a temporal Treatment and Prognosis association between GAS infection and OCD/tic symptoms in children who met the published PANDAS diagnostic criteria.80,81 In Although antibiotic therapy does not affect the clinical course of another study, no correlation was observed between clinical exac- PSAGN, therapy can eradicate the nephritogenic GAS strain that erbations in these patients and serum antibodies cross-reactive may still be present and thus reduce the risk of its with brain tissues.82 Inaccurate diagnosis and therapy of PANDAS to others. Penicillin is the antibiotic of choice; a macrolide is the is widespread in the pediatric medicine community;83 new classifi- preferred agent for penicillin-allergic patients. No immunosup- cation schemes will help delineate risks for this particular subtype pressant or anti-inflammatory therapeutic agents have been shown of OCD or tic disorders. Current data indicate PANDAS remains an to accelerate the resolution of the renal lesions in PSAGN. There- hypothesis, perhaps applicable to a very select subset of patients, fore, treatment consists primarily of supportive measures directed but in which complicated interventions such as immune globulin at the complications of the disease. Children with PSAGN can or plasmapheresis may not be warranted.81,84 Singer et al. propose occasionally have hypertension that is severe and is associated a broader concept of childhood neuropsychiatric symptoms with encephalopathy. Circulatory congestion can also be severe (CANS) and de-emphasis of tics and GAS.85 and can lead to pulmonary edema and congestive heart failure. Although oliguria often is seen in children with PSAGN, anuria POSTSTREPTOCOCCAL REACTIVE ARTHRITIS and renal failure are uncommon. Overall, the prognosis for chil- dren with PSAGN is favorable; >95% of children have spontane- The term “poststreptococcal reactive arthritis” (PSRA) was first ous and complete resolution of symptoms, edema, and renal used in 1959 to describe an entity in patients who had arthritis dysfunction. Urinalysis results are abnormal in <5% of individuals following an episode of GAS pharyngitis but lacked other major 15 years after the acute episode.77 criteria of ARF.76 While ARF peaks in early childhood (4 to 9 years of age), PSRA has a bimodal distribution with a first peak at 8 to Prevention 14 years and a second peak in early adulthood.86 The arthritis of ARF classically develops 14 to 21 days after an episode of GAS In contrast to ARF, which can be prevented with antibiotic therapy pharyngitis and responds rapidly to NSAID therapy, whereas PSRA of the antecedent GAS infection, there is no evidence that PSAGN does not respond readily to NSAIDs and occurs about 10 days can be prevented once pharyngitis or pyoderma with a nephri- following the GAS pharyngitis. In addition, the arthritis of PSRA togenic strain of GAS has occurred. However, antibiotic treatment is cumulative, persistent, and can involve large joints, small joints, of patients with PSAGN who are still harboring the nephritogenic or the axial skeleton, while the arthritis of ARF is migratory, tran- strain can limit its transmission to others. During outbreaks of sient, and usually involves only the large joints. All PSRA patients GAS pyoderma caused by nephritogenic strains, prophylactic have serologic evidence of a recent GAS infection. A small propor- administration of penicillin to children at risk may be beneficial.78 tion of such patients may go on to develop valvular heart disease; Because recurrences of PSAGN are rare, long-term antibiotic thus they should be monitored carefully for several months for prophylaxis after an episode is not indicated. carditis. In contrast to the arthritis of ARF, PSRA may have an extended duration (median 2 months) and can be recurrent. Some physicians administer secondary prophylaxis to these patients for PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC a period of as short as 3 months and as long as 12 months. DISORDERS ASSOCIATED WITH STREPTOCOCCAL If carditis is not observed, prophylaxis can be discontinued. If INFECTIONS (PANDAS) carditis is detected, the patient should be classified as having ARF and should continue to receive secondary prophylaxis. Unfortu- In 1998, investigators described a series 50 patients with childhood- nately, validated diagnostic criteria for PSRA have not been onset obsessive-compulsive disorder (OCD) and/or tics and established.86

Key Points. Group A Streptococcus and Clinical Syndromes

EPIDEMIOLOGY, PATHOGENESIS, AND IMMUNITY • >130 distinct M-protein genotypes identified, which tend • >600 million cases of pharyngitis and >100 million cases of to be associated with infectious and nonsuppurative pyoderma annually worldwide syndromes • 15.6 million people have rheumatic heart disease worldwide • Genome sequencing shows that bacteriophages have been • Infections can be nonsevere and of short duration or rapidly important in organism’s evolutionary genetics (e.g., virulence invasive and fulminant determinants, toxins, etc.) • Unique among pyogenic bacteria in causing postinfectious, • Pathogenesis of serious disease can occur by 3 mechanisms: immunologically mediated diseases (acute rheumatic fever, acute suppuration, toxin elaboration, and immune-mediated glomerulonephritis) inflammation

706 Key Points. Group A Streptococcus and Clinical Syndromes—cont’d

• Expression of multiple specific virulence factors can lead to TREATMENT OF SUPPURATIVE INFECTIONS evasion of hosts innate clearance response, uncontrollable • Penicillin retains exquisite activity in vitro; no β-lactam antibiotic proinflammatory response, damage to phagocytic cells, resistance exists accelerated apoptosis of immune cells, inactivation of terminal • Clindamycin usually is given in addition to a β-lactam agent for complement components, -induced T-lymphocyte severe invasive or toxin-mediated disease to overcome the activation, and more “Eagle effect” (loss of bactericidal capacity of β-lactam at high • Opsonic anti-M-protein antibodies rise 6 to 8 weeks following density of bacteria/stationary growth phase) and to inhibit protein infection and protect against M type-specific invasive infection synthesis/virulence factors CLINICAL MANIFESTATIONS • Due to lack of compelling evidence of efficacy of IGIV therapy, use is reserved for severely affected patients under-responsive to • Causes wide spectrum of simple and complicated oropharyngeal other therapeutic measures and respiratory tract infections, skin and soft-tissue infections, invasive infections, and toxin-mediated syndromes PREVENTION • Necrotizing cellulitis, myositis, fasciitis can be suspected when • Vaccine development is thwarted by hypervariability and diversity seemingly minor skin/soft-tissue infection is associated with of surface M proteins, and potential immunologic responses that disproportionate pain, hyper- or hypoesthenia, local pallor, might cross-react with cardiac or neural tissue tenseness, blistering lesion • Novel approaches explore the use of conserved or genetically • Proven cause of nonsuppurative acute rheumatic fever and engineered surface proteins acute glomerulonephritis (see text) • Possible cause of nonsuppurative postinfectious reactive arthritis and neuropsychiatric disorders (see text) Streptococcus pyogenes (Group A Streptococcus) 118

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