Epidemiology, clinical manifestations, and diagnosis of streptococcal toxic shock syndrome Author Dennis L Stevens, MD, PhD Section

Editor Daniel J Sexton, MD Deputy Editor Elinor L Baron, MD, DTMH Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jan 2012. | This topic last updated: Dec 7, 2011. INTRODUCTION Group A streptococcus (GAS, eg, Streptococcus pyogenes) is an aerobic grampositive coccus that causes pharyngitis and a spectrum of skin and soft tissue infections such as impetigo, erysipelas, and localized cellulitis [1]. These infections respond well to antibiotic therapy alone. Together with Staphylococcus aureus, S. pyogenes accounts for the vast majority of soft tissue infections. (See "Impetigo" and "Skin abscesses, furuncles, and carbuncles" and "Cellulitis and erysipelas".) Less commonly, GAS causes invasive disease, which is complicated by toxic shock syndrome (TSS) in approximately one-third cases. The epidemiology, clinical features, and diagnosis of GAS TSS will be reviewed here. Treatment of GAS TSS and a discussion of GAS invasive disease, including necrotizing infections of the skin and fascia, gangrenous myositis, and GAS bacteremia, are discussed separately. (See "Treatment of streptococcal toxic shock syndrome" and "Necrotizing infections of the skin and fascia" and "Spontaneous gangrenous myositis caused by Streptococcus pyogenes" and "Group A streptococcal (Streptococcus pyogenes) bacteremia in adults".) DEFINITIONS Severe invasive GAS infections are defined as bacteremia, pneumonia, or any other infection associated with the isolation of GAS from a normally sterile body site [2]. Invasive infections also include necrotizing fasciitis and spontaneous gangrenous myositis. Group A streptococcal TSS is defined as any GAS infection associated with the acute onset of shock and organ failure. (See 'Diagnosis' below.) PATHOGENESIS Group A streptococcal TSS, like staphylococcal toxic syndrome, is mediated by toxins that act as superantigens. The exotoxins (superantigens) can activate the immune system by bypassing the usual antigen-mediated immune response sequence resulting in the release of large quantities of inflammatory cytokines. The cytokines cause capillary leak and tissue damage, leading to shock and multiorgan failure. (See "Group A streptococcus: Virulence factors and pathogenic mechanisms", section on 'Cytokine induction'.) Acquisition of group A streptococcus The most common portals of entry for streptococcal infections are the skin, vagina, or pharynx. However, among patients who develop GAS TSS, a portal of entry cannot be identified in 45 percent of cases [3]. These patients frequently develop deep seated infections such as necrotizing fasciitis or myonecrosis within 24 to 72 hours at the exact site of minor trauma such as a bruise, strained muscle, or sprained ankle, frequently without a visible break in the skin. Virulence factors The specific virulence factors associated with GAS TSS have not been entirely elucidated. Nevertheless, there has been an increasing understanding of the factors that may be involved. M protein M protein is an important virulence determinant of GAS, and strains lacking M protein are less virulent. M protein is a filamentous protein anchored to the cell membrane that has antiphagocytic properties. The more distal antigenic epitopes of the protein can be used to identify over 80 different serotypes of GAS. M types 1, 3, 12, and 28 have been the most common isolates from patients with shock and multiorgan failure (table 1) [3,4]. Historically, typing of GAS has been accomplished by serologic methods (serotyping) using specific antibody against M proteins, and these strains were designated M types. Genetic methods using gene

probes have confirmed the validity of serotyping. In this nomenclature, strains are designated as emm types; emm types 1, 3, 12, 28 and 89 have been the most common [5]. Exotoxins Streptococcal pyrogenic exotoxins are also elaborated by GAS. Three antigenically distinct forms (A, B, and C) have been identified. These toxins induce cytotoxicity, pyrogenicity, and enhancement of the lethal effects of endotoxin. Pyrogenic exotoxin A (SPEA) and/or B (SPEB) are found in the majority of cases of severe GAS infection. SPEA is most common in the United States [3,4,6-9], whereas SPEB predominates in Sweden and the United Kingdom [10,11]. Additional pyrogenic exotoxins have been identified including SSA (streptococcal superantigen), a novel pyrogenic exotoxin isolated from an M-3 strain [12], and MF (mitogenic factor), produced by many different M-types of GAS [13,14]. EPIDEMIOLOGY Invasive infections associated with GAS TSS have been reported with increasing frequency, predominantly from North America and Europe [3,5,10,15-22]. There are an estimated 3.5 cases per 100,000 persons with a case-fatality rate of 36 to 43 percent for streptococcal toxic shock syndrome [2,5,23-25]. Up to one-third of these cases developed GAS TSS in reported case series [24,26]. The rate of TSS among patients with necrotizing fasciitis is 50 percent [2,27]. Streptococcus suis has emerged as a cause of streptococcal toxic shock-like syndrome (STSLS) [28]. Although this pathogen is traditionally associated with bacterial meningitis, a highly pathogenic strain has emerged with the ability to produce massive quantities of proinflammatory cytokines. (See "Epidemiology of bacterial meningitis in adults".) Risk factors for GAS The demographics of invasive GAS infections have changed over the last 40 years [6,16]. Persons of all ages may be afflicted with GAS TSS and most are not immunosuppressed, although diabetes and alcoholism are risk factors described in many different studies [6,11,16,29-32]. This is in sharp contrast to earlier reports of invasive GAS infections associated with bacteremia in which most patients were either less than 10 or greater than 60 years of age; had underlying diseases such as cancer, renal failure, leukemia, and severe burns; or were receiving corticosteroids or other immunosuppressive drugs [29-31]. (See "Group A streptococcal (Streptococcus pyogenes) bacteremia in adults".) The following risk factors have been associated with the development of severe GAS infections [3]: Minor trauma Injuries resulting in hematoma, bruising, or muscle strain Surgical procedures (eg, suction lipectomy, hysterectomy, vaginal delivery [33], bunionectomy, bone pinning, breast reconstruction [34], cesarean section [35]) Viral infections (eg, varicella, influenza) [36] Use of nonsteroidal antiinflammatory drugs (NSAIDs)

Among children, varicella infection (eg, chicken pox) has been a major risk factor for invasive GAS infections including GAS TSS [36]. However, with the introduction of universal varicella vaccination, the rate of varicella-related invasive GAS infections as a percentage of all invasive GAS infections has been dramatically reduced as illustrated in a retrospective study over a period of nine years [37]. The rate of varicella-related invasive GAS infections as a percentage of all invasive GAS infections were: Prevaccine era (1993 to 1995) 27 percent During initial utilization (1996 to 1998) 16 percent Widespread vaccine use (1999 to 2001) 2 percent

The association between NSAIDs and severe GAS infections is uncertain. The link may be attributable to the use of NSAIDs to relieve the symptoms of more severe trauma, which is a predominant risk factor. In a retrospective analysis of these cases, however, NSAIDs may have either masked the presenting symptoms, thus delaying a diagnosis, or predisposed to more severe streptococcal infection and shock [3]. Direct predisposition to GAS TSS by NSAIDs could be mediated via inhibition of

neutrophil function, suppression of fever, and augmentation of cytokine release (eg, tumor necrosis factor) [38]. GAS infections usually occur sporadically. They are not generally associated with clusters of cases or minor epidemics, although outbreaks of severe GAS infections have occurred in closed environments such as nursing homes [39,40] and in hospitalized patients [41]. CLINICAL PRESENTATION Manifestations Toxic shock syndrome due to GAS typically presents with pain that precedes physical findings of infection [3]. The pain typically involves soft tissue of an extremity but may also mimic peritonitis, pelvic inflammatory disease, pneumonia, acute myocardial infarction, cholecystitis, or pericarditis [3,42-44]. Clinical signs of soft tissue infection typically consist of localized swelling and erythema followed by ecchymoses and sloughing of skin which progresses to necrotizing fasciitis or myositis in 70 to 80 percent of cases. An influenza-like syndrome characterized by fever, chills, myalgia, nausea, vomiting, and diarrhea is observed in about 20 percent of patients [34]. A diffuse, scarlatina-like erythema occurs in about 10 percent of cases. Fever is frequently observed although hypothermia may be present in patients with shock. Altered mental status is observed in about half of patients. About half of patients are normotensive on presentation but become hypotensive within the subsequent four hours. Shock is due to both capillary leak and vasodilatation. Despite aggressive therapy, the systolic pressure remains depressed after eight hours in 90 percent of patients [3]. A variety of clinical presentations may be observed patients without soft tissue findings (about 20 percent of cases). These included endophthalmitis, perihepatitis, peritonitis, postpartum sepsis, myocarditis, pneumonia, and overwhelming sepsis. GAS TSS is a very rare complication of streptococcal pharyngitis in adults, but may be more common in children [45]. Puerperal sepsis Puerperal sepsis, postpartum infection caused by group A streptococcus, was first described by Semmelweis in the 1850s. In the United States, about 220 cases occur annually, for an overall rate of 6 cases/100,000 live births [46]. In 2002 the case fatality rate reported was about 3.5 percent. Complications The complications of GAS TSS are severe. They include bacteremia, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation, renal failure [43], and rarely Waterhouse-Friderichsen syndrome [47]. Renal dysfunction is present in all patients by 48 to 72 hours and many patients require dialysis for 10 to 20 days. In patients who survive, the serum creatinine concentration returns to baseline within four to six weeks. ARDS occurs in approximately 55 percent of patients, generally developing after the onset of hypotension [3]. Almost all patients with ARDS require supplemental oxygen, intubation, and mechanical ventilation. (See "Acute respiratory distress syndrome: Definition; clinical features; and diagnosis".) Laboratory findings Although initial laboratory studies may reveal only mild leukocytosis, the mean percentage of immature neutrophils (including band forms, metamyelocytes, and myelocytes) may reach 40 to 50 percent [3]. The serum creatinine concentration is frequently elevated, and precedes the development of hypotension in 40 to 50 percent of cases [3]. Hypotension, myoglobinuria and hemoglobinuria (due to toxin induced hemolysis) can contribute to the development of acute renal failure.

Other common findings include hypoalbuminemia, hypocalcemia, positive blood cultures (in approximately 60 percent of cases), and an increase in the serum creatinine kinase concentration, which suggests the presence of necrotizing fasciitis or myositis [3]. (See "Spontaneous gangrenous myositis caused by Streptococcus pyogenes".) DIFFERENTIAL DIAGNOSIS The abrupt onset of shock in a previously healthy individual has a limited number of causes. Staphylococcal toxic shock syndrome must be considered, particularly in a female during menstruation, or in either sex in association with recent surgery or any localized staphylococcal abscess. In contrast to GAS TSS, bacteremia is uncommon in staphylococcal TSS and has a much lower mortality than GAS TSS [22]. (See "Staphylococcal toxic shock syndrome".) Gram-negative sepsis can mimic GAS TSS but is uncommon in healthy patients outside the hospital setting. Typhoid fever is a notable exception. Although sporadic cases of Salmonella bacteremia occur in association with food-borne illnesses, typhoid fever is often related to natural disasters such as hurricanes, floods, and earthquakes or travel to an endemic country. Renal impairment frequently precedes hypotension in GAS TSS whereas renal failure (also due to acute tubular necrosis) develops after hypotension in gram-negative shock. In addition, the white blood count is generally normal or elevated with a marked left shift in GAS TSS, but is usually normal or low in typhoid fever. Rocky Mountain spotted fever (RMSF) is another disorder that can mimic the findings in GAS TSS. Both cause shock in otherwise healthy individuals. However, severe headache and rash are present in most patients with RMSF, whereas headache is rare and rash is present in only 10 percent of patients with GAS TSS. The character of the rash is also different; it is most often petechial in RMSF and diffusely erythematous in GAS TSS. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

GAS TSS is usually associated with a normal to elevated WBC with a dramatic left shift whereas this is uncommon in RMSF. In addition, the course of illness is much more rapid in GAS TSS. Despite these general differences, the two disorders may be difficult to distinguish if the rash characteristic of RMSF and a local infection possibly due to GAS are absent. Acute meningococcemia may be confused with GAS TSS. The rash is petechial and meningitis is common in meningococcemia but is infrequent in GAS TSS. (See "Clinical manifestations of meningococcal infection".) Some patients with GAS TSS have respiratory symptoms and develop lobar consolidation and empyema. The respiratory symptoms and hypotension may make it difficult to distinguish these patients from those with overwhelming Streptococcus pneumoniae sepsis. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia".) Leptospirosis may mimic severe streptococcal infections but the epidemiology of leptospirosis (eg, infection after exposure to environmental sources, such as animal urine, contaminated water or soil, or infected animal tissue primarily in tropical regions) is specific enough to help rule out this diagnosis. In addition, conjunctival suffusion, when it occurs, is one of the most reliable distinguishing features in leptospirosis since it rarely occurs with any other infectious illness. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of leptospirosis".) Heat stroke has been confused with some cases of GAS TSS largely because of the presence of elevated temperature, dehydration with evidence of renal impairment, confusion, hypotension, and sunburn-type erythema. The history of heat exposure is helpful in distinguishing the two illnesses. (See "Severe hyperthermia (heat stroke) in adults".)

DIAGNOSIS GAS TSS must be considered in any patient presenting from the community in shock. A history of recent trauma and severe pain and fever favor a diagnosis of GAS TSS. The Working Group on Severe Streptococcal Infections established the following clinical guideline for diagnosis of GAS TSS [21]:

Isolation of GAS from a normally sterile site (eg, blood cerebrospinal, pleural, or peritoneal fluid, tissue biopsy, or surgical wound) plus Hypotension (systolic blood pressure 90 mm Hg in adults or <5th percentile for age in children)

plus two or more of the following: Renal impairment (creatinine in adults, 2 mg/dL; in children, two-times upper limit of normal for age; in patients with pre-existing renal disease twofold elevation over baseline) Coagulopathy (eg, thrombocytopenia, disseminated intravascular coagulation) Liver involvement (eg, two-times upper limit of normal for age of transaminases or bilirubin; in patients with pre-existing liver disease twofold elevation over baseline) Adult respiratory distress syndrome Erythematous macular rash, may desquamate Soft tissue necrosis (eg, necrotizing fasciitis, myositis, or gangrene)

If GAS is isolated from a nonsterile site (eg, throat, vagina, skin lesion) but the patient fulfills the other criteria noted above, a diagnosis of probable GAS TSS can be made if no other etiology for the illness is identified. Recovery of the organism from blood cultures usually takes from 8 to 24 hours. When surgery is performed for debridement of infected fascia or muscle, Gram stain of involved tissue showing grampositive cocci in pairs and chains provides an early and definitive diagnosis in the vast majority of cases. SUMMARY Severe invasive group A streptococcal (GAS) infections are defined as bacteremia, pneumonia, necrotizing fasciitis, gangrenous myositis, or any other infection associated with the isolation of GAS from a normally sterile body site. GAS toxic shock syndrome (GAS TSS) is defined as any GAS infection associated with the acute onset of shock and organ failure. (See 'Definitions' above.) GAS TSS is mediated by toxins that act to activate the immune system, resulting in the release of large quantities of inflammatory cytokines that cause capillary leak and tissue damage, leading to shock and multiorgan failure. (See 'Pathogenesis' above.) The prevalence of GAS infections increased in the 1980s and has remained approximately 3.5 cases per 100,000 people. Up to one-third of these cases develop GAS TSS. (See 'Epidemiology' above.) Persons of all ages may be afflicted with GAS TSS and most are not immunosuppressed. Risk factors associated with invasive GAS include minor trauma, surgical procedures, viral infections (eg, varicella), and use of nonsteroidal antiinflammatory drugs (NSAIDs). (See 'Risk factors for GAS' above.) The most common initial symptom of GAS TSS is diffuse or localized pain, which is abrupt in onset, severe, and usually precedes tenderness or physical findings. (See 'Clinical presentation' above.) Shock at the time of admission or within four to eight hours is present in virtually all patients with GAS TSS. The complications of GAS TSS are severe and include bacteremia, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation, and renal failure. (See 'Complications' above.) The differential diagnosis of shock in a previously healthy individual includes staphylococcal toxic shock syndrome, gram-negative sepsis, Rocky Mountain spotted fever, acute meningococcemia, Streptococcus pneumoniae sepsis, leptospirosis, and heat stroke. (See 'Differential diagnosis' above.) The diagnosis of GAS TSS requires isolation of GAS from a normally sterile site (eg, blood cerebrospinal, pleural, or peritoneal fluid, tissue biopsy, or surgical wound) and hypotension plus evidence of failure of two of more organ systems. (See 'Diagnosis' above.)

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