Chapter 150: Toxic Shock Syndromes

The two classic toxic shock syndromes are attributed to Staphylococcus aureus or to group A Streptococcus (Streptococcus pyogenes). Each is a life-threatening illness stemming from toxin production by gram–positive organisms, creating hemodynamic compromise and fulminant multiorgan dysfunction. This cascade makes diagnosis a challenge, with the features looking like the more common entities of sepsis and septic shock. Characteristic epidemiology, pathophysiology, clinical presentations, and management strategies set these syndromes apart (Table 150–1). Early recognition and definitive treatment are the keys to improving patient outcomes.

INTRODUCTION AND EPIDEMIOLOGY

Staphylococcal toxic shock syndrome (TSS) was first described in 1978 in a series of seven children presenting with systemic illness punctuated by fever, headache, confusion, vomiting, diarrhea, scarlatiniform rash, desquamation, hypotension, and multiorgan dysfunction.¹ A toxigenic strain of S. aureus isolated from mucosal (nasopharyngeal, tracheal, vaginal) and sequestered sites (abscess, empyema) in five of the patients was the causative organism. During the early 1980s, TSS was linked to tampon use in young menstruating women,^2,3 with incidence rates as high as 13.7 per 100,000 menstruating women between the ages of 15 and 24.⁴ Education on the proper frequency and duration of use of tampons coupled with the removal of highly absorbent tampons from the market are widely credited with reducing menstrual TSS rates, although tampon use remains an important risk factor for menstrual TSS to this day in the United States, Canada, and Western Europe.

Nonmenstrual TSS is associated with a wide range of skin and soft tissue infections including abscesses, cellulitis, mastitis, and infected surgical and postpartum wounds, including vaginal and cesarean deliveries.⁵ Sinusitis and superimposed infections of burns, abrasions, and varicella lesions have been described in other cases, particularly in children. Patients with influenza may develop TSS in the setting of secondary S. aureus respiratory tract infections (e.g., pneumonia, tracheitis).⁶ Because the vagina and nares are known sites of S. aureus colonization, retained foreign bodies, including female barrier contraceptives (e.g., diaphragm, contraceptive sponge) and nasal packing material, are risk factors for developing nonmenstrual TSS. Nasal packing is not a current common trigger, and routine prescription of antibiotics is not needed to stop this from occurring.⁸ Nonmenstrual TSS affects men and women alike, and patients tend to be older and have more comorbid illnesses than those seen with the menstrual form of the disease.

Population-based surveillance shows that TSS incidence has been stable in the United States for the past 30 years.^9,10 Women between the age of 13 and 24 years have a higher incidence of menstrual TSS, at a rate of 1.41 per 100,000 persons.⁹ The overall case fatality rate for TSS is 4.1%, with higher rates in nonmenstrual TSS (5%) compared to menstrual TSS (3%).¹¹

PATHOPHYSIOLOGY

TSS is a superantigen-mediated disease. Toxigenic S. aureus strains produce pyrogenic exotoxins including toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxins that bind directly to the major histocompatibility complex class II molecule and T-cell receptor on antigen-presenting cells.¹² Massive T-cell and antigen-presenting cell activation leads to enhanced cytokine expression (e.g., interleukin-1, -2, and -6; tumor necrosis factor-α; interferon-γ), establishing a proinflammatory state. Increased vascular permeability, hemodynamic shock, metabolic acidosis, coagulopathy, and multiorgan dysfunction ensue, mirroring that of the cascade triggered by lipopolysaccharide (endotoxin) in gram-negative sepsis.

Almost all menstrual TSS cases are tied to TSST-1.^13,14 Disease starts with colonization of the vagina by a toxigenic strain of S. aureus capable of producing TSST-1. Approximately 9% of women are vaginally colonized with S. aureus, only 1% of whom are considered toxigenic.¹⁵ TSST-1 must cross the vaginal epithelium for clinical disease to occur, and the host cannot possess neutralizing antibodies to TSST-1 that might confer immunity. One reason why menstrual TSS rates have remained low yet consistent throughout the years may be due to the development of durable immunity to TSST-1,¹⁵ perhaps from either transient or persistent asymptomatic colonization with toxigenic S. aureus.¹⁶

In contrast to menstrual TSS, TSST-1 is implicated in only half of nonmenstrual TSS cases,¹⁷ with the remaining share attributed to staphylococcal enterotoxin B and other members of that family.¹⁸ Vulnerability to nonmenstrual TSS usually starts with infection or colonization involving a toxigenic strain of S. aureus at a localized site, notably mucosa, skin, wound, lung, or a foreign body.

CLINICAL FEATURES

A case definition created for the National Notifiable Diseases Surveillance System by the U.S. Centers for Disease Control and Prevention (Table 150–2) provides criteria for reporting TSS in its most severe form, although many of these symptoms may not be evident on initial evaluation of the patient presenting to the emergency department and should not be used to exclude the diagnosis of TSS. These definitions are periodically updated at the National Notifiable Diseases Surveillance System Web page (http://wwwn.cdc.gov/nndss).

Time of onset of initial symptoms is highly variable, ranging from as little as 48 hours in postoperative nonmenstrual TSS⁵ to several days after the start of menstruation in menstrual TSS.³ Patients presenting early on in the disease process may exhibit a nonspecific prodrome consisting of any combination of fever, chills, malaise, myalgias, headache, sore throat, vomiting, diarrhea, or abdominal pain. The progression of an unexplained febrile illness to include hypotension, erythroderma, and multiorgan dysfunction should raise clinical suspicion for TSS. Hypotension with a systolic blood pressure of ≤90 mm Hg in adults or less than the fifth percentile for children <16 years of age heralds severe disease as a consequence of systemic vasodilation and increased capillary permeability. Decreased urinary output signals acute kidney injury, which may result from renal hypoperfusion, rhabdomyolysis, or other causes. Lethargy, agitation, and confusion can result from shock or be related to cerebral edema. Respiratory failure can occur from acute respiratory distress syndrome or pulmonary edema from toxic cardiomyopathy. Patients with TSS may also present to care with second- or third-degree heart block or, more rarely, ventricular arrhythmias.

The erythroderma of TSS is characterized as a painless, diffuse, red, macular rash resembling "sunburn." The rash can be either patchy or confluent, and it can be modest and evanescent, involving the palms and soles. Desquamation, notably of the hands and feet, begins anywhere from 1 to 3 weeks after the initial onset of symptoms. Mucosal involvement can include conjunctival and scleral hemorrhage as well as vaginal, cervical, or oropharyngeal hyperemia ("strawberry tongue") and ulceration. In the patient at risk for menstrual TSS, pelvic examination gauges mucosal disease and allows a look for retained foreign bodies such as tampons.

Surgical wounds infected or colonized with toxigenic S. aureus in nonmenstrual TSS patients may have little or no erythema, induration, or purulent drainage to raise clinical suspicion of infection,^5,19 likely due to unique properties associated with TSST-1 and staphylococcal enterotoxin B. Any wound in a patient presenting with concern for TSS should be considered a potential source for toxigenic S. aureus.

DIAGNOSIS

Timely diagnosis of TSS relies on identifying patient risk factors; recognizing an evolving pattern of febrile illness, hemodynamic compromise, and organ injury; and considering the diagnosis before profound illness occurs even if all of the case criteria are not met. TSS is a clinical diagnosis.

Laboratory evaluation reveals the adverse sequelae of organ hypoperfusion and dysfunction, but nothing more specific. Usually, a CBC, comprehensive metabolic panel with liver function tests, coagulation studies, creatine phosphokinase level (particularly if myalgias are a primary complaint), urinalysis, chest radiograph, and an ECG are obtained to assess organ function. Leukocytosis, anemia, or thrombocytopenia may be present. Azotemia indicative of acute kidney injury can be accompanied by electrolyte disturbances including hyponatremia, hypocalcemia, and hypophosphatemia.²⁰ Metabolic acidosis in the presence of hypotension is common. Hypoalbuminemia from capillary leakage and liver function abnormalities with coagulopathy can also be seen. Absent coagulopathy, CT of the brain accompanied by lumbar puncture is often needed in those with altered sensorium.

Obtain blood cultures, but positive blood cultures are uncommon: S. aureus is grown in less than 5% of TSS cases.⁵ In contrast, cultures from wounds, mucosal sites, and retained foreign materials are frequently positive for S. aureus. Get all possible cultures early, optimally before initiating antibiotic therapy, to facilitate identification of a toxin-producing strain of S. aureus and to allow antibiotic susceptibility testing.

Differential Diagnosis

Streptococcal toxic shock syndrome and myonecrosis due to Clostridium perfringens, both commonly associated with traumatic and surgical wounds, are important considerations in the differential diagnosis of TSS. Toxic shock syndrome due to Clostridium sordellii, associated with gynecologic surgery, childbirth, miscarriage, and abortions, can also present similarly, but often without fever. Staphylococcal scalded skin syndrome, mediated by exfoliative toxin A or B, can present with fever, lethargy, and desquamation similar to TSS, but is not typically accompanied by hypotension or multiorgan dysfunction. In the absence of erythroderma, TSS is indistinguishable from sepsis or septic shock due to any number of gram-positive or gram-negative bacteria. Other infectious diseases classically associated with fever, rash, and multiorgan dysfunction include Rocky Mountain spotted fever and leptospirosis. Also, consider meningococcemia if any severe headache or a petechial rash is seen. Noninfectious illnesses including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Kawasaki's disease are occasional alternative diagnoses.

TREATMENT

The initial management of TSS in the ED is based on treating shock and eliminating the source of infection. Start with aggressive isotonic crystalloid fluid resuscitation, and use vasopressors and inotropes as needed if volume alone does not resolve hypotension or organ hypoperfusion. Mechanical ventilation may be necessary for respiratory failure. Drain abscesses and other infected fluid collections, obtain surgical consultation for debridement of potentially infected wounds, and remove retained foreign bodies that might represent a focus for toxigenic S. aureus (e.g., tampons, nasal or surgical packing material). Patients suspected of having TSS require hospital admission, usually to the intensive care unit, given the hemodynamic compromise, respiratory failure, and multiorgan dysfunction.

Administer antibiotics to treat infection, eliminate S. aureus carriage, and reduce recurrences, although the role of antibiotics in curbing the inflammatory response of TSS is unclear (Table 150–3). With the growing prevalence of methicillin-resistant S. aureus (MRSA), decisions about empiric antistaphylococcal therapy should hinge on local S. aureus antibiotic resistance patterns. Both community- and hospital-acquired MRSA strains have been reported to cause TSS through TSST-1²¹ and staphylococcal enterotoxin production, although the exact proportion of TSS cases attributable to MRSA is not known. Empiric therapy should consist of vancomycin, 15 milligrams/kg IV every 12 hours (maximum single dose of 2.25 grams), with adjustment of the dosing interval based on creatinine clearance. Linezolid, 600 milligrams IV every 12 hours, is an alternative to treat MRSA and may also directly suppress TSST-1 production.²² If the concern for MRSA is low, an antistaphylococcal penicillin, such as oxacillin, 2 grams IV every 4 hours, or nafcillin, 2 grams IV every 4 hours, is adequate. Clindamycin, 900 milligrams IV every 8 hours, is added as a second agent given its ability to inhibit protein synthesis and toxin production in TSS,²³ but should not be used as monotherapy. The duration of antibiotic therapy is based on the clinical response and typically ranges from 7 to 14 days.

Reserve IV immune globulin for cases where supportive care, source control, and antibiotic therapy fail to elicit improvement within the first 6 hours of care. Although dosing recommendations will vary by patient age and comorbidity, many require higher doses of IV immune globulin to inhibit staphylococcal toxins.²⁴ Give IV immune globulin only after consultation with infectious disease or critical care specialists. An initial dose of 1 to 2 grams/kg is recommended. Immunoglobulin A deficiency is an absolute contraindication to the use of IV immune globulin. High-dose corticosteroids are not recommended in the treatment of TSS.²⁵

INTRODUCTION AND EPIDEMIOLOGY

Streptococcal toxic shock syndrome (STSS) is a complication of invasive infections involving group A Streptococcus (S. pyogenes), including skin and soft tissue infections, pneumonia, and bloodstream infections. First recognized in 1987, STSS shared many of the same clinical features of TSS seen with S. aureus.²⁶ However, in a case series of 20 patients published just 2 years later, STSS emerged as a disease associated with necrotizing fasciitis and myositis, marked by a significantly higher morbidity and mortality compared with that of TSS.²⁷ Annual incidence rates for invasive group A Streptococcus (GAS) infection have ranged from 3 to 6 cases per 100,000 persons,^28,29,30 with those age 65 years and older or under the age of 1 greatest affected. In prospective population-based surveillance across 11 European countries in 2003 and 2004, 13% of invasive GAS infections were complicated by STSS, with half of all STSS cases reported in patients with necrotizing fasciitis.²⁹ More recently, population-based surveillance at sentinel sites in the United States have reported STSS in 3.4% of invasive GAS infections.³¹ Mortality rates for STSS are high, ranging from 19% to 44% in recent studies.^28,29,30,32

Despite the preponderance of invasive GAS infections at the extremes of age, STSS cases occur in all age groups. Underlying medical conditions including heart, liver, and kidney disease; diabetes mellitus; alcoholism; and drug abuse are more common in patients who develop STSS,^30,33 but many patients are healthy prior to the illness.^27,34 Surgical procedures, traumatic injuries, vaginal or caesarean delivery, varicella infection in children,³⁵ and influenza are all associated with STSS and other invasive GAS infections. Rare outbreaks of severe GAS infection with some progressing to STSS have occurred in daycare centers,³⁶ healthcare facilities,³⁷ and other institutional settings.

In recent years, STSS has been linked to infections involving group B, C, and G streptococci.³⁸ Streptococcus suis (a pathogen in pigs) is another newly identified trigger of invasive soft tissue infections accompanied by an STSS-like syndrome in China.³⁹

PATHOPHYSIOLOGY

As with S. aureus TSS, STSS is mediated by toxins that function as super-antigens. Streptococcal pyrogenic exotoxins, predominantly A and B, are produced by GAS in severe infections. These toxins also bind to the major histocompatibility complex class II molecule and T-cell receptor on antigen-presenting cells, thereby activating T cells and triggering cytokine expression.¹² Fever, increased vascular permeability, hemodynamic compromise, and multiorgan dysfunction are the products of this systemic inflammatory response. Virulence factors including M proteins confer resistance to phagocytosis and may impart other properties that further enhance the severity of disease.

Breaches in skin and mucosal surfaces (e.g., oropharynx, vagina), as well as minor trauma without obvious skin disruption resulting in hematoma, contusion, or muscle injury, are common starting points for severe GAS infections. In many cases, a portal of entry is never identified.

CLINICAL FEATURES

Fulminant STSS, as defined by the Centers for Disease Control and Surveillance case definition (Table 150–4), is often preceded by a nonspecific prodrome of fever, chills, sweats, malaise, arthralgias, cough, sore throat, rhinorrhea, anorexia, nausea, vomiting, abdominal pain, and diarrhea in adults and children alike.^27,40 A diffusely erythematous and macular rash is infrequently seen in STSS and may progress to desquamation, although its presence is not required to solidify the diagnosis of STSS. Confusion, somnolence, and agitation may follow. Given the strong association between STSS and necrotizing soft tissue infections, many patients are likely to present initially with pain out of proportion to physical findings at a localized site, often an extremity or the abdomen.²⁷ Progressive violaceous discoloration, skin crepitus and necrosis, and bullae formation at the site are ominous signs of underlying necrotizing fasciitis and myositis. Compartment syndrome can be a complication. Refractory hypotension rapidly ensues from a combination of vasodilation, capillary leakage, and myocardial depression from toxic cardiomyopathy.³⁴ Acute kidney injury, myocardial and cerebral ischemia, acute respiratory distress syndrome, rhabdomyolysis from muscle destruction, liver dysfunction, and disseminated intravascular coagulation can lead to death within hours to days.

DIAGNOSIS

As with S. aureus TSS, the surveillance case definition for STSS may not be fully met on the initial presentation.

Laboratory evaluation has no specific diagnostic role, although it usually includes CBC, comprehensive metabolic panel with liver function tests, coagulation studies, creatine phosphokinase level (particularly if myositis or necrotizing fasciitis is suspected), arterial blood gas analysis, urinalysis, chest radiograph, and an ECG. Athough leukocytosis may be modest, a marked bandemia, sometimes in excess of 40%, can be present.²⁷ Anemia, thrombocytopenia, and coagulopathy may be evident. Transaminitis, azotemia, metabolic acidosis, hypoalbuminemia, and hypocalcemia are common findings, particularly as hypotension and capillary leakage progress. In necrotizing soft tissue infections, creatine phosphokinase will be elevated.

Obtain blood and wound cultures prior to administering antibiotics when possible to confirm the presence of GAS and guide therapy. Blood cultures are positive in up to 60% of STSS cases; cultures from infected sites almost always yield GAS.^27,40

Consult a surgeon immediately for all patients believed to have a necrotizing soft tissue infection. CT and MRI showing soft tissue destruction establishes this diagnosis but should never delay timely surgical evaluation.

Differential Diagnosis

Staphylococcal TSS, myonecrosis associated with C. perfringens or Clostridium septicum, nonclostridial myonecrosis due to mixed anaerobes and other bacteria, and C. sordellii toxic shock syndrome are principal contenders in the differential diagnosis of STSS. Other systemic infections including meningococcemia, Rocky Mountain spotted fever, and leptospirosis are potential candidates as well.

TREATMENT

Management of STSS begins with aggressive isotonic fluid resuscitation to restore volume and tissue perfusion. In light of the profound refractory hypotension and capillary leakage associated with STSS, large volumes of IV crystalloid fluid (10 to 20 L/d) may be required. Vasopressors or inotropic therapy are often necessary. More than half of patients with STSS will develop acute respiratory distress syndrome, often requiring intubation and mechanical ventilation.

Obtain surgical consultation for early and often extensive operative debridement, fasciotomy, and even amputation if a significant burden of infected and necrotic tissue exists. Admit to the intensive care unit.

Given the overlap in clinical presentations between STSS and septic shock and the high mortality associated with both, empiric broad-spectrum antibiotic therapy to cover GAS and other potential pathogens is best until culture data are available (Table 150–5). Use a β-lactamase inhibitor (e.g., piperacillin-tazobactam, 4.5 grams IV every 6 hours) or a carbapenem (e.g., meropenem, 1 gram IV every 8 hours) in combination with clindamycin, 900 milligrams IV every 8 hours,⁴¹ the latter for suppression of toxin formation.⁴² In areas where MRSA is prevalent, add vancomycin, 15 milligrams/kg IV every 12 hours (maximum single dose of 2.25 grams). Adjust antibiotic dosing for acute kidney injury.

Once the presence of GAS is identified, consider narrowing antibiotic therapy to penicillin G, 4 million units IV every 4 hours (for a total of 24 million units per day), in combination with clindamycin.⁴³ The duration of antibiotic therapy should be at least 14 days but may be longer based on the extent of the infection and the patient's clinical response.

Although retrospective studies have shown decreased mortality with IV immune globulin,^44,45 a multicenter, randomized controlled trial has failed to find benefit.⁴⁶ Obtain consultation before giving IV immune globulin to treat STSS.⁴⁷

Surveillance case definitions for TSS and STSS are available from the Centers for Disease Control and Prevention Web site at http://www.cdc.gov/nndss.