Toxic shock syndrome (TSS) is an acute febrile illness resulting in multiple organ system dysfunction caused most commonly by a bacterial exotoxin. Disease characteristics also include hypotension, vomiting, myalgia, watery diarrhea, vascular collapse, and an erythematous sunburn-like cutaneous rash that desquamates during recovery. Box E1 summarizes the clinical case definition of TSS.

TSS

• Case reported incidence peak: 14 cases/100,000 menstruating women annually in 1980; has since fallen to 1 case/100,000 persons
• Occurs most commonly between ages 10 and 30 yr in healthy, young, menstruating White females
• Case-fatality ratio of 3%

• Fever (>38.0° C; 100.4° F)
• Diffuse macular erythrodermatous rash that involves both skin and mucous membranes, resembles sunburn, and also involves the palms and soles. The rash then desquamates 1 to 2 wk after disease onset in survivors
• Orthostatic hypotension
• Gastrointestinal symptoms: Vomiting, diarrhea, abdominal tenderness
• Constitutional symptoms: Myalgia, headache, photophobia, rigors, altered sensorium, conjunctivitis, arthralgia
• Respiratory symptoms: Dysphagia, pharyngeal hyperemia, strawberry tongue
• Genitourinary symptoms: Vaginal discharge, vaginal hyperemia, adnexal tenderness
• End-organ failure
• Severe hypotension and acute renal failure
• Hepatic failure
• Cardiovascular symptoms: Disseminated intravascular coagulation, pulmonary edema, acute respiratory distress syndrome (ARDS), endomyocarditis, heart block

• Menstruation-associated TSS: 45% of cases associated with tampons, diaphragm, or vaginal sponge use. There has been a decline in these cases and in the case:fatality ratio.
• Nonmenstruation-associated TSS: 55% of cases associated with puerperal sepsis, postcesarean delivery endometritis, mastitis, sinusitis, wound or skin infection, septorhinoplasty (nasal packings), pelvic inflammatory disease, respiratory infections following influenza, enterocolitis, and burns. The number of cases is increasing and the case:fatality ratio has not declined.
• Causative agent: Staphylococcus aureus infection of a susceptible individual (10% of population lacking sufficient levels of antitoxin antibodies), which liberates the disease mediator TSST-1 (exotoxin). Although most cases are caused by methicillin-susceptible S. aureus (MSSA), cases of TSS from methicillin-resistant S. aureus (MRSA) have occurred, particularly those due to the more virulent, community-associated MRSA strains.
• S. aureus exotoxins are superantigens that can activate large numbers of T cells (up to 20% at one time), resulting in a massive cytokine production: Interleukin (IL-1), IL-2, tumor necrosis factor, and interferon-gamma that then mediate the signs and symptoms of the disease.
• Other causative agents: Coagulase-negative staphylococci producing enterotoxins B or C, and exotoxin A-producing group A beta-hemolytic streptococci.
• Risk factors for staphylococcal TSS are summarized in Box E2.

• Staphylococcal food poisoning
• Septic shock
• Mucocutaneous lymph node syndrome
• Scarlet fever
• Rocky Mountain spotted fever
• Meningococcemia
• Toxic epidermal necrolysis
• Kawasaki syndrome
• Leptospirosis
• Legionnaires disease
• Hemolytic-uremic syndrome
• Stevens-Johnson syndrome
• Scalded skin syndrome
• Erythema multiforme
• Acute rheumatic fever

Broad-spectrum syndrome with multiorgan system involvement and variable but acute clinical presentation, including the following diagnostic criteria for staphylococcal TSS:

• Fever (>38° C; 100.4° F)
• Classic desquamating rash (1 to 2 wk)
• Hypotension/orthostatic systolic blood pressure ≤90 mm Hg
• Syncope
• Negative throat and cerebrospinal fluid cultures
• Negative serologic test for Rocky Mountain spotted fever, rubeola, and leptospirosis
• Clinical involvement of three or more of the following:
  1. Cardiopulmonary: Acute respiratory distress syndrome (ARDS), pulmonary edema, endomyocarditis, second- or third-degree atrioventricular block
  2. Central nervous system: Altered sensorium without focal neurologic findings
  3. Hematologic: Thrombocytopenia (platelets <100,000)
  4. Liver: Elevated liver function test results
  5. Renal: >5 cells/high-power field, negative urine cultures, azotemia, and increased creatinine (double normal)
  6. Mucous membrane involvement: Vagina, oropharynx, conjunctiva
  7. Musculoskeletal: Myalgia, creatine phosphokinase twice normal
  8. Gastrointestinal: Vomiting, diarrhea

For streptococcal TSS the diagnostic criteria is as follows:

• Definite case: Isolation of group A β-hemolytic streptococci (GABHS) from a sterile site
• Probable case: Isolation of GABHS from a nonsterile site
• Hypotension: Presence of two of the following findings:
  1. Acute kidney injury or failure
  2. Elevated aminotransferase
  3. Erythematous macular rash, soft tissue necrosis
  4. Coagulopathy, including thrombocytopenia and disseminated intravascular coagulation
  5. Acute respiratory distress syndrome

• Pan culture (cervix and vagina, throat, nasal passages, urine, blood, cerebrospinal fluid, wound) for Staphylococcus, Streptococcus (Table E1), and other pathogenic organisms
• Electrolytes to detect hypokalemia, hyponatremia
• CBC with differential and clotting profile for anemia (normocytic or normochromic), thrombocytopenia, leukocytosis, coagulopathy, and bacteremia
• Chemistry profile to detect decreased protein, increased aspartate aminotransferase, increased alanine aminotransferase, hypocalcemia, elevated blood urea nitrogen and creatinine, hypophosphatemia, increased lactate dehydrogenase, increased creatine phosphokinase
• Urinalysis to detect white blood cells (>5 cells/high-power field), proteinemia, microhematuria
• Arterial blood gases to assess respiratory function and acid-base status
• Serologic tests considered for Rocky Mountain spotted fever, rubeola, and leptospirosis

• Chest x-ray examination to evaluate pulmonary edema
• ECG to evaluate arrhythmia
• Sonography, computed tomography scan, or MRI considered if pelvic abscess or tuboovarian abscess suspected

• Therapeutic principles for management of TSS are outlined in Box E3
• For optimal outcome: High index of suspicion and early and aggressive supportive management in an intensive care unit setting
• Aggressive fluid resuscitation (maintenance of circulating volume, cardiac output, systolic blood pressure)
• Thorough search for a localized infection or nidus: Incision and drainage, debridement, removal of tampon or vaginal sponge
• Central hemodynamic monitoring, Swan-Ganz catheter, and arterial line for surveillance of hemodynamic status and response to therapy
• Foley catheter to monitor hourly urine output
• Possible military antishock trousers as temporary measure
• Acute ventilator management if severe respiratory compromise
• Renal dialysis for severe renal impairment
• Surgical intervention for indicated conditions (i.e., ruptured tubo-ovarian abscess, wound abscess, mastitis)
• Hyperbaric oxygen treatment can be used adjunctively

• Isotonic crystalloid (normal saline solution) for volume replacement following “7-3” rule (refers to the response in millimeters of mercury [mm Hg] of the pulmonary artery wedge pressure to volume replacement).
• Electrolyte replacement (K⁺, C⁺).
• Packed red blood cells, coagulation factor replacement, fresh frozen plasma to treat anemia or dilation and curettage.
• Vasopressor therapy for hypotension refractory to fluid volume replacement (e.g., dopamine beginning at 2 to 5 μg/kg/min).
• Steroids have been used but are not generally recommended due to lack of evidence of benefit.
• It is not clear whether antibiotics alter the course of acute TSS. Most authors recommend that patients receive 10 to 14 days of combination antibiotic therapy. In staphylococcal TSS, effective agents are clindamycin (900 mg intravenous [IV] tid in adults or 25 to 40 mg/kg per day in children) plus vancomycin (adults: 30 mg/kg per day IV in two divided doses; children: 40 mg/kg per day IV in four divided doses). Oxacillin or nafcillin sodium (2 g IV every 4 h in adults; children: 100 to 150 mg/kg per 24 h divided in four doses) can be used instead of vancomycin if TSS is due to MSSA. An alternative to vancomycin is linezolid.
• In streptococcal TSS, effective agents are penicillin G 24 million units/day in divided doses plus clindamycin 900 mg IV q8h. Alternative agents are ceftriaxone 2 g IV q24h plus clindamycin 900 mg IV q8h.
• Broad-spectrum antibiotic including gram-negative coverage added if concurrent sepsis suspected with TSS.
• Intravenous immune globulin (IVIG): While no controlled trials exist, most authors recommend IVIG (400 mg/kg in a single dose administered over several hours) in severe cases of TSS that are not responding to fluids or vasopressors. It may neutralize superantigen and decrease tissue damage.
• Tetracycline added if considering Rocky Mountain spotted fever.

Severely ill patient: May require prolonged hospitalization and supportive management with gradual recovery and/or sequelae from severe end-organ involvement (ARDS or renal failure requiring dialysis)

• Majority of patients: Complete recovery
• Early-onset complications (within 2 wk):
  1. Skin desquamation
  2. Impaired digit sensation
  3. Denuded tongue
  4. Vocal cord paralysis
  5. Acute tubular necrosis
  6. ARDS
• Late-onset complications (after 8 wk):
  1. Nail splitting and loss
  2. Alopecia
  3. Central nervous system sequelae
  4. Renal impairment
  5. Cardiac dysfunction
• Recurrent TSS:
  1. More common in menstruation-related cases.
  2. Less common in patients treated with beta-lactamase-resistant antistaphylococcal antibiotics.
  3. Patients with history of TSS: If suspect signs and symptoms occur, have high index of suspicion and low threshold for evaluation and treatment.
  4. Screen for nasal carriage of S. aureus in patients with S. aureus TSS and treat with mupirocin in those with positive cultures.

• Avoidance of tampons or use of low-absorbency tampons only (<4 h in situ) and alternate with napkins
• Education for patients concerning signs and symptoms of TSS
• Avoidance of tampons for patients with history of TSS

• Complete recovery for most patients
• Long-term management of early- and late-onset complications for minority of patients

• For multidisciplinary management, involving primary physician, gynecologist, internist, infectious disease specialist, and other supportive care specialists
• To tertiary-level hospital

Antibiotic prophylaxis against invasive group A streptococcal infection with benzathine penicillin G plus rifampin, clindamycin, or azithromycin is recommended for immunocompromised household contacts of patients with streptococcal TSS-like syndrome.

Toxic Shock Syndrome (Patient Information)