Basics
Description
Toxic shock syndrome is an acute febrile illness characterized by hypotension and gastrointestinal and respiratory distress progressing to multisystem organ failure. The clinical syndrome is caused by bacterial exotoxins produced most commonly by the following: ‚
- TSS toxin-1 (TSST-1) " “producing strains of Staphylococcus aureus " ”referred to as TSS
- Group A Ž ²-hemolytic streptococci (GAS or Streptococcus pyogenes), referred to as streptococcal toxic shock " “like syndrome (STSS)
- Cases have also been reported in association with groups B, C, and G1 streptococci and Streptococcus mitis.
Epidemiology
- In the 1980s, most cases were associated with superabsorbent tampon use; subsequently, these products have been removed from the market, resulting in a decline in menstrual-related staphylococcal TSS.
- Developing countries bear a much higher burden for STSS.
- Currently, ¢ ˆ ¼50% of cases are non " “menstrual related.
Incidence
- TSS: 3.4 cases per 100,000 in 2003
- Current incidence of menses-related TSS: 1 " “5 per 100,000 women of menstrual age per year
- STSS: 2 " “4 cases per 100,000 in developed countries with >10 per 100,000 per year in developing countries
- STSS incidence is highest among young children and associated with focal infections, pneumonia, or bacteremia.
Risk Factors
- Use of superabsorbent tampon, diaphragm, or contraceptive sponge; local or invasive staphylococcal or streptococcal infection
- Recent gynecologic procedure
- Focal infections including surgical and postpartum wounds, sinus, soft tissue, and musculoskeletal infections and respiratory infections
- STSS most often occurs with skin and soft tissue infections.
- Preceding varicella infection increases risk.
General Prevention
- Scrupulous wound care
- Limitation of intravaginal foreign body use (e.g., tampon, sponge) and strict adherence to manufacturer 's directions
- Early recognition and appropriate treatment of infections
Pathophysiology
- Both Staphylococcus aureus and Streptococcus pyogenes can produce exotoxins.
- Some exotoxins function as superantigens, interacting with immune cells to induce massive cytokine production leading to the predominant symptoms.
- Cytokines result in fever, capillary leak, hypotension, and end-organ dysfunction.
Diagnosis
History
- Patients may report use of tampons, contraceptive sponge, or diaphragm.
- TSS may occur at any time during menses.
- Inquire about recent wounds or surgical procedures including catheters (e.g., intravenous, peritoneal dialysis).
- Incubation period for postoperative TSS may be as short as 12 hours.
- Patient may report recent childbirth or abortion.
- Patients may report abrupt onset of high fever, chills, malaise, headache, pharyngitis, erythroderma fatigue, and dizziness or syncope.
- Gastrointestinal symptoms including profuse watery diarrhea, vomiting, abdominal pain
Physical Exam
- Initial exam should evaluate for soft tissue or musculoskeletal focus of infection or retained foreign body.
- Patients are typically ill appearing and may have general erythroderma.
- Skin findings may be less prominent with severe hypotension.
- Vitals signs: fever, tachycardia, tachypnea, orthostasis, or frank hypotension
- Tachycardia with normotension may occur early in disease.
- Skin: erythroderma, peripheral cyanosis, and edema
- Desquamation: begins on trunk and extremities 5 " “7 days after symptom onset
- There may be vesicle or bullae formation or presence of violaceous hue.
- Mucosa: bulbar conjunctival injection and oral mucosal hyperemia
- Mental status: may be altered, somnolent, agitated, disoriented, or obtunded
- Mental status changes may worsen as disease progresses.
- Caveats for physical exam
- Patients may not have all symptoms upon presentation.
Diagnostic Tests & Interpretation
- U.S. Centers for Disease Control and Prevention (CDC) criteria for diagnosis of staphylococcal TSS requires 6 criteria for confirmed cases and 5 for probable:
- Fever 38.9 ‚ °C (102.0 ‚ °F) or higher
- Diffuse macular erythroderma
- Desquamation 1 " “2 weeks after onset, particularly affecting palms and soles
- Hypotension defined as systolic blood pressure below 5th percentile for children, orthostatic changes >15 mm Hg, or orthostatic syncope or dizziness
- Involvement of three or more organ systems: gastrointestinal, muscular, mucous membrane, renal, hepatic, hematologic, or neurologic
- Negative blood (may be positive for S. aureus), throat, or CSF cultures and/or negative titers for Rocky Mountain spotted fever (RMSF), leptospirosis, or measles
- U.S. CDC criteria for diagnosis of streptococcal TSS. Confirmed cases meet clinical definition in addition to isolation of GAS from normally sterile site; probable cases meet clinical definition with isolation of GAS from nonsterile site:
- Hypotension as defined above
- Any 2 of the following: renal impairment, coagulopathy, hepatic impairment, acute respiratory distress syndrome (ARDS), erythematous macular rash that may desquamate, or soft tissue necrosis
Lab
Initial laboratory evaluation should be aimed at diagnosing organ dysfunction to guide supportive therapy and identifying potential source and pathogen to guide antimicrobial therapy. ‚
- Cultures
- Blood cultures: ideally obtained prior to antimicrobial therapy but still helpful if patient has been on outpatient therapy prior to presentation
- Positive in 60% of STSS but <5% of staphylococcal TSS
- Other cultures
- Culture of other fluids (abscess, pleural, cerebrospinal) should be guided by clinical presentation.
- S. aureus may be isolated from vagina or cervix in menstrual TSS, although asymptomatic carriage can occur.
- Culture of GAS from the throat or other nonsterile site may be helpful although does not confirm STSS.
- Antibodies (Ab)
- TSST-1 Ab are available for informational purposes/research only.
- Antistreptolysin O (ASO), antideoxyribonuclease B, or other streptococcal extracellular products
- May increase 4 " “6 weeks after infection in streptococcal-mediated disease
- May not be helpful in acute phases of disease
- Arterial blood gas
- Helpful in cases of respiratory distress and poor perfusion to help guide ventilation strategies
- Complete blood count
- Leukocytosis with left shift (neutropenia is an ominous sign)
- Thrombocytopenia may indicate ongoing disseminated intravascular coagulation (DIC).
- Renal profile: may reflect acute kidney injury with elevated creatinine
- Hepatic profile: may have elevations in liver enzymes and evidence of synthetic dysfunction with decreased fibrinogen and coagulation factor levels
- Coagulation studies
- May reveal prolonged prothrombin and partial thromboplastin times (PT/PTT) with or without evidence of DIC; low fibrinogen, elevated fibrin degradation products.
- Urinalysis
- May reveal sterile pyuria
- Lumbar puncture
- May reveal CSF pleocytosis
- Gram stain positive for organisms or overt abnormalities indicating meningitis argue against STSS or TSS.
- Creatine phosphokinase (CPK)
- May be elevated, reflecting skeletal muscle involvement
Imaging
Chest x-ray should be obtained if there is evidence of respiratory distress or oxygen requirement. ‚
- May show diffuse bilateral infiltrates in ARDS
Differential Diagnosis
- Septic shock from other bacterial or viral
- Streptococcal scarlatiniform eruption
- Leptospirosis
- RMSF or ehrlichiosis if travel to or living in endemic areas
- Kawasaki disease:
- TSS may present simultaneously with Kawasaki disease.
- Coronary artery dilatation has been reported in cases presenting as TSS.
- Toxic epidermal necrolysis (TEN)
- Drug-induced hypersensitivity reaction
Treatment
Special Therapy
- Remove all foreign bodies.
- Incision and drainage and or surgical debridement for abscess, myositis, and necrotizing fasciitis
Medication
First-line therapy should be broad initially and guided by local rates of methicillin-resistant Staphylococcus aureus (MRSA). ‚
- Vancomycin IV (15 mg/kg every 6 hours, max daily dose 4,000 mg) should be administered as first line if MRSA is a consideration.
- Renal toxicity is a known adverse effect.
- Dose should be adjusted for renal impairment and serum creatinine followed.
- Trough levels (before 4th dose) should be used to adjust dose under the guidance of an experienced pharmacist.
- Clindamycin IV (40 mg/kg divided every 6 " “8 hours, max daily dose 2,700 mg) should be administered in addition to 1st-line therapy to end production of toxins.
- Ceftriaxone (100 mg/kg divided every 12 " “24 hours, max daily dose 2,000 mg) should be added empirically for gram-negative coverage until organism or diagnosis is confirmed.
- Antistaphylococcal penicillins (i.e., nafcillin, oxacillin, dicloxacillin) may be considered in place of vancomycin if local MRSA rates are low.
- IVIG is commonly used as adjunct therapy to antibiotics, but its efficacy is unclear.
- Proposed mechanism is by providing neutralizing antibodies to exotoxins and inhibiting T-cell activation.
- Continue antibiotic therapy for at least 10 " “14 days; total treatment length should be guided by initial focus of infection if present.
- Consultation with infectious disease specialist is recommended in cases where the diagnosis is unclear.
- Therapy can be changed to oral when patient is tolerating oral nutrition.
Initial Stabilization
Treatment of suspected TSS or STSS should occur ideally at a tertiary care center with close access to a pediatric intensive care unit. ‚
- Initial resuscitation should proceed rapidly to support adequate tissue perfusion and oxygenation.
- IV isotonic fluid bolus should be given initially with further fluid boluses and pressor therapy guided by perfusion and vital signs
- Be mindful of potential cardiac dysfunction when providing fluid resuscitation.
- Stabilize airway if respiratory distress
- Antibiotic therapy should be administered as soon as possible.
Ongoing Care
Aside from antimicrobial therapy, the mainstays of treatment are supportive care for organ dysfunction. ‚
- Temperature usually returns to normal within 2 days if on effective therapy.
- Gastrointestinal, hepatic, and musculoskeletal changes resolve rapidly with rare permanent sequelae except for muscle weakness.
- Full-thickness desquamation of fingers, toes, palms, and soles begins 10 " “12 days after onset.
- Hair and nail loss may occur 4 " “16 weeks after illness onset; should resolve within 5 " “6 months.
- Encephalopathy is common but rarely causes seizures; usually resolves within 4 " “5 days.
- Poor prognosis is often heralded by development of pulmonary edema and worsening cardiac function.
- Cardiac and pulmonary failure are the most common causes of death.
- Toxin-mediated cardiomyopathy should resolve with effective treatment.
Prognosis
- Nonmenstrual TSS has a case fatality rate of 5%; menstrual TSS case fatality rate was approximately 1.8% between 1987 and 1996.
- STSS case fatality rate exceeds 50%.
- Recurrences are associated with inadequate treatment or persistent focus.
- Death usually occurs within the first few days but may occur as late as 2 weeks following onset.
Complications
Multisystem organ failure secondary to distributive shock/hypotension, including the following: ‚
- Pulmonary edema
- DIC
- Acute renal failure (oliguric and nonoliguric)
- Hepatic failure
- Myocardial dysfunction; may have arrhythmias
- Cerebral edema with toxic or ischemic encephalopathy
- Metabolic disturbances
- Tissue death and potentially limb amputation
- Neuropsychological disturbances including memory loss; abnormal electroencephalograms (EEGs) are rare
Additional Reading
- Bisno ‚ AL, Stevens ‚ DC. Streptococcal infection of skin and soft-tissues. N Engl J Med. 1996;334(4):240 " “245. ‚ [View Abstract]
- Byer ‚ RL, Bachur ‚ RG. Clinical deterioration among patients with fever and erythroderma. Pediatrics. 2006;118(6):2450 " “2460. ‚ [View Abstract]
- Low ‚ DE. Toxic shock syndrome: major advances in pathogenesis, but not treatment. Crit Care Clin. 2013;29(3):651 " “675. ‚ [View Abstract]
- O 'Loughlin ‚ RE, Roberson ‚ A, Cieslak ‚ PR, et al. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000 " “2004. Clin Infect Dis. 2007;45(7):853 " “862. ‚ [View Abstract]
- Shah ‚ SS, Hall ‚ M, Srivastava ‚ R, et al. Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. Clinical Infect Dis. 2009;49(9):1369 " “1376. ‚ [View Abstract]
Codes
ICD09
- 040.82 Toxic shock syndrome
- 041.11 Methicillin susceptible Staphylococcus aureus in conditions classified elsewhere and of unspecified site
- 041.01 Streptococcus infection in conditions classified elsewhere and of unspecified site, streptococcus, group A
ICD10
- A48.3 Toxic shock syndrome
- B95.61 Methicillin suscep staph infct causing dis classd elswhr
- B95.0 Streptococcus, group A, causing diseases classd elswhr
SNOMED
- 18504008 Toxic shock syndrome (disorder)
- 240450004 Staphylococcal toxic shock syndrome (disorder)
- 240451000 Streptococcal toxic shock syndrome (disorder)
FAQ
- Q: Can TSS recur?
- A: Yes. Inadequate eradication of the nidus of infection or inadequate treatment may result in recurrence. Poor immune function may also contribute to recurrence.
- Q: Can TSS be diagnosed in patients who have no risk factors?
- A: Yes. There have been reports meeting the case definition where none of the known associated factors was present.
- Q: Should I wait for confirmation of the diagnosis prior to treating with antibiotics?
- A: No. Antibiotic therapy should be initiated immediately in any patient suspected of having TSS.