Toxic shock syndrome

Toxic shock syndrome (TSS) is a rare toxin-mediated life-threatening acute condition caused by toxin-producing strains of Streptococcus pyogenes and Staphylococcus aureus. These bacterial strains produce superantigenic exotoxins, which trigger massive cytokine release and cause endothelial cell wall damage; this can lead to capillary leak syndrome and end-organ damage. Risk factors for TSS include prolonged tampon placement, wounds (including surgical wounds), and invasive/aggressive Group A Streptococcus (GAS) infections (e.g., necrotizing fasciitis). TSS initially manifests with flu-like prodromal symptoms followed rapidly by symptoms of a systemic inflammatory response syndrome, which may progress to shock and multiple organ failure. Diagnostic studies often demonstrate end-organ dysfunction, and positive cultures can help narrow antibiotic therapy. TSS is a clinical diagnosis and treatment should be initiated as soon as TSS is suspected. Rapid recognition of TSS, followed by fluid resuscitation, appropriate antibiotic selection, reduction/neutralization of the toxin load, and removal of the infection source are essential for the management of TSS. TSS can be fatal if treatment is not initiated promptly; streptococcal TSS has a mortality rate of ∼ 30–80%.

Streptococcus pyogenes and Staphylococcus aureus both cause TSS; however, streptococcal TSS and staphylococcal TSS often differ in their etiologies, clinical presentation, laboratory findings, and mortality rates.

• Incidence: ∼ 0.5–3/100,000 ^[7][11]
• Age: Invasive GAS infections and subsequent complications are more common in young children and adults > 65 years of age. ^[3][9][12]

Epidemiological data refers to the US, unless otherwise specified.

TSS is most commonly caused by toxin-producing strains of Streptococcus pyogenes and Staphylococcus aureus ^[3]

TSS is a systemic inflammatory response, similar to sepsis; see also “Pathophysiology” in “Sepsis.”

• Superantigen production: Causative organisms (S. pyogenes and S. aureus) produce superantigens (see “Superantigens implicated in TSS”)
• Superantigen-mediated T-cell activation ^[1]
  • Superantigens bypass processing and presentation by antigen-presenting cells.
  • Superantigens directly connect the MHC class II molecule on antigen-presenting cells to the T-cell receptor on T-cells by forming a bridge outside of the normal binding sites → nonspecific T-cell activation → rapid activation of excessive numbers of T cells → massive cytokine release ^[1][2][3]
• SIRS: ↑↑↑ Cytokines → generalized endothelial disruption → capillary leak syndrome → generalized edema → intravascular hypovolemia → organ dysfunction and disseminated intravascular coagulation (DIC)

Very small amounts of superantigens can rapidly activate excessive numbers of T cells, triggering a massive release of proinflammatory cytokines, resulting in SIRS

TSS typically manifests as a prodrome of nonspecific symptoms, followed by hypotension and rapid progression (8–12 hours) to end-organ involvement. ^[3]

Onset

• Streptococcal TSS: variable onset
• Staphylococcal TSS
  • Menstrual etiology: peak onset on days 3–4 of menstruation ^[1][11]
  • Postsurgical and postpartum TSS: typically < 48 hours after surgery or delivery ^[8][17]

Prodrome ^[1]

• Flu-like symptoms: high fever, chills, myalgia, headache, nausea, vomiting, diarrhea
• Dermal rash: more common in menstrual staphylococcal TSS than in nonmenstrual staphylococcal TSS and streptococcal TSS ; ^[7][18]
  • Transient erythematous macular (sunburn-like) rash
  • Commonly involves the palms and soles
  • Typically desquamates 1–2 weeks after onset.
• Mucosal involvement ^[8][19]
  • Strawberry tongue
  • Nonpurulent conjunctivitis
  • Oropharyngeal hyperemia
• Evidence of points of entry: superficial cuts or burns; surgical wounds ^[3]
• Evidence of underlying GAS infections: deep infections, e.g., cellulitis, myositis, necrotizing fasciitis (may occur following blunt trauma)

Suspect underlying necrotizing fasciitis or myositis in patients with pain out of proportion to physical findings on examination.

Shock and end-organ dysfunction ^[3]

• Early: : tachycardia, tachypnea, high fever, altered mental status ^[10][20]
• Late
  • Hypotension
  • Delayed capillary refill
  • Worsening altered mental status
  • Evidence of organ failure
  • Signs of deranged clotting, e.g., purpura fulminans
  • Mucosal ulceration

General principles

• Suspect TSS in a previously healthy individual presenting with hypotension and rapidly progressive multiorgan dysfunction preceded by fever with or without a rash.
• The presence of any risk factor for TSS should further raise suspicion of TSS.
• Obtain blood cultures and initiate empiric antibiotic therapy for TSS as soon as TSS is suspected.
• Workup for sepsis and obtain additional focused cultures based on the suspected site(s) of primary infection.
• Consider differential diagnoses of TSS and obtain diagnostics as needed.
• Consider imaging to assess for alternate diagnoses, underlying conditions, and complications.
• Consider toxin studies in patients with suspected staphylococcal TSS.

Initiate empiric antibiotic therapy for TSS as soon as TSS is suspected; do not wait for the results of laboratory studies.

Laboratory studies ^[21][22]

Workup for sepsis

Findings are typically nonspecific but may show evidence of infection and end-organ involvement.

• CBC
  • Normal or ↑ WBC with significant left shift
  • Anemia ^[9]
  • Thrombocytopenia
• Coagulation screen: ↑ PT, ↑ PTT, ↓ fibrinogen, ↑ fibrin degradation products
• Liver chemistries: ↑ ALT/AST, ↑ total bilirubin, ↓ albumin, ↓ total protein
• Basal metabolic panel ^[9]
  • Serum: ↑ BUN, ↑ creatinine
  • Hypocalcemia ^[23]
• VBG/ABG: ↑ lactate; ABG may show signs of respiratory failure
• Inflammatory markers: ↑ ESR, ↑ CRP
• Creatine kinase: may be elevated
• Urinalysis: urinary sediment, ↑ urine leukocytes without UTI (sterile pyuria)

Bacteriology

• Blood cultures: Obtain blood cultures in all patients, preferably before administering empiric antibiotics.
  • Streptococcal TSS: typically positive (∼ 60% of cases)
  • Staphylococcal TSS: typically negative (positive in < 5% of cases)
• Focused cultures
  • Perform a complete physical examination to identify any potential primary sites of infection.
  • Obtain cultures from any suspected source(s) of infection (e.g., skin, vagina, nares, wounds)
• CSF culture: Consider to rule out alternative diagnoses (e.g., meningitis, encephalitis) in patients with fever and altered mental status.

Blood cultures are typically negative in staphylococcal TSS.

Toxin-specific studies

• TSST-1 assay of S. aureus culture isolate ^[24]
  • Consider in patients with suspected staphylococcal TSS.
  • A positive TSST-1 assay supports a diagnosis of staphylococcal TSS.
• TSST-1 antibody titers ^{[1][3][11][24]}
  • Consider in patients with menstrual TSS or recurrent staphylococcal TSS.
  • Undetectable or low antibody titers indicate an increased risk of recurrent TSS.
    • Approximately 90% of patients with menstrual TSS have low or undetectable TSST-1 antibody levels during the illness.
    • Up to two-thirds of these patients do not develop protective antibodies following recovery.

Imaging

Imaging is not needed to make a diagnosis of TSS, but it may be considered if patients have the following symptoms:

• Severe muscle pain: CT or MRI of the affected region to evaluate for myositis, necrotizing fasciitis , or an abscess
• Altered mental status: CT head to rule out an alternate intracranial cause ^[25]
• Respiratory symptoms: CXR to evaluate for concurrent pneumonia or the development of ARDS

The symptoms of TSS overlap with many other conditions, including the following:

• Sepsis
• Necrotizing soft tissue infections
• Stevens-Johnson syndrome
• Staphylococcal scalded skin syndrome
• DRESS syndrome
• Kawasaki disease
• Scarlet fever
• Rocky Mountain spotted fever
• Leptospirosis
• Meningococcemia
• See also “Differential diagnoses by associated finding” in “Fever.”

Approach ^{[1][3][11][26]}

• Hemodynamic resuscitation as needed
• Identify and manage the source of infection; obtain cultures of the suspected primary site(s) of infection.
• Initiate empiric antibiotic therapy for TSS within 1 hour of presentation; consider IVIG as adjunctive therapy in streptococcal TSS.
• Consider measures to prevent recurrent TSS, especially in patients with staphylococcal TSS.
• TSS is a reportable disease in the US; see “Public health surveillance” below for details.

TSS is a life-threatening emergency that requires early diagnosis and a multidisciplinary approach to management.

Hemodynamic resuscitation

• Urgent IV fluid resuscitation is indicated for hemodynamically unstable patients.
• Hypotension refractory to fluids: Administer vasopressors for septic shock.
• See “Management of sepsis” for further guidance.

Management of source(s) of infection ^[3][8]

• Examine for skin lesions and wounds.
• Remove any foreign bodies (e.g., tampons, nasal packs, surgical packs).
• Drain infected fluid collections (e.g., abscess).
• Urgent surgical consult for suspected necrotizing fasciitis/myositis.

Obtain cultures from any potential site(s) of infection.

Antibiotic therapy ^[11][27][28]

• Indication: all patients with suspected TSS; preferably initiated within an hour of presentation
• Coverage required
  • A bactericidal antibiotic that covers both S. pyogenes and S. aureus (i.e., vancomycin, beta-lactam antibiotic)
  • PLUS a protein-synthesis inhibitor (e.g., clindamycin, linezolid).
  • Tailor antibiotic therapy to the antibiotic sensitivities once known.
  • For patients with penicillin allergy, replace the beta-lactam antibiotic with vancomycin.
• Total duration of antibiotic therapy: not well-defined; 2 weeks minimum
• Treat concurrent or underlying infection: e.g., see “Antibiotic therapy for skin and soft tissue infection”

Protein synthesis-inhibiting antibiotics inhibit toxin production but as they are bacteriostatic, they should be used in combination with a bactericidal antistreptococcal and/or antistaphylococcal antibiotic.

Adjunctive therapy ^[11]

• Consider IVIG in adults with streptococcal TSS (e.g., those with hypotension refractory to vasopressors). ^[3][27]

Consults and disposition

• Urgent consultation of appropriate specialists:
  • Based on the location of the infection: ENT, OB/GYN, surgery, orthopedics
  • To guide medical management: critical care and infectious disease
• Consider admission to an intensive care unit, as patients can deteriorate rapidly.

• Suspect TSS in an otherwise healthy individual presenting with hypotension and rapidly progressive multi-organ dysfunction preceded by fever with/without a rash.
• Assess for signs of sepsis; if present, see also “Acute management checklist for sepsis.”
• In patients with hypotension and signs of shock:
  • Start IV fluid resuscitation.
  • If the patient remains hypotensive, consider vasopressors
• Initiate empiric antibiotic therapy for TSS within 1 hour of presentation.
• Identify and manage any likely source of infection.
• Urgently consult appropriate surgical services, as needed: ENT, OB/GYN, general surgery, orthopedics.
• Consult critical care/infectious disease to guide management.
• Toxic shock syndrome is a reportable disease; see “Public health surveillance.”

• TSS is a reportable disease in the United States. ^[21][22]
• The CDC has described features that are typical of streptococcal TSS and nonstreptococcal TSS for reporting purposes only; these criteria should not be used for diagnosis or to guide treatment.

Use these criteria for reporting only, not diagnosis! Early, aggressive treatment is recommended to prevent dangerous sequelae even if not all criteria have been met.

• Recurrent TSS ^[6]
• Organ failure
• Limb loss
• Death
  • Streptococcal TSS: mortality rate 30–80% ^[1][3][7]
  • Staphylococcal TSS: mortality rate 5–10% (menstrual staphylococcal TSS < 5%, nonmenstrual staphylococcal TSS up to 20%) ^[3][7][10]

We list the most important complications. The selection is not exhaustive.

• Most often occurs with staphylococcal TSS
• Caused by persistent colonization by TSST-1-producing strains of S. aureus in patients with an inadequate antibody response to a previous episode of TSS ^[6]
• TSST-1 antibody titers help identify patients at risk of developing recurrent TSS.
• Arrange a follow-up appointment for patients with staphylococcal TSS after discharge to screen for colonization of TSST-1-producing S. aureus.
• Consider nasal decolonization with mupirocin and/or vaginal decolonization with antistaphylococcal antibiotics. ^[11][24]
• Consider topical decolonization with chlorhexidine washes in patients with recurrent skin and soft tissue staphylococcal infections. ^[30]
• Educate patients to avoid the use of tampons, menstrual cups, or sponges if they have a history of menstrual TSS. ^[11]