Toxic Shock Syndrome (TSS)

1. Introduction and Definition

Toxic Shock Syndrome (TSS) is an acute, life-threatening, multisystem disorder characterized by high fever, hypotension, diffuse erythroderma (rash), and multiple organ dysfunction. Historically associated with menstruation and high-absorbency tampon use in the late 1970s and early 1980s, TSS is now recognized as a complication of various staphylococcal and streptococcal infections in men, women, and children.

The syndrome is primarily toxin-mediated, caused by superantigens produced by Staphylococcus aureus or Streptococcus pyogenes (Group A Streptococcus [GAS]). While Staphylococcal and Streptococcal TSS share pathophysiologic mechanisms, they differ significantly in clinical presentation, epidemiology, and mortality.

2. Etiology and Epidemiology

2.1. Staphylococcal TSS

• Causative Agent: Staphylococcus aureus.
• Toxins: The majority of menstrual TSS cases are caused by Toxic Shock Syndrome Toxin-1 (TSST-1). Non-menstrual cases are associated with TSST-1 or staphylococcal enterotoxins (types A, B, C, D, E, and H).
• Epidemiology:
  • Menstrual TSS: Associated with prolonged use of high-absorbency tampons. The neutral pH and oxygen levels during menstruation facilitate toxin production.
  • Non-Menstrual TSS: Occurs in children and adults associated with focal infections such as abscesses, burns, infected insect bites, surgical wounds, nasal packing, sinusitis, tracheitis, and pneumonia.
  • MRSA vs. MSSA: The majority of S. aureus strains causing TSS are methicillin-susceptible (MSSA), although MRSA-associated TSS occurs.

2.2. Streptococcal TSS (STSS)

• Causative Agent: Streptococcus pyogenes (Group A Streptococcus).
• Toxins: Primarily Streptococcal Pyrogenic Exotoxins (SpeA and SpeC), which act as superantigens.
• Epidemiology: Often associated with severe invasive disease (necrotizing fasciitis, bacteremia, pneumonia). The portal of entry is often the skin (cuts, burns, varicella lesions) or mucous membranes, though in 50% of cases, no portal is identified.

3. Pathogenesis: The Superantigen Concept

The hallmark of TSS pathogenesis is the action of superantigens.

1. Mechanism: Conventional antigens activate only 0.01% to 0.1% of T-cells by binding to the specific antigen-binding groove of the MHC Class II molecule and the T-cell receptor (TCR). Superantigens, however, bind directly to the outer portion of the MHC Class II molecule and the V$\beta$ region of the TCR, bypassing the need for antigen processing.
2. Cytokine Storm: This "short-circuiting" activates a massive number of T-cells (up to 20% of the total T-cell pool). This results in the uncontrolled release of proinflammatory cytokines, particularly Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-$\alpha$).
3. Clinical Effects: These cytokines mediate the clinical features:
   • TNF-$\alpha$ and IL-1: Fever, hypotension, shock, and increased capillary permeability (capillary leak syndrome) leading to hypoalbuminemia and edema.
   • Direct Tissue Injury: Toxin-mediated endothelial damage leads to disseminated intravascular coagulation (DIC) and multiorgan failure.
4. Lack of Antibody Response: In Staphylococcal TSS, a critical risk factor is the host's lack of neutralizing antibodies against the toxin. Most adults have protective antibodies to TSST-1; those who develop TSS fail to mount an adequate antibody response during the acute illness, predisposing them to recurrence.

4. Clinical Manifestations

4.1. Staphylococcal TSS

The onset is typically abrupt.

• Prodrome: High fever (>38.9°C), chills, myalgia, vomiting, and diarrhea.
• Dermatologic: A diffuse, macular erythroderma (sunburn-like rash) appears within 24 hours. There is often hyperemia of the conjunctival, oropharyngeal, and vaginal mucous membranes. "Strawberry tongue" may be present.
• Hypotension: Systolic BP <90 mm Hg (or <5th percentile for age in children) leading to shock.
• Desquamation: A classic feature occurring 1–2 weeks after onset, typically involving the palms and soles.
• Multisystem Involvement: Confusion/encephalopathy, renal failure (elevated BUN/Creatinine), hepatic dysfunction, and thrombocytopenia are common.

4.2. Streptococcal TSS

Clinically distinct from Staphylococcal TSS in several ways:

• Pain: Severe, localized pain at a site of soft tissue infection is a hallmark early symptom, often preceding physical findings of infection (e.g., in necrotizing fasciitis).
• Focal Infection: Most patients have an identifiable focus, such as cellulitis, fasciitis, or pneumonia.
• Rash: A scarlatiniform or generalized rash occurs but is less common than in Staphylococcal TSS.
• Course: Progression to shock and acute respiratory distress syndrome (ARDS) is often rapid and fulminant.

5. Diagnostic Criteria

Diagnosis is clinical, supported by laboratory evidence of multisystem involvement and the exclusion of other causes.

5.1. Staphylococcal TSS Case Definition (CDC 2011)

1. Clinical Criteria:

• Fever: Temperature $\ge$ 38.9°C (102.0°F).
• Rash: Diffuse macular erythroderma.
• Desquamation: 1–2 weeks after onset (palms/soles).
• Hypotension: SBP $\le$ 90 mmHg (adults) or <5th percentile (children).
• Multisystem Involvement (3 or more of the following):
  • GI: Vomiting or diarrhea at onset.
  • Muscular: Severe myalgia or CPK >2x upper limit of normal.
  • Mucous Membrane: Vaginal, oropharyngeal, or conjunctival hyperemia.
  • Renal: BUN or Creatinine >2x normal or pyuria without UTI.
  • Hepatic: Bilirubin or Transaminases >2x normal.
  • Hematologic: Platelets <100,000/mm³.
  • CNS: Disorientation or alteration in consciousness without focal signs.

2. Laboratory Criteria:

• Negative serologies for RMSF, Leptospirosis, Measles.
• Blood/CSF cultures negative (except S. aureus blood culture may be positive).

3. Classification:

• Confirmed: Meets laboratory criteria + all 5 clinical criteria (including desquamation, unless patient dies before it occurs).
• Probable: Meets laboratory criteria + 4/5 clinical criteria.

5.2. Streptococcal TSS Case Definition

1. Isolation of Group A Streptococcus:

• From a sterile site (Definite Case).
• From a non-sterile site (Probable Case).

2. Clinical Signs:

• Hypotension PLUS two or more of:
  • Renal impairment.
  • Coagulopathy.
  • Liver involvement.
  • ARDS.
  • Generalized erythematous macular rash (may desquamate).
  • Soft tissue necrosis (necrotizing fasciitis, myositis, gangrene).

6. Differential Diagnosis

• Septic Shock: Bacterial sepsis (Meningococcemia, Gram-negative sepsis).
• Kawasaki Disease: Shares features like fever, rash, mucosal changes, and desquamation. However, Kawasaki disease rarely presents with hypotension/shock, diffuse myalgia, or renal failure (azotemia).
• Multisystem Inflammatory Syndrome in Children (MIS-C): A post-COVID-19 hyperinflammatory syndrome with significant overlap (fever, rash, shock, cardiac dysfunction). Serology for SARS-CoV-2 helps distinguish.
• Drug Reactions: Stevens-Johnson Syndrome (SJS), DRESS syndrome.
• Other Infections: Rocky Mountain Spotted Fever (RMSF), Leptospirosis, Measles, Scarlet Fever.

7. Management

Successful management requires early recognition, aggressive resuscitation, source control, and specific antimicrobial therapy.

7.1. Immediate Stabilization (Resuscitation)

• Fluid Resuscitation: Patients often have profound hypovolemia due to capillary leak. Aggressive fluid replacement with crystalloids is essential to restore perfusion.
• Inotropic Support: Vasopressors (e.g., epinephrine, norepinephrine) are frequently required for refractory hypotension.
• Respiratory Support: Oxygenation and ventilation for patients with ARDS or depressed sensorium.

7.2. Source Control

• Search and Eliminate: Locate the nidus of toxin production.
• Interventions: Remove tampons or nasal packing immediately. Drain abscesses. Debride infected wounds. In cases of necrotizing fasciitis (Strep TSS), prompt and aggressive surgical debridement is critical and life-saving.

7.3. Antimicrobial Therapy

Empiric therapy must cover both S. aureus (including MRSA) and S. pyogenes.

• Protein Synthesis Inhibitor (The "Eagle Effect"):

  • Clindamycin: Clindamycin is a crucial component of therapy. Unlike beta-lactams, its efficacy is not affected by the inoculum size (Eagle effect). More importantly, it is a protein synthesis inhibitor that suppresses the production of bacterial toxins (TSST-1, SpeA) and M-proteins.
  • Dose: Parenteral Clindamycin is recommended as adjunctive therapy.

• Bactericidal Agent:

  • A beta-lactamase-resistant antistaphylococcal agent (e.g., Nafcillin or Oxacillin) or Cefazolin is used for MSSA.
  • Vancomycin is added if MRSA is suspected or prevalent in the community.
  • For Streptococcal TSS, Penicillin G + Clindamycin is the standard regimen.

• Duration: Therapy is typically continued for 10–14 days, depending on the focus of infection.

7.4. Adjunctive Therapies

• Intravenous Immunoglobulin (IVIG):
  • Mechanism: IVIG contains neutralizing antibodies against bacterial superantigens. It may dampen the cytokine storm.
  • Indication: Considered for severe cases of Staphylococcal or Streptococcal TSS refractory to standard therapy.
  • Dose: Regimens vary; high-dose (1–2 g/kg) is often suggested.
• Corticosteroids: Efficacy is debated; not routinely recommended unless there is adrenal insufficiency or specific indication (e.g., refractory shock).

8. Prognosis and Complications

• Mortality:
  • Staphylococcal TSS: Mortality is lower, approximately 3–5% for treated cases.
  • Streptococcal TSS: Mortality is significantly higher, ranging from 30% to 70%, largely due to the aggressive nature of invasive streptococcal disease and rapid onset of shock.
• Recurrence: Recurrent episodes of Staphylococcal TSS can occur, especially in menstrual cases if tampon use is continued, because protective antibodies may not develop after the initial attack.
• Sequelae: Hair and nail loss may occur 1–2 months after recovery. Renal and cardiac functions usually recover, but severe limb ischemia (purpura fulminans) may require amputation.

9. Prevention

• Menstrual TSS: Avoid high-absorbency tampons; change tampons frequently (every 4–8 hours); alternate with pads. History of TSS is a contraindication to future tampon use.
• Wound Care: Proper cleansing and monitoring of wounds, burns, and surgical sites.
• Chemoprophylaxis: Not routinely recommended for contacts of Strep TSS cases unless they are severely immunocompromised or ill.

Summary Table: Staphylococcal vs. Streptococcal TSS