Toxic Shock Syndrome

Toxic shock syndrome (TSS) is an acute, multi-systemic disease caused by the toxin-producing bacteria, Staphylococcus aureus and Streptococcus pyogenes. Staphylococcal TSS is more common and associated with tampons and nasal packing. Streptococcal TSS is commonly due to invasive group A streptococcal (GAS) infections, such as bacteremia and necrotizing fasciitis, and has a higher mortality rate. Patients present with fever, tachycardia, hypotension, an erythematous rash, and evidence of multi-system organ dysfunction. The diagnosis is based on clinical, laboratory, and culture data. Management involves intravenous fluid (IVF) resuscitation, antibiotics, vasopressor support, and identification and management of the potential infectious source.

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Epidemiology and Etiology

Epidemiology

  • Staphylococcal toxic shock syndrome (TSS):
    • More common than streptococcal TSS
    • Incidence: 6–7 cases per 100,000 people annually  
      • Half are associated with menstruation.
      • Incidence declined with the withdrawal of highly absorbent tampons.
    • More common in women
    • Mortality: 1.8%
  • Streptococcal TSS:
    • Incidence: 4 cases per 100,000 people annually
    • Develops in up to ⅓ of patients with invasive group A Streptococcus (GAS) infections
      • S. pyogenes bacteremia
      • Necrotizing fasciitis
    • Mortality: 30%–79%

Etiology

Toxic shock syndrome (TSS) is an acute, multi-systemic disease caused by toxin-producing bacteria:

  • Staphylococcus aureus
  • Streptococcus pyogenes (GAS)

Risk factors:

  • Staphylococcal TSS:
    • Prolonged or highly absorbent tampon use
    • Vaginal colonization with toxin-producing S. aureus
    • Nasal packing
    • Surgical and postpartum wound infections
  • Streptococcal TSS:
    • No site of entry is found in 45% of patients.
    • Minor trauma
    • Surgical procedures
    • Viral infections (e.g., varicella, influenza)

Pathophysiology

  • TSS is an immune-mediated disorder caused by a superantigen (SAg):
    • S. aureus:
      • TSS toxin type-1 (TSST-1)
      • Enterotoxin B
    • GAS: streptococcal pyrogenic exotoxins (Spe) A and C
  • SAg binds to major histocompatibility complex (MHC) class II on antigen-presenting cells (APCs).
  • MHC on APCs cross-links with the β region of the T cell receptor (TCR).
  • Stimulates T cell activation and an exaggerated cytokine release
  • Results in an excessive inflammatory response with systemic capillary leak (shock) and organ damage

Clinical Presentation

Both staphylococcal and streptococcal TSS present similarly, with a rapid onset of signs and symptoms (within hours).

General signs and symptoms

  • Symptoms:
    • Fever and chills
    • Orthostasis
    • Syncope
    • Nausea and vomiting
    • Abdominal pain
    • Watery diarrhea
    • Myalgias
  • Vitals:
    • Temperature:
      •  ≥ 38.9°C (102°F)
      • Hypothermia can also be seen.
    • Hypotension (systolic blood pressure ≤ 90 mm Hg): usually not responsive to intravenous fluid (IVF) resuscitation

Multi-organ involvement

  • Cutaneous:
    • Diffuse macular erythroderma (resembles a sunburn)
    • Desquamation 1–2 weeks later
    • Cyanosis
    • Extremity non-pitting edema
    • Streptococcal TSS:
      • Localized pain and swelling at an area of trauma or infection
      • Should evaluate for necrotizing fasciitis (rapidly progressive erythema, edema, pain, crepitus, skin bullae, necrosis, or ecchymosis)
  • Mucous membranes:
    • Conjunctival or scleral hemorrhage
    • Vaginal hyperemia
    • Oropharyngeal mucosa hyperemia
    • Superficial ulcerations or bullae
  • Respiratory:
    • Acute respiratory distress syndrome (ARDS)
    • Pleural effusions
    • Pulmonary edema
  • Hepatic: liver dysfunction
  • Hematologic: disseminated intravascular coagulopathy (DIC)
  • Renal: renal failure
  • Neurologic:
    • Headache
    • Encephalopathy:
      • Somnolence
      • Confusion
      • Irritability
      • Hallucinations

Diagnosis

Laboratory evaluation

  • Blood and wound cultures:
    • S. aureus isolation is not required for a diagnosis of staphylococcal TSS.
    • GAS isolation is used to confirm the diagnosis of streptococcal TSS.
  • Complete blood cell (CBC) count:
    • Leukopenia or leukocytosis with left shift
    • Anemia
    • Thrombocytopenia
  • Basic metabolic panel:
    • ↑ Blood urea nitrogen (BUN) and creatinine
    • ↓ Sodium, calcium, and phosphorus
  • Hepatic function tests:
    • ↑ Aspartate and alanine aminotransferases (AST and ALT), total bilirubin
    • ↓ Albumin
  • ↑ Creatine phosphokinase (CPK)
  • Coagulation studies to evaluate for DIC

Supporting workup

  • Lumbar puncture in patients with fever and altered mental status to rule out meningitis
  • Chest radiograph to evaluate for ARDS in patients with respiratory distress
  • Computed tomography (CT) or magnetic resonance imaging (MRI) of soft tissues to localize sites of infection

Clinical criteria

The following criteria are used to define TSS, according to the Centers for Disease Control and Prevention (CDC):

Staphylococcal TSS:

  • Fever ≥ 38.9°C (102°F)
  • Diffuse macular rash
  • Desquamation 1–2 weeks after the onset of the rash
  • Severe hypotension
  • Multi-organ dysfunction (≥ 3 of the following):
    • Renal: ↑ BUN or creatinine
    • Hepatic: ↑ AST, ALT, or total bilirubin 
    • Gastrointestinal: vomiting or diarrhea
    • Muscular: severe myalgia or ↑ CPK
    • Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia
    • Hematologic: thrombocytopenia
    • Central nervous system: altered, confused, disoriented, or unresponsive
  • Negative blood or cerebrospinal fluid cultures (except S. aureus)
  • Negative tests for Rocky Mountain spotted fever, measles, or leptospirosis

Streptococcal TSS:

  • Hypotension
  • Multi-organ dysfunction (≥ 2 of the following): 
    • Respiratory: ARDS or pleural effusions with hypoalbuminemia
    • Cutaneous: an erythematous rash that may desquamate, soft tissue necrosis, gangrene, or necrotizing fasciitis
    • Renal: ↑ creatinine
    • Hepatic: ↑ AST, ALT, or total bilirubin 
    • Hematologic: thrombocytopenia or DIC
  • Blood culture isolation of GAS

Management

  • Intensive care management:
    • IVF resuscitation
    • Antibiotics:
      • Clindamycin (suppresses toxin production)
      • Plus vancomycin
      • Plus piperacillin-tazobactam, cefepime, or meropenem
      • Regimen should be tailored once the culture data is available.
    • Vasopressor support
    • Ventilator support for patients in ARDS
    • Hemodialysis may be required for renal failure.
    • Intravenous immune globulin (IVIG): 
      • Can be used in severe cases
      • Favored in streptococcal TSS
  • Examine for a cause:
    • Retained tampons
    • Evidence of soft tissue infections or necrotizing fasciitis
  • Source control:
    • Surgical wound irrigation
    • Debridement of devitalized tissue
    • Irrigation of potentially colonized sites (e.g., nasal sinuses, vagina)

Differential Diagnosis

  • Septic shock: organ dysfunction resulting from a dysregulated systemic host response to an infection (usually bacterial), resulting in vasodilation, vascular leak, and volume depletion. Patients commonly present with fever, tachycardia, tachypnea, fluid-responsive hypotension, and altered mentation. Prompt recognition is essential, and combines the clinical presentation with supporting infectious data. Management requires aggressive IVF resuscitation, vasopressors, and antibiotics.
  • Stevens-Johnsons syndrome: a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. Stevens-Johnson syndrome runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Patients will present with a flu-like prodrome, followed by cutaneous bullae and sloughing on the face, thorax, and mucous membranes. Diagnosis is clinical. Prompt withdrawal of the causative agent is required, and management is largely supportive. 
  • Meningococcal meningitis: a bacterial infection of the meninges and subarachnoid space, due to Neisseria meningitidis. Patients present with insidiously progressive symptoms, including fever, headache, photophobia, malaise, nuchal rigidity, and a petechial or purpuric rash. Diagnosis is based on cerebrospinal fluid analysis and cultures. Management includes antibiotics and corticosteroids.
  • Rocky Mountain spotted fever: a disease caused by Rickettsia rickettsii that presents with fever, fatigue, headache, and a rash following a tick bite. The rash begins on the distal extremities and spreads centrally. The diagnosis is made based on the clinical features, biopsy of the rash, and serologic testing. Treatment involves antibiotics, including doxycycline.
  • Leptospirosis: a zoonotic disease caused by Leptospira. Rodents are the most important reservoir. Symptoms can include a flu-like illness and rash. Systemic disease occurs in a minority of patients, and includes hemorrhage, renal failure, and jaundice. The diagnosis is made with serology and dark field microscopy. Management is primarily with penicillin.
  • Measles: a highly contagious viral infection caused by a paramyxovirus that presents with fever, cough, coryza, conjunctivitis, and a maculopapular rash that will eventually desquamate. The diagnosis is clinical and supported by serologic testing. Management involves isolation and supportive treatment.

References

  1. Chu, V.H. (2020). Staphylococcal toxic shock syndrome. In Baron, E.L. (Ed.), Uptodate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/staphylococcal-toxic-shock-syndrome
  2. Stevens, D.L. (2020). Invasive group A streptococcal infection and toxic shock syndrome. Epidemiology, clinical manifestations, and diagnosis. In Baron, E.L. (Ed.), Uptodate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/invasive-group-a-streptococcal-infection-and-toxic-shock-syndrome-epidemiology-clinical-manifestations-and-diagnosis
  3. Stevens, D.L. (2020). Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention. In Baron, E.L. (Ed.), Uptodate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/invasive-group-a-streptococcal-infection-and-toxic-shock-syndrome-treatment-and-prevention
  4. Centers for Disease Control and Prevention. Toxic shock syndrome (other than streptococcal) (TSS) 2011 case definition. Retrieved January 16, 2021, from https://wwwn.cdc.gov/nndss/conditions/toxic-shock-syndrome-other-than-streptococcal/case-definition/2011/
  5. Centers for Disease Control and Prevention. Streptococcal toxic shock syndrome (STSS) (Streptococcus pyogenes) 2010 case definition. Retrieved January 16, 2021, from https://wwwn.cdc.gov/nndss/conditions/streptococcal-toxic-shock-syndrome/case-definition/2010/
  6. DeVries, A.S., Lesher, L., Schlievert, P.M., Rogers, T., Villaume, L.G., Danila, R., & Lynfield, R. (2011). Staphylococcal toxic shock syndrome 2000-2006: Epidemiology, clinical features, and molecular characteristics. PloS one, 6(8), e22997. https://doi.org/10.1371/journal.pone.0022997
  7. Bush, L.M., & Vazquez-Pertejo, M.T. (2019). Toxic shock syndrome (TSS). [online] MSD Manual Professional Version. Retrieved January 16, 2021, from https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-cocci/toxic-shock-syndrome-tss
  8. Venkataraman, R., & Sharma, S. (2020). Toxic shock syndrome. In Pinsky, M.R. (Ed.), Medscape. Retrieved January 16, 2021, from https://emedicine.medscape.com/article/169177-overview

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