1. Streptococcal & Staphylococcal Toxic Shock Syndrome (TSS) David A Wininger, MD Internal Medicine Residency Program Director Associate Professor, Clinical Internal Medicine Division of Infectious Diseases The Ohio State University Wexner Medical Center 614-293-3989 David.wininger@osumc.edu

2. Learning Objectives  Describe the nature and mechanisms of action of streptococcal and staphylococcal virulence factors as it related to Toxic Shock Syndrome (TSS)  Describe the role of molecular signals and cytokines involved in the pathophysiology of Toxic Shock Syndrome (TSS)  Compare and contrast the epidemiology, clinical manifestations, diagnosis, management and prognosis of streptococcal and staphylococcal Toxic Shock Syndrome (TSS)

3. Group A Streptococci: Virulence Factors  Toxins  Pyrogenic exotoxins SpeA, SpeB, SpeC, SpeF, etc. Streptococcal TSS Scarlet Fever  Structural  M-Protein  Lipoteichoic acid  F-Protein  Capsule  Enzymes  Streptolysin S  Streptolysin O  Streptokinases  DNases  C5a peptidase

4. Staphylococcus aureus TSST-1 & Enterotoxins are Superantigens  Or 2 separate slides

5. Superantigens in Staph and Strep Staphylococcal  Toxic Shock Syndrome Toxin - 1 (TSST-1)  Staphylococcal enterotoxins  At least 15 types  Staphylococcal exotoxins  Homologous to the enterotoxins Streptococcal  SPE-A, SPE-C (Scarlet Fever- coded by bacteriophage)  SPE-B, SPE-E, SPE-G, etc.  SSA (Streptococcal Superantigen)

6. Superantigens (such as TSST-1)

7. Cytokine Release after Nonspecific Superantigen Stimulation of T-cells  Primarily CD4+ T cell response is triggered by superantigen  T-helper Th1 response  IL-2, IFN-γ, IL-1β and TNF-α Immune Response  Given lack of Th2 response, antibody expression is decreased during response to superantigens  Lack of protective antibody to TSST-1 after first episode leaves ~50% patients vulnerable to recurrence

8. Toxic Shock Syndrome Epidemiology Staphylococcus aureus  TSST-1 producing strains  Menstruating women  Hyper absorbent tampons  Non-menstrual disease results from colonization of any site:  Surgical wounds (may not look hot)  Post-influenza lung  Other skin/soft tissue  Contraceptive diaphragms  5% mortality now that condition is routinely recognized

9. Toxic Shock Syndrome Epidemiology Streptococcus pyogenes (Group A)  M-serotypes 1 or 3  Mucoid strains – prominent capsules  Produce SPE’s  Can occur in patients of any age  Patients at risk: HIV infection, Diabetes mellitus, Cancer, Heart or Lung disease, Chicken-pox/Shingles, Injection drug use, Ethanol abuse  Mortality almost 50%

10. Toxic Shock Syndrome: Clinical Manifestations (Staphylococcal or Streptococcal)

11. Streptococcal Toxic Shock Syndrome Common Clinical Manifestations Cellulitis  Myositis  Necrotizing fasciitis (“Flesh Eating Strep”)

12. Toxic Shock Syndrome (TSS): Diagnosis Staphylococcal TSS  Usually a clinical diagnosis  Diagnostic criteria have been developed  Often lack positive cultures for staph  Staph can be cultured from colonized sites (mucosal surfaces)  Lack of anti-TSST1 antibodies during acute syndrome is expected.

13. Toxic Shock Syndrome (TSS): Diagnosis Streptococcal TSS  Cultures from involved sites are usually positive  Positive growth from sterile site (blood, deep tissue) is more definitive than positive culture from non-sterile site like superficial skin  Clinical diagnostic criteria are similar to those for Staph TSS

14. Toxic Shock Syndrome (TSS): Management Staphylococcal TSS  Supportive care  IV fluids, other blood pressure support, intensive care as needed (ventilator, renal dialysis, etc.)  Removal of potential focus  Anti-staphylococcal antibiotics even if cultures are negative.  Consider IVIG for more severe cases but usually not necessary

15. Toxic Shock Syndrome (TSS): Management Streptococcal TSS  Supportive care as with staph  Aggressive surgical debridement or other removal of infected source (site is usually overt)  Anti-streptococcal antibiotics (penicillin + clindamycin)  Clindamycin blocks protein synthesis (↓ toxin production)  IVIG more likely to be used, since cases are often more severe

16. Summary  Toxic Shock Syndrome (TSS) is mediated by superantigen toxins produced by Staphylococcus aureus and Group A Streptococcus.  Staphylococcal TSS is more likely to be a culture negative presentation of septic shock, while Streptococcal TSS is likely to manifest with a severe overt localizable infection of soft tissue or another body site.  Both aggressive supportive care and antimicrobial coverage of the causative organism are critical for successful management of TSS.  Intravenous immunoglobulin is a consideration for the management of severe TSS, since one hallmark of the acute condition is absence of antibodies against the superantigen toxin.

18. Thank you for completing this module If you have any questions, write to me at david.wininger@osumc.edu or try my office at 614-293-3989. david.wininger@osumc.edu David Wininger, MD

19. References  Medical Microbiology, 7th Ed. Murray, Rosenthal & Pfaller; Chapter 18 & 19, selected pages.  Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, Seventh Edition Chapter 195 and Chapter 198 selected pages (available electronically in Prior Health Sciences Library among the Core 25 Textbooks)

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