Toxic shock syndrome (TSS) is a toxin-mediated disease caused by Staphylococcus aureus or Streptococcus pyogenes bacteria that results in shock and organ failure. It is associated with the use of tampons and barrier contraceptives. A 15-year-old female presented with headache, fever, rash, abdominal pain and vomiting consistent with TSS, having left a tampon in for over 12 hours. She received IV antibiotics and supportive care and was discharged after improvement. TSS is a medical emergency treated with antibiotics to reduce bacterial load and prevent further endotoxin production.

1. Toxic Shock Syndrome Janet Zhang M.D. 1/5/2012

2. S.M. HPI: 15 yo G0 presented to Pediatric Urgent Clinic with complaints of headache, fever, rash, abdominal pain and nausea/vomiting. Pt states that it started with a headache 2 days prior, followed by fever of 102 F the night before. She then developed abdominal/epigastric pain, and tender rash of the hands, feet, thighs and perineum. Rash started around the perineum and spread to the rest of the body. Rash is also associated with burning sensation and tingling of the extremities. LMP 1 week prior to presentation. Using tampons and left 1 in for > 12 hours. Also accidentally dropped a tampon in the toilet at school and fished out to use it. OB/GYN Hx: Menarche 12, heavy periods, 8 day flow, uses super plus tampons. Sexually active, using condoms.

3. S.M. PMH: none PSH: tonsillectomy Meds: none Allergies: NKDA FHx: non contributory Social Hx: no smoking, occasional EtOH Vitals: 37.2 C/98.9 F (Clinic), BP 99/62, Pulse 85, Temp 99.5 °F (37.5 °C), Resp 16, SpO2 98% (ED)

4. S.M. Exam: Abdomen: Soft. Normal appearance. Bowel sounds are normal. She exhibits no distension and no mass. There is no hepatosplenomegaly. Tenderness is present in the epigastric area. She has no rigidity, no rebound, no guarding and no CVA tenderness. Genitourinary: Vulva exhibits erythema. Vulva exhibits no exudate, no lesion, no rash and no tenderness. No discharge found. Vulva hyperemic and swollen. Tender. Skin: Fine red scarlitini-like rash on inner thighs, hands and feet. Few on abdomen. ED Exam: “Rash on the perineum that is spreading down her legs. She has another rash on her upper back and chest. The rash is raised red and tender to palpation.”

5. Labs 9/2/2011 WBC'S AUTO 7.6 RBC AUTO 4.86 HGB 13.3 HCT AUTO 39.6 MCV 81.4 MCH 27.4 MCHC 33.7 RDW, BLOOD 16.4 (H) PLT'S AUTO 236 MPV 8.0 LYMPHS % AUTO 11.2 (L) MONOS % AUTO 5.4 NEUTROPHILS % AUTO 78.8 (H) EOS % AUTO 4.5 BASO'S % AUTO 0.1 RBC NUCLEATED, AUTO 0.0 TBILI 1.8 (H) ALKP 151 ALT 151 (H) ESR WEST 23 (H) CRP 64.0 (H) AST 138 (H) Creatinine 0.8 UA GLUC <30 (NEG) UA KETONES <10 (NEG) UA SP GR 1.026 UA HGB 0.50 (2+) (A) PH UA 7.5 UA PROT 30 (1+) (A) UA NO2 NEGATIVE LE, UA POSITIVE (A) UROBILINOGEN UA QL >12.0 (4+) (A) UA BILI 1.0 (1+) (A) RBC, UA/HPF 4-10 (A) UA WBC'S/HPF >25 (A) UA BACT/HPF FEW (A) SQUAM EPITHE CELL URNS AUTO QUAL FEW (A) TRANSIT EPITHE CELL UA AUTO QUAL FEW (A) GC/chlamydia negative HIV, Hep B and syphilis negative Blood culture negative x 2 Urine Culture negative MRSA Culture negative Genital Culture: +GBS

6. S.M. Hospital Course: Transferred from pediatric urgent clinic to ED for additional evaluation/stabilization. Started on IV Nafcillin, Gentamicin and Clindamycin in the ED. Admitted to ICU where she improved clinically and rash resolved. She was then transferred to the pediatric service where they discontinued previous antibiotics and started her on Rocephin. Pt was discharged on HD #3 with 7 day course of PO Clindamycin per Peds ID and outpatient follow up.

7. Toxic Shock Syndrome Toxin mediated, acute systemic disease resulting in shock and multi-system organ failure Staphylococcus aureus and Group A Streptococcus pyogenes are the most common organisms Gram positive infections are responsible for > 50% of sepsis in the US. Mortality rate higher than meningococcal septicemia Staphylococcal TSS first reported in 1978 and increased in incidence in the early 1980s in the US Associated with use of high absorbency tampons in women During this time, peak incidence was 6.2 – 12.3 cases per 100,000 per year With changes in tampon manufacture and usage, incidence fell to 1 case per 100,000 per year 133 cases of toxic shock syndrome in United States reported to CDC in 2003 The rate of vaginal colonization by Staph aureus remains approximately 1-5% of healthy women and remain unchanged compared to the 1980s.

8. Toxic Shock Syndrome Nonmenstrual TSS associated with Staph comprise about 50% of cases Associated with barrier contraceptive (diaphragm, IUD), vaginal and cesarean deliveries, surgical and postpartum wound infections, mastitis, sinusitis, burns, cutaneous infections… Streptococcal toxic shock syndrome attributed to Streptoccocus pyogenes was reported in 1987 Secondary to invasive Group A Strep soft tissue infections Mortality of approximately 30-40% Incidence of between 1.5 – 5.2 cases per 100,000 per year Higher rates at extremes of age and ethnic minorities Higher incidence in patients with underlying chronic illness, post varicella infection and NSAIDs use

9. Pathophysiology Bacterial endotoxins act as superantigens Protein toxins that have the ability to trigger excessive T-cell activation with downstream activation of other cell types and cytokine release Conventional antigen presentation activates 0.01% of host T-cells compared to superantigen binding which activates up to 20-30% of host T-cells Also associated with rapid increase in cytokine production from T-cells T-cell activation leads to additional recruitment of T and B cells to the site of infection

10. Pathophysiology Staphylococcal TSS-T1 (Toxic shock syndrome Toxin 1) is responsible for 95% of menstrual related TSS. TSS-T1 able to cross mucosal barriers Also detectable in 50% of non menstrual TSS Not all patients colonized with Staph aureus or strep pyogenes develop TSS and interaction between host immune system and pathogen play an important role Absence of antibodies against superantigens is a major risk factor to developing TSS > 85% of women aged 13-40 have TSS-T1 antibodies that are thought to be protective Low or negative antibody titers are found in 90.5% of patients with menstrual TSS More than 50% of these patients fail to seroconvert within 2 months of their illness

11. Clinical Manifestation Hallmark symptoms include fever, shock and multi-system failure Staphylococcal TSS: starts with flu like prodromal illness including fever, GI distress and severe myalgia. Desquamation is a late feature and happens 10-21 days after initial onset of symptoms. Blood cultures are positive in < 5% of Staph TSS Menstrual and non menstrual TSS are identical clinically Up to 95% of patients diagnosed with menstrual TSS have onset of illness during menses Fever and rash more prevalent in early disease Recurrence of menstrual TSS well documented but rare in non menstrual TSS

12. Clinical Manifestation Postoperative nonmenstrual TSS usually occurs within 48 hours of surgery Nonmenstrual TSS patient are more likely to acquire infection nosocomially and to have had prior antibiotic treatment. Nonmenstrual TSS are more commonly associated with CNS and renal complications Streptococcal TSS typically arise from deep seated invasive soft tissue infections such as necrotising fasciitis, cellulitis and myositis which are extremely painful.

14. Derm manifestations Diffuse macular erythroderma followed by desquamation in 1-2 weeks Conjunctival injection

15. Mucosal (oral and genital) hyperemia Strawberry tongue

17. Treatment Aim to decrease bacterial load and endotoxin production Penicillinase resistant penicillin, cephalosporin for suspected Staphylococcus aureus TSS Vancomycin for suspected MRSA Group A Streptococcus very sensitive to B-lactam agents including Penicillin G (first line treatment) Although PCN is bactericidal, it is less effective against high organism load (ineffective if treatment delayed by > 2 hours) Given with Clindamycin which is inhibitory of protein synthesis of superantigen production Inhibitory of endotoxin production in both Staph and Group A Strep

19. Treatment Possible consideration of starting IV immunoglobulins if no clinical response within the first 6 hours of IV antibiotics IV immunoglobulin G (IVIG) may reduce mortality. High dose corticosteroid may also improve outcome as shown in isolated case reports

20. Additional Treatments/Considerations Remove tampon or other infectious sources Supportive measures for shock with fluid resuscitation and pressors Possible vaginal irrigation with betadine solution Avoidance of tampons, barrier contraceptives (e.g. diaphragm, IUDs) in patients who do not seroconvert to prevent recurrence

21. Prognosis Staphylococcal toxic shock has an associated 5% mortality in menstrual related cases. Nonmenstrual related Staph TSS has 2-3x higher mortality rate Streptococcal toxic shock is very virulent with up to 70% mortality Patients with deficient antibody response against TSS-T1 are at increased risk of primary and recurrent TSS Recurrence rate is up to 40% in individuals who do not generate appropriate titers of antibodies against TSS-T1

22. Disparity Magnitude of inflammatory response may be governed by host genetic factors such as MHC class II haplotype 90-95% of middle aged women have detectable antibody titers against TSST-1. Patients with TSS have poor antibody production against TSST-1 with titers < 1:5, whereas healthy patients have titers > 1:100 Possible variable effects on immune system based on estradiol levels Low concentration augmenting immune response by release of IL-6 and TNF High levels inhibiting release

23. References Lappin E, Ferguson A. Gram-positive toxic shock syndromes. Lancet Infect Dis 2009; 9: 281-90. Drage L. Life-threatening rashes: Dermatologic signs of four infectious diseases. Mayo Clinic Proceedings 74.1 Jan 1999: 68-72. Herzer C. Toxic Shock Syndrome: Broadening the Differential Diagnosis. J Am Board Family Practice Mar-Apr 2001: 14(2): 131. Andrews J, Shamshirsaz A, Diekema D. Nonmentrual toxic shock syndrome due to methicillin resistant Staphlococcus aureus. Obstetrics and Gynecology Vol. 112, No. 4, October 2008