1. Toxic Shock Syndrome and Streptococcal Toxic Shock Syndrome Dr. Batizy, D.O. January 26, 2006

2. Toxic Shock Syndrome Severe life threatening syndrome characterized by: Severe life threatening syndrome characterized by: High fevers High fevers Severe hypotension Severe hypotension Diffuse erythroderma Diffuse erythroderma Mucous membrane hyperemia Mucous membrane hyperemia Pharyngitis Pharyngitis Diarrhea Diarrhea

3. Toxic Shock Syndrome May progress rapidly May progress rapidly Multisystem disfunction Multisystem disfunction Severe electrolyte disturbances Severe electrolyte disturbances Renal failure Renal failure Shock Shock

4. Toxic Shock Syndrome Discovered in 1978 in apparently healthy children – Staph aureus isolated Discovered in 1978 in apparently healthy children – Staph aureus isolated TSS epidemic – 1981 associated with increased tampon use TSS epidemic – 1981 associated with increased tampon use Incidence has dropped significantly, Incidence has dropped significantly, Currently most cases are unrelated to menses Currently most cases are unrelated to menses Case Definition of Toxic Shock Syndrome, table 142-1 Case Definition of Toxic Shock Syndrome, table 142-1

5. Case Definition of Toxic Shock Syndrome, Table 142-1 Fever – temp >102.0 F (>38.9 C) Fever – temp >102.0 F (>38.9 C) Rash: diffuse macular erythroderma Rash: diffuse macular erythroderma Hypotension Hypotension Multisystem envolvement (three or more) Multisystem envolvement (three or more) GI: vomiting or diarrhea at onset of illness GI: vomiting or diarrhea at onset of illness Muscular: sever myalgia or creatine phosphokinase level at least twice the upper limit of normal Muscular: sever myalgia or creatine phosphokinase level at least twice the upper limit of normal Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia

6. Renal: blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or urinary sediment with pyuria (greater than or equal to 5 leukocytes per highpower field) in the absence of urinary tract infection Renal: blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or urinary sediment with pyuria (greater than or equal to 5 leukocytes per highpower field) in the absence of urinary tract infection Hepatic: total bilirubin, alanine aminotransferase enzyme, or asparate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory Hepatic: total bilirubin, alanine aminotransferase enzyme, or asparate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory Hematologic: platelets less than 100,000/ml Hematologic: platelets less than 100,000/ml

7. CNS: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent CNS: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent Lab criteria: negative results on the following tests, if obtained: Lab criteria: negative results on the following tests, if obtained: Blood, throat, or cerebrospinal fliud cultures (blood culture may be positive for Staphlococcus aureus Blood, throat, or cerebrospinal fliud cultures (blood culture may be positive for Staphlococcus aureus Rise in titer to Rocky Mountain Spotted fever, leptospirosis, or measles Rise in titer to Rocky Mountain Spotted fever, leptospirosis, or measles

8. Case Definition of TSS Case classification Case classification Probable: five of six clinical findings are present Probable: five of six clinical findings are present Confirmed: all six clinical findings are present, including desquamation, unless patient dies before desquamation occurs Confirmed: all six clinical findings are present, including desquamation, unless patient dies before desquamation occurs

9. Epidemiology TSS – initially a disease of young healthy menstruating women, comprised fifty percent of cases reported in 1986-87 TSS – initially a disease of young healthy menstruating women, comprised fifty percent of cases reported in 1986-87 Tampon use increased risk up to 33% Tampon use increased risk up to 33% In 2000, 135 reported cases, 3 were in men, and 2 fatalities were from menstrual-related TSS (MRTSS) In 2000, 135 reported cases, 3 were in men, and 2 fatalities were from menstrual-related TSS (MRTSS) FDA - Tampons now made of cotton and rayon, should be changed every 4-8 hrs FDA - Tampons now made of cotton and rayon, should be changed every 4-8 hrs

10. Epidemiology Non-menstrual related cases of Toxic Shock Syndrome (NMTSS) Non-menstrual related cases of Toxic Shock Syndrome (NMTSS) Increasing since 1980 Increasing since 1980 41% NMTSS 41% NMTSS Men comprise one-tenth of population Men comprise one-tenth of population Mortality rate 3.3 x that of MRTSS in women Mortality rate 3.3 x that of MRTSS in women S. aureus isolated from 98% of women with TSS S. aureus isolated from 98% of women with TSS Women with MRTSS most likely colonized with Staph aureus before the onset of menstruation Women with MRTSS most likely colonized with Staph aureus before the onset of menstruation

11. Epidemiology TSS associated with influenza or influenza-like illnesses – mortality rate (43%) TSS associated with influenza or influenza-like illnesses – mortality rate (43%) Nasal packing (nasal tampons) also associated with TSS Nasal packing (nasal tampons) also associated with TSS

12. Pathophysiology Most TSS associated with S. aureus Most TSS associated with S. aureus TSST-1: toxic shock syndrome toxin, exotoxin TSST-1: toxic shock syndrome toxin, exotoxin Induce fever via the hypothalamus or via IL-1 and TNF Induce fever via the hypothalamus or via IL-1 and TNF T-lymphocyte “superantigenation” and overstimulation T-lymphocyte “superantigenation” and overstimulation Induce interferon production Induce interferon production Enhance delayed hypersensitivity Enhance delayed hypersensitivity Supress neutrophil migration and IG secretion Supress neutrophil migration and IG secretion Enhance host suseptibility to exotoxins Enhance host suseptibility to exotoxins

13. Pathophysiology Enterotoxins B and C Enterotoxins B and C Similar chemical structure to TSST-1 Similar chemical structure to TSST-1 Seen primarily in NMTSS Seen primarily in NMTSS Elicit similar clinical manifestations as TSST-1 Elicit similar clinical manifestations as TSST-1

14. Pathophysiology Vaginal conditions favorable to TSST-1 Vaginal conditions favorable to TSST-1 Temp 39-40 C Temp 39-40 C Neutral pH Neutral pH PO2 > 5% PO2 > 5% Supplemental CO2 Supplemental CO2 Menstruation – neutralizes vaginal pH Menstruation – neutralizes vaginal pH Tampon use may increase O2 and CO2 Tampon use may increase O2 and CO2 Synthetic fibers in tampon composition Synthetic fibers in tampon composition Synergistic relationship between S. aureus and E. coli Synergistic relationship between S. aureus and E. coli

15. Pathophysiology Vasodilation – rapid and massive onset Vasodilation – rapid and massive onset Hypotension Hypotension Decreased vasomotor tone, blood pooling, decreased vascular return Decreased vasomotor tone, blood pooling, decreased vascular return Nonhydrostatic leakage of fluid into the interstitium, contributing to hypotension and nonpitting edema of the head and neck Nonhydrostatic leakage of fluid into the interstitium, contributing to hypotension and nonpitting edema of the head and neck Depressed cardiac function Depressed cardiac function Total body water deficits from vomiting and diarrhea and fever Total body water deficits from vomiting and diarrhea and fever

16. Pathophysiology IL-1 IL-1 Hypoalbuminemia, hypoferrinemia, and proteolysis manifest as peripheral edema, anemia, and rhabdomyolysis seen in TSS Hypoalbuminemia, hypoferrinemia, and proteolysis manifest as peripheral edema, anemia, and rhabdomyolysis seen in TSS TNF TNF Acidosis, shock, and multisystem organ failure Acidosis, shock, and multisystem organ failure Multisystem organ failure Multisystem organ failure Direct result from toxin Direct result from toxin Rapid onset of hypotension and decreased perfusion Rapid onset of hypotension and decreased perfusion Small amts of TSST-1 and enterotoxins B and C can be detected in pts with TSS up to 1 year Small amts of TSST-1 and enterotoxins B and C can be detected in pts with TSS up to 1 year

17. Clinical Features TSS must be considered when TSS must be considered when Unexplained febrile illness with erythroderma, hypotension, and diffuse organ pathology Unexplained febrile illness with erythroderma, hypotension, and diffuse organ pathology Pts with NMTSS present 3 rd to 5 th days of menses Pts with NMTSS present 3 rd to 5 th days of menses Postoperative NMTSS – approx 2 days Postoperative NMTSS – approx 2 days

18. Clinical Features Mild TSS: Mild TSS: Fever Fever Chills Chills myalgias myalgias Abdominal pain Abdominal pain Sore throat Sore throat Nausea Nausea Vomiting Vomiting Diarrhea Diarrhea Self-limiting Self-limiting

19. Clinical Features Severe Severe Acute onset Acute onset Early multiorgan envolvement Early multiorgan envolvement Prodrome Prodrome Headache, malaise, myalgias, nausea, vomiting, and diarrhea Headache, malaise, myalgias, nausea, vomiting, and diarrhea Sudden onset of fevers and chills 1-4 days prior to presentation Sudden onset of fevers and chills 1-4 days prior to presentation Orthostatic lightheadedness, profuse watery diarrhea, sore throat, paresthesias, photophobia, abdominal pain, and cough Orthostatic lightheadedness, profuse watery diarrhea, sore throat, paresthesias, photophobia, abdominal pain, and cough

20. Clinical Presentation PE PE Hypotension Hypotension Pt appears acutely ill Pt appears acutely ill Change in mental status Change in mental status Oliguria Oliguria Nonpitting edema of face and extremities Nonpitting edema of face and extremities Watery diarrhea Watery diarrhea Pharygitis strawberry red tongue Pharygitis strawberry red tongue Tender erythematous external genitalia diffuse vaginal hyperemia, strawberry cervix, scant purulent cervical discharge, bilat adenexal tenderness Tender erythematous external genitalia diffuse vaginal hyperemia, strawberry cervix, scant purulent cervical discharge, bilat adenexal tenderness

21. Clinical Features Rash – diffuse painless blanching erythroderma, fades in three days Rash – diffuse painless blanching erythroderma, fades in three days Followed by full-thickness desquamation particularly of palms and soles of feet Followed by full-thickness desquamation particularly of palms and soles of feet Severely affected patients may have hair and nail loss 2-3 months later Severely affected patients may have hair and nail loss 2-3 months later

22. Clinical Features Focal neuro findings are rare Focal neuro findings are rare Varying degrees of altered consciousness Varying degrees of altered consciousness Toxic encephalopathy - confusion, disorientation, agitation, hysteria, somnolence, and seizures Toxic encephalopathy - confusion, disorientation, agitation, hysteria, somnolence, and seizures CT and LP will help deliniate CT and LP will help deliniate

23. Clinical Features Lab findings Lab findings Leukocytosis Leukocytosis lymphocytopenia lymphocytopenia Anemia Anemia ARF: azotemia, myoglobinuria, sterile pyuria, RBC casts ARF: azotemia, myoglobinuria, sterile pyuria, RBC casts Liver abnormalities Liver abnormalities Metabolic acidosis 2 nd to hypotension Metabolic acidosis 2 nd to hypotension Electrolyte abnormalities Electrolyte abnormalities Arrhythmias Arrhythmias ARDS ARDS

24. Differential Diagnosis Acute pyelonephritis Acute pyelonephritis Septic shock Septic shock Acute rheumatic fever Acute rheumatic fever Scarlet fever: strep or staph etiologies Scarlet fever: strep or staph etiologies Leigionare’s disease Leigionare’s disease PID PID HUS HUS

25. Differential Diagnosis Acute viral syndrome Acute viral syndrome Leptospirosis Leptospirosis SLE SLE Rocky Mountain Spotted fever Rocky Mountain Spotted fever Tick typhus Tick typhus Gastroenteritis Gastroenteritis Kawasaki disease Kawasaki disease Reye syndrome Reye syndrome Toxic epidermal necrolysis Toxic epidermal necrolysis Erythema multiforme Erythema multiforme

26. Treatment Aggressive shock management Aggressive shock management Continuous monitoring: central Continuous monitoring: central Aggressive fluid replacement – 4-20 L of crystalloid and FFP Aggressive fluid replacement – 4-20 L of crystalloid and FFP Ventilatory management if ARDS develops Ventilatory management if ARDS develops Complete blood work and cultures Complete blood work and cultures Removal of foreign bodies, i.e. tampon or nasal packing Removal of foreign bodies, i.e. tampon or nasal packing Antistaphlococcal penicillin or cephalosporin Antistaphlococcal penicillin or cephalosporin

27. Treatment Nafcillin or oxacillin 2g IV every 4hrs Nafcillin or oxacillin 2g IV every 4hrs Cefazolin 2g IV every 6hrs Cefazolin 2g IV every 6hrs Oral anti-staphlococcal ABx for the next 10 -14 days Oral anti-staphlococcal ABx for the next 10 -14 days

28. Treatment Pt not treated with β-lactamase-stable abx can have recurrence Pt not treated with β-lactamase-stable abx can have recurrence MRTSS – recurrence occurs in second month after the initial disease, recurring on the same day of the menstrual cycle MRTSS – recurrence occurs in second month after the initial disease, recurring on the same day of the menstrual cycle Initial episode is the most severe Initial episode is the most severe

29. Streptococcocal Toxic Shock Syndrome Group A Strep Group A Strep Soft tissue infection, early shock, multisystem organ failure, higher mortality than TSS, “Flesh eating bacteria” Soft tissue infection, early shock, multisystem organ failure, higher mortality than TSS, “Flesh eating bacteria” Most serious – Strep necrotizing fasciitis and myositis Most serious – Strep necrotizing fasciitis and myositis STSS STSS Most commonly affects 20 – 50 yr olds without prior illness Most commonly affects 20 – 50 yr olds without prior illness

30. STSS Risk factors Risk factors Extremes of age Extremes of age Diabetes Diabetes EtOH EtOH Drug abuse Drug abuse NSAIDS NSAIDS Immunodeficiency Immunodeficiency Rarely develops from symptomatic pharyngitis Rarely develops from symptomatic pharyngitis

31. STSS 2000-3000 cases annually; with 500 to 1500 cases of necrotizing fasciitis 2000-3000 cases annually; with 500 to 1500 cases of necrotizing fasciitis Mortality rate of 30 – 80% Mortality rate of 30 – 80% 70% of cases progress to necrotizing fasciitis 70% of cases progress to necrotizing fasciitis Surgical intervention Surgical intervention Mortality Mortality Strep fasciitis – 60% Strep fasciitis – 60% Strep Myositis – 85-100% Strep Myositis – 85-100%

32. Case Definition of Streptococcocal Toxic Shock Syndrome An illness with An illness with Hypotension Hypotension Multiorgan involvement with two or more of the following: Multiorgan involvement with two or more of the following: Renal impairment Renal impairment Coagulopathy Coagulopathy Liver involvement Liver involvement ARDS ARDS Generalized erythematous macular rash that may desquamate Generalized erythematous macular rash that may desquamate Soft tissue necrosis Soft tissue necrosis

33. Case Definition of Streptococcal Toxic Shock Syndrome Laboratory Criteria Laboratory Criteria Isolation of group A streptococcus Isolation of group A streptococcus Case Classification Case Classification Probable – clinical case definition in the absence of another identified etiology with isolation of group A strep from a nonsterile site Probable – clinical case definition in the absence of another identified etiology with isolation of group A strep from a nonsterile site Confirmed – clinical case definition with isolation of group A streptococcus from an otherwise sterile site Confirmed – clinical case definition with isolation of group A streptococcus from an otherwise sterile site

34. STSS Epidemiology Epidemiology Incidence – 1-5 per 100,000 Incidence – 1-5 per 100,000 STSS associated Necrotizing Fasciitis 13-46% STSS associated Necrotizing Fasciitis 13-46% Pathophysiology Pathophysiology GAS invasive infections – more virulent exotoxins than TSS GAS invasive infections – more virulent exotoxins than TSS SPE – Streptococcal pyogenic exotoxins SPE – Streptococcal pyogenic exotoxins SPE A – Scarlet fever toxin – most potent and commonly isolated SPE in STSS cases SPE A – Scarlet fever toxin – most potent and commonly isolated SPE in STSS cases SPE A and B – pyrogenicity, superactivation of T-cells, synthesis of TNF, IL-1 and IL-6, leading to acidosis, shock, organ failure SPE A and B – pyrogenicity, superactivation of T-cells, synthesis of TNF, IL-1 and IL-6, leading to acidosis, shock, organ failure

35. STSS Patients without immunity to M-type SPE A and B producing strains of GAS are most susceptible to STSS Patients without immunity to M-type SPE A and B producing strains of GAS are most susceptible to STSS Portal of entry Portal of entry Vagina, pharynx, mucosa, and skin, most are unidentifiable Vagina, pharynx, mucosa, and skin, most are unidentifiable Commonly begins at site of minor skin trauma Commonly begins at site of minor skin trauma

36. STSS Clinical Features Clinical Features Pain most common with preceding local tenderness Pain most common with preceding local tenderness May present as May present as Peritonitis Peritonitis PID PID Pneumonia Pneumonia Pericarditis Pericarditis Fever Fever Severe pain Severe pain Swelling Swelling Redness Redness Compartment syndrome Compartment syndrome

37. STSS PE PE Fever Fever Shock on admission or within 4-8hrs Shock on admission or within 4-8hrs Vesicles and/or bullae at infection site Vesicles and/or bullae at infection site ARDS ARDS Less commonly erythematous rash Less commonly erythematous rash Labs Labs Mild increase in WBC Mild increase in WBC LFT 2x normal LFT 2x normal

38. STSS Labs Labs Decreased platelets Decreased platelets Disseminated intravascular coagulopathy Disseminated intravascular coagulopathy Renal dysfunction – requiring dyalysis Renal dysfunction – requiring dyalysis Blood cultures - +GAS 60% Blood cultures - +GAS 60% Tissue cultures – 90% Tissue cultures – 90%

39. STSS Diagnosis Diagnosis Differential is the same as for TSS with the addition of invasive and noninvasive GAS infections, necrotizing fasciitis, myositis, serious infections caused by C. perforingens and C. septicum, and mixed aneorbic and aerobic organisms Differential is the same as for TSS with the addition of invasive and noninvasive GAS infections, necrotizing fasciitis, myositis, serious infections caused by C. perforingens and C. septicum, and mixed aneorbic and aerobic organisms Treatment Treatment Aggressive shock management with early use of vasopressors Aggressive shock management with early use of vasopressors

40. STSS IV ABx should be started in the ED once cultures have been taken. Inability to obtain Cx should not delay administration of IV ABx IV ABx should be started in the ED once cultures have been taken. Inability to obtain Cx should not delay administration of IV ABx Pen G 24 million U/d divided Pen G 24 million U/d divided Clindamycin 900mg IV q 8hr Clindamycin 900mg IV q 8hr Erythromycin 1g IV q 6 hr in PCN allergic pts Erythromycin 1g IV q 6 hr in PCN allergic pts Ceftriaxone 2g IV q 24 hr with Clindamycin 900mg IV q 8hr Ceftriaxone 2g IV q 24 hr with Clindamycin 900mg IV q 8hr IVIG 2g/kg q 48 hr in patients without IGA deficiency improve 30 day mortality IVIG 2g/kg q 48 hr in patients without IGA deficiency improve 30 day mortality

41. STSS Surgery Surgery Prompt consultation in addition to IV ABx Prompt consultation in addition to IV ABx Exploration Exploration Debridement Debridement 70% of cases require debridement, fasciotomy, or amputation 70% of cases require debridement, fasciotomy, or amputation

42. TSS and STSS 1.) Toxic Shock Syndrome is only a disease of young healthy menstruating women. T/F 1.) Toxic Shock Syndrome is only a disease of young healthy menstruating women. T/F 2.) The rash of TSS is a diffuse, blanching, erythroderma, classically described as a “painless sunburn”, that fades within 3-4 days of its appearance and is followed by full-thickness desquamation of the palms and soles during convalescence. T/F 2.) The rash of TSS is a diffuse, blanching, erythroderma, classically described as a “painless sunburn”, that fades within 3-4 days of its appearance and is followed by full-thickness desquamation of the palms and soles during convalescence. T/F

43. TSS and STSS 3.) STSS is defined as any group A streptococcocal (GAS) infection with invasive soft tissue infection, early onset of shock, and organ failure. T/F 3.) STSS is defined as any group A streptococcocal (GAS) infection with invasive soft tissue infection, early onset of shock, and organ failure. T/F 4.) STSS associated with GAS invasive infections most commonly affects individual between the ages of 20 – 50 with a predisposing illness. T/F 4.) STSS associated with GAS invasive infections most commonly affects individual between the ages of 20 – 50 with a predisposing illness. T/F Answers: 1.) F, 2.) T, 3.) T, 4.) F Answers: 1.) F, 2.) T, 3.) T, 4.) F

44. TSS and STSS Tintinalli et al; Emergency Medicine: A Comprehensive Study Guide. Chap. 142, pg. 913-918. Tintinalli et al; Emergency Medicine: A Comprehensive Study Guide. Chap. 142, pg. 913-918.