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Volume 1, Number 3—July 1995

Streptococcal Toxic-Shock Syndrome: Spectrum of Disease, Pathogenesis, and New Concepts in Treatment

Dennis L. Stevens
Author affiliation: Professor of Medicine, University of Washington School of Medicine, Seattle,Washington
Chief, Infectious Disease Section, Veterans Affairs Medical Center, Boise, Idaho, USA

Main Article

Table 1

Case definition of streptococcal toxic-shock syndrome (streptococcal TSS) and necrotizing fasciitis*

I. Streptococcal TSS
A. Isolation of group A Streptococcus
1. From a sterile site
2. From a nonsterile body site
B. Clinical signs of severity
1. Hypotension
2. Clinical and laboratory abnormalities (requires two or more of the following):
a)Renal impairment
c)Liver abnormalities
d)Acute respiratory distress syndrome
e)Extensive tissue necrosis, i.e., necrotizing fasciitis
f)Erythematous rash
Definite Case = A1 + B(1+2)
Probable Case = A2 + B(1+2
II. Necrotizing fasciitis
A. Definite case
1. Necrosis of soft tissues with involvement of the fascia PLUS
2.Serious systemic disease, including one or more of the following:
b)Shock (systolic blood pressure <90 mm of Hg).
c)Disseminated intravascular coagulopathy
d)Failure of organ systems
a.respiratory failure
b.liver failure
c.renal failure
3.Isolation of group A Streptococcus from a normally sterile body site
B.Suspected case
1.1+2 and serologic confirmation of group A streptococcal infection by a 4-fold rise against:
a)streptolysin O
b)DNase B
2.1+2 and histologic confirmation:
Gram-positive cocci in a necrotic soft tissue infection

*Streptococcal toxic-shock syndrome (streptococcal TSS) is defined as any group A streptococcal infection associated with the early onset of shock and organ failure. Definitions describing criteria for shock, organ failure, definite cases,and probable cases are included below. Source: reference 61.

Main Article

  1. Stevens  DL, Tanner  MH, Winship  J, Swarts  R, Reis  KM, Schlievert  PM, Reappearance of scarlet fever toxin A among streptococci in the Rocky Mountain West: severe group A streptococcal infections associated with a toxic shock-like syndrome. N Engl J Med. 1989;321:17.PubMedGoogle Scholar
  2. The Working Group on Severe Streptococcal Infections. Defining the group A streptococcal toxic shock syndrome: rationale and consensus definition. JAMA. 1993;269:3901. DOIPubMedGoogle Scholar
  3. Sennert  D. De febribus libri quator. Editio novissima. Cui accessit fasciculus medicamentorum contra pestem. Libri IV. De peste, Pestilentibusque ac Malingis Febribus. Venice: Francisum Baba, 1641.
  4. Douglass  W. The practical history of a new epidemical eruptive miliary fever, with an Angina Ulcusculosa, which prevailed in Boston, New England in the years 1735 and 1736. Boston: T. Fleet, 1736.
  5. Dillon  HC. Impetigo contagiosa: suppurative and nonsuppurative complication. Clinical, bacteriologic and epidemiologic characteristics of impetigo. Am J Dis Child. 1968;115:53041.PubMedGoogle Scholar
  6. Wannamaker  LW, Rammelkamp  CH Jr, Denny  FW, Brink  WR, Houser  HB, Hahn  EO, Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am J Med. 1951;10:67395. DOIPubMedGoogle Scholar
  7. Weaver  GH. Scarlet Fever. In: Abt IA, ed., Pediatrics. Philadelphia: W.B. Saunders Co., 1925:298-362.
  8. Stevens  DL. Invasive group A streptococcus infections. Clin Infect Dis. 1992;14:213.PubMedGoogle Scholar
  9. Kohler  W, Gerlach  D, Knoll  H. Streptococcal outbreaks and erythrogenic toxin type A. Zbl Bakt Hyg. 1987;266:10415.
  10. Martin  PR, Hoiby  EA. Streptococcal serogroup A epidemic in Norway 1987-1988. Scand J Infect Dis. 1990;22:4219. DOIPubMedGoogle Scholar
  11. Holm  S. Fatal group A streptococcal infections. Presented at the 89th Conference of the American Society for Microbiology, New Orleans, LA, 1989.
  12. Wheeler  MC, Roe  MH, Kaplan  EL, Schlievert  PM, Todd  JK. Outbreak of group A streptococcus septicemia in children: clinical, epidemiologic, and microbiological correlates. JAMA. 1991;266:5337. DOIPubMedGoogle Scholar
  13. Gaworzewska  ET, Coleman  G. Correspondence: group A streptococcal infections and a toxic shock-like syndrome. N Engl J Med. 1989;321:1546.
  14. Schwartz  B, Facklam  R, Breiman  R. The changing epidemiology of group A streptococcal infections in the U.S.: association with changes in serotype. Presented at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, 1990; Abstract 88.
  15. Bartter  T, Dascal  A, Carroll  K, Curley  FJ. "Toxic strep syndrome": manifestation of group A streptococcal infection. Arch Intern Med. 1988;148:14214. DOIPubMedGoogle Scholar
  16. Hribalova  V. Streptococcus pyogenes and the toxic shock syndrome. Ann Intern Med. 1988;108:772.PubMedGoogle Scholar
  17. Greenberg  RN, Willoughby  BG, Kennedy  DJ, Otto  TJ, McMillian  R, Bloomster  TG. Hypocalcemia and "toxic" syndrome associated with streptococcal fasciitis. South Med J. 1983;76:9168.PubMedGoogle Scholar
  18. Jackson  MA, Olson  LC, Burry  VF. Pediatric group A streptococcal (GAS) disease with multi-organ dysfunction. Presented at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, 1990; Abstract 195.
  19. Thomas  JC, Carr  SJ, Fujioka  K, Waterman  SH. Community-acquired group A streptococcal deaths in Los Angeles County. J Infect Dis. 1989;160:10867.PubMedGoogle Scholar
  20. Francis  J, Warren  RE. Streptococcus pyogenes bacteraemia in Cambridge: a review of 67 episodes. Q J Med. 1988;256:60313.
  21. Barnham  M. Invasive streptococcal infections in the era before the acquired immune deficiency syndrome: a 10 years' compilation of patients with streptococcal bacteraemia in North Yorkshire. J Infect Dis. 1989;18:23148.
  22. Braunstein  H. Characteristics of group A streptococcal bacteremia in patients at the San Bernardino County Medical Center. Rev Infect Dis. 1991;13:811.PubMedGoogle Scholar
  23. Schwartz  B, Facklam  RR, Brieman  RF. Changing epidemiology of group A streptococcal infection in the USA. Lancet. 1990;336:116771. DOIPubMedGoogle Scholar
  24. Holm  SE, Norrby  A, Bergholm  AM, Norgren  M. Aspects of pathogenesis of serious group A streptococcal infections in Sweden, 1988-1989. J Infect Dis. 1992;166:317.PubMedGoogle Scholar
  25. Stegmayr  B, Bjorck  S, Holm  S, Nisell  J, Rydvall  A, Settergren  B. Septic shock induced by group A streptococcal infections: clinical and therapeutic aspects. Scand J Infect Dis. 1992;24:58997. DOIPubMedGoogle Scholar
  26. Demers  B, Simor  AE, Vellend  H, Schlievert  PM, Byrne  S, Jamieson  F, Severe invasive group A streptococcal infections in Ontario, Canada: 1987-1991. Clin Infect Dis. 1993;16:792800.PubMedGoogle Scholar
  27. Auerbach  SB, Schwartz  B, Facklam  RR, Breiman  R, Jarvis  WR. Outbreak of invasive group A streptococcal (GAS) disease in a nursing home. Presented at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, 1990; Abstract 171.
  28. Hohenboken  JJ, Anderson  F, Kaplan  EL. Invasive group A streptococcal (GAS) serotype M-1 outbreak in a long-term care facility (LTCF) with mortality. Presented at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, 1994; Abstract J189.
  29. Johnson  DR, Stevens  DL, Kaplan  EL. Epidemiologic analysis of group A streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis. J Infect Dis. 1992;166:37482.PubMedGoogle Scholar
  30. Belani  K, Schlievert  P, Kaplan  E, Ferrieri  P. Association of exotoxin-producing group A streptococci and severe disease in children. Pediatr Infect Dis J. 1991;10:3514. DOIPubMedGoogle Scholar
  31. Hauser  AR, Goshorn  SC, Kaplan  E, Stevens  DL, Schlievert  PM. Molecular analysis of the streptococcal pyrogenic exotoxins. Presented at the Third International American Society for Microbiology Conference on Streptococcal Genetics. Minneapolis, MN, 1990.
  32. Hauser  AR, Stevens  DL, Kaplan  EL, Schlievert  PM. Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome. J Clin Microbiol. 1991;29:15627.PubMedGoogle Scholar
  33. Musser  JM, Hauser  AR, Kim  MH, Schlievert  PM, Nelson  K, Selander  RK. Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proc Natl Acad Sci U S A. 1991;88:266872. DOIPubMedGoogle Scholar
  34. Mollick  JA, Miller  GG, Musser  JM, Cook  RG, Grossman  D, Rich  RR. A novel superantigen isolated from pathogenic strains of Streptococcus pyogenes with aminoterminal homology to staphylococcal enterotoxins B and C. J Clin Invest. 1993;92:7109. DOIPubMedGoogle Scholar
  35. Iwasaki  M, Igarashi  H, Hinuma  Y, Yutsudo  T. Cloning, characterization and overexpression of a Streptococcus pyogenes gene encoding a new type of mitogenic factor. FEBS Lett. 1993;331:18792. DOIPubMedGoogle Scholar
  36. Norrby-Teglund  A, Newton  D, Kotb  M, Holm  SE, Norgren  M. Superantigenic properties of the group A streptococcal exotoxin SpeF (MF). Infect Immun. 1994;62:522733.PubMedGoogle Scholar
  37. Meleney  FL. Hemolytic Streptococcus gangrene. Arch Surg. 1924;9:31764.
  38. Adams  EM, Gudmundsson  S, Yocum  DE, Haselby  RC, Craig  WA, Sundstrom  WR. Streptococcal myositis. Arch Intern Med. 1985;145:10203. DOIPubMedGoogle Scholar
  39. Svane  S. Peracute spontaneous streptococcal myositis: a report on 2 fatal cases with review of literature. Acta Chir Scand. 1971;137:15563.PubMedGoogle Scholar
  40. Yoder  EL, Mendez  J, Khatib  R. Spontaneous gangrenous myositis induced by Streptococcus pyogenes: case report and review of the literature. Rev Infect Dis. 1987;9:3825.PubMedGoogle Scholar
  41. Nather  A, Wong  FY, Balasubramaniam  P, Pang  M. Streptococcal necrotizing myositis a rare entity: a report of two cases. Clin Orthop Relat Res. 1987;215:20611.PubMedGoogle Scholar
  42. Stevens  DL, Musher  DM, Watson  DA, Eddy  H, Hamill  RJ, Gyorkey  F, Spontaneous, nontraumatic gangrene due to Clostridium septicum. Rev Infect Dis. 1990;12:28696.PubMedGoogle Scholar
  43. Bullowa  JGM, Wischik  S. Complications of varicella. I: their occurrence among 2,534 patients. Am J Dis Child. 1935;49:9236.
  44. Fast  DJ, Schlievert  PM, Nelson  RD. Toxic shock syndrome-associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumor necrosis factor production. Infect Immun. 1989;57:2914.PubMedGoogle Scholar
  45. Hackett  SP, Schlievert  PM, Stevens  DL. Cytokine production by human mononuclear cells in response to streptococcal exotoxins. Clin Res. 1991;39:189A.
  46. Hallas  G. The production of pyrogenic exotoxins by group A streptococci. J Hyg (Camb). 1985;95:477. DOIGoogle Scholar
  47. Lancefield  RC. Current knowledge of type specific M antigens of group A streptococci. J Immunol. 1962;89:30713.PubMedGoogle Scholar
  48. Mollick  JA, Rich  RR. Characterization of a superantigen from a pathogenic strain of Streptococcus pyogenes. Clin Res. 1991;39:213A.
  49. Hackett  SP, Stevens  DL. Streptococcal toxic shock syndrome: synthesis of tumor necrosis factor and interleukin-1 by monocytes stimulated with pyrogenic exotoxin A and streptolysin O. J Infect Dis. 1992;165:87985.PubMedGoogle Scholar
  50. Kotb  M, Tomai  M, Majumdar  G, Walker  J, Beachey  EH. Cellular and biochemical responses of human T lymphocytes stimulated with streptococcal M protein. Presented at the 11th Lancefield International Symposium on Streptococcal Diseases, Siena, Italy, 1990; Abstract L77.
  51. Watanabe-Ohnishi  R, Low  DE, McGeer  A, Stevens  DL, Schlievert  PM, Newton  D, Selective depletion of Vb-bearing T cells in patients with severe invasive group A streptococcal infections and streptococcal toxic shock syndrome. J Infect Dis. 1995;171:7484.PubMedGoogle Scholar
  52. Stevens  DL, Bryant  AE, Hackett  SP. Gram-positive shock. Curr Opin Infect Dis. 1992;5:35563. DOIGoogle Scholar
  53. Hackett  S, Ferretti  J, Stevens  D. Cytokine induction by viable group A streptococci: suppression by streptolysin O. Presented at the 93rd Conference of the American Society for Microbiology, Las Vegas, NV, 1994; Abstract B-249.
  54. Muller-Alouf  H, Alouf  JE, Gerlach  D, Ozegowski  JH, Fitting  C, Cavaillon  JM. Comparative study of cytokine release by human peripheral blood mononuclear cells stimulated with Streptococcus pyogenes superantigenic erythrogenic toxins, heat-killed streptococci and lipopolysaccharide. Infect Immun. 1994;62:491521.PubMedGoogle Scholar
  55. Hackett  SP, Stevens  DL. Superantigens associated with staphylococcal and streptococcal toxic shock syndromes are potent inducers of tumor necrosis factor beta synthesis. J Infect Dis. 1993;168:2325.PubMedGoogle Scholar
  56. Kapur  V, Majesky  MW, Li  LL, Black  RA, Musser  JM. Cleavage of Interleukin 1B (IL-1B) precursor to produce active IL-1B by a conserved extracellular cysteine protease from Streptococcus pyogenes. Proc Natl Acad Sci U S A. 1993;90:767680. DOIPubMedGoogle Scholar
  57. Cleary  R, Chen  C, Lapenta  D, Bormann  N, Heath  D, Haanes  E. A virulence regulon in Streptococcus pyogenes. Presented at the Third International American Society for Microbiology Conference on Streptococcal Genetics, Minneapolis, MN, 1990; Abstract 19.
  58. Cleary  PP, Kaplan  EL, Handley  JP, Wlazlo  A, Kim  MH, Hauser  AR, Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980s. Lancet. 1992;339:51821. DOIPubMedGoogle Scholar
  59. Nida  SK, Ferretti  JJ. Phage influence on the synthesis of extracellular toxins in group A streptococci. Infect Immun. 1982;36:74550.PubMedGoogle Scholar
  60. Johnson  LP, Tomai  MA, Schlievert  PM. Bacteriophage involvement in group A streptococcal pyrogenic exotoxin A production. J Bacteriol. 1986;166:6237.PubMedGoogle Scholar
  61. Stevens  DL. Invasive group A streptococcal infections: the past, present and future. Pediatr Infect Dis J. 1994;13:5616.PubMedGoogle Scholar
  62. Kim  KS, Kaplan  EL. Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. J Pediatr. 1985;107:6814. DOIPubMedGoogle Scholar
  63. Gatanaduy  AS, Kaplan  EL, Huwe  BB, McKay  C, Wannamaker  LW. Failure of penicillin to eradicate group A streptococci during an outbreak of pharyngitis. Lancet. 1980;2:498502. DOIPubMedGoogle Scholar
  64. Brook  I. Role of beta-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococci. Pediatr Infect Dis. 1985;4:4915.PubMedGoogle Scholar
  65. Kohler  W. Streptococcal toxic shock syndrome. Zbl Bakt. 1990;272:25764.
  66. Eagle  H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med. 1952;13:3899. DOIPubMedGoogle Scholar
  67. Stevens  DL, Gibbons  AE, Bergstrom  R, Winn  V. The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis. 1988;158:238.PubMedGoogle Scholar
  68. Stevens  DL, Bryant  AE, Yan  S. Invasive group A streptococcal infection: new concepts in antibiotic treatment. Int J Antimicrob Agents. 1994;4:297301. DOIPubMedGoogle Scholar
  69. Stevens  DL, Yan  S, Bryant  AE. Penicillin-binding protein expression at different growth stages determines penicillin efficacy in vitro and in vivo: an explanation for the inoculum effect. J Infect Dis. 1993;167:14015.PubMedGoogle Scholar
  70. Yan  S, Mendelman  PM, Stevens  DL. The in vitro antibacterial activity of ceftriaxone against Streptococcus pyogenes is unrelated to penicillin-binding protein 4. FEMS Microbiol Lett. 1993;110:3138. DOIPubMedGoogle Scholar
  71. Yan  S, Bohach  GA, Stevens  DL. Persistent acylation of high-molecular weight penicillin-binding proteins by penicillin induces the post-antibiotic effect in Streptococcus pyogenes. J Infect Dis. 1994;170:60914.PubMedGoogle Scholar
  72. Stevens  DL, Maier  KA, Mitten  JE. Effect of antibiotics on toxin production and viability of Clostridium perfringens. Antimicrob Agents Chemother. 1987;31:2138.PubMedGoogle Scholar
  73. Gemmell  CG, Peterson  PK, Schmeling  D, Kim  Y, Mathews  J, Wannamaker  L, Potentiation of opsonization and phagocytosis of Streptococcus pyogenes following growth in the presence of clindamycin. J Clin Invest. 1981;67:124956. DOIPubMedGoogle Scholar
  74. Stevens  DL, Bryant  AE, Hackett  SP. Antibiotic effects on bacterial viability, toxin production and host response. Clin Infect Dis. 1995;20(Suppl 2):S1547.PubMedGoogle Scholar
  75. Barry  W, Hudgins  L, Donta  ST, Pesanti  EL. Intravenous immunoglobulin therapy for Toxic shock syndrome. JAMA. 1992;267:33156. DOIPubMedGoogle Scholar
  76. Yong  JM. Letter. Lancet. 1994;343:1427. DOIPubMedGoogle Scholar
  77. Greenberg  LJ, Gray  ED, Yunis  E. Association of HL-A5 and immune responsiveness in vitro to streptococcal antigens. J Exp Med. 1975;141:93443. DOIGoogle Scholar
  78. Weinstein  L, Barza  M. Gas gangrene. N Engl J Med. 1972;289:1129.
  79. Zabriskie  JB, Lavenchy  D, Williams  RCJ, Rheumatic-fever associated B-cell alloantigens as identified by monoclonal antibodies. Arthritis Rheum. 1985;28:104751. DOIPubMedGoogle Scholar
  80. Schwartz  B, Elliot  JA, Butler  JC, Simon  PA, Jameson  BL, Welch  GE, Clusters of invasive group A streptococcal infections in family, hospital, and nursing home settings. Clin Infect Dis. 1992;15:27784.PubMedGoogle Scholar

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