European Journal of Pediatrics

, Volume 152, Issue 2, pp 82–92 | Cite as

Probable role ofStreptococcus pyogenes in Kawasaki disease

  • T. Akiyama
  • K. Yashiro
Review
Received:
Accepted:

Abstract

Over the past 25 years, the clinical course of Kawasaki disease has been defined, the prevalence and nature of the cardiovascular effects widely understood, and pathological changes in the most severe cases well described. However, the aetiology and pathogenesis of this puzzling disease have remained unclear, thus specific therapy is not yet available. Because of some close clinical similarities between this disease and streptococcal scarlet fever, particular attention has been paid to the possible role ofStreptococcus pyogenes as an aetiological agent in this illness. Until now, however, group A β-haemolytic streptococci have never been consistently isolated from any patients; in addition, the titre of antistreptolysin 0 is not raised, and lack of response to antibiotics is a feature of this disease. Our long series of investigations over more than 10 years, which will be covered in the present review, were performed in an attempt at elucidating causative agent(s) of Kawasaki disease. This has led to our firm belief in the probable role ofS. pyogenes in the pathogenesis of this disease, despite the lack of fulfillment of Koch's postulates, on the basis of the following findings. Patients with Kawasaki disease recovering from the acute, febrile phase of the illness exhibited an exaggerated cell-mediated reactivity, as measured by the macrophage migration inhibition test, to group A β-haemolytic streptococci, their pyrogenic exotoxin and streptolysin 0 as well as to several mammalian muscle cell extracts which are allegedly related antigenically to the cell wall and/or cytoplasmic membrane ofS. pyogenes. Protoplast-like “spherical bodies” varying in diameter from 0.5 to 1.5 μm, and devoid of cell walls, were detected in the buffy coats of peripheral blood from patients with this disease, and stained distinctly by immuno-electron microscopy using, as a primary antibody, a rabbit antiserum toS. pyogenes- derived protoplasts, and followed by absorption with protoplasts fromStaphylococcus aureus andEscherichia coli. Newborn mice infected withS. pyogenes having no capacity to confer cell-mediated immunity even in adult murine hosts, and reinfected 4–6 weeks later with another strain of the same species of bacteria which is able to elicit cellular immunity, showed a lack of humoral response to streptococcal antigens, leaving intact cell-mediated immunity. Such a biased immunological characteristic is an exact counterpart of that of Kawasaki disease patients. Consequently, in the subsequent experiment, peripheral blood lymphocytes from patients with this disease were cultured in the presence of pokeweed mitogen, streptolysin O andS. pyogenes-derived C-polysaccharide, confirming their refractoriness toS. pyogenes-associated antigens coupled with normal response to the unrelated antigen. A considerable amount of streptococcal pyrogenic exotoxin and its 100% incidence in the patient's sera were detected by the use of an enzyme-linked immunosorbent assay reinforced with a monoclonal antibody specific for the streptococcal exotoxin.

Key words

Kawasaki disease Streptococcus pyogenes Streptococcal pyrogenic exotonin Immunological tolerance 

Abbreviations

ASLO

anti-streptolysin O

CFA

complete Freund's adjuvant

EA

early antigen

EB

Epstein-Barr virus

KD

Kawasaki disease

MIF

migration inhibitory factor

MIT

macrophage migration inhibition test

PWM

pokeweed mitogen

SIO

streptolysin O

SPE

streptococcal pyrogenic exotoxin

VCA

viral capsid antigen

This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Akiyama T (1980) Antigenic alteration on the membrane of cells from animals infected with intracellular parasites. Kitasato Med 10:245–261Google Scholar
  2. 2.
    Akiyama T (1984) Molecular biology of host-parasite relationship in infectious diseases, especially in salmonellosis, tuberculosis, and leprosy. Microbiology 355:362Google Scholar
  3. 3.
    Akiyama T, Yamaura N (1976) Application of the macrophage migration inhibition test to screen patients with early cancer and obtain prognostic determinations of cancer treatment. Jpn J Microbiol 20:131–140PubMedGoogle Scholar
  4. 4.
    Akiyama T, Hiraishi S, Osawa N, Yashiro K (1985) Possible tole ofStreptococcus pyogenes in mucocutaneous lymph node syndrome. Acta Paediatr Jpn 27:205–213Google Scholar
  5. 5.
    Akiyama T, Hiraishi S, Osawa N, Yashiro K (1986) Possible tole ofS. pyogenes in mucocutaneous lymph node syndrome II. Heightened cellular reactivity to stimulation by mammalian myocardial and arterial antigens in MCLS patients. Acta Paediatr Jpn 28:788–796Google Scholar
  6. 6.
    Akiyama T, Nakazato K, Osawa N, Tamaki H, Yamamoto N, Yamashina S, Yashiro K (1987) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. III. Electron microscopic observation on group A β-hemolytic streptococci inoculated into mice. Acta Paediatr Jpn 29:417–425PubMedGoogle Scholar
  7. 7.
    Akiyama I, Osawa N, Yashiro K (1987) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome, IV. Immunological tolerance following exposure of neonatal mice to live attenuated strains ofS. pyogenes. Acta Paediatr Jpn 29:426–432PubMedGoogle Scholar
  8. 8.
    Akiyama T, Nakazato K, Osawa N, Tamaki H, Yamaura N, Yashiro K (1987) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. V. Further electron microscopic observations on group A β-hemolytic streptococci inoculated into immune mice. Acta Paediatr Jpn 29:721–726PubMedGoogle Scholar
  9. 9.
    Akiyama T, Hiraishi S, Osawa N, Yamaura N, Yashiro K (1988) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. VI. Heightened cellular reactivity to streptolyson-O in mice infected withS. pyogenes and in MCLS patients. Acta Paediatr Jpn 30:68–72Google Scholar
  10. 10.
    Akiyama T, Osawa N, Watanabe M, Yamaura N, Yashiro K (1988) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. VII. A weak response to Epstein-Barr viral capsid antigen in mice infected neonatally withS. pyogenes. Acta Paediatr Jpn 30:654–661PubMedGoogle Scholar
  11. 11.
    Akiyama T, Itoh Y, Nakazato K, Tamauchi H, Yashiro K (1991) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. XI. Immunoelectron microscopic observation of protoplast-like “spherical bodies” detected in peripheral blood of MCLS patients. Acta Paediatr Jpn 33:292–299PubMedGoogle Scholar
  12. 12.
    Akiyama T, Osawa N, Oyake T, Shimanuki K, Yashiro K (1991) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. XII. Variable responses of platelets in MCLS seem to be explainable by streptococcal pyrogenic exotoxin. Acta Paediatr Jpn 33:20–26PubMedGoogle Scholar
  13. 13.
    Akiyama T, Shimanuki K, Yashiro K (1992) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. XV. Potential utility of SPE-toxoid for prophylaxis and treatment of MCLS Acta Paediatr Jpn (in press)Google Scholar
  14. 14.
    Alouf JE (1980) Streptococcal toxins (streptolyin O, streptolysin S, erythrogenic toxin). Pharmacol Ther 11:661–717PubMedGoogle Scholar
  15. 15.
    Bell DM, Anderson LJ, Berkowitz ID, Brink EW, et al (1981) Kawasaki syndrome: description of two outbreaks in the United States. N Engl J Med 304:1568–1575PubMedGoogle Scholar
  16. 16.
    Breese BB, Breese GH (1978) Beta-hemolytic streptococcal disease, vol 8. Houghton Mifflin, Boston, pp 143–153Google Scholar
  17. 17.
    Dean AG, Hicks R, Melish ME, Palumbo NP (1982) An epidemic of Kawasaki syndrome in Hawaii. J Pediatr 100:552–557PubMedGoogle Scholar
  18. 18.
    Derick CL, Swift HF (1929) Reactins of rabbits to nonhemolytic strepetococci. I. General tuberculin-like hypersensitiveness. allergy or hyperergy following the secondary reaction. J Exp Med 49:615–636Google Scholar
  19. 19.
    Dick GF, Dick GH (1923) Experimental scarlet fever. JAMA 81:1166–1167Google Scholar
  20. 20.
    Frobisher MJr, Brown JH (1927) Transmissible toxicogenicity of streptococci. Bull Johns Hopkins Hosp 41:167–173Google Scholar
  21. 21.
    Green CA (1942) Hemolytic streptococcal infections and acute rheumatism. Ann Rheum Dis 3:4–41Google Scholar
  22. 22.
    Gronowicz E, Coutinbo A, Melchers F (1976) A plaque assay for all cells secreting Ig of a given type or class. Eur J Immunol 6:588–590PubMedGoogle Scholar
  23. 23.
    Harvey HS, Dunlap MB (1962) Risk to children exposed in home to respiratory bacteria. Am J Dis Child 103:777–785PubMedGoogle Scholar
  24. 24.
    Humphrey JH, Pagel W (1949) The tissue response to heatkilled streptococci in the skin of normal subjects, and in persons with rheumatic fever, rheumatoid arthritis, subacute bacterial endocarditis and erythema nodosum. Br J Exp Pathol 30:282–288PubMedGoogle Scholar
  25. 25.
    Inazumi Y, Boku E, Ikeda S, Kaneko Y, Murai T, Oguro H (1983) Follow-up study of β-streptococcus on throat in healthy school children (in Japanese). Kansenshogaku Zasshi 57:318–332PubMedGoogle Scholar
  26. 26.
    Iwanaga M, Noro S, Osato T, Sakurada N, Saeki Y, Takeda K (1981) Kawasaki disease and Epstein-Barr virus. Lancet I:938–939Google Scholar
  27. 27.
    Jeljaszewicz J (1978) Streptococcal erythrogenic toxin. In: Jeljaszewicz, J, Wadstrom T (eds) Bacterial toxins and cell membranes. Academic Press, New York, pp 216–222Google Scholar
  28. 28.
    Kaplan MH (1963) Immunologic relation of streptococcal and tissue antigens. I. Properties of an antigen in certain strains of group A streptococci exhibiting an immunologic cross-reaction with human heart tissue. J Immunol 90:595–606PubMedGoogle Scholar
  29. 29.
    Kaplan MH, Svec KH (1964) Immunologic relation of streptococcal and tissue antigens. III. Presence in human sera of streptococcal antibody cross-reactive with heart tissue. Association with streptococcal infection, rheumatic fever, and glomerulonephritis. J Exp Med 119:651–666PubMedGoogle Scholar
  30. 30.
    Kawai M, Akiyama T, Hiraishi S, Ikewaki N, Osawa N, Watanabe M, Yamaura N, Yashiro K (1989) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. IX. Quantitation by ELISA of streptococcal pyrogenic exotoxin in the serum of MCLS patients. Acta Paediatr Jpn 31:529–536PubMedGoogle Scholar
  31. 31.
    Kawasaki T (1967) Acute febrile mucocutaneous lymph node syndrome, with accompanying specific peeling of the fingers and the toes (in Japanese). Allergy 16:178–222PubMedGoogle Scholar
  32. 32.
    Kikuta H (1984) Kawasaki disease and unusual primary infection with Epstein-Barr virus. Pediatrics 73:413–414PubMedGoogle Scholar
  33. 33.
    Kikuta H, Matsumoto S (1985) Recurrent Kawasaki disease and pattern of antibodies of Epstein-Barr virus (in Japanese). Prog Med 5:116–120Google Scholar
  34. 34.
    Kotani S (1987) Evaluation of evidence related to streptococci in the etiology of Kawasaki disease. In: Shulman ST (ed) Kawasaki disease. Liss, New York, pp 101–111Google Scholar
  35. 35.
    Kuno-Sakai H (1985) Increase of immunoglobulin-bearing peripheral blood lymphocytes in children with Kawasaki disease. Acta Paediatr Jpn 27:127–130Google Scholar
  36. 36.
    Lee LA, Burns J, Glode M, Harmon C, Weston W (1983) No autoantibodies to nuclear antigens in the Kawasaki syndrome. N Engl J Med 308:1034Google Scholar
  37. 37.
    Leung DYM, Geha RS, Grady S, Krensky A, Meade R, Reinherz EL, Siegel RL (1982) Immunoregulatory abnormalities in mucocutaneous lymph node syndrome. Clin Immunol Immunopathol 23:100–112PubMedGoogle Scholar
  38. 38.
    Melish ME, Euthesen K, Hicks RV, Kihara S, Marchette NJ, Reddy DV, Sam E (1983) Kawasaki syndrome in the United States. Pediatr Jpn 24:281–290Google Scholar
  39. 39.
    Niwa K, Miyamoto H, Nakajima H, Terai M (1987) Thrombocytopenia in mucocutaneous lymph node syndrome (in Japanese). J Jpn Pediatr Soc 91:2913–2916Google Scholar
  40. 40.
    Osawa N, Akiyama T, Ikewaki N, Yamaura N, Yashiro K (1989) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. VIII. Immunological tolerance toS. pyogenes-associated antigens seems essential to induction of MCLS. Acta Paediatr Jpn 31:462–468PubMedGoogle Scholar
  41. 41.
    Osawa N, Akiyama T, Hiraishi S, Hirata Y, Yashiro K (1991) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. XIII. No recovery of β-hemolytic streptococci from pharynx of MCLS patients. Acta Paediatr Jpn 33:166–171PubMedGoogle Scholar
  42. 42.
    Oyake T, Akiyama T (1990) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. X. Effects of streptococcal pyrogenic exotoxin on the development of immunological abnormalities in tolerant mice (in Japanese). J Jpn Pediatr Soc 94:2320–2327Google Scholar
  43. 43.
    Read SE, Falk RE, Fischetti VA, Utermohlen V, Zabriskie JB (1974) Cellular reactivity studies to streptococcal antigens. J Clin Invest 54:439–450PubMedGoogle Scholar
  44. 44.
    Riley HD (1976) Mucocutaneous lymph node syndrome (Kawasaki disease). J Infect Dis 134:302–305PubMedGoogle Scholar
  45. 45.
    Sasazuki T, Harada F (1987) Genetical studies of Kawasaki disease (in Japanese). Annual reports of research committee on MCLS sponsored by Japanese Ministry of Education 134–138Google Scholar
  46. 46.
    Shimanuki K, Akiyama T, Hasobe T, Yashiro K (1992) Possible role ofS. pyogenes in mucocutaneous lymph node syndrome. XIV. Further quantitation of streptococal pyrogenic exotoxin in the serum of MCLS patients (in Japanese). J Jpn Pediatr Soc (in press)Google Scholar
  47. 47.
    Swift HF, Derick CL (1929) Reactions of rabbits to nonhemolytic streptococci. II. Skin reactions in intravenously immunized animals. J Exp Med 49:883–897Google Scholar
  48. 48.
    Ueno T, Matsumi F (1983) Kawasaki syndrome and streptococcal infection. Acta Paediatr Jpn 25:130–146Google Scholar
  49. 49.
    Vazquez JJ, Dixon FJ (1957) Immunohistochemical study of lesions in rheumatic fever, systemic lupus erythematosus and rheumatoid arthritis. Lab Invest 6:205–217PubMedGoogle Scholar
  50. 50.
    Weeks CR, Ferretti JJ (1984) The gene for type A streptococcal exotoxin (erythrogenic toxin) is located in bacteriophage T 12. Infect Immun 46:531–536PubMedGoogle Scholar
  51. 51.
    Weeks CR, Ferretti JJ (1986) Nucleotide sequence of the type A streptococcal exotoxin (erythrogenic toxin) gene fromS. pyogenes bacteriophage T 12. Infect Immun 52:114–150Google Scholar
  52. 52.
    Yamaguchi T, Amano Y, Iimura T, Kashiwagi Y, Ohkubo N, Onogawa T (1982) 1979-fiscal year survey for throat carricrs of hemolytic streptococci among children in Tokyo (in Japanese). Kansenshogaku Zasshi 56:85–96PubMedGoogle Scholar
  53. 53.
    Yokoyama T, Ichinose E, Kato H (1980) Aspirin treatment and platelet function in Kawasaki disease. Kurume Med J 27:57–61PubMedGoogle Scholar
  54. 54.
    Zabriskie JB, Freimer EH (1966) An immunological relationship between the group A streptococcus and mammalian muscle. J Exp Med 124:661–679PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • T. Akiyama
    • 1
  • K. Yashiro
    • 2
  1. 1.Department of MicrobiologyKitasato University School of MedicineSagamiharaJapan
  2. 2.Department of PaediatricsKitasato University School of MedicineSagamiharaJapan

Personalised recommendations