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. 1992 May 1;175(5):1207–1212. doi: 10.1084/jem.175.5.1207

Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer Reaction of relapsing fever

PMCID: PMC2119219  PMID: 1569394

Abstract

The Jarisch-Herxheimer Reaction (J-HR) is a clinical syndrome occurring soon after the first adequate dose of an antimicrobial drug to treat infectious diseases such as Lyme disease, syphilis, and relapsing fever. Previous attempts to identify factors mediating this reaction, that may cause death, have been unsuccessful. We conducted a prospective trial in Addis Ababa, Ethiopia on 17 patients treated with penicillin for proven louse-borne relapsing fever due to Borrelia recurrentis to evaluate the association of symptoms with plasma levels of tumor necrosis factor (TNF), interleukins 6, and 8 (IL-6 and -8). 14 of the 17 (82%) patients experienced a typical J-HR consisting of rigors, a rise in body temperature (1.06 +/- 0.2 degrees C) peaking at 2 h, leukopenia (7.4 +/- 0.6 x 10(-3) cells/mm3) at 4 h, a slight decrease, and then rise of mean arterial blood pressure. Spirochetes were cleared from blood in 5 +/- 1 h after penicillin. There were no fatalities, but constitutional symptoms were severe during J-HR. Plasma TNF, IL-6, and -8 were raised in several patients on admission, but a seven-, six-, and fourfold elevation of these plasma cytokine concentrations over admission levels was detected, respectively, occurring in transient form coincidental with observed pathophysiological changes of J-HR. Elevated plasma cytokine levels were not detected in the three patients who did not suffer J-HR. We conclude that the severe pathophysiological changes characterizing the J-HR occurring on penicillin treatment of louse-borne relapsing fever are closely associated with transient elevation of plasma TNF, IL-6, and -8 concentrations.

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Selected References

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  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Abramowicz D., Schandene L., Goldman M., Crusiaux A., Vereerstraeten P., De Pauw L., Wybran J., Kinnaert P., Dupont E., Toussaint C. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation. 1989 Apr;47(4):606–608. doi: 10.1097/00007890-198904000-00008. [DOI] [PubMed] [Google Scholar]
  3. Bryceson A. D. Clinical pathology of the Jarisch-Herxheimer reaction. J Infect Dis. 1976 Jun;133(6):696–704. doi: 10.1093/infdis/133.6.696. [DOI] [PubMed] [Google Scholar]
  4. Bryceson A. D., Cooper K. E., Warrell D. A., Perine P. L., Parry E. H. Studies of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating Borrelia endotoxin. Clin Sci. 1972 Sep;43(3):343–354. doi: 10.1042/cs0430343. [DOI] [PubMed] [Google Scholar]
  5. Butler T., Spagnuolo P. J., Goldsmith G. H., Aikawa M. Interaction of Borrelia spirochetes with human mononuclear leukocytes causes production of leukocytic pyrogen and thromboplastin. J Lab Clin Med. 1982 May;99(5):709–721. [PubMed] [Google Scholar]
  6. DeForge L. E., Remick D. G. Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. Biochem Biophys Res Commun. 1991 Jan 15;174(1):18–24. doi: 10.1016/0006-291x(91)90478-p. [DOI] [PubMed] [Google Scholar]
  7. DeForge L. E., Remick D. G. Sandwich ELISA for detection of picogram quantities of interleukin-8. Immunol Invest. 1991 Feb;20(1):89–97. doi: 10.3109/08820139109054928. [DOI] [PubMed] [Google Scholar]
  8. Debets J. M., Leunissen K. M., van Hooff H. J., van der Linden C. J., Buurman W. A. Evidence of involvement of tumor necrosis factor in adverse reactions during treatment of kidney allograft rejection with antithymocyte globulin. Transplantation. 1989 Mar;47(3):487–492. doi: 10.1097/00007890-198903000-00018. [DOI] [PubMed] [Google Scholar]
  9. Eskandari M. K., Nguyen D. T., Kunkel S. L., Remick D. G. WEHI 164 subclone 13 assay for TNF: sensitivity, specificity, and reliability. Immunol Invest. 1990 Feb;19(1):69–79. doi: 10.3109/08820139009042026. [DOI] [PubMed] [Google Scholar]
  10. Friedland J. S., Warrell D. A. The Jarisch-Herxheimer reaction in leptospirosis: possible pathogenesis and review. Rev Infect Dis. 1991 Mar-Apr;13(2):207–210. doi: 10.1093/clinids/13.2.207. [DOI] [PubMed] [Google Scholar]
  11. Galloway R. E., Levin J., Butler T., Naff G. B., Goldsmith G. H., Saito H., Awoke S., Wallace C. K. Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrentis infection. Am J Med. 1977 Dec;63(6):933–938. doi: 10.1016/0002-9343(77)90548-4. [DOI] [PubMed] [Google Scholar]
  12. Gudjónsson H., Skog E. The effect of prednisolone on the Jarisch-Herxheimer reaction. Acta Derm Venereol. 1968;48(1):15–18. [PubMed] [Google Scholar]
  13. Habicht G. S., Beck G., Benach J. L., Coleman J. L., Leichtling K. D. Lyme disease spirochetes induce human and murine interleukin 1 production. J Immunol. 1985 May;134(5):3147–3154. [PubMed] [Google Scholar]
  14. Martich G. D., Danner R. L., Ceska M., Suffredini A. F. Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med. 1991 Apr 1;173(4):1021–1024. doi: 10.1084/jem.173.4.1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
  16. Parry E. H., Warrell D. A., Perine P. L., Vukotich D., Bryceson A. D. Some effects of louse-borne relapsing fever on the function of the heart. Am J Med. 1970 Oct;49(4):472–479. doi: 10.1016/s0002-9343(70)80041-9. [DOI] [PubMed] [Google Scholar]
  17. Perine P. L., Parry E. H., Vukotich D., Warrell D. A., Bryceson A. D. Bleeding in louse-borne relapsing fever. I. Clinical studies in 37 patients. Trans R Soc Trop Med Hyg. 1971;65(6):776–781. doi: 10.1016/0035-9203(71)90091-5. [DOI] [PubMed] [Google Scholar]
  18. Sheron N., Lau J. N., Hofmann J., Williams R., Alexander G. J. Dose-dependent increase in plasma interleukin-6 after recombinant tumour necrosis factor infusion in humans. Clin Exp Immunol. 1990 Dec;82(3):427–428. doi: 10.1111/j.1365-2249.1990.tb05465.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Spriggs D. R., Sherman M. L., Michie H., Arthur K. A., Imamura K., Wilmore D., Frei E., 3rd, Kufe D. W. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. J Natl Cancer Inst. 1988 Sep 7;80(13):1039–1044. doi: 10.1093/jnci/80.13.1039. [DOI] [PubMed] [Google Scholar]
  20. Starnes H. F., Jr, Pearce M. K., Tewari A., Yim J. H., Zou J. C., Abrams J. S. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol. 1990 Dec 15;145(12):4185–4191. [PubMed] [Google Scholar]
  21. Teklu B., Habte-Michael A., Warrell D. A., White N. J., Wright D. J. Meptazinol diminishes the Jarisch-Herxheimer reaction of relapsing fever. Lancet. 1983 Apr 16;1(8329):835–839. doi: 10.1016/s0140-6736(83)91384-3. [DOI] [PubMed] [Google Scholar]
  22. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  23. Ulich T. R., Guo K. Z., Remick D., del Castillo J., Yin S. M. Endotoxin-induced cytokine gene expression in vivo. III. IL-6 mRNA and serum protein expression and the in vivo hematologic effects of IL-6. J Immunol. 1991 Apr 1;146(7):2316–2323. [PubMed] [Google Scholar]
  24. Van Zee K. J., DeForge L. E., Fischer E., Marano M. A., Kenney J. S., Remick D. G., Lowry S. F., Moldawer L. L. IL-8 in septic shock, endotoxemia, and after IL-1 administration. J Immunol. 1991 May 15;146(10):3478–3482. [PubMed] [Google Scholar]
  25. Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med. 1989 Jan 1;169(1):333–338. doi: 10.1084/jem.169.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Warrell D. A., Perine P. L., Bryceson A. D., Parry E. H., Pope H. M. Physiologic changes during the Jarisch-Herxheimer reaction in early syphilis. A comparison with louse-borne relapsing fever. Am J Med. 1971 Aug;51(2):176–185. doi: 10.1016/0002-9343(71)90236-1. [DOI] [PubMed] [Google Scholar]
  27. Warrell D. A., Pope H. M., Parry E. H., Perine P. L., Bryceson A. D. Cardiorespiratory disturbances associated with infective fever in man: studies of Ethiopian louse-borne relapsing fever. Clin Sci. 1970 Jul;39(1):123–145. doi: 10.1042/cs0390123. [DOI] [PubMed] [Google Scholar]
  28. Whittle H. C., Pope H. M. The febrile response to treatment in Gambian sleeping sickness. Ann Trop Med Parasitol. 1972 Mar;66(1):7–14. doi: 10.1080/00034983.1972.11686792. [DOI] [PubMed] [Google Scholar]
  29. Wright D. J. Reaction following treatment of murine borreliosis and Shwartzman type reacion with borrelial sonicates. Parasite Immunol. 1980 Autumn;2(3):201–221. doi: 10.1111/j.1365-3024.1980.tb00054.x. [DOI] [PubMed] [Google Scholar]
  30. Young E. J., Weingarten N. M., Baughn R. E., Duncan W. C. Studies on the pathogenesis of the Jarisch-Herxheimer reaction: development of an animal model and evidence against a role for classical endotoxin. J Infect Dis. 1982 Nov;146(5):606–615. doi: 10.1093/infdis/146.5.606. [DOI] [PubMed] [Google Scholar]
  31. Zein Z. A. Louse borne relapsing fever (LBRF): mortality and frequency of Jarisch-Herxheimer reaction. J R Soc Health. 1987 Aug;107(4):146–147. doi: 10.1177/146642408710700410. [DOI] [PubMed] [Google Scholar]

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