Leading articles
New insights into the patboptrysiology of the Jarisch-Herxhebner reaction
The Jarisch-Herxheimer Reaction (J-HR) is a pathophysiological phenomenon about which most medical students are taught and unwit-
tingly probably fail to recognize during clinical practice. The J-HR is classically a syndrome in which there is a transient worsening of symptoms occurring soon after the first adequate dose of an appropriate antimicrobial drug used to treat an infectious disease. The reaction consists of a sudden rise, then more gradual fall in body temperature; a transient rise followed by a more profound fall in blood pressure, and worsening of constitutional symptoms. The intensity of J-HR varies between different infections and in its most severe form is life-threatening. The identity of systemic mediators causing the reaction has been sought with little definitive success for almost a century since the phenomenon was first documented. However, recent evidence from clinical experiments on the J-HR of relapsing fever strongly supports the hypothesis that cytokines are implicated. In 1895, Jarisch (an Austrian dermatologistsyphilologist), described that the spots of roseola syphilis became more defined and numerous on treatment with mercury (Jarisch, 1895). Some seven years later, Herxheimer (a German dermatologist-syphilologist) documented a systemic reaction consisting of fever, sweating, and anorexia occurring within 24 h of the treatment of syphilis using mercury inunctions (Herxheimer & Krause, 1902). This transient syndrome now bears the names of these two dermatologists. It is now recognized that J-HR occurs on antibiotic treatment of many bacterial (Bryceson, 1976) and some protozoal infections, such as African trypanosomiasis (Whittle & Pope, 1972). However, studies on the J-HR of two spirochaetal infections, namely syphilis and louse-born relapsing fever are now established as paradigms for clinical investigation of the syndrome. Physiological changes occurring during the J-HR asociated with penicillin treatment of early syphilis have been precisely described (Warrell et al., 1971) and are experienced by about 80% of patients (Young et at., 1982). The principal physiological change is an increase in body temperature, by more than 0-8°C, peaking 6-8 h after penicillin and often associated with rigors. In addition, there is peripheral blood leucocytosis, a fall in lymphocyte count, and a fall in systemic arterial blood pressure with an increase in metabolic rate. Leucocyte pyrogen (endotoxin) was suggested as a mediator of the observed physiological changes (Warrell et al., 1971); however, endotoxin was not detected in the blood of syphilitic patients experiencing J-HR in response to penicillin (Young et al., 1082). In addition,
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
192, p. 118. American Society for Microbiology, Washington, D C Quinn, J. P., Dudek, E. J., Divincenzo, C. A., Locks, D. A. & Lerner, S. A. (1986). Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections. Journal of Infectious Diseases 154, 289-94. Rasmussen, B. A., Gluzman, Y. & Tally, F. P. (1990). Cloning and sequencing of the class B /Mactamase gene (CCTA) from Bacteroides fragilis TAL3636. Antimicrobial Agents and Chemotherapy 34, 1590-2. Saino, Y., Kobayashi, F., Inoue, M. & Mitsuhashi, S. (1982). Purification and properties of inducible penicillin ^-lactamase isolated from Pseudomonas maltophilia. Antimicrobial Agents and Chemotherapy 22, 564-70. Sanden, C. C , Sanden, W. E., Thomson, K. S. & Iaconis, J. P. (1989). Meropenem: activity against resistant Gram-negative bacteria and interactions with /7-lactamases. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 187-96. Sato, K., Fujii, R., Okatomo, R., Inoue, M. & Mitsuhashi, S. (1985). Biochemical properties of /Mactamase produced by Flavobacterium odoratum. Antimicrobial Agents and Chemotherapy 27, 612-4. Shannon, K., King, A. &. Phillips, I. (1986). 0-Lactamases with high activity against imipenem and Sch34343 from Aeromonas hydrophila. Journal of Antimicrobial Chemotherapy 17, 45-50. Thompson, J. S. & Malamy, M. H. (1990). Sequencing the gene for an imipenem-cefoxitinhydrolyzing enzyme (CfiA) from Bacteroides fragilis TAL2480, reveals strong similarity between CfiA and Bacillus cereus /7-lactamase II. Journal of Bacteriology 172, 2584-93. Watanabe, M., lyobe, S., Inoue, M. & Mitsuhashi, S. (1991). Transferable imipenem resistance in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 35, 147-51. Yang, Y. J. & Livennore, D. M. (1989). Interactions of meropenem with class I chromosomal ^-lactamases. Journal of Antimicrobial Chemotherapy 23, Suppl. A. 207-17. Yang, Y. J., Wu, P. J. & Livermore, D. M. (1990). Biochemical characterization of a /Mactamase that hydrolyzes penems and carbapenems from two Serralia marcescens isolates. Antimicrobial Agents and Chemotherapy 34, 755-8. YoUuji, A., Minami, S., Inoue, M. & Mitsuhashi, S. (1983). Properties of novel ^-lactamase produced by Bacteroides fragilis. Antimicrobial Agents and Chemotherapy 24, 925-9.
613
614
Leading articles
sibility that it had leaked into the circulation from intestinal Gram-negative organisms. A major recent advance in the study of hostmicrobial interactions has been the discovery that cytokines mediate many of the systemic effects of infection such as fever, anorexia, and the synthesis of acute phase proteins (Friedland & Griffin, 1991). Cytokines are polypeptide hormones released principally from macrophages but also from other cells, for example endothelial cells, in response to a variety of infectious stimuli. Lipopolysaccharide is known to be a potent soluble stimulus of cytokine release, and in addition, phagocytosis of pathogens, such as Mycobacterium tuberculosis by macrophages, is also a strong signal for cytokine production. An important cytokine known to mediate some of the host response to infection is Tumor Necrosis Factor (TNF), and a sequence of other Interleukins (IL) (1 to 10) have now been described. Discrete physiological functions of individual cytokines arc now becoming apparent; for example, IL-6 (previously known as Interferon /J2) stimulates proliferation of B cells and causes hepatocytes to secrete acute phase proteins (Gauldie et al., 1987). IL-8 has been shown to be the most powerful chemoattractant yet discovered for polymorphonuclear leucocytes (Strieter et al., 1989). Considerable knowledge about the pathophysiological roles of cytokines has been gained from the use of animal models of infection. This is particularly exemplified by TNF which has been shown to be pivotal in mediation of Gram-negative lipopolysaccharide induced injury in animals, and has been detected in the circulation of man and primates during bacteraemia (Hesse et al., 1988) and in human volunteers receiving endotoxin (Michie et al., 1988). The pathophysiological significance of TNF was demonstrated by the discovery that in animal models of bacteraemia monoclonal antibodies directed against this cytokine prevent death (Tracey et al., 1987) and reduce the appearance in the circulation of other cytokines, namely IL-1/? and IL-6 (Fong et al., 1989). Thus, immunological, physiological, and metabolic effects of infection appear to be mediated by the orchestrated release of a network of cytokines. Extrapolation of data derived from cell and animal experiments to the situation of human infection has proved complicated, and it is now clear that the response to bacteraemia in man involves a complex pattern of cytokines (Waage et al., 1989). It is thought that large differences of
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
when rabbits infected with Treponema pallidum were challenged with penicillin, a reaction resembling J-HR was observed, but endotoxaemia was not detected. Interestingly, the rabbits still developed fever when rendered unresponsive to endotoxin before antibiotic treatment, thus strengthening the argument that classical endotoxin may not be involved. The J-HR associated with antibiotic treatment of louse-borne relapsing fever is clinically the most severe form of the reaction. Relapsing fever, caused by Borrelia recurrentis which lives in the haemolymph of the human body louse, is a disease associated with poor socio-economic conditions and is endemic in some East African and South American countries, for example, Ethiopia and Bolivia, respectively. It is thought that the organism penetrates the skin after the louse is crushed and gains access to the systemic circulation. Patients present with high fever and frequent chills (Bryceson, 1976) and the diagnosis can be readily confirmed by the demonstration of spirochaetes on Wright's stained blood smears. High concentrations'of spirochaetes, up to 103 organisms per mL, have been recorded in blood during this condition. In a study of 97 patients in northern Ethiopia, approximately 80% of antibiotic treated patients experienced J-HR and the mortality was 4% (Zein, 1987). Physiological changes associated with this condition have been extensively studied (Parry et al., 1970; Warrell et al., 1970; Perine et al., 1971) and consist of a highly predictable syndrome with around a 1°C rise in body temperature, with severe rigors, occurring about 90 min after antibiotic (either penicillin or tetracycline). Cardiac output initially increases and then falls, remaining low for several hours (Warrell et al., 1970). This form of J-HR lasts about 8 h, but clinically severe events occur principally in the first 3 h. The aetiology of such profound physiological changes has been investigated and in-vivo bioassay of plasma injected into rabbits caused fever and hypotension, which not unreasonably, was thought initially to be due to endotoxin (Bryceson et al., 1972). Subsequent studies suggested activation of Hageman factor, prekallikrein and proteins of the complement system in B. recurrentis infection and suggested that endotoxin may play a role in the evolution of J-HR following antibiotic treatment (Galloway et al., 1977). However, in the latter study preparations of borrelia organisms produced negative Limulus lysate tests for- endotoxin, and it was concluded that if endotoxin was aetiological there was the pos-
Leading articles
spp. In addition, since therapeutic amelioration of J-HR has at the best only been partially successful (Teklu et al., 1983), the rational use of therapeutic agents directed against the cytokine cascade is attractive. GEORGE E. GRIFFIN Division of Communicable Diseases, St Georges Hospital Medical School, Tooting, London SW17 ORE. UK
References Bryceson, A. D. M. (1976). Clinical pathology of the Jarisch-Herxheimer reaction. Journal of Infectious Diseases 133, 696-704. Bryceson, A. D. M., Cooper, K. E., Warrell, D. A., Perine, P. L. & Parry, E. H. 0. (1972). Studio of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever evidence for the presence of circulating Borrelia endotoxin. Clinical Science 43, 343-54. Fong, Y., Tracey, K. J., MoMawer, L. L., Hesse, D. G., Manogue, K. B.t Kenney, J. S. et al. (1989). Antibodies to cachectin/tumor necrosis factor reduce interleukin Ifi and interleukin 6 appearance during lethal bacteremia. Journal of Experimental Medicine 170, 1627-33. Friedland, J. S. & Griffin, G. E. (1991). Cytokines and bacterial infection. In Cytokines in Health and Disease: Physiology and Pathophysiology (Kunkel, S. L. & Remick, D. G., Eds). Marcel Dekker, New York, in press. Galloway, R. E., Levin, J., Butler, T., Naff, G. B., Goldsmith, G. H., Saito, H. et al. (1977). Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrenlis infection. American Journal of Medicine 63, 933-8. Gauldie, J., Richards, C , Harnish, D., Lansdorp, P. & Baumann, H. (1987). Interferon 02/B-cell stimulatory factor 2 shares identity with monocytederived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proceedings of the National Academy of Sciences of the USA 84, 7251-5. Herxbeimer, K. & Krause. (1902). Ueber cine bti Syphilitischen vorkommende Quecksilberreaktion. Deutsche Medizinische Wochenschrifl 28, 895-7. Hesse, D. G., Tracey, K. J., Fong, Y. Manogue, K. R., Palladino, M. A., Cerami, A. el al. (1988). Cytokine appearance in human endotoxemia and primate bacteremia. Surgery, Gynecology and Obstetrics 166, 147-153. Jarisch, A. (1985). Therepeutische Versuche bei Syphilis. Wiener Medizinische Wochenschrifi 45, 721-42. Michie, H. R., Manogue, K. R., Spriggs, D. R., Revhaug, A., O'Dwyer, S., Dinarello, C. A. el al. (1988). Detection of circulating tumor necrosis factor after endotoxin administration. New England Journal of Medicine 318, 1481-6.
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
TNF plasma levels which have been detected between individual bacteraemic patients may represent variability of infectious stimuli, and more importantly that patients with serious infection commonly present clinically at unpredictable times in the infectious process when early events, such as initial pulsatile release of cytokincs, have occurred (Friedland & Griffin, 1991). This is particularly true for TNF, which in all situations investigated, in vitro or in vivo, is released in short pulsatile bursts lasting 2-3 h. Since many of the features of J-HR resemble those caused by administration of TNF to humans, it was thought reasonable to hypothesize that this cytokine might play an important role in the pathophysiology of that condition. In addition, since J-HR of relapsing fever is clinically the most severe form of the phenomenon, it has been used as a model to correlate observed physiological changes with plasma cytokine levels. A major advantage of the J-HR in kinetic studies, such as these, is that its predictable time course allows well defined studies to be carried out. The clinical experiments were carried out in Addis Ababa, Ethiopia, on 17 patients with proven B. recurrentis infection (Remick et al., 1991). Eighty-three per cent of patients experienced a classical J-HR on penicillin treatment with a 1-2°C rise of temperature with rigors at 90 ± 15 min after intramuscular penicillin. The peak of J-HR was strongly associated with high plasma levels of TNF (up to 469 ng/L) occurring in a single peak coincidental with the severity of symptoms. In addition, single pulsatile peaks of IL-6 (up to 28,467 ng/L) and IL-8 (up to 12,000 ng/L) occurred just after that of TNF. In a previous study of meningococcal septicaemia, TNF plasma levels of 140 ng/L were closely associated with mortality (Waage et al., 1989), but in this study no deaths occurred during the J-HR. Raised plasma cytokine levels were not detected in the three (17%) patients not experiencing J-HR. Thus, it appears very likely that J-HR of louse-borne relapsing fever is mediated by the action of cytokincs relased into the circulation. The highly predictable nature of the J-HR makes this clinical phenomenon an elegant model of cytokine release and immunopathology in man. Studies of cytokine profiles in plasma in other forms of J-HR are currently being carried out. It is attractive to postulate that the principal mediation of cytokine release we have demonstrated is through rapid phagocytic removal from the circulation of Borrelia
615
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Leading tracks P. & Espevik, T. (1989). The complex pattern of cytokines in serum from patients with meningococcal septic shock: association between interleukin 6, interleukin 1, and fatal outcome. Journal of Experimental Medicine 169, 333-8. Warrell, D. A., Perine, P. L., Bryceson, A. D. M., Parry, E. H. O & Pope, H. M. (1971). Physiologic changes during the Jarisch-Herxheimer reaction in early syphilis. A comparison with louse-borne relapsing fever. American Journal of Medicine 51, 176-85. Warrell, D. A., Pope, H. M., Parry, E. H. O., Perine, P. L. & Bryceson, A. D. M. (1970). Cardiorespiratory disturbances associated with infective fever in man: studies of Ethiopian louse-borne relapsing fever. Clinical Science 39, 123-45. Whittle, H. C. & Pope, H. M. (1972). The febrile response to treatment in Gambiao sleeping sickness. Annals of Tropical Medicine and Parasitology 66, 7-14. Young, E. J., Weingarten, N. M., Baughn, R. E. & Duncan, W. C. (1982). Studies on the pathogcnesis of the Jarisch-Herxheimer reaction: development of an animal model and evidence against a role for classical endotoxin. Journal of Infectious Diseases 146, 606-15. Zein, Z. A. (1987). Louse borne relapsing fever (LBRF): mortality and frequency of Jarisch-Herxheimer reaction. Journal of the Royal Society of Health 107, 146-7.
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
Parry, E H. O., Warrell, D. A., Perine, P. L., Varkotich, D. & Bryceson, A. D. M. (1970). Some effects of louse-borne relapsing fever on the function of the heart American Journal of Medicine 49, 472-9. Ferine, P. L., Kidan, T. G., Warrell, D. A., Bryceson, A. D. M.
New insights into the patboptrysiology of the Jarisch-Herxhebner reaction
The Jarisch-Herxheimer Reaction (J-HR) is a pathophysiological phenomenon about which most medical students are taught and unwit-
tingly probably fail to recognize during clinical practice. The J-HR is classically a syndrome in which there is a transient worsening of symptoms occurring soon after the first adequate dose of an appropriate antimicrobial drug used to treat an infectious disease. The reaction consists of a sudden rise, then more gradual fall in body temperature; a transient rise followed by a more profound fall in blood pressure, and worsening of constitutional symptoms. The intensity of J-HR varies between different infections and in its most severe form is life-threatening. The identity of systemic mediators causing the reaction has been sought with little definitive success for almost a century since the phenomenon was first documented. However, recent evidence from clinical experiments on the J-HR of relapsing fever strongly supports the hypothesis that cytokines are implicated. In 1895, Jarisch (an Austrian dermatologistsyphilologist), described that the spots of roseola syphilis became more defined and numerous on treatment with mercury (Jarisch, 1895). Some seven years later, Herxheimer (a German dermatologist-syphilologist) documented a systemic reaction consisting of fever, sweating, and anorexia occurring within 24 h of the treatment of syphilis using mercury inunctions (Herxheimer & Krause, 1902). This transient syndrome now bears the names of these two dermatologists. It is now recognized that J-HR occurs on antibiotic treatment of many bacterial (Bryceson, 1976) and some protozoal infections, such as African trypanosomiasis (Whittle & Pope, 1972). However, studies on the J-HR of two spirochaetal infections, namely syphilis and louse-born relapsing fever are now established as paradigms for clinical investigation of the syndrome. Physiological changes occurring during the J-HR asociated with penicillin treatment of early syphilis have been precisely described (Warrell et al., 1971) and are experienced by about 80% of patients (Young et at., 1982). The principal physiological change is an increase in body temperature, by more than 0-8°C, peaking 6-8 h after penicillin and often associated with rigors. In addition, there is peripheral blood leucocytosis, a fall in lymphocyte count, and a fall in systemic arterial blood pressure with an increase in metabolic rate. Leucocyte pyrogen (endotoxin) was suggested as a mediator of the observed physiological changes (Warrell et al., 1971); however, endotoxin was not detected in the blood of syphilitic patients experiencing J-HR in response to penicillin (Young et al., 1082). In addition,
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
192, p. 118. American Society for Microbiology, Washington, D C Quinn, J. P., Dudek, E. J., Divincenzo, C. A., Locks, D. A. & Lerner, S. A. (1986). Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections. Journal of Infectious Diseases 154, 289-94. Rasmussen, B. A., Gluzman, Y. & Tally, F. P. (1990). Cloning and sequencing of the class B /Mactamase gene (CCTA) from Bacteroides fragilis TAL3636. Antimicrobial Agents and Chemotherapy 34, 1590-2. Saino, Y., Kobayashi, F., Inoue, M. & Mitsuhashi, S. (1982). Purification and properties of inducible penicillin ^-lactamase isolated from Pseudomonas maltophilia. Antimicrobial Agents and Chemotherapy 22, 564-70. Sanden, C. C , Sanden, W. E., Thomson, K. S. & Iaconis, J. P. (1989). Meropenem: activity against resistant Gram-negative bacteria and interactions with /7-lactamases. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 187-96. Sato, K., Fujii, R., Okatomo, R., Inoue, M. & Mitsuhashi, S. (1985). Biochemical properties of /Mactamase produced by Flavobacterium odoratum. Antimicrobial Agents and Chemotherapy 27, 612-4. Shannon, K., King, A. &. Phillips, I. (1986). 0-Lactamases with high activity against imipenem and Sch34343 from Aeromonas hydrophila. Journal of Antimicrobial Chemotherapy 17, 45-50. Thompson, J. S. & Malamy, M. H. (1990). Sequencing the gene for an imipenem-cefoxitinhydrolyzing enzyme (CfiA) from Bacteroides fragilis TAL2480, reveals strong similarity between CfiA and Bacillus cereus /7-lactamase II. Journal of Bacteriology 172, 2584-93. Watanabe, M., lyobe, S., Inoue, M. & Mitsuhashi, S. (1991). Transferable imipenem resistance in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 35, 147-51. Yang, Y. J. & Livennore, D. M. (1989). Interactions of meropenem with class I chromosomal ^-lactamases. Journal of Antimicrobial Chemotherapy 23, Suppl. A. 207-17. Yang, Y. J., Wu, P. J. & Livermore, D. M. (1990). Biochemical characterization of a /Mactamase that hydrolyzes penems and carbapenems from two Serralia marcescens isolates. Antimicrobial Agents and Chemotherapy 34, 755-8. YoUuji, A., Minami, S., Inoue, M. & Mitsuhashi, S. (1983). Properties of novel ^-lactamase produced by Bacteroides fragilis. Antimicrobial Agents and Chemotherapy 24, 925-9.
613
614
Leading articles
sibility that it had leaked into the circulation from intestinal Gram-negative organisms. A major recent advance in the study of hostmicrobial interactions has been the discovery that cytokines mediate many of the systemic effects of infection such as fever, anorexia, and the synthesis of acute phase proteins (Friedland & Griffin, 1991). Cytokines are polypeptide hormones released principally from macrophages but also from other cells, for example endothelial cells, in response to a variety of infectious stimuli. Lipopolysaccharide is known to be a potent soluble stimulus of cytokine release, and in addition, phagocytosis of pathogens, such as Mycobacterium tuberculosis by macrophages, is also a strong signal for cytokine production. An important cytokine known to mediate some of the host response to infection is Tumor Necrosis Factor (TNF), and a sequence of other Interleukins (IL) (1 to 10) have now been described. Discrete physiological functions of individual cytokines arc now becoming apparent; for example, IL-6 (previously known as Interferon /J2) stimulates proliferation of B cells and causes hepatocytes to secrete acute phase proteins (Gauldie et al., 1987). IL-8 has been shown to be the most powerful chemoattractant yet discovered for polymorphonuclear leucocytes (Strieter et al., 1989). Considerable knowledge about the pathophysiological roles of cytokines has been gained from the use of animal models of infection. This is particularly exemplified by TNF which has been shown to be pivotal in mediation of Gram-negative lipopolysaccharide induced injury in animals, and has been detected in the circulation of man and primates during bacteraemia (Hesse et al., 1988) and in human volunteers receiving endotoxin (Michie et al., 1988). The pathophysiological significance of TNF was demonstrated by the discovery that in animal models of bacteraemia monoclonal antibodies directed against this cytokine prevent death (Tracey et al., 1987) and reduce the appearance in the circulation of other cytokines, namely IL-1/? and IL-6 (Fong et al., 1989). Thus, immunological, physiological, and metabolic effects of infection appear to be mediated by the orchestrated release of a network of cytokines. Extrapolation of data derived from cell and animal experiments to the situation of human infection has proved complicated, and it is now clear that the response to bacteraemia in man involves a complex pattern of cytokines (Waage et al., 1989). It is thought that large differences of
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
when rabbits infected with Treponema pallidum were challenged with penicillin, a reaction resembling J-HR was observed, but endotoxaemia was not detected. Interestingly, the rabbits still developed fever when rendered unresponsive to endotoxin before antibiotic treatment, thus strengthening the argument that classical endotoxin may not be involved. The J-HR associated with antibiotic treatment of louse-borne relapsing fever is clinically the most severe form of the reaction. Relapsing fever, caused by Borrelia recurrentis which lives in the haemolymph of the human body louse, is a disease associated with poor socio-economic conditions and is endemic in some East African and South American countries, for example, Ethiopia and Bolivia, respectively. It is thought that the organism penetrates the skin after the louse is crushed and gains access to the systemic circulation. Patients present with high fever and frequent chills (Bryceson, 1976) and the diagnosis can be readily confirmed by the demonstration of spirochaetes on Wright's stained blood smears. High concentrations'of spirochaetes, up to 103 organisms per mL, have been recorded in blood during this condition. In a study of 97 patients in northern Ethiopia, approximately 80% of antibiotic treated patients experienced J-HR and the mortality was 4% (Zein, 1987). Physiological changes associated with this condition have been extensively studied (Parry et al., 1970; Warrell et al., 1970; Perine et al., 1971) and consist of a highly predictable syndrome with around a 1°C rise in body temperature, with severe rigors, occurring about 90 min after antibiotic (either penicillin or tetracycline). Cardiac output initially increases and then falls, remaining low for several hours (Warrell et al., 1970). This form of J-HR lasts about 8 h, but clinically severe events occur principally in the first 3 h. The aetiology of such profound physiological changes has been investigated and in-vivo bioassay of plasma injected into rabbits caused fever and hypotension, which not unreasonably, was thought initially to be due to endotoxin (Bryceson et al., 1972). Subsequent studies suggested activation of Hageman factor, prekallikrein and proteins of the complement system in B. recurrentis infection and suggested that endotoxin may play a role in the evolution of J-HR following antibiotic treatment (Galloway et al., 1977). However, in the latter study preparations of borrelia organisms produced negative Limulus lysate tests for- endotoxin, and it was concluded that if endotoxin was aetiological there was the pos-
Leading articles
spp. In addition, since therapeutic amelioration of J-HR has at the best only been partially successful (Teklu et al., 1983), the rational use of therapeutic agents directed against the cytokine cascade is attractive. GEORGE E. GRIFFIN Division of Communicable Diseases, St Georges Hospital Medical School, Tooting, London SW17 ORE. UK
References Bryceson, A. D. M. (1976). Clinical pathology of the Jarisch-Herxheimer reaction. Journal of Infectious Diseases 133, 696-704. Bryceson, A. D. M., Cooper, K. E., Warrell, D. A., Perine, P. L. & Parry, E. H. 0. (1972). Studio of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever evidence for the presence of circulating Borrelia endotoxin. Clinical Science 43, 343-54. Fong, Y., Tracey, K. J., MoMawer, L. L., Hesse, D. G., Manogue, K. B.t Kenney, J. S. et al. (1989). Antibodies to cachectin/tumor necrosis factor reduce interleukin Ifi and interleukin 6 appearance during lethal bacteremia. Journal of Experimental Medicine 170, 1627-33. Friedland, J. S. & Griffin, G. E. (1991). Cytokines and bacterial infection. In Cytokines in Health and Disease: Physiology and Pathophysiology (Kunkel, S. L. & Remick, D. G., Eds). Marcel Dekker, New York, in press. Galloway, R. E., Levin, J., Butler, T., Naff, G. B., Goldsmith, G. H., Saito, H. et al. (1977). Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrenlis infection. American Journal of Medicine 63, 933-8. Gauldie, J., Richards, C , Harnish, D., Lansdorp, P. & Baumann, H. (1987). Interferon 02/B-cell stimulatory factor 2 shares identity with monocytederived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proceedings of the National Academy of Sciences of the USA 84, 7251-5. Herxbeimer, K. & Krause. (1902). Ueber cine bti Syphilitischen vorkommende Quecksilberreaktion. Deutsche Medizinische Wochenschrifl 28, 895-7. Hesse, D. G., Tracey, K. J., Fong, Y. Manogue, K. R., Palladino, M. A., Cerami, A. el al. (1988). Cytokine appearance in human endotoxemia and primate bacteremia. Surgery, Gynecology and Obstetrics 166, 147-153. Jarisch, A. (1985). Therepeutische Versuche bei Syphilis. Wiener Medizinische Wochenschrifi 45, 721-42. Michie, H. R., Manogue, K. R., Spriggs, D. R., Revhaug, A., O'Dwyer, S., Dinarello, C. A. el al. (1988). Detection of circulating tumor necrosis factor after endotoxin administration. New England Journal of Medicine 318, 1481-6.
Downloaded from http://jac.oxfordjournals.org/ at Deakin University on March 15, 2015
TNF plasma levels which have been detected between individual bacteraemic patients may represent variability of infectious stimuli, and more importantly that patients with serious infection commonly present clinically at unpredictable times in the infectious process when early events, such as initial pulsatile release of cytokincs, have occurred (Friedland & Griffin, 1991). This is particularly true for TNF, which in all situations investigated, in vitro or in vivo, is released in short pulsatile bursts lasting 2-3 h. Since many of the features of J-HR resemble those caused by administration of TNF to humans, it was thought reasonable to hypothesize that this cytokine might play an important role in the pathophysiology of that condition. In addition, since J-HR of relapsing fever is clinically the most severe form of the phenomenon, it has been used as a model to correlate observed physiological changes with plasma cytokine levels. A major advantage of the J-HR in kinetic studies, such as these, is that its predictable time course allows well defined studies to be carried out. The clinical experiments were carried out in Addis Ababa, Ethiopia, on 17 patients with proven B. recurrentis infection (Remick et al., 1991). Eighty-three per cent of patients experienced a classical J-HR on penicillin treatment with a 1-2°C rise of temperature with rigors at 90 ± 15 min after intramuscular penicillin. The peak of J-HR was strongly associated with high plasma levels of TNF (up to 469 ng/L) occurring in a single peak coincidental with the severity of symptoms. In addition, single pulsatile peaks of IL-6 (up to 28,467 ng/L) and IL-8 (up to 12,000 ng/L) occurred just after that of TNF. In a previous study of meningococcal septicaemia, TNF plasma levels of 140 ng/L were closely associated with mortality (Waage et al., 1989), but in this study no deaths occurred during the J-HR. Raised plasma cytokine levels were not detected in the three (17%) patients not experiencing J-HR. Thus, it appears very likely that J-HR of louse-borne relapsing fever is mediated by the action of cytokincs relased into the circulation. The highly predictable nature of the J-HR makes this clinical phenomenon an elegant model of cytokine release and immunopathology in man. Studies of cytokine profiles in plasma in other forms of J-HR are currently being carried out. It is attractive to postulate that the principal mediation of cytokine release we have demonstrated is through rapid phagocytic removal from the circulation of Borrelia
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