736
25. Schumann
RR, Leong SR, Flaggs GW, et al. Structure and function of lipopolysaccharide binding protein. Science 1990; 249: 1429-31. 26. Waage A, Halstensen A, Espevik T. Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet
1987; i: 355-57. 27. Girardin E, Grau G, Dayer J, Roux-Lombard P, J5 Study Group, Lambert PH. Tumour necrosis factor and interleukin-1 in serum of children with severe infectious purpura. N Engl J Med 1988; 319: 397-400. 28. Calandra T, Baumgartner JD, Grau GE, et al. Prognosis values of tumor necrosis factor/cachectin, interleukin-1, alpha-interferon and gammainterferon in the serum of patients with septic shock. J Infect Dis 1990; 161: 982-87. 29. Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-86.
30. Bagby GJ, Plessala KJ, Wilson LA. Thompson KJ, Nelson S. Divergent efficacy of antibody to tumor necrosis factor-&agr; in intravascular and peritonitis models of sepsis. J Infect Dis 1990; 163: 83-88.
B, Falk W, Männel DN, Krammer PH. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 1990; 145: 3762-66. 32. McIntyre KW, Stepan GJ, Kolinsky KD, et al. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 1991; 173: 931-39. 33. Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J 1991; 31. Echtenacher
5: 338-43.
Septic shock: treatment
The initial approach to management of the patient in septic shock is institution of corrective measures that are designed, firstly, to confirm and characterise the condition and to correct rapidly any potentially reversible factors, and, secondly, to begin specific therapy of the underlying cause. A detailed discussion of these measures is beyond the scope of this article, but several general principles emerge. Firstly, it is essential to ensure adequate oxygenation and to establish suitable means to monitor the haemodynamic status, which ideally will include measurement of right atrial and pulmonary capillary wedge pressure as well as intra-arterial pressure. Modem management practice in shock emphasises that the administration of fluid, inotropes, and vasopressors must be tailored to the needs of each patient and will usually need frequent modification as the condition evolves. Metabolic abnormalities such as hypoxaemia or severe acidosis need to be identified and remedied. Sometimes these abnormalities are not immediately apparent; for example, hypocalcaemia is a common complication of rhabdomyolysis and may be the cause of refractory hypotension. Finally, every effort must be made to identify the source of sepsis in order to drain abscesses and choose the most appropriate empirical antimicrobial therapy. Although it will seldom be possible (or perhaps even desirable) to use an antibiotic directed against just one bacterial species, outcome is improved by choosing a regimen that proves to be active against the infecting
organism.2 Despite the improvement in outcome of patients with shock and multi-organ failure made by applying the above principles, mortality in patients with severe, established shock remains 50% to 75%. In the USA, septic shock is estimated to cause 100 000 deaths annually.3 This high mortality has stimulated considerable interest in improving outcome by applying insights into the basic mechanisms of the disease. The possibility of manipulating the host factors that seem to mediate tissue damage has received particular attention. Here we review clinical experience with these
why many doctors felt strongly that high-dose steroids given early in shock were beneficial.4 Although there were experimental data that tended to confirm this impression, clinical fmdings were confused. Most early trials were flawed in design, but in the last 10 years three major studies have overcome many of the early difficulties. Sprung et als compared the effects of methylprednisolone (30 mg/kg), dexamethasone (6 mg/kg, one or two doses), and no steroids in patients with severe established shock. Steroids delayed death but did not reduce overall mortality; in addition, patients given dexamethasone had an increased incidence of bacterial superinfections. Subsequently, two further studies have evaluated the effect of early intervention with high-dose methylprednisolone in septic shock.6,7Both studies were placebo-controlled, and both were careful to control for the many variables that can influence outcome. Importantly, both trials insisted that patients only be enrolled if they could be treated within 2 h of shock being recognised. Results of the two trials were strikingly similar: neither found any evidence of benefit from steroids, and steroid recipients had significantly more secondary bacterial infections. Taken together, these studies provide no support for the routine use of high-dose steroids in septic shock. The experience of Hoffman et al8 was different. They reported a double-blind, placebo-controlled trial of dexamethasone in severe typhoid fever. Patients who were in shock or who had an abnormal level of consciousness received dexamethasone 3 mg/kg, followed by eight doses of 1 mg/kg over the next 48 h. There were 2 deaths in the 20 patients given dexamethasone compared with 10 deaths in the 38 placebo recipients (p=0003). The favourable outcome in this small study contrasts with the opposite result reported in the two large trials noted above.6,7However, it is of interest that there appears to be a less clearcut association between cytokine levels and outcome in typhoid fever compared with other types of gram-negative sepsis9 (Richens, Exley, and Cohen, unpublished observations). to understand
types of treatments. ADDRESSES:
High-dose steroids Corticosteroids are anti-inflammatory and antipyretic. They induce a feeling of well-being in the patient which can give a subjective sense of improvement. Furthermore, they have profound effects on many of the mediator systems implicated in the pathogenesis of shock, and it is not difficult
Infectious Diseases Unit, Departments of Bacteriology and Medicine, Hammersmith Hospital and Royal Postgraduate Medical School, London, UK (J. Cohen, FRCP); and Division of Infectious Diseases, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (Prof M. P Glauser, MD) Correspondence to Dr J Cohen, Infectious Diseases Unit, Department of Bacteriology, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN, UK
737
Thus, it is possible that the pathogenesis of severe typhoid fever makes this disease more amenable to steroid therapy than septic shock from other causes. We must conclude that, with the possible exception of typhoid fever, there is no indication for high-dose steroids in the management of septic shock.
Antibody to endotoxin core glycolipid Endotoxin is the component of gram-negative bacteria principally responsible for the syndrome of septic shock. The chemical structure of endotoxin is discussed in the accompanying review (see Prof Glauser et al, p 732). The 0-specific oligosaccharide side chains of endotoxin are very immunogenic, and anti-O antibodies are effective at inhibiting the effects of endotoxin and, by virtue of their
opsonophagocytic properties, eradicating the corresponding organism. However, because they are specific for a particular 0 serotype, their clinical application is limited. An alternative approach has been to develop antibodies against the structurally conserved core glycolipid of endotoxin or against lipid A itself, since these antibodies might offer cross-protection against the toxic component of all gramnegative bacteria.10 Clinical trials based on this approach have been done with intravenous immunoglobulin, hyperimmune globulin, pooled anti-O antibody, and polyclonal antibody, and results have been reviewed.l1-13 Two large clinical trials of monoclonal antibodies to endotoxin core glycolipid have received much recent attention.
E5 is a murine IgM anti-lipid A monoclonal antibody. In a prospective, randomised, placebo-controlled trial, 486 patients with suspected gram-negative sepsis received either placebo or two intravenous doses 24 h apart of 2 mg/kg E5.14 The two groups of patients were reasonably well matched, but the APACHE IIscore was not available for 203 patients, potentially an important source of bias. Of the 468 evaluable patients, 316 had a documented gram-negative infection, and this group were further subdivided on the basis of whether they were in shock at presentation. Among 137 patients not in shock at entry to the study, those treated with E5 had a significantly lower 30-day mortality (p 0-03) and significant improvement (p = 0-04) in the resolution of "major morbidities" (ie, complications of shock such as disseminated intravascular coagulation and acute renal failure). However, mortality of E5 and placebo-treated patients was not different among 179 patients who were in shock, nor among 152 patients who did not have gramnegative sepsis. Administration of E5 was safe; it caused a rise in antibody to murine immunoglobulin in about half the patients, but this was usually of low titre and of no clinical importance. Since this study suggested that E5 was effective in a subgroup of patients, defmed retrospectively, a second multicentre study was initiated to verify the finding. The second trial was done with HA-lA," a human monoclonal antibody to endotoxin core glycolipid. In a study similar in design to that described for E5, patients with suspected gram-negative infection were randomised to receive an albumen placebo or a single 100 mg dose of HA-IA intravenously.16 Of 543 patients enrolled in the study, 317 had microbiologically documented gramnegative infection, but analysis focused on the 200 patients who were found to have gram-negative-rod bacteraemia. HA-IA significantly reduced mortality in this group, from 49% in placebo-treated patients to 30% in HA-IA =
recipients (p 0-014). HA-IA had no effect in 117 patients with non-bacteraemic gram-negative infection. The antibody was also protective in patients who were in shock at the time of randomisation: 27 of 47 (57%) placebo-treated patients died after 28 days compared with 18 of 54 (33%) HA-IA recipients, a reduction of 42% (p=0-017). Although it was not a primary endpoint of the trial, it is of note that 27 of 93 (29%) placebo patients were discharged from hospital compared with 53 of 103 (51%) HA-IA recipients (p=0002). As with the E5 antibody, HA-IA proved to be safe, and no patient developed antibodies to =
HA-1A.
Superficially, these two trials provide compelling evidence that antibody to endotoxin core glycolipid can substantially reduce the mortality associated with gramnegative sepsis, but in many respects the data present clinicians with a dilemma. In both studies, efficacy was demonstrated in only a subset of the patients entered in the trial: in the case of E5, it was 137 of 468 (29%) patients with gram-negative infection who were not in shock, while in the HA-1 A trial, it was 200 of 543 (37 %) patients who proved to have gram-negative rod bacteraemia. In both cases, identification of the patients who would benefit depended on knowing the results of bacteriological cultures, which would only be available some 18 h after the patient became ill, and we do not know if antibody given at this time would still be beneficial. Conversely, if antibody were given empirically to patients thought to be at risk of gram-negative sepsis, but before microbiological confirmation, fully two thirds of patients would be unlikely to benefit. A striking difference between the studies was the groups of patients that responded to antibody. Put simply, E5 was most effective in non-shocked patients, while the protective effect of HA-1A was best seen in bacteraemic patients who were in shock at presentation. There are of course many possible explanations for this observation, but it underlines the fact that we have no clear idea of how these antibodies work. The original experiments to test the hypothesis of cross protection provided by antibodies to endotoxin core glycolipid were done with cell-wall-mutant strains of gram-negative bacteria used as immunogens to raise polyclonal antisera, and in particular one strain of Escherichia coli called J5. Although some studies showed protection with polyclonal anti-J5 antisera, it has not been possible to show formally that protection was attributable to cross-protective antibodies. Indeed favourable outcome could not be correlated with anti-J5 titres in either of two clinical studies done with human polyclonal anti-J5 (D. Heumann and J.-D. Baumgarmer, unpublished observations). With a method for solubilising endotoxin core glycolipid in a physiological manner to try and circumvent non-specific binding,19 it was shown that the J5 antisera used in one study18 contained only a threefold increase in IgG and IgM anti-J5 antibody compared with control preimmune serum .20 Moreover, it now appears that anti-J5 antibodies are in fact highly specific for the J5 bacterium and they do not cross react with endotoxin from other bacteria,19 hence the mechanism of protection seen with anti-J5 antiserum remains unknown. Similar uncertainties exist over the monoclonal antibodies to endotoxin. HA-IA, for example, was reported to be protective in mice when used as hybridoma fluid,l5 but a purified monoclonal antibody obtained from the same clone was not protective when tested in similar animal experiments and did not suppress endotoxin-induced
738
necrosis factor (TNF) production in vivo.21 Furthermore, the specificity of these antibodies for lipid A is uncertain, due in part to the fact that immunoglobulins tend to bind non-specifically to the highly amphiphilic core oligosaccharide and lipid A molecules. Finally, it has been difficult to show unambiguously that the monoclonal antibodies can neutralise endotoxin. Thus, the inability to identify accurately those patients most suitable for treatment, and uncertainties regarding mode of action, are clear indications of the need for further carefully designed trials with anti-endotoxin antibodies.
Thus, there has been considerable interest in the
tumour
Tumour necrosis factor
experimental evidence suggests that TNF important mediator of septic shock. Blocking or neutralising the TNF response in sepsis may thus have therapeutic potential. Early animal and human studies22 suggested that TNF had a very brief half-life in the circulation, raising the concern that by the time the patient came to medical attention the opportunity to neutralise Considerable
is
of using monoclonal antibodies to TNF in the treatment and/or prophylaxis of severe sepsis (see the accompanying review by Glauser et al for further discussion of the use of anti-cytokine antibodies). The only published experience to date is a small phase-1study in which 14 patients in severe established shock were treated with a single dose of a murine monoclonal antibody to TNF.29 In several patients there were favourable changes in temperature, pulse rate, and blood pressure that seemed to coincide with administration of antibody, but overall survival was not different from that which would be predicted in patients of this kind. Large-scale trials of efficacy with anti-TNF antibody will begin soon.
possibility
Conclusions
an
TNF would have been lost. In fact, this seems not to be so-sequential measurements in septic patients show TNF concentrations to be raised for many days Z3 Furthermore, rising TNF concentrations are associated with poor outcome, while stable or falling concentrations correlate with survival. 24 Although these results are encouraging, they need to be interpreted with care. Close inspection of published reports reveals large differences in the proportion of patients with positive TNF assays, and in the absolute values observed (varying over several logs). These differences are likely to be largely methodological in origin, and the relationship between TNF concentrations measured by various immunoassays and "true" (ie, biologically important) TNF remains to be established. Some insight into the apparent failure of steroids in shock is provided by studies of the regulation of TNF. Beutler et al2S showed that dexamethasone suppressed endotoxininduced TNF mRNA, irrespective of whether the steroid was added before or after endotoxin stimulation. Moreover, immunoreactive TNF could not be found in cell culture supernatant if dexamethasone was added before or together with endotoxin, but, in contrast, normal quantities of TNF were present if the steroid was added 2 h after endotoxin, showing that dexamethasone prevented release of TNF when given before or during macrophage stimulation but not if given afterwards. The implication of this finding is that in general clinical practice it will not be possible to give steroids suficiently early to influence TNF production. This is borne out by a study in which steroids were given to patients in shock to try and prevent onset of adult respiratory distress syndrome (ARDS); although there was an overall association between TNF concentrations and ARDS, TNF concentrations in placebo and steroid recipients were not different.26 A potentially important advantage of making TNF a target for intervention (rather than endotoxin) is the possibility that TNF might play a part in pathogenesis of shock due to gram-positive bacteria. Septicaemia associated with Streptococcus pyogenes, for example, is clinically indistinguishable from "classical" gram-negative septic shock.27 Cell-free supernatants from cultures of grampositive bacteria have been shown to induce TNF from human peripheral blood monocytes in vitro 211 and serum TNF concentrations are as high in patients with grampositive sepsis as in those with gram-negative sepsis.26
The time has passed when the management of septic shock could be summarised as supportive care and the administration of antibiotics. Increased awareness of the concepts of oxygen delivery and uptake from the tissues, more efficient control of the intravascular volume, and a better understanding of the underlying mechanisms of tissue injury have provided new opportunities to improve outcome in this serious disease. It is to be hoped that some of the approaches we have discussed will soon be translated into clinical practice.
REFERENCES 1. Shoemaker
WC, Kram HB, Appel PL. Therapy of shock based on pathophysiology, monitoring, and outcome prediction. Crit Care Med
2.
1990; 18: S19-S25. Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia IV. Re-evaluation of clinical features and
treatment in 612 patients. Am J Med 1980; 68: 344-55. 3. Parrillo JE. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113: 227-42. 4. Sheagren JN. Glucocorticoid therapy in the management of severe sepsis. In: Root RK, Sande MA, eds. Septic shock. New York: Churchill Livingstone, 1985: 201-18. 5. Sprung C, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984; 311: 1137-43. 6. Hinshaw LB, Peduzzi P, Young E, et al. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987; 317: 659-65. 7. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 653-58. 8. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med 1984; 310: 82-88. 9. Roine I, Herrera P, Ledermann W, Peltola H. Tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 levels in typhoid fever. Interscience Conference on Antimicrobial Agents and Chemotherapy; 1990 Oct 21-24; Atlanta. Washington DC: American Society of Microbiology, 1990: 136. 10. Appelmelk BJ, Cohen J. The protective role of antibodies to the lipopolysaccharide core region. In: Morrison DC, Ryan JL, eds. Bacterial lipopolysaccharides. Atlanta: CRC Press (in press). 11. Cohen J. Intravenous immunoglobulin (IVIG) for gram-negative infection-a critical review. J Hosp Infect 1988; 12 (suppl D): 47-54. 12. Baumgartner J-D, Glauser MP. Controversies in the use of passive immunotherapy for bacterial infections in the critically ill patient. Rev Infect Dis 1987; 9: 194-205. 13. Baumgartner J-D. Monoclonal anti-endotoxin antibodies for the treatment of Gram-negative bacteremia and septic shock. Eur J Clin Micro Infect Dis 1990; 9: 711-16. 14. Gorelick K, Scannon PJ, Hannigan J, Wedel N, Ackerman SK. Randomized placebo-controlled study of E5 monoclonal antiendotoxin antibody. In: Borrebaeck CA, Larrick JW, eds. Therapeutic monoclonal antibodies. New York: Stockton Press, 1990: 253-61.
739
15. Teng NN, Kaplan HS, Hebert JM, et al. Protection against gramnegative bacteremia and endotoxemia with human monoclonal IgM antibodies. Proc Natl Acad Sci USA 1985; 82: 1790-94. 16. Ziegler EJ, Fisher CJ Jr, Sprung C, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. N Engl J Med 1991; 324: 429-36. 17. Ziegler EJ, McCutchan JA, Fierer J, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Eschenchia coli. N Engl J Med 1982; 307: 1225-30. 18. Baumgartner J-D, Glauser MP, McCutchan JA, et al. Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 1985; ii: 59-63. 19. Heumann D, Baumgartner J-D, Jacot-Guillarmod H, Glauser MP. Antibodies to core lipopolysaccharide determinants: absence of cross reactivity with heterologous lipopolysaccharides. J Infect Dis 1991; 163: 762-68. 20. Baumgartner JD, Heumann D, Calandra T, Glauser MP. Antibodies to lipopolysaccharides after immunization of humans with the rough mutant. Escherichia coli J5. J Infect Dis 1991; 163: 769-72.
21. Baumgartner J-D, Heumann D, Gerain J, Weinbreck P, Grau GE, Glauser MP. Association between protective efficacy of anti-
lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific antibodies and core LPS antibodies. J Exp Med 1990; 171: 889-96.
22. Michie
et al. Detection of circulating necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-86. 23. Cohen J. Clinical role of tumour necrosis factor in septic shock. Update Intensive Care Emergency Med 1991; 14: 262-68.
HR, Manogue KR, Spriggs DR,
tumor
24. Calandra
et al. Prognostic values of factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. J Infect
tumor
T, Baumgartner J-D, Grau GE,
necrosis
Dis 1990; 161: 982-87. 25. Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 1986; 232: 977-80. 26. Marks JD, Marks CB, Luce JM, et al. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methyl prednisolone administration. Am Rev Respir Dis 1990; 141: 94-97.
S, Wendon J, Monteil M, Gordon AM. Septic scarlet fever due Streptococcus pyogenes cellulitis. Q J Med 1988; 69: 921-25. 28. Bayston KF, Tomlinson M, Cohen J. In vitro induction of tumour necrosis factor alpha by cell free supernatants from clinical isolates of Gram positive bacteria. Interscience Conference on Antimicrobial Agents and Chemotherapy; 1990 Oct 21-24; Atlanta. Washington DC: American Society of Microbiology, 1990: 136. 29. Exley AR, Cohen J, Buurman WA, et al. Monoclonal antibody to TNF in severe septic shock. Lancet 1990; 335: 1275-77. 27. Shaunak to
PUBLIC HEALTH Possible transmission of Mycobacterium leprae in group of UK leprosy contacts
infectious leprosy in residential accommodation in the UK prompted a study of the cellular and humoral response to Mycobacterium leprae in two groups of individuals who were in contact with the index case for almost a year. In the younger staff group (mean age 44 years) 23 of 30 individuals had positive Mitsuda skin tests, 25 showed lymphocyte transformation to a soluble sonicate of M leprae and 2 had slightly raised IgM antibody concentrations to the terminal disaccharide of Mleprae phenolic glycolipid-1. In the older group of residents (mean age 83 years) 7 of 36 individuals were skin-test-positive, 25 of 33 were positive by lymphocyte transformation, but none had raised antibody levels. When retested on two further occasions, the same 2 individuals in the younger group still had raised antibody concentrations, 1 of
A
case
of
whom had
a
persistent lepromin skin-test
response
for over 8 months and showed a pronounced increase in lymphocyte transformation to mycobacterial antigens. The findings suggest that transmission of M leprae may have occurred in these 2 contacts, who were therefore given 6 months’ chemoprophylaxis with rifampicin.
a
Introduction Viable Mycobacterium leprae is shed in large numbers from the upper respiratory tract of patients with untreated lepromatous leprosy, and it is presumed that most individuals in close contact with an infectious case will be exposed to viable organisms. However, the incidence of clinical leprosy, even in highly endemic areas, is only about 1 per 1000. Thus, most people seem able to combat the infection successfully. A few individuals will progress to an early form of infection, known as indeterminate leprosy, which may resolve spontaneously, or develop further into clinical leprosy (classified as a spectrum from tuberculoid to
lepromatous leprosy). The immunological status of leprosy contacts has been investigated in many studies. The finding of higher concentrations of antibodies in contacts than in endemic controls has been taken to indicate transmission or ADDRESSES: Department of Clinical Sciences, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK (H. M. Dockrell, PhD, S. Young, PhD, A. MacFarlane, MSc); Mid Downs Health Authority, Linwood, Butlers Green Road, Haywards Heath, West Sussex, UK (H. Eastcott, MFPHM); Department of Microbiology, Aga Khan University, Faculty of Health Sciences, Stadium Road, PO Box 3500, Karachi, Pakistan (R. Hussain, PhD); and Hospital for Tropical Diseases, St Pancras Way, London, UK (M. Waters, FRCP). Correspondence to Dr H M. Dockrell.
25. Schumann
RR, Leong SR, Flaggs GW, et al. Structure and function of lipopolysaccharide binding protein. Science 1990; 249: 1429-31. 26. Waage A, Halstensen A, Espevik T. Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet
1987; i: 355-57. 27. Girardin E, Grau G, Dayer J, Roux-Lombard P, J5 Study Group, Lambert PH. Tumour necrosis factor and interleukin-1 in serum of children with severe infectious purpura. N Engl J Med 1988; 319: 397-400. 28. Calandra T, Baumgartner JD, Grau GE, et al. Prognosis values of tumor necrosis factor/cachectin, interleukin-1, alpha-interferon and gammainterferon in the serum of patients with septic shock. J Infect Dis 1990; 161: 982-87. 29. Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-86.
30. Bagby GJ, Plessala KJ, Wilson LA. Thompson KJ, Nelson S. Divergent efficacy of antibody to tumor necrosis factor-&agr; in intravascular and peritonitis models of sepsis. J Infect Dis 1990; 163: 83-88.
B, Falk W, Männel DN, Krammer PH. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 1990; 145: 3762-66. 32. McIntyre KW, Stepan GJ, Kolinsky KD, et al. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 1991; 173: 931-39. 33. Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J 1991; 31. Echtenacher
5: 338-43.
Septic shock: treatment
The initial approach to management of the patient in septic shock is institution of corrective measures that are designed, firstly, to confirm and characterise the condition and to correct rapidly any potentially reversible factors, and, secondly, to begin specific therapy of the underlying cause. A detailed discussion of these measures is beyond the scope of this article, but several general principles emerge. Firstly, it is essential to ensure adequate oxygenation and to establish suitable means to monitor the haemodynamic status, which ideally will include measurement of right atrial and pulmonary capillary wedge pressure as well as intra-arterial pressure. Modem management practice in shock emphasises that the administration of fluid, inotropes, and vasopressors must be tailored to the needs of each patient and will usually need frequent modification as the condition evolves. Metabolic abnormalities such as hypoxaemia or severe acidosis need to be identified and remedied. Sometimes these abnormalities are not immediately apparent; for example, hypocalcaemia is a common complication of rhabdomyolysis and may be the cause of refractory hypotension. Finally, every effort must be made to identify the source of sepsis in order to drain abscesses and choose the most appropriate empirical antimicrobial therapy. Although it will seldom be possible (or perhaps even desirable) to use an antibiotic directed against just one bacterial species, outcome is improved by choosing a regimen that proves to be active against the infecting
organism.2 Despite the improvement in outcome of patients with shock and multi-organ failure made by applying the above principles, mortality in patients with severe, established shock remains 50% to 75%. In the USA, septic shock is estimated to cause 100 000 deaths annually.3 This high mortality has stimulated considerable interest in improving outcome by applying insights into the basic mechanisms of the disease. The possibility of manipulating the host factors that seem to mediate tissue damage has received particular attention. Here we review clinical experience with these
why many doctors felt strongly that high-dose steroids given early in shock were beneficial.4 Although there were experimental data that tended to confirm this impression, clinical fmdings were confused. Most early trials were flawed in design, but in the last 10 years three major studies have overcome many of the early difficulties. Sprung et als compared the effects of methylprednisolone (30 mg/kg), dexamethasone (6 mg/kg, one or two doses), and no steroids in patients with severe established shock. Steroids delayed death but did not reduce overall mortality; in addition, patients given dexamethasone had an increased incidence of bacterial superinfections. Subsequently, two further studies have evaluated the effect of early intervention with high-dose methylprednisolone in septic shock.6,7Both studies were placebo-controlled, and both were careful to control for the many variables that can influence outcome. Importantly, both trials insisted that patients only be enrolled if they could be treated within 2 h of shock being recognised. Results of the two trials were strikingly similar: neither found any evidence of benefit from steroids, and steroid recipients had significantly more secondary bacterial infections. Taken together, these studies provide no support for the routine use of high-dose steroids in septic shock. The experience of Hoffman et al8 was different. They reported a double-blind, placebo-controlled trial of dexamethasone in severe typhoid fever. Patients who were in shock or who had an abnormal level of consciousness received dexamethasone 3 mg/kg, followed by eight doses of 1 mg/kg over the next 48 h. There were 2 deaths in the 20 patients given dexamethasone compared with 10 deaths in the 38 placebo recipients (p=0003). The favourable outcome in this small study contrasts with the opposite result reported in the two large trials noted above.6,7However, it is of interest that there appears to be a less clearcut association between cytokine levels and outcome in typhoid fever compared with other types of gram-negative sepsis9 (Richens, Exley, and Cohen, unpublished observations). to understand
types of treatments. ADDRESSES:
High-dose steroids Corticosteroids are anti-inflammatory and antipyretic. They induce a feeling of well-being in the patient which can give a subjective sense of improvement. Furthermore, they have profound effects on many of the mediator systems implicated in the pathogenesis of shock, and it is not difficult
Infectious Diseases Unit, Departments of Bacteriology and Medicine, Hammersmith Hospital and Royal Postgraduate Medical School, London, UK (J. Cohen, FRCP); and Division of Infectious Diseases, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (Prof M. P Glauser, MD) Correspondence to Dr J Cohen, Infectious Diseases Unit, Department of Bacteriology, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN, UK
737
Thus, it is possible that the pathogenesis of severe typhoid fever makes this disease more amenable to steroid therapy than septic shock from other causes. We must conclude that, with the possible exception of typhoid fever, there is no indication for high-dose steroids in the management of septic shock.
Antibody to endotoxin core glycolipid Endotoxin is the component of gram-negative bacteria principally responsible for the syndrome of septic shock. The chemical structure of endotoxin is discussed in the accompanying review (see Prof Glauser et al, p 732). The 0-specific oligosaccharide side chains of endotoxin are very immunogenic, and anti-O antibodies are effective at inhibiting the effects of endotoxin and, by virtue of their
opsonophagocytic properties, eradicating the corresponding organism. However, because they are specific for a particular 0 serotype, their clinical application is limited. An alternative approach has been to develop antibodies against the structurally conserved core glycolipid of endotoxin or against lipid A itself, since these antibodies might offer cross-protection against the toxic component of all gramnegative bacteria.10 Clinical trials based on this approach have been done with intravenous immunoglobulin, hyperimmune globulin, pooled anti-O antibody, and polyclonal antibody, and results have been reviewed.l1-13 Two large clinical trials of monoclonal antibodies to endotoxin core glycolipid have received much recent attention.
E5 is a murine IgM anti-lipid A monoclonal antibody. In a prospective, randomised, placebo-controlled trial, 486 patients with suspected gram-negative sepsis received either placebo or two intravenous doses 24 h apart of 2 mg/kg E5.14 The two groups of patients were reasonably well matched, but the APACHE IIscore was not available for 203 patients, potentially an important source of bias. Of the 468 evaluable patients, 316 had a documented gram-negative infection, and this group were further subdivided on the basis of whether they were in shock at presentation. Among 137 patients not in shock at entry to the study, those treated with E5 had a significantly lower 30-day mortality (p 0-03) and significant improvement (p = 0-04) in the resolution of "major morbidities" (ie, complications of shock such as disseminated intravascular coagulation and acute renal failure). However, mortality of E5 and placebo-treated patients was not different among 179 patients who were in shock, nor among 152 patients who did not have gramnegative sepsis. Administration of E5 was safe; it caused a rise in antibody to murine immunoglobulin in about half the patients, but this was usually of low titre and of no clinical importance. Since this study suggested that E5 was effective in a subgroup of patients, defmed retrospectively, a second multicentre study was initiated to verify the finding. The second trial was done with HA-lA," a human monoclonal antibody to endotoxin core glycolipid. In a study similar in design to that described for E5, patients with suspected gram-negative infection were randomised to receive an albumen placebo or a single 100 mg dose of HA-IA intravenously.16 Of 543 patients enrolled in the study, 317 had microbiologically documented gramnegative infection, but analysis focused on the 200 patients who were found to have gram-negative-rod bacteraemia. HA-IA significantly reduced mortality in this group, from 49% in placebo-treated patients to 30% in HA-IA =
recipients (p 0-014). HA-IA had no effect in 117 patients with non-bacteraemic gram-negative infection. The antibody was also protective in patients who were in shock at the time of randomisation: 27 of 47 (57%) placebo-treated patients died after 28 days compared with 18 of 54 (33%) HA-IA recipients, a reduction of 42% (p=0-017). Although it was not a primary endpoint of the trial, it is of note that 27 of 93 (29%) placebo patients were discharged from hospital compared with 53 of 103 (51%) HA-IA recipients (p=0002). As with the E5 antibody, HA-IA proved to be safe, and no patient developed antibodies to =
HA-1A.
Superficially, these two trials provide compelling evidence that antibody to endotoxin core glycolipid can substantially reduce the mortality associated with gramnegative sepsis, but in many respects the data present clinicians with a dilemma. In both studies, efficacy was demonstrated in only a subset of the patients entered in the trial: in the case of E5, it was 137 of 468 (29%) patients with gram-negative infection who were not in shock, while in the HA-1 A trial, it was 200 of 543 (37 %) patients who proved to have gram-negative rod bacteraemia. In both cases, identification of the patients who would benefit depended on knowing the results of bacteriological cultures, which would only be available some 18 h after the patient became ill, and we do not know if antibody given at this time would still be beneficial. Conversely, if antibody were given empirically to patients thought to be at risk of gram-negative sepsis, but before microbiological confirmation, fully two thirds of patients would be unlikely to benefit. A striking difference between the studies was the groups of patients that responded to antibody. Put simply, E5 was most effective in non-shocked patients, while the protective effect of HA-1A was best seen in bacteraemic patients who were in shock at presentation. There are of course many possible explanations for this observation, but it underlines the fact that we have no clear idea of how these antibodies work. The original experiments to test the hypothesis of cross protection provided by antibodies to endotoxin core glycolipid were done with cell-wall-mutant strains of gram-negative bacteria used as immunogens to raise polyclonal antisera, and in particular one strain of Escherichia coli called J5. Although some studies showed protection with polyclonal anti-J5 antisera, it has not been possible to show formally that protection was attributable to cross-protective antibodies. Indeed favourable outcome could not be correlated with anti-J5 titres in either of two clinical studies done with human polyclonal anti-J5 (D. Heumann and J.-D. Baumgarmer, unpublished observations). With a method for solubilising endotoxin core glycolipid in a physiological manner to try and circumvent non-specific binding,19 it was shown that the J5 antisera used in one study18 contained only a threefold increase in IgG and IgM anti-J5 antibody compared with control preimmune serum .20 Moreover, it now appears that anti-J5 antibodies are in fact highly specific for the J5 bacterium and they do not cross react with endotoxin from other bacteria,19 hence the mechanism of protection seen with anti-J5 antiserum remains unknown. Similar uncertainties exist over the monoclonal antibodies to endotoxin. HA-IA, for example, was reported to be protective in mice when used as hybridoma fluid,l5 but a purified monoclonal antibody obtained from the same clone was not protective when tested in similar animal experiments and did not suppress endotoxin-induced
738
necrosis factor (TNF) production in vivo.21 Furthermore, the specificity of these antibodies for lipid A is uncertain, due in part to the fact that immunoglobulins tend to bind non-specifically to the highly amphiphilic core oligosaccharide and lipid A molecules. Finally, it has been difficult to show unambiguously that the monoclonal antibodies can neutralise endotoxin. Thus, the inability to identify accurately those patients most suitable for treatment, and uncertainties regarding mode of action, are clear indications of the need for further carefully designed trials with anti-endotoxin antibodies.
Thus, there has been considerable interest in the
tumour
Tumour necrosis factor
experimental evidence suggests that TNF important mediator of septic shock. Blocking or neutralising the TNF response in sepsis may thus have therapeutic potential. Early animal and human studies22 suggested that TNF had a very brief half-life in the circulation, raising the concern that by the time the patient came to medical attention the opportunity to neutralise Considerable
is
of using monoclonal antibodies to TNF in the treatment and/or prophylaxis of severe sepsis (see the accompanying review by Glauser et al for further discussion of the use of anti-cytokine antibodies). The only published experience to date is a small phase-1study in which 14 patients in severe established shock were treated with a single dose of a murine monoclonal antibody to TNF.29 In several patients there were favourable changes in temperature, pulse rate, and blood pressure that seemed to coincide with administration of antibody, but overall survival was not different from that which would be predicted in patients of this kind. Large-scale trials of efficacy with anti-TNF antibody will begin soon.
possibility
Conclusions
an
TNF would have been lost. In fact, this seems not to be so-sequential measurements in septic patients show TNF concentrations to be raised for many days Z3 Furthermore, rising TNF concentrations are associated with poor outcome, while stable or falling concentrations correlate with survival. 24 Although these results are encouraging, they need to be interpreted with care. Close inspection of published reports reveals large differences in the proportion of patients with positive TNF assays, and in the absolute values observed (varying over several logs). These differences are likely to be largely methodological in origin, and the relationship between TNF concentrations measured by various immunoassays and "true" (ie, biologically important) TNF remains to be established. Some insight into the apparent failure of steroids in shock is provided by studies of the regulation of TNF. Beutler et al2S showed that dexamethasone suppressed endotoxininduced TNF mRNA, irrespective of whether the steroid was added before or after endotoxin stimulation. Moreover, immunoreactive TNF could not be found in cell culture supernatant if dexamethasone was added before or together with endotoxin, but, in contrast, normal quantities of TNF were present if the steroid was added 2 h after endotoxin, showing that dexamethasone prevented release of TNF when given before or during macrophage stimulation but not if given afterwards. The implication of this finding is that in general clinical practice it will not be possible to give steroids suficiently early to influence TNF production. This is borne out by a study in which steroids were given to patients in shock to try and prevent onset of adult respiratory distress syndrome (ARDS); although there was an overall association between TNF concentrations and ARDS, TNF concentrations in placebo and steroid recipients were not different.26 A potentially important advantage of making TNF a target for intervention (rather than endotoxin) is the possibility that TNF might play a part in pathogenesis of shock due to gram-positive bacteria. Septicaemia associated with Streptococcus pyogenes, for example, is clinically indistinguishable from "classical" gram-negative septic shock.27 Cell-free supernatants from cultures of grampositive bacteria have been shown to induce TNF from human peripheral blood monocytes in vitro 211 and serum TNF concentrations are as high in patients with grampositive sepsis as in those with gram-negative sepsis.26
The time has passed when the management of septic shock could be summarised as supportive care and the administration of antibiotics. Increased awareness of the concepts of oxygen delivery and uptake from the tissues, more efficient control of the intravascular volume, and a better understanding of the underlying mechanisms of tissue injury have provided new opportunities to improve outcome in this serious disease. It is to be hoped that some of the approaches we have discussed will soon be translated into clinical practice.
REFERENCES 1. Shoemaker
WC, Kram HB, Appel PL. Therapy of shock based on pathophysiology, monitoring, and outcome prediction. Crit Care Med
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1990; 18: S19-S25. Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia IV. Re-evaluation of clinical features and
treatment in 612 patients. Am J Med 1980; 68: 344-55. 3. Parrillo JE. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113: 227-42. 4. Sheagren JN. Glucocorticoid therapy in the management of severe sepsis. In: Root RK, Sande MA, eds. Septic shock. New York: Churchill Livingstone, 1985: 201-18. 5. Sprung C, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984; 311: 1137-43. 6. Hinshaw LB, Peduzzi P, Young E, et al. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987; 317: 659-65. 7. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 653-58. 8. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med 1984; 310: 82-88. 9. Roine I, Herrera P, Ledermann W, Peltola H. Tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 levels in typhoid fever. Interscience Conference on Antimicrobial Agents and Chemotherapy; 1990 Oct 21-24; Atlanta. Washington DC: American Society of Microbiology, 1990: 136. 10. Appelmelk BJ, Cohen J. The protective role of antibodies to the lipopolysaccharide core region. In: Morrison DC, Ryan JL, eds. Bacterial lipopolysaccharides. Atlanta: CRC Press (in press). 11. Cohen J. Intravenous immunoglobulin (IVIG) for gram-negative infection-a critical review. J Hosp Infect 1988; 12 (suppl D): 47-54. 12. Baumgartner J-D, Glauser MP. Controversies in the use of passive immunotherapy for bacterial infections in the critically ill patient. Rev Infect Dis 1987; 9: 194-205. 13. Baumgartner J-D. Monoclonal anti-endotoxin antibodies for the treatment of Gram-negative bacteremia and septic shock. Eur J Clin Micro Infect Dis 1990; 9: 711-16. 14. Gorelick K, Scannon PJ, Hannigan J, Wedel N, Ackerman SK. Randomized placebo-controlled study of E5 monoclonal antiendotoxin antibody. In: Borrebaeck CA, Larrick JW, eds. Therapeutic monoclonal antibodies. New York: Stockton Press, 1990: 253-61.
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15. Teng NN, Kaplan HS, Hebert JM, et al. Protection against gramnegative bacteremia and endotoxemia with human monoclonal IgM antibodies. Proc Natl Acad Sci USA 1985; 82: 1790-94. 16. Ziegler EJ, Fisher CJ Jr, Sprung C, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. N Engl J Med 1991; 324: 429-36. 17. Ziegler EJ, McCutchan JA, Fierer J, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Eschenchia coli. N Engl J Med 1982; 307: 1225-30. 18. Baumgartner J-D, Glauser MP, McCutchan JA, et al. Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 1985; ii: 59-63. 19. Heumann D, Baumgartner J-D, Jacot-Guillarmod H, Glauser MP. Antibodies to core lipopolysaccharide determinants: absence of cross reactivity with heterologous lipopolysaccharides. J Infect Dis 1991; 163: 762-68. 20. Baumgartner JD, Heumann D, Calandra T, Glauser MP. Antibodies to lipopolysaccharides after immunization of humans with the rough mutant. Escherichia coli J5. J Infect Dis 1991; 163: 769-72.
21. Baumgartner J-D, Heumann D, Gerain J, Weinbreck P, Grau GE, Glauser MP. Association between protective efficacy of anti-
lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific antibodies and core LPS antibodies. J Exp Med 1990; 171: 889-96.
22. Michie
et al. Detection of circulating necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-86. 23. Cohen J. Clinical role of tumour necrosis factor in septic shock. Update Intensive Care Emergency Med 1991; 14: 262-68.
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S, Wendon J, Monteil M, Gordon AM. Septic scarlet fever due Streptococcus pyogenes cellulitis. Q J Med 1988; 69: 921-25. 28. Bayston KF, Tomlinson M, Cohen J. In vitro induction of tumour necrosis factor alpha by cell free supernatants from clinical isolates of Gram positive bacteria. Interscience Conference on Antimicrobial Agents and Chemotherapy; 1990 Oct 21-24; Atlanta. Washington DC: American Society of Microbiology, 1990: 136. 29. Exley AR, Cohen J, Buurman WA, et al. Monoclonal antibody to TNF in severe septic shock. Lancet 1990; 335: 1275-77. 27. Shaunak to
PUBLIC HEALTH Possible transmission of Mycobacterium leprae in group of UK leprosy contacts
infectious leprosy in residential accommodation in the UK prompted a study of the cellular and humoral response to Mycobacterium leprae in two groups of individuals who were in contact with the index case for almost a year. In the younger staff group (mean age 44 years) 23 of 30 individuals had positive Mitsuda skin tests, 25 showed lymphocyte transformation to a soluble sonicate of M leprae and 2 had slightly raised IgM antibody concentrations to the terminal disaccharide of Mleprae phenolic glycolipid-1. In the older group of residents (mean age 83 years) 7 of 36 individuals were skin-test-positive, 25 of 33 were positive by lymphocyte transformation, but none had raised antibody levels. When retested on two further occasions, the same 2 individuals in the younger group still had raised antibody concentrations, 1 of
A
case
of
whom had
a
persistent lepromin skin-test
response
for over 8 months and showed a pronounced increase in lymphocyte transformation to mycobacterial antigens. The findings suggest that transmission of M leprae may have occurred in these 2 contacts, who were therefore given 6 months’ chemoprophylaxis with rifampicin.
a
Introduction Viable Mycobacterium leprae is shed in large numbers from the upper respiratory tract of patients with untreated lepromatous leprosy, and it is presumed that most individuals in close contact with an infectious case will be exposed to viable organisms. However, the incidence of clinical leprosy, even in highly endemic areas, is only about 1 per 1000. Thus, most people seem able to combat the infection successfully. A few individuals will progress to an early form of infection, known as indeterminate leprosy, which may resolve spontaneously, or develop further into clinical leprosy (classified as a spectrum from tuberculoid to
lepromatous leprosy). The immunological status of leprosy contacts has been investigated in many studies. The finding of higher concentrations of antibodies in contacts than in endemic controls has been taken to indicate transmission or ADDRESSES: Department of Clinical Sciences, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK (H. M. Dockrell, PhD, S. Young, PhD, A. MacFarlane, MSc); Mid Downs Health Authority, Linwood, Butlers Green Road, Haywards Heath, West Sussex, UK (H. Eastcott, MFPHM); Department of Microbiology, Aga Khan University, Faculty of Health Sciences, Stadium Road, PO Box 3500, Karachi, Pakistan (R. Hussain, PhD); and Hospital for Tropical Diseases, St Pancras Way, London, UK (M. Waters, FRCP). Correspondence to Dr H M. Dockrell.
