Correspondence

Cytokine Therapy in Septic Shock

N Engl J Med 1995; 333:942-943October 5, 1995

Article

To the Editor:

The review of interactions between the immune system and the hypothalamic–pituitary–adrenal axis by Chrousos (May 18 issue)1 contains controversial comments on therapeutic options in sepsis. The suggestion to use β₂-agonists and α₂-noradrenergic antagonists to stimulate the secretion of interleukin-6 overlooks the effect of these agents on the circulation. In particular, the administration of such drugs would be likely to compound the decreased systemic vascular resistance and hypotension that are characteristic of septic shock. The notion that interleukin-6 might prove useful in septicemia can itself be contested. The results that suggest a beneficial effect of interleukin-6 treatment in the animal model cited are not readily extrapolated to other animal models2 or to humans. Plasma interleukin-6 concentrations are markedly elevated in patients with severe septicemia without the addition of exogenous cytokine. High plasma levels correlate with a poor prognosis and not with survival.3,4 Interleukin-6 is pivotal in stimulating the acute-phase response, and plasma interleukin-6 may be viewed as an acute-phase reactant. The question whether targeted local therapy with interleukin-6 might be beneficial in some infections is not relevant when one is considering sepsis, which is a systemic disorder.

There are considerable data on steroid therapy in septicemia. In general, steroids are not beneficial. Children with meningitis are one of the few groups of patients in whom steroid treatment has been shown to help reduce morbidity (deafness), but not mortality.5 This was seen principally in meningitis due to Haemophilus influenzae, against which the most effective measure is now prevention by vaccination. A working group of the Infectious Diseases Society of America recommended that steroids should not be used in patients with septicemia.6

Jon S. Friedland, Ph.D., M.R.C.P.
Royal Postgraduate Medical School, London W12 0NN, United Kingdom

Joanna C. Porter, M.R.C.P.
St. George's Hospital, London SW17 0RE, United Kingdom

6 References

1. 1

   Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332:1351-1362
   Full Text | Web of Science | Medline

2. 2

   Libert C, Vink A, Coulie P, et al. Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. Eur J Immunol 1992;22:2625-2630
   CrossRef | Web of Science | Medline

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   Hack CE, De Groot ER, Felt-Bersma RJ, et al. Increased plasma levels of interleukin-6 in sepsis. Blood 1989;74:1704-1710
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4. 4

   Friedland JS, Suputtamongkol Y, Remick DG, et al. Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA levels during septicemic and localized Pseudomonas pseudomallei infection. Infect Immun 1992;60:2402-2408
   Web of Science | Medline

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   Odio CM, Faingezicht I, Paris M, et al. The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med 1991;324:1525-1531
   Full Text | Web of Science | Medline

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   McGowan JE Jr, Chesney PJ, Crossley KB, LaForce FM. Guidelines for the use of systemic glucocorticosteroids in the management of selected infections. J Infect Dis 1992;165:1-13
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Chrousos replies:

To the Editor: It is true that interleukin-6 levels reflect inflammatory activity and, hence, prognosis, but this does not imply that interleukin-6 is detrimental to survival, nor do interleukin-6 levels simply reflect disease activity. It is now thought that hypotension, decreased perfusion of vital organs, acidosis, and death are effects of tumor necrosis factor α (TNF-α) and interleukin-1, rather than direct actions of microorganism toxins.1 These cytokines, although serving important local functions, are detrimental to the host when elevated systemically in severe sepsis. Since the secretion of interleukin-6 is induced by TNF-α and interleukin-1,2 its plasma levels correlate with the severity of systemic inflammation. Therapies directed against TNF-α and interleukin-1 have reached phase 1 trials3; the current therapies (parenteral fluids, inotropic agents and vasoactive drugs, and antimicrobial agents) prevent death in only 50 to 60 percent of cases. Since interleukin-6 inhibits the secretion of TNF-α and interleukin-1,2 it may be of therapeutic value. Exogenous interleukin-6, in doses that dramatically stimulate the pituitary–adrenal axis, can be administered safely to humans.4 By stimulating the central stress system, selective α₂-noradrenergic antagonists increase the response of interleukin-6, catecholamines, and glucocorticoids to bacterial lipopolysaccharide while at the same time inhibiting TNF-α secretion — all propitious changes.5 Neither α₂-antagonists, which increase peripheral noradrenergic activity, nor β-mimetic agents, which are currently used in the treatment of septic shock, would be expected to decrease vascular resistance or exacerbate hypotension. The overall effect of interleukin-6 in the inflammatory response may depend on the balance of its local immune-enhancing effects and its multifaceted antiinflammatory actions, such as the inhibition of other cytokines, stimulation of glucocorticoid secretion, and promotion of the acute-phase reaction. The lack of a therapeutic effect of glucocorticoids in sepsis may be due to a number of factors, including glucocorticoid resistance of the immune and cardiovascular systems. The latter would explain the vascular hypocontractility of patients with refractory septic shock. Indeed, glucocorticoid deficiency in primates produces lethal cardiovascular hypocontractility when a stressor is encountered.6

George P. Chrousos, M.D.
Department of Health and Human Services, Bethesda, MD 20892

6 References

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   Dinarello CA. Anti-cytokine strategies. Eur Cytokine Netw 1992;3:7-17
   Medline

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   Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 1990;4:2860-2867
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   Stone R. Search for sepsis drugs goes on despite past failures. Science 1994;264:365-367
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   Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993;77:1690-1694
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5. 5

   Hasko G, Elenkov IJ, Kvetan V, Vizi ES. Differential effect of selective block of α₂-adrenoreceptors on plasma levels of tumour necrosis factor-α, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice. J Endocrinol 1995;144:457-462
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6. 6

   Udelsman R, Ramp J, Gallucci WT, et al. Adaptation during surgical stress: a reevaluation of the role of glucocorticoids. J Clin Invest 1986;77:1377-1381
   CrossRef | Web of Science | Medline

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