- Email: [email protected]
Screening with exercise thallium testing after coronary-artery-bypass grafting
CORRESPONDENCE
Sir—The Lancet (Feb 28, p 615)1 devotes no less than eight pages to an important study of prediction of major cardiac events (death and myocardial infarction) by thallium-201 singlephoton-emission computed tomography (SPECT) in patients after CABG who are symptom-free. Michael Lauer and colleagues’ main suggestion of thallium scintigraphy for all such patients as proposed in their algorithm seems unwarranted. Although a normal exercise or stress-thallium test is indeed reassuring (negative predictive value 91%), reversible perfusion defects were identified in only 36% of patients who had events (sensitivity) and were also present in 20% of patients who had none (specificity 80%). Thus, a simple Bayesian analysis* reveals that assuming an event prevalence of about 5% per year in this population 2 (according to the study cohort it is even less), only 8·7% of scan-positive patients will have an event, and most results (91·3%) would be false-positive ones. Translation of this to a population of about half a million patients undergoing CABG per year in the USA would create not only serious cost-benefit difficulties but would also generate many unnecessary and potentially harmful angiographies, and perhaps revascularisation procedures. The highly specialised nature of the Cleveland Clinic, which is not applicable to all other centres and the well known rate of intraobserver and interobserver variation in interpreting SPECT results3 should also be taken into account. Furthermore, their clinical and exercise test data as reported in figure 5 yielded a sensitivity, specificity, and positive and negative predictive values of 56%, 86%, 31%, and 94%, respectively. These data yield an overall accuracy of 81%, which is very similar to the overall performance of the detection of reversible defects in thallium SPECT for identifying future events (overall accuracy=true positive+true negative test results/all tests: 20+359/503=75%). Surprisingly, one of the two most effective drugs for secondary prevention of myocardial infarction and sudden cardiac death—blockers—were used in less than 20% of patients. Optimum use of blockers in this population would probably have resulted in at least some reduction in observed events, further decreasing the prior probability of disease and the yield of scanning *Table and reference available from the author or The Lancet, on request.
1586
symptom-free patients. Thus, by contrast with the ability of exercise or stress thallium testing to accurately diagnose coronary artery disease in patients with chest pain,4 our ability to predict future coronary events in “stable” patients with coronary artery disease remains very imperfect5 and patients after CABG are no exception. A Schattner Kaplan Medical Centre, Hebrew University Hadassah School of Medicine, PO Box 1, Rehovot, 76100, Israel 1
2
3
4
5
Lauer MS, Lytle B, Pashkow F, Snader CE, Marwick TH. Prediction of death and myocardial infarction by screening with exercise-thallium testing after coronaryartery-bypass grafting. Lancet 1998; 351: 615–22. Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death. Differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998; 97: 535–43. Massie BM, Botvinick EH, Brundage BH. Correlation of thallium-201 scintigraphs with coronary anatomy: factors affecting region by region sensitivity. Am J Cardiol 1979; 44: 616–22. Maddahi J, Rodrigues E, Berman DS. Assessment of myocardial perfusion by single-photon agents. In: Pohost GM, O’Rourke RA, eds. Principles and practice of cardiovascular imaging. Boston: Little Brown, 1991: 203. Ambrose JA, Fuster V. Can we predict future acute coronary events in patients with stable coronary artery disease? JAMA 1997; 277: 343–44.
Author’s reply Sir—Andrew Kelion and Adrian Banning argue that a screening test is only of value if it has both high sensitivity and specificity. Hennekens and Buring1 have pointed out, however, that there are very few screening tests that meet these criteria; therefore, sensitivity and specificity, usually have to be traded off against one another. Sensitivity, they argue, should be favoured when the penalty of missing a serious problem is high and when the risk of the testing itself is low. In the case of exercise thallium testing after CABG, the consequences of missing exercise induced ischaemia includes potentially preventable death, which is very serious indeed; furthermore, the test itself is non-invasive, inexpensive, and safe. Thus, exercise thallium testing, is a better screening test than use of clinical variables. We required that patients be judged symptom-free by two observers who were blinded to each others’ assessments and to our hypothesis; thus a serious bias favouring referral
of high-risk patients with “known” incomplete surgical revascularisation was unlikely. In fact, well over 80% of the patients in our study had had complete revascularisation. Furthermore, even if such a preferential referral pattern were present, this should have had no impact on the association between exercise thallium results and outcome. We acknowledged that the association between thallium perfusion defects and outcome might be a reflection of left-ventricular dysfunction related to preoperative infarctions. Nonetheless, the association persisted even after adjustment for a history of myocardial infarction and Q waves. We also noted that reversible defects were better discriminators of risk than fixed electrocardiographic defects alone (tables 2 and 3), arguing that a major component of risk was related to ischaemia, as opposed to only dysfunction. Finally, the presence of extensive defects (⭓4/12 segments) as a surrogate of left-ventricular dysfunction was a weaker prediction of risk than reversible defects (tables 2 and 3). Thus our findings are unlikely to be merely a reflection of unappreciated left-ventricular dysfunction. We disagree with Kelion and Banning’s contention that aggressive medical management with polypharmacy should be routinely given to all patients after CABG. Over 60% of our population could be identified as at very low risk for events (⭐1% per year); it would be hard to justify such a routine aggressive approach when the baseline risk is that low. The questionable benefits of aggressive pharmacology in low-risk patients have been noted in randomised clinical trials.2 A Schattner argues that screening exercise thallium studies should not be done in symptom-free post-CABG patients because of a high rate of false positives. The use Bayes’ theorem has been extensively studied when evaluating diagnostic tests, in which the matter of interest is whether or not a particular pathological entity is present. Our study was mainly concerned with a prognostic test; we sought to identify patients at high and low risk for serious clinical events, which is why we chose to present data on sensitivity and specificity in secondary, not primary, analyses. Our study was not designed to assess the cost effectiveness of routine screening with stress thallium testing— ie, we could not measure the cost per year of life saved. However, we did
THE LANCET • Vol 351 • May 23, 1998
CORRESPONDENCE
find that the cost of identifying highrisk patients was remarkably low, about $1000 per patient. Because the Cleveland Clinic is a highly specialised surgical centre with complication rates lower than average, the expected lower event rates would, if anything, have weakened the power of our study. Similarly difficulties with intraobserver and interobserver variability would have introduced noise into the study and, again if anything, weakened any association between stress test abnormalities and subsequent events. Finally with the substantial sideeffects of -blockers, it does not make sense to use them in patients who are at very low risk for events—ie, patients with normal stress imaging studies. Michael S Lauer Department of Cardiology, Section of Heart Failure and Cardiac Transplantation Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA 1
2
Hennekens C, Buring J. Screening: epidemiology in medicine. Boston: Little, Brown, 1987: 334. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–09.
Interleukin 10 in febrile patients and patients with sepsis Sir—Jaap van Dissel and co-workers (March 28, p 951)1 report that fatal outcome in febrile patients is associated with an anti-inflammatory cytokine profile of a high ratio of interleukin 10 (IL-10) and tumour necrosis factor ␣. Death from sepsis is the result of disregulated immune and metabolic responses of the host to infection. An overwhelming systemic proinflammatory reaction is frequently followed by an overactive compensatory anti-inflammatory response (CARS)2 in which leucocyte function is impaired. Little is known about the precise mechanisms of the development of CARS. In patients with sepsis, a decreased monocyte HLA-DR surface expression can be shown during CARS.3 Furthermore, decreased expression of HLA-DR on monocytes from patients with sepsis has predictive value for fatal outcome.3 Since the expression of HLA-DR on monocytes is downregulated by the antiinflammatory cytokine IL-10,4 we postulated that IL-10 is a potential candidate for the induction of CARS. We investigated the expression of HLA-DR on monocytes in two patients
THE LANCET • Vol 351 • May 23, 1998
and related our findings to plasma concentrations of IL-10 during followup. HLA-DR expression was analysed by flow cytometry and plasma concentrations of IL-10 were measured by ELISA. CARS was defined as HLADR expression of less than 30% the expression in healthy controls.3,5 Monocytes from patient 1 showed HLA-DR expression of less than 30% of that of a healthy control at admission on the intensive care unit until day 8, which gradually increased within the normal range by day 12. Plasma concentrations of IL-10 were increased during the episode of decreased HLADR expression. In parallel with the decreased expression of HLA-DR and increased plasma concentrations of IL10, a protracted clinical recovery was seen in this patient, which necessitated a stay of 15 days at the intensive-care unit. In the second patient, HLA-DR expression on monocytes at day 1 did not differ significantly from value for the healthy control, but decreased moderately during follow-up, although did not fall below the level of 30% of controls. Plasma concentrations of IL10 in patient 2 were low and did not increase during follow-up. A fast recovery occurred in this patient who left the intensive-care unit on day 7. In the patient with CARS, a longterm decrease of HLA-DR expression on monocytes coincided with an increase of IL-10 plasma concentration and a protracted clinical recovery. We suggest that in patients with sepsis, the anti-inflammatory cytokine profile as reported by van Dissel and colleagues can be used as a marker of the compensatory anti-inflammatory response syndrome. Since patients with sepsis have to be treated according to their individual immune status,3,5 this finding may have therapeutic consequences. *Anneke C Muller Kobold, Jaap E Tulleken, Jan G Zijlstra, Jan-Willem Cohen Tervaert *Department of Clinical Immunology and Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, Netherlands (e-mail [email protected]) 1
2
3
van Dissel JT, van Langevelde P, Westerdorp RGJ, Kwappenberg K, Frölich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351: 950–53. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996; 24: 1125–28. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: Restoration by IFN gamma treatment. Nat Med 1997; 3: 678–81.
4
5
Spittler A, Schiller C, Willheim M, Tempfer C, Winkler S, Boltz Nitulescu G. IL-10 augments CD23 expression on U937 cells and down-regulates IL-4-driven CD23 expression on cultured human blood monocytes: effects of IL-10 and other cytokines on cell phenotype and phagocytosis. Immunology 1995; 85: 311–17. Kox WJ, Bone RC, Krausch D, et al. Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Intern Med 1997; 157: 389–93.
Sir—Can the finding of Jaap van Dissel and colleagues1 that anti-inflammatory cytokine profile with a high ratio of IL-10 to TNF␣ is associated with fatal outcome in febrile patients with community-acquired infection1 be generalised to other disorders associated with systemic inflammatory response syndrome and multiorgan system failure, for example, heatstroke.2 We measured IL-10 concentrations in 23 heatstroke patients who presented with a mean rectal temperature of 42·3 (SE 0·16)ºC and severe neurological abnormalities (Glasgow coma score 3·7 [1·7]) after exposure to hot weather while on pilgrimage in Makkah. Five patients were in shock (systolic blood pressure <90 mm Hg) and seven required immediate intubation and mechanical ventilation. The severity of the illness at presentation, measured by the simplified acute physiology score, was 16 (3·7) which would be predictive of 30% mortality in a general intensivecare-unit population. Plasma was collected immediately on admission and before cooling measures were initiated. IL-10 assays were done and are described elsewhere.3 TNF␣ was measured by standard ELISA. IL-10 was detected in the plasma of all heatstroke patients who had a mean concentration of 1289 (SE 525 pg/mL). TNF␣ was not detected in any of the 23 patients.4 There was no significant correlation between IL-10 concentration and severity of illness at presentation. After cooling, three patients died and three sustained neurological injury. There was no difference in plasma concentrations of IL-10 between survivors and nonsurvivors, or in those with or without neurological complications. These and previously reported data2,4,5 show that, as in sepsis, heatstroke is associated with circulating pro-inflammatory and anti-inflammatory cytokines. However, the plasma concentration of IL-6, soluble TNF receptors, but not IL-10, correlate with severity and poor outcome. A high concentration of IL10 has no prognostic importance in heatstroke. Thus the association between IL-10 concentration and fatal
1587
Sir—The Lancet (Feb 28, p 615)1 devotes no less than eight pages to an important study of prediction of major cardiac events (death and myocardial infarction) by thallium-201 singlephoton-emission computed tomography (SPECT) in patients after CABG who are symptom-free. Michael Lauer and colleagues’ main suggestion of thallium scintigraphy for all such patients as proposed in their algorithm seems unwarranted. Although a normal exercise or stress-thallium test is indeed reassuring (negative predictive value 91%), reversible perfusion defects were identified in only 36% of patients who had events (sensitivity) and were also present in 20% of patients who had none (specificity 80%). Thus, a simple Bayesian analysis* reveals that assuming an event prevalence of about 5% per year in this population 2 (according to the study cohort it is even less), only 8·7% of scan-positive patients will have an event, and most results (91·3%) would be false-positive ones. Translation of this to a population of about half a million patients undergoing CABG per year in the USA would create not only serious cost-benefit difficulties but would also generate many unnecessary and potentially harmful angiographies, and perhaps revascularisation procedures. The highly specialised nature of the Cleveland Clinic, which is not applicable to all other centres and the well known rate of intraobserver and interobserver variation in interpreting SPECT results3 should also be taken into account. Furthermore, their clinical and exercise test data as reported in figure 5 yielded a sensitivity, specificity, and positive and negative predictive values of 56%, 86%, 31%, and 94%, respectively. These data yield an overall accuracy of 81%, which is very similar to the overall performance of the detection of reversible defects in thallium SPECT for identifying future events (overall accuracy=true positive+true negative test results/all tests: 20+359/503=75%). Surprisingly, one of the two most effective drugs for secondary prevention of myocardial infarction and sudden cardiac death—blockers—were used in less than 20% of patients. Optimum use of blockers in this population would probably have resulted in at least some reduction in observed events, further decreasing the prior probability of disease and the yield of scanning *Table and reference available from the author or The Lancet, on request.
1586
symptom-free patients. Thus, by contrast with the ability of exercise or stress thallium testing to accurately diagnose coronary artery disease in patients with chest pain,4 our ability to predict future coronary events in “stable” patients with coronary artery disease remains very imperfect5 and patients after CABG are no exception. A Schattner Kaplan Medical Centre, Hebrew University Hadassah School of Medicine, PO Box 1, Rehovot, 76100, Israel 1
2
3
4
5
Lauer MS, Lytle B, Pashkow F, Snader CE, Marwick TH. Prediction of death and myocardial infarction by screening with exercise-thallium testing after coronaryartery-bypass grafting. Lancet 1998; 351: 615–22. Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death. Differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998; 97: 535–43. Massie BM, Botvinick EH, Brundage BH. Correlation of thallium-201 scintigraphs with coronary anatomy: factors affecting region by region sensitivity. Am J Cardiol 1979; 44: 616–22. Maddahi J, Rodrigues E, Berman DS. Assessment of myocardial perfusion by single-photon agents. In: Pohost GM, O’Rourke RA, eds. Principles and practice of cardiovascular imaging. Boston: Little Brown, 1991: 203. Ambrose JA, Fuster V. Can we predict future acute coronary events in patients with stable coronary artery disease? JAMA 1997; 277: 343–44.
Author’s reply Sir—Andrew Kelion and Adrian Banning argue that a screening test is only of value if it has both high sensitivity and specificity. Hennekens and Buring1 have pointed out, however, that there are very few screening tests that meet these criteria; therefore, sensitivity and specificity, usually have to be traded off against one another. Sensitivity, they argue, should be favoured when the penalty of missing a serious problem is high and when the risk of the testing itself is low. In the case of exercise thallium testing after CABG, the consequences of missing exercise induced ischaemia includes potentially preventable death, which is very serious indeed; furthermore, the test itself is non-invasive, inexpensive, and safe. Thus, exercise thallium testing, is a better screening test than use of clinical variables. We required that patients be judged symptom-free by two observers who were blinded to each others’ assessments and to our hypothesis; thus a serious bias favouring referral
of high-risk patients with “known” incomplete surgical revascularisation was unlikely. In fact, well over 80% of the patients in our study had had complete revascularisation. Furthermore, even if such a preferential referral pattern were present, this should have had no impact on the association between exercise thallium results and outcome. We acknowledged that the association between thallium perfusion defects and outcome might be a reflection of left-ventricular dysfunction related to preoperative infarctions. Nonetheless, the association persisted even after adjustment for a history of myocardial infarction and Q waves. We also noted that reversible defects were better discriminators of risk than fixed electrocardiographic defects alone (tables 2 and 3), arguing that a major component of risk was related to ischaemia, as opposed to only dysfunction. Finally, the presence of extensive defects (⭓4/12 segments) as a surrogate of left-ventricular dysfunction was a weaker prediction of risk than reversible defects (tables 2 and 3). Thus our findings are unlikely to be merely a reflection of unappreciated left-ventricular dysfunction. We disagree with Kelion and Banning’s contention that aggressive medical management with polypharmacy should be routinely given to all patients after CABG. Over 60% of our population could be identified as at very low risk for events (⭐1% per year); it would be hard to justify such a routine aggressive approach when the baseline risk is that low. The questionable benefits of aggressive pharmacology in low-risk patients have been noted in randomised clinical trials.2 A Schattner argues that screening exercise thallium studies should not be done in symptom-free post-CABG patients because of a high rate of false positives. The use Bayes’ theorem has been extensively studied when evaluating diagnostic tests, in which the matter of interest is whether or not a particular pathological entity is present. Our study was mainly concerned with a prognostic test; we sought to identify patients at high and low risk for serious clinical events, which is why we chose to present data on sensitivity and specificity in secondary, not primary, analyses. Our study was not designed to assess the cost effectiveness of routine screening with stress thallium testing— ie, we could not measure the cost per year of life saved. However, we did
THE LANCET • Vol 351 • May 23, 1998
CORRESPONDENCE
find that the cost of identifying highrisk patients was remarkably low, about $1000 per patient. Because the Cleveland Clinic is a highly specialised surgical centre with complication rates lower than average, the expected lower event rates would, if anything, have weakened the power of our study. Similarly difficulties with intraobserver and interobserver variability would have introduced noise into the study and, again if anything, weakened any association between stress test abnormalities and subsequent events. Finally with the substantial sideeffects of -blockers, it does not make sense to use them in patients who are at very low risk for events—ie, patients with normal stress imaging studies. Michael S Lauer Department of Cardiology, Section of Heart Failure and Cardiac Transplantation Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA 1
2
Hennekens C, Buring J. Screening: epidemiology in medicine. Boston: Little, Brown, 1987: 334. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–09.
Interleukin 10 in febrile patients and patients with sepsis Sir—Jaap van Dissel and co-workers (March 28, p 951)1 report that fatal outcome in febrile patients is associated with an anti-inflammatory cytokine profile of a high ratio of interleukin 10 (IL-10) and tumour necrosis factor ␣. Death from sepsis is the result of disregulated immune and metabolic responses of the host to infection. An overwhelming systemic proinflammatory reaction is frequently followed by an overactive compensatory anti-inflammatory response (CARS)2 in which leucocyte function is impaired. Little is known about the precise mechanisms of the development of CARS. In patients with sepsis, a decreased monocyte HLA-DR surface expression can be shown during CARS.3 Furthermore, decreased expression of HLA-DR on monocytes from patients with sepsis has predictive value for fatal outcome.3 Since the expression of HLA-DR on monocytes is downregulated by the antiinflammatory cytokine IL-10,4 we postulated that IL-10 is a potential candidate for the induction of CARS. We investigated the expression of HLA-DR on monocytes in two patients
THE LANCET • Vol 351 • May 23, 1998
and related our findings to plasma concentrations of IL-10 during followup. HLA-DR expression was analysed by flow cytometry and plasma concentrations of IL-10 were measured by ELISA. CARS was defined as HLADR expression of less than 30% the expression in healthy controls.3,5 Monocytes from patient 1 showed HLA-DR expression of less than 30% of that of a healthy control at admission on the intensive care unit until day 8, which gradually increased within the normal range by day 12. Plasma concentrations of IL-10 were increased during the episode of decreased HLADR expression. In parallel with the decreased expression of HLA-DR and increased plasma concentrations of IL10, a protracted clinical recovery was seen in this patient, which necessitated a stay of 15 days at the intensive-care unit. In the second patient, HLA-DR expression on monocytes at day 1 did not differ significantly from value for the healthy control, but decreased moderately during follow-up, although did not fall below the level of 30% of controls. Plasma concentrations of IL10 in patient 2 were low and did not increase during follow-up. A fast recovery occurred in this patient who left the intensive-care unit on day 7. In the patient with CARS, a longterm decrease of HLA-DR expression on monocytes coincided with an increase of IL-10 plasma concentration and a protracted clinical recovery. We suggest that in patients with sepsis, the anti-inflammatory cytokine profile as reported by van Dissel and colleagues can be used as a marker of the compensatory anti-inflammatory response syndrome. Since patients with sepsis have to be treated according to their individual immune status,3,5 this finding may have therapeutic consequences. *Anneke C Muller Kobold, Jaap E Tulleken, Jan G Zijlstra, Jan-Willem Cohen Tervaert *Department of Clinical Immunology and Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, Netherlands (e-mail [email protected]) 1
2
3
van Dissel JT, van Langevelde P, Westerdorp RGJ, Kwappenberg K, Frölich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351: 950–53. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996; 24: 1125–28. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: Restoration by IFN gamma treatment. Nat Med 1997; 3: 678–81.
4
5
Spittler A, Schiller C, Willheim M, Tempfer C, Winkler S, Boltz Nitulescu G. IL-10 augments CD23 expression on U937 cells and down-regulates IL-4-driven CD23 expression on cultured human blood monocytes: effects of IL-10 and other cytokines on cell phenotype and phagocytosis. Immunology 1995; 85: 311–17. Kox WJ, Bone RC, Krausch D, et al. Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Intern Med 1997; 157: 389–93.
Sir—Can the finding of Jaap van Dissel and colleagues1 that anti-inflammatory cytokine profile with a high ratio of IL-10 to TNF␣ is associated with fatal outcome in febrile patients with community-acquired infection1 be generalised to other disorders associated with systemic inflammatory response syndrome and multiorgan system failure, for example, heatstroke.2 We measured IL-10 concentrations in 23 heatstroke patients who presented with a mean rectal temperature of 42·3 (SE 0·16)ºC and severe neurological abnormalities (Glasgow coma score 3·7 [1·7]) after exposure to hot weather while on pilgrimage in Makkah. Five patients were in shock (systolic blood pressure <90 mm Hg) and seven required immediate intubation and mechanical ventilation. The severity of the illness at presentation, measured by the simplified acute physiology score, was 16 (3·7) which would be predictive of 30% mortality in a general intensivecare-unit population. Plasma was collected immediately on admission and before cooling measures were initiated. IL-10 assays were done and are described elsewhere.3 TNF␣ was measured by standard ELISA. IL-10 was detected in the plasma of all heatstroke patients who had a mean concentration of 1289 (SE 525 pg/mL). TNF␣ was not detected in any of the 23 patients.4 There was no significant correlation between IL-10 concentration and severity of illness at presentation. After cooling, three patients died and three sustained neurological injury. There was no difference in plasma concentrations of IL-10 between survivors and nonsurvivors, or in those with or without neurological complications. These and previously reported data2,4,5 show that, as in sepsis, heatstroke is associated with circulating pro-inflammatory and anti-inflammatory cytokines. However, the plasma concentration of IL-6, soluble TNF receptors, but not IL-10, correlate with severity and poor outcome. A high concentration of IL10 has no prognostic importance in heatstroke. Thus the association between IL-10 concentration and fatal
1587