Journal of Anesthesia

, Volume 26, Issue 5, pp 658–663

Interleukin-18 levels reflect the long-term prognosis of acute lung injury and acute respiratory distress syndrome

  • Hideyuki Makabe
  • Masahiro Kojika
  • Gaku Takahashi
  • Naoya Matsumoto
  • Shigehiro Shibata
  • Yasushi Suzuki
  • Yoshihiro Inoue
  • Shigeatsu Endo
Original Article



The purpose of this study was to investigate the relationship between the blood levels of interleukin (IL)-18 measured in the early stage of acute respiratory failure and the prognosis for patient survival.


The study subjects were 38 patients with acute respiratory failure treated at our institution during the 4-year period from April 2004 to March 2008. The underlying clinical condition was defined as acute respiratory distress syndrome (ARDS; n = 12) or acute lung injury (ALI; n = 26). The serum levels of interleukin (IL)-18, IL-12, and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assays.


The ARDS group showed significantly higher serum levels of IL-18, IL-12, and TNF-α even at an early stage after disease onset compared with the ALI group. A negative correlation was noted between the PaO2/FIO2 ratio (P/F ratio) and serum IL-18 level. Analysis of all 38 patients with ALI/ARDS revealed a 30-day mortality rate of 7.9 %, 60-day mortality rate of 15.8 %, and 90-day mortality rate of 18.4 %. The early-stage serum levels of IL-18, IL-12, and TNF-α were significantly higher in the non-survivors at 60 and 90 days, but not at 30 days, than in the corresponding survivors.


The present data demonstrate an inverse correlation between serum IL-18 level and the P/F ratio, suggesting the possible involvement of IL-18 in the pathogenesis of respiratory failure in patients with ALI/ARDS. Early-stage serum IL-18, IL-12, and TNF-α levels appear to reflect the >60-day prognosis in patients with ALI/ARDS.


Interleukin 18 Sepsis ALI ARDS Prognosis 


  1. 1.
    Nakamura K, Okamura H, Nagata K, Komatsu T, Tamura T. Purification of a factor which provides a costimulatory signal for gamma interferon production. Infect Immunol. 1993;61:64–70.Google Scholar
  2. 2.
    Okamura H, Tsutsui H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe T, Okura T, Nukada Y, Hattori K, Akita K, Namba M, Tanabe F, Konishi K, Fukuda S, Kurimoto M. Cloning of a new cytokine that induces IFN-γ production by T cells. Nature (Lond). 1995;378:88–91.CrossRefGoogle Scholar
  3. 3.
    Tsutsui H, Matsui K, Kawada N, Hyodo Y, Hayashi N, Okamura H, HIgashino K, Nakanishi K. IL-18 accounts for both TNF-α and Fas ligand-mediated hepatotoxic pathway in endotoxin-induced liver injury in mice. J Immunol. 1997;159:3961–7.PubMedGoogle Scholar
  4. 4.
    Endo S, Inada K, Yamada Y, Wakabayashi G, Ishikura H, Tanaka T, Sato S. Interleukin 18 (IL-18) levels in patients with sepsis. J Med. 2000;31:15–20.PubMedGoogle Scholar
  5. 5.
    Endo S, Sato, Inoue Y, Fujino Y, Wakabayashi G, Inada K, Sato S. Interleukin 18 levels reflect the severity of acute pancreatitis. Res Mol Pathol Pharmacol 2001;110:285–91.Google Scholar
  6. 6.
    Nakae H, Zheng Y-J, Wada, Tajimi K, Endo S. Involvement of IL-18 and soluble Fas in patients with postoperative hepatic failure. Eur Surg Res. 2003;35:61–6.Google Scholar
  7. 7.
    Pohan HT, Suhendro BR, Matondang AH, Djauzi S, Inada K, Endo S. Interleukin-18 levels in adult dengue fever and dengue hemorrhagic fever. Med J Indonesia. 2004;13:86–9.Google Scholar
  8. 8.
    Imai S, Sato N, Inoue Y, Endo S. A study of interleukin 18 and sFas in septic multiple organ dysfunction syndrome. J Iwate Med Assoc. 2005;57:497–503.Google Scholar
  9. 9.
    Shinoda M, Wakabayashi G, Shimazu M, Saito H, Hoshino K, Tanabe M, Morikawa Y, Endo S, Ishii H, Kitajima M. Increased serum and hepatic tissue levels of interleukin-18 in patients with fulminant hepatic failure. J Gastroenterol Hepatol. 2006;21:1731–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Jordan JA, Guo R-F, Yun EC, Sarma V, Warner RL, Crouch LD, Senaldi G, Ulich TR, Ward PA. Role of IL-18 in acute lung inflammation. J Immunol. 2001;167:7060–8.PubMedGoogle Scholar
  11. 11.
    Endo S, Sato N, Suzuki Y, Kojika M, Ogawa M, Imai S, Takahashi G, Hakozaki M, Miyata M, Kikuchi S, Yaegashi Y. Effective therapy for IL-18 and P/F ratio treated with PMX-DHP; A case report (in Japanese with English abstract). Jpn J Crit Care Endotoxemia. 2006;10:162–8.Google Scholar
  12. 12.
    Hoshikawa K, Kojika M, Kikkawa T, Akitomi S, Matsumoto N, Takahashi G, Aoki K, Suzuki Y, Endo S. A study of interleukin 18 levels in a patient with septic ARDS: a case report. Med Postgrad 2009;47:265–8 (in Japanese with English abstract).Google Scholar
  13. 13.
    Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644–55/Crit Care Med 1992;20:864–74.Google Scholar
  14. 14.
    Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European consensus conference on ARDS. Definition, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–24.PubMedGoogle Scholar
  15. 15.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE. A severity of disease classification system. Crit Care Med. 1985;13:818–29.PubMedCrossRefGoogle Scholar
  16. 16.
    Vincent JL. Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG. Use of the SOFA score to asses the incidence of organ dysfunction/failure in intensive care units: results of a multicentre, prospective study. Crit Care Med 1998;26:1793–800.Google Scholar
  17. 17.
    Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF. Plasma tumor necrosis factor in patients with septic shock: mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis. 1990;141:94–7.PubMedGoogle Scholar
  18. 18.
    Chang SW. Endotoxin-induced pulmonary leukostasis in the rat: role of platelet-activating factor and tumor necrosis factor. J Lab Clin Med. 1994;123:65–72.PubMedGoogle Scholar
  19. 19.
    Tsutsui H, Nakanishi K, Matsui K, Higashino K, Okamura H, Miyazawa Y, Kaneda K. IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. J Immunol. 1996;157:3967–73.PubMedGoogle Scholar
  20. 20.
    Puren AJ, fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin 18 (IFN-gamma-inducing factor) induces IL-8 and IL-1 beta via TNF-alpha production from non-CD14+ human blood mononuclear cells. J Clin Invest. 1998;101:711–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Takahashi G, Endo S, Sato N, Kojika M, Hakozaki M, Imai S, Miyata M, Suga Y, Suzuki Y, Wakabayashi G. Clinical significance of interleukin 18 in cases of multiple organ dysfunction syndromes associated with diffuse peritonitis. J Iwate Med Assoc. 2006;58:23–9.Google Scholar
  22. 22.
    Okamoto M, Kato S, Oizumi K, Kinoshita M, Inoue Y, Hoshino K, Akira S, McKenzie AN, Young HA, Hoshino T. Interleukin 18 (IL-18) in synergy with IL-12 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia. Blood. 2002;99:1289–98.PubMedCrossRefGoogle Scholar
  23. 23.
    Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Luhr OR, Antonsen K, Karlsson M, Aardal S, Thorsteinsson A, Frostell CG, Bonde J. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med. 1999;159:1849–61.PubMedGoogle Scholar
  25. 25.
    Bersten AD, Edibam C, Hunt T, Australian and New Zealand Intensive Care Society Clinical Trials Group. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med. 2002;165:443–8.PubMedGoogle Scholar
  26. 26.
    Takeda S, Ishizaka A, Fujino Y, Fukuoka T, Nagano O, Yamada Y, Takezawa J, Multi-Center Clinical Trial Committee, Japanese Society of Respiratory Care Medicine. Time to change diagnostic criteria of ARDS: toward the disease entity-based subgrouping. Pulm Pharmacol Ther. 2005;18:115–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Vincent JL, Sakr Y, Groeneveld J, Zandstra DF, Hoste E, Malledant Y, Lei K, Sprung CL. ARDS of early or late onset: does it make a difference? Chest. 2010;137:81–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Doyle RL, Szaflarski N, Modin GW, Wiener-Kronish JP, Matthay MA. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med. 1995;152:1818–24.PubMedGoogle Scholar
  29. 29.
    Sloane PJ, Gee MH, Gottlieb JE, Albertine KH, Peters SP, Burns JR, Machiedo G, Fish JE. A multicenter registry of patients with acute respiratory distress syndrome: physiology and outcome. Am Rev Respir Dis. 1992;146:419–26.PubMedGoogle Scholar
  30. 30.
    Vasilyev S, Schaap RN, Mortensen JD. Hospital survival rates of patients with acute respiratory failure in modern respiratory intensive care units: an international, multicenter, prospective survey. Chest. 1995;107:1083–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Morris AH, Wallace CJ, Menlove RL, Clemmer TP, Orme Jr. JF, Weaver LK, Dean NC, Thomas F, East TD, Pace NL, Suchyta MR, Beck E, Bombino M, Sittig S, Bohm S, Hoffmann B, Becks H, Butler S, Pearl J, Rasmusson B. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;149:295–305.Google Scholar
  32. 32.
    Villar J, Blanco J, Anon JM, Santos-Bouza A, Blanch L, Ambrós A, Gandía F, Carriedo D, Mosteiro F, Basaldúa S, Fernández RL, Kacmarek RM. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med. 2011;37:1932–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Kikuchi S, Kojika M, Shibata S, Takahashi G, Onodera M, Fujino Y, Suzuki Y, Inoue Y, Endo S. Assessment of high mobility group box 1 values in the early stage after the onset of ALI/ARDS and the outcome. J Iwate Med Assoc. 2009;61:283–93.Google Scholar
  34. 34.
    Zeiher BG, Arigas A, Vincent JL, Dmitrienko A, Jackson K, Thompson BT, STRIVE Study Group. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med. 2004;32:1695–702.PubMedCrossRefGoogle Scholar
  35. 35.
    Endo S, Sato N, Yaegashi Y, Suzuki Y, Kojika M, Yamada Y, Yoshida Y, Nakadate T, Aoki H, Inoue Y. Sivelestat sodium hydrate improves septic acute lung injury by reducing alveolar dysfunctions. Res Commun Mol Pathol Pharmacol. 2006;119:53–65.PubMedGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2012

Authors and Affiliations

  • Hideyuki Makabe
    • 1
  • Masahiro Kojika
    • 1
  • Gaku Takahashi
    • 1
  • Naoya Matsumoto
    • 1
  • Shigehiro Shibata
    • 1
  • Yasushi Suzuki
    • 1
  • Yoshihiro Inoue
    • 1
  • Shigeatsu Endo
    • 1
  1. 1.Department of Critical Care MedicineSchool of Medicine, Iwate Medical UniversityMoriokaJapan

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