Review
BibTex RIS Cite

Covid-19 Tedavisinde İmmun Plazma Uygulamaları

Year 2021, , 87 - 92, 01.05.2021
https://doi.org/10.17343/sdutfd.906321

Abstract

Yüzyılda bir yaşanan ve ne zaman sonlanacağı öngörülemeyen şiddetli akut solunum yolu sendromu koronavirüsü-2 (SARS-CoV-2) pandemisi tüm dünyada hız kesmeden devam etmektedir. Umut verici aşı ve ilaç çalışmalarına rağmen pandeminin kontrol altına alınamaması nedeni ile iyileşen hastalardan elde edilen immun plazmanın koronavirüs hastalığı 2019 (COVID-19) tedavisinde uygulanması, alternatif tedavi seçeneklerinden biri olarak güncelliğini korumaktadır. İyileşen hasta plazmalarının salgın hastalıklarda kullanımı yeni bir yöntem olmayıp tarihte birçok bulaşıcı hastalığın tedavisinde kullanılmıştır. İmmun plazma içinde bulunan Nötralizan antikorların (Nab) bilinen etki mekanizması virusun hücre içine girişinin, füzyonunun ve çıkışının engellenmesidir. Plazma tedavisinin erken dönemde (7 gün) kullanılmasının hastalık şiddetini azaltarak hem hastanede kalış süresini kısalttığını hem de sağ kalımı arttırdığını gösteren çalışmalar mevcuttur. Güvenlik ile ilişkili olarak biriken veriler; immun plazma tedavisinin diğer plazma ürünleri ile benzer yan etkilere sahip olduğu yönündedir. İmmun plazmanın, duyarlı kişilerde doğrudan SARS-CoV-2’yi hedefleyebilecek etkili ve hızlı bir tedavi stratejisi olabileceği düşünülmektedir . Bu derlemede güncel veriler ışığında COVID-19 pandemisinde hızla kullanım alanı bulan plazma tedavisi uygulamaları tartışılacaktır.

References

  • 1. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) — China, 2020[J]. China CDC Weekly 2020. http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
  • 2. Winau F Winau R. Emil von Behring and serum therapy. microbes and Infection 2002; 4:185-8.
  • 3. Zingher A. Convalescent Whole Blood, Plasma and Serum In Prophylaxis Of Measles. JAMA.1924;82(15):1180–87.
  • 4. Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006;145(8):599-609.
  • 5. Soo YO, Cheng Y, Wong R, Hui DS, Lee CK, Tsang KK, Ng MH, Chan P, Cheng G, Sung JJ. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect. 2004;10(7):676-8.
  • 6. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007;357(14):1450-1.
  • 7. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.
  • 8. World Health Organization. Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks. Interim guidance for national health authorities and blood transfusion services. Geneva, Switzerland: WHO, 2014.
  • 9. Tiberghien, Pierre et al. Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how?. Vox sanguinis 2020;115(6): 488-94.
  • 10. Joyner MJ, Senefeld JW, Klassen SA, MillsJR, Johnson PW, Theel ES, et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. Preprint. medRxiv.2020;2020.08.12.20169359.
  • 11. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-24-2020
  • 12. T.C Sağlık Bakanlığı Sağlık Hizmetleri Genel Müdürlüğü Kan ve Kan Ürünleri Dairesi Başkanlığı COVID-19 İmmün (Konvalesan) Plazma Tedarik ve Klinik Kullanım Rehberi. 2020,Ankara.
  • 13. https://www.aa.com.tr/tr/koronavirus/turkiyede-ilk-plazma-tedavisi-uygulanan-kovid-19-hastasi-iyilesti/1821009
  • 14. Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med. 2021;384(11):1015-1027.
  • 15. Ju B, Zhang Q, Ge J, Wang R, Sun J, Ge X et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020;584(7819):115-119.
  • 16. Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol. 2020;20(6):339-341.
  • 17. Rojas M, Rodríguez Y, Monsalve DM, Acosta-Ampudia Y, Camacho B, Gallo JE et al. Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmun Rev. 2020;19(7):102554.
  • 18. Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020;130(6):2757-2765.
  • 19. Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S. The spike protein of SARS-CoV-a target for vaccine and therapeutic development. Nat Rev Microbiol. 2009;7(3):226-36.
  • 20. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol .2020;(17):613–20.
  • 21. Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, et al. Neutralizing antibody re-sponses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their im-plications. MedRxiv 2020.https://doi.org/10.1101/2020.03.30.20047365.
  • 22. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020;382(17):e38.
  • 23. Abe Y, Horiuchi A, Miyake M, Kimura S. Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev. 1994;139:5-19.
  • 24. Basta M, Van Goor F, Luccioli S, Billings EM, Vortmeyer AO, Baranyi LI, et al. F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat Med. 2003;9(4):431-8.
  • 25. McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020;19(6):102537.
  • 26. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181(5):1036-45.
  • 27. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang Jet al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(5):460-70.
  • 28. Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER et al. Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020;95(9):1888-97.
  • 29. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-updates-emergency-use-authorization-covid-19-convalescent-plasma-reflect-new-data
  • 30. https://www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/treatment/overview-of-covid-19-interventions-v4.1.0.pdf
  • 31. Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021;325(12):1185-1195.
  • 32. https://shgm.saglik.gov.tr/TR-65033/covid-19-immun-konvalesan-plazma-tedarik-ve-klinik-kullanim-rehberi-yayinlanmistir.html
  • 33. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-9496.
  • 34. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020;92(10):1890-1901.
  • 35. Benjamin, R.J. and McLaughlin, L.S. (2012), Plasma components: properties, differences, and uses. Transfusion, 52: 9S-19S. https://doi.org/10.1111/j.1537-2995.2012.03622.x
  • 36. https://shgmkanhizmetleridb.saglik.gov.tr/TR-76536/covid-19-immun-konvalesan-plazma-tedarik-ve-klinik-kullanim-rehberi-guncellendi.html
  • 37. Taşkın G. İmmün plazma tedavisi. Yamanel HL, editör. Yoğun Bakım ve COVID-19. 1. Baskı. Ankara: Türkiye Klinikleri; 2020. p.103- 7.
  • 38. Okba N, Müller MA, Li W, Wang C, GeurtsvanKessel CH, Corman VM, et al. Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus Disease Patients. Emerg Infect Dis. 2020;26(7):1478-1488. https://dx.doi.org/10.3201/eid2607.200841
  • 39. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 117(17):9490-6.
  • 40. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J et al.Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020;323(16):1582-9.
  • 41. Brown BL, McCullough J. Treatment for emerging viruses: Convalescent plasma and COVID-19. Transfus Apher Sci. 2020;59(3):102790.
  • 42. Özel İÖ. COVID-19 ve konvalesan plazma tedavisi. Atak Yücel A, editör. İmmünoloji ve COVID-19. 1. Baskı. Ankara: Türkiye Klinikleri; 2020. p.67-72.
  • 43. Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108(3):759-69.
  • 44. Tetro JA. Is COVID-19 receiving ADE from other coronaviruses? microbes and Infection. 2020; 22:72-3.
  • 45. Ulrich H, Pillat MM, Tárnok A. Dengue Fever, COVID-19 (SARS-CoV-2), and Antibody-Dependent Enhancement (ADE): A Perspective. Cytometry A. 2020;97(7):662-667.
  • 46. Negro F. Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis? Swiss Med Wkly. 2020;150:w20249. doi: 10.4414/smw.2020.20249. PMID: 32298458.

Immune Plasma Applications in Covid-19 Treatment

Year 2021, , 87 - 92, 01.05.2021
https://doi.org/10.17343/sdutfd.906321

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, which is experienced once in a century and whose end is unpredictable, continues unabated around the world. Despite promising vaccine and drug studies, since the pandemic cannot be controlled, immune plasma continues to be up-to-date as one of the alternative treatment options in the treatment of coronavirus disease 2019 (COVID-19). The use of healed patient plasma in epidemic diseases is not a new method but has been used in the treatment of many infectious diseases in history. The known mechanism of action of neutralizing antibodies (Nab) in the immune plasma is to prevent the entry, fusion, and exit of the virus into the cell. Studies are showing that the use of plasma therapy in the early period (<7 days) decreases the severity of the disease and reduces the length of hospital stay and increases survival. Data accumulated about security; It is that immune plasma treatment has similar side effects with other plasma products. It is thought that immune plasma can be an effective and rapid treatment strategy that can directly target SARS-CoV-2 in susceptible individuals. In this review, in light of current data, plasma therapy applications that are rapidly used in the COVID-19 pandemic will be discussed.

References

  • 1. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) — China, 2020[J]. China CDC Weekly 2020. http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
  • 2. Winau F Winau R. Emil von Behring and serum therapy. microbes and Infection 2002; 4:185-8.
  • 3. Zingher A. Convalescent Whole Blood, Plasma and Serum In Prophylaxis Of Measles. JAMA.1924;82(15):1180–87.
  • 4. Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006;145(8):599-609.
  • 5. Soo YO, Cheng Y, Wong R, Hui DS, Lee CK, Tsang KK, Ng MH, Chan P, Cheng G, Sung JJ. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect. 2004;10(7):676-8.
  • 6. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007;357(14):1450-1.
  • 7. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.
  • 8. World Health Organization. Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks. Interim guidance for national health authorities and blood transfusion services. Geneva, Switzerland: WHO, 2014.
  • 9. Tiberghien, Pierre et al. Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how?. Vox sanguinis 2020;115(6): 488-94.
  • 10. Joyner MJ, Senefeld JW, Klassen SA, MillsJR, Johnson PW, Theel ES, et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. Preprint. medRxiv.2020;2020.08.12.20169359.
  • 11. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-24-2020
  • 12. T.C Sağlık Bakanlığı Sağlık Hizmetleri Genel Müdürlüğü Kan ve Kan Ürünleri Dairesi Başkanlığı COVID-19 İmmün (Konvalesan) Plazma Tedarik ve Klinik Kullanım Rehberi. 2020,Ankara.
  • 13. https://www.aa.com.tr/tr/koronavirus/turkiyede-ilk-plazma-tedavisi-uygulanan-kovid-19-hastasi-iyilesti/1821009
  • 14. Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med. 2021;384(11):1015-1027.
  • 15. Ju B, Zhang Q, Ge J, Wang R, Sun J, Ge X et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020;584(7819):115-119.
  • 16. Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol. 2020;20(6):339-341.
  • 17. Rojas M, Rodríguez Y, Monsalve DM, Acosta-Ampudia Y, Camacho B, Gallo JE et al. Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmun Rev. 2020;19(7):102554.
  • 18. Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020;130(6):2757-2765.
  • 19. Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S. The spike protein of SARS-CoV-a target for vaccine and therapeutic development. Nat Rev Microbiol. 2009;7(3):226-36.
  • 20. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol .2020;(17):613–20.
  • 21. Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, et al. Neutralizing antibody re-sponses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their im-plications. MedRxiv 2020.https://doi.org/10.1101/2020.03.30.20047365.
  • 22. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020;382(17):e38.
  • 23. Abe Y, Horiuchi A, Miyake M, Kimura S. Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev. 1994;139:5-19.
  • 24. Basta M, Van Goor F, Luccioli S, Billings EM, Vortmeyer AO, Baranyi LI, et al. F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat Med. 2003;9(4):431-8.
  • 25. McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020;19(6):102537.
  • 26. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181(5):1036-45.
  • 27. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang Jet al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(5):460-70.
  • 28. Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER et al. Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020;95(9):1888-97.
  • 29. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-updates-emergency-use-authorization-covid-19-convalescent-plasma-reflect-new-data
  • 30. https://www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/treatment/overview-of-covid-19-interventions-v4.1.0.pdf
  • 31. Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021;325(12):1185-1195.
  • 32. https://shgm.saglik.gov.tr/TR-65033/covid-19-immun-konvalesan-plazma-tedarik-ve-klinik-kullanim-rehberi-yayinlanmistir.html
  • 33. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-9496.
  • 34. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020;92(10):1890-1901.
  • 35. Benjamin, R.J. and McLaughlin, L.S. (2012), Plasma components: properties, differences, and uses. Transfusion, 52: 9S-19S. https://doi.org/10.1111/j.1537-2995.2012.03622.x
  • 36. https://shgmkanhizmetleridb.saglik.gov.tr/TR-76536/covid-19-immun-konvalesan-plazma-tedarik-ve-klinik-kullanim-rehberi-guncellendi.html
  • 37. Taşkın G. İmmün plazma tedavisi. Yamanel HL, editör. Yoğun Bakım ve COVID-19. 1. Baskı. Ankara: Türkiye Klinikleri; 2020. p.103- 7.
  • 38. Okba N, Müller MA, Li W, Wang C, GeurtsvanKessel CH, Corman VM, et al. Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus Disease Patients. Emerg Infect Dis. 2020;26(7):1478-1488. https://dx.doi.org/10.3201/eid2607.200841
  • 39. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 117(17):9490-6.
  • 40. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J et al.Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020;323(16):1582-9.
  • 41. Brown BL, McCullough J. Treatment for emerging viruses: Convalescent plasma and COVID-19. Transfus Apher Sci. 2020;59(3):102790.
  • 42. Özel İÖ. COVID-19 ve konvalesan plazma tedavisi. Atak Yücel A, editör. İmmünoloji ve COVID-19. 1. Baskı. Ankara: Türkiye Klinikleri; 2020. p.67-72.
  • 43. Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108(3):759-69.
  • 44. Tetro JA. Is COVID-19 receiving ADE from other coronaviruses? microbes and Infection. 2020; 22:72-3.
  • 45. Ulrich H, Pillat MM, Tárnok A. Dengue Fever, COVID-19 (SARS-CoV-2), and Antibody-Dependent Enhancement (ADE): A Perspective. Cytometry A. 2020;97(7):662-667.
  • 46. Negro F. Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis? Swiss Med Wkly. 2020;150:w20249. doi: 10.4414/smw.2020.20249. PMID: 32298458.
There are 46 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Reviews
Authors

Esra Nurlu Temel 0000-0003-4618-168X

Publication Date May 1, 2021
Submission Date March 30, 2021
Acceptance Date April 7, 2021
Published in Issue Year 2021

Cite

Vancouver Nurlu Temel E. Covid-19 Tedavisinde İmmun Plazma Uygulamaları. Med J SDU. 2021;28(COVİD-19 ÖZEL SAYI):87-92.

                                                                                               14791 


Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi/Medical Journal of Süleyman Demirel University is licensed under Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International.