Extracorporeal photopheresis in the treatment of the novel coronavirus disease COVID-19 (a case series)

Cover Page

Cite item

Abstract

Rationale: Most people infected with SARS-CoV-2 have asymptomatic or minor clinical manifestations and recover without any aggressive therapy. However, there are patient categories in need of specific treatment and those at high risk of severe disease. Control of viremia with antiviral therapy may not be the best therapeutic strategy, since, in addition to substantial toxicity, antiviral agents can suppress the production of antiviral antibodies and disintegrate adoptive immunity against SARS-CoV-2. Due to a high correlation between the symptoms severity in patients with COVID-19 and inflammation, anti-inflammatory corticosteroids have been proposed to treat the disease. However, clinical data do not support the systemic administration of corticosteroids for the treatment of patients with severe COVID-19. Such treatment may have a negative effect due to suppression of the adoptive immune system. In this regard, the development or use of already available of agents that modulate inflammation without compromising the adoptive immune response could be the most effective therapeutic strategy.

Aim: To evaluate clinical efficacy and safety of the cell biotherapy technique, the extracorporeal photopheresis (ECP), in the treatment of patients with moderately severe new coronavirus disease COVID-19.

Materials and methods: The study included four patients (three women and one man, age 42 to 60 years), with SARS-CoV-2 infection confirmed by gene amplification. All patients had CT-confirmed bilateral multisegmental viral pneumonia (grades > 2, i.e. with 25 to 60% involvement of the lungs). Prior to admission, all patients received antibiotics (azithromycin 500 mg daily and levo-floxacin / amoxicillin clavulanate 500 mg BID) and antipyretics for torpid fever of up to 38.5-39 °C. The outpatient treatment lasted for 8 to 14 days, with signs of progressive respiratory failure. In addition to the moderately severe and torpid course of viral pneumonia, three patients showed hematology test abnormalities, such as hypochromic anemia, leukopenia, leukopenia/lymphopenia, and moderate thrombocytopenia. Three patients had high C-reactive protein (CRP) levels. Inpatient treatment consisted of azithromycin 500 mg daily, levofloxacin 500 mg BID, hydroxychloroquine 200 mg BID, and low molecular weight heparin (enoxaparin 0.4 ml, 4000 anti-Xa IU, s.c. BID). Despite the treatment, the patients showed signs of progressive respiratory failure, with increasing dyspnea and gradual decrease in saturation from 96% to 92%. Isolation of peripheral blood mononuclear cells was done in an intermittent blood separator "Haemonetics MCS+” (USA), with subsequent cell irradiation with an extracorporeal blood irradiator (OKUFKE 320/400-600/650-01 "Yulia”, ZAO NPKF "METOM”, Russia). Ammifurin (ZAO "Pharmcenter VILAR”, Russia) was used as a photosensitizer. Three patients had two ECP sessions with an interval of 24 hours, and one patient had one ECP session.

Results: In three patients who had received two ECP sessions, there was a regression of radiographic signs of viral pneumonia from CT2 to CT1 (less than 25% of lung tissue involvement) during the next four days (96 hours). In one patient, the follow-up CT showed resolving pneumonia with less than 5% involvement of the lungs. The patients (n = 3) with baseline high CRP levels showed their normalization at 4 days after two ECP sessions. At 24 hours after a single ECP session, leukocyte count and differential, as well as platelets were restored. In three patients, viral RNA tests within 2 to 4 days after ECP were negative. These results were associated with normalization of body temperature, no further progression of respiratory failure, and a reduction in hospital stay.

Conclusion: The use of ECP in 4 patients with moderately severe SARS-CoV-2 infection has contributed to the rapid relief of clinical symptoms, resolution of the inflammation and restoration of respiratory abnormalities in all of them. These observations allow us to consider ECP as an effective and safe method of treatment for moderately severe COVID-19 and a promising adjuvant method in the high-risk patients in order to prevent an unfavorable disease outcome.

About the authors

A. V. Kildyushevsky

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: kildushev@yandex.ru
ORCID iD: 0000-0002-7079-8383

Alexander V. Kildyushevsky - MD, PhD, Professor, Leading Research Fellow, Department of Clinical Hematology and Immunotherapy.

61/2 Shchepkina ul., Moscow, 129110, Tel.: +7 (903) 614 86 65

Russian Federation

A. V. Molochkov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: derma@monikiweb.ru
ORCID iD: 0000-0002-6456-998X

Anton V. Molochkov - MD, PhD, Professor, Deputy Director.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

O. R. Zhuravlev

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru
ORCID iD: 0000-0002-8457-2537

Oleg R. Zhuravlev - Junior Research Fellow, Department of Clinical Hematology and Immunotherapy.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

T. A. Mitina

Moscow Regional Research and Clinical Institute (MONIKI)

Email: mi_69@inbox.ru
ORCID iD: 0000-0001-7493-0030

Tatiana A. Mitina - MD, PhD, Head of the Department of Clinical Hematology and Immunotherapy.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

K. A. Belousov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: kbel88@mail.ru
ORCID iD: 0000-0001-9028-7671

Kirill A. Belousov - Research Fellow, Department of Clinical Hematology and Immunotherapy.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

S. G. Zakharov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: hematologymoniki@mail.ru
ORCID iD: 0000-0003-2847-4374

Sergey G. Zakharov - Research Fellow, Department of Clinical Hematology and Immunotherapy.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

E. A. Stepanova

Moscow Regional Research and Clinical Institute (MONIKI)

Email: stepanovamoniki@gmail.com
ORCID iD: 0000-0002-9037-0034

Elena A. Stepanova - MD, PhD, Leading Research Fellow, Diagnostic Department.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

D. Yu. Semenov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: moniki@monikiweb.ru
ORCID iD: 0000-0003-2845-1703

Dmitry Yu. Semenov - MD, PhD, Professor, Director.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

References

  1. Kim JM, Chung YS, Jo HJ, Lee NJ, Kim MS, Woo SH, Park S, Kim JW, Kim HM, Han MG. Identification of Coronavirus Isolated from a Patient in Korea with COVID-19. Osong Public Health Res Perspect. 2020;11(1):3-7. doi: 10.24171/j.phrp.2020.11.1.02.
  2. Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. 2020;25(10):2000180. doi: 10.2807/1560-7917.ES.2020.25.10.2000180.
  3. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J, Guo Q, Song T, He J, Yen HL, Peiris M, Wu J. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020;382(12):1177-9. doi: 10.1056/NEJMc2001737.
  4. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020. Epub ahead of print. doi: 10.1001/jama.2020.2648.
  5. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020;323(14):1406-7. Epub ahead of print. doi: 10.1001/jama.2020.2565.
  6. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18): 1708-20. doi: 10.1056/NEJMoa2002032.
  7. Ioannidis I, Ye F, McNally B, Willette M, Flano E. Toll-like receptor expression and induction of type I and type III interferons in primary airway epithelial cells. J Virol. 2013;87(6):3261-70. doi: 10.1128/JVI.01956-12.
  8. Lafferty EI, Qureshi ST, Schnare M. The role of toll-like receptors in acute and chronic lung inflammation. J Inflamm (Lond). 2010;7:57. doi: 10.1186/1476-9255-7-57.
  9. Simmons G, Reeves JD, Rennekamp AJ, Am-berg SM, Piefer AJ, Bates P. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc Natl Acad Sci U S A. 2004;101(12):4240-5. doi: 10.1073/pnas.0306446101.
  10. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. doi: 10.1038/s41422-020-0282-0.
  11. Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, Penaranda S, Bankamp B, Maher K, Chen MH, Tong S, Tamin A, Lowe L, Frace M, DeRisi JL, Chen Q, Wang D, Erdman DD, Peret TC, Burns C, Ksiazek TG, Rollin PE, Sanchez A, Liffick S, Holloway B, Limor J, McCaust-land K, Olsen-Rasmussen M, Fouchier R, Gunther S, Osterhaus AD, Drosten C, Pallansch MA, Anderson LJ, Bellini WJ. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003;300(5624): 1394-9. doi: 10.1126/science.1085952.
  12. Yang ZY, Huang Y, Ganesh L, Leung K, Kong WP, Schwartz O, Subbarao K, Nabel GJ. pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN. J Virol. 2004;78(11): 5642-50. doi: 10.1128/JVI.78.11.5642-5650.2004.
  13. Wu HS, Chiu SC, Tseng TC, Lin SF, Lin JH, Hsu YH, Wang MC, Lin TL, Yang WZ, Ferng TL, Huang KH, Hsu LC, Lee LL, Yang JY, Chen HY, Su SP, Yang SY, Lin SY, Lin TH, Su IS. Serologic and molecular biologic methods for SARS-associated coronavirus infection, Taiwan. Emerg Infect Dis. 2004;10(2): 304-10. doi: 10.3201/eid1002.030731.
  14. Nie Y, Wang G, Shi X, Zhang H, Qiu Y, He Z, Wang W, Lian G, Yin X, Du L, Ren L, Wang J, He X, Li T, Deng H, Ding M. Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection. J Infect Dis. 2004;190(6):1119-26. doi: 10.1086/423286.
  15. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9. doi: 10.1001/jama.2020.1585.
  16. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol. 2020;20(5):277. doi: 10.1038/s41577-020-0305-6.
  17. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017;39(5):517-28. doi: 10.1007/s00281-017-0639-8.
  18. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Lu-zuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-4. doi: 10.1038/na-ture02145.
  19. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3. doi: 10.1038/s41586-020-2012-7.
  20. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181 (2):271 -80.e8. doi: 10.1016/j.cell.2020.02.052.
  21. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14(2):185-92. doi: 10.1007/s11684-020-0754-0.
  22. Sun P, Lu X, Xu C, Wang Y, Sun W, Xi J. CD-sACE2 inclusion compounds: An effective treatment for coronavirus disease 2019 (COVID-19). J Med Virol. 2020. Epub ahead of print. doi: 10.1002/jmv.25804.
  23. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60. doi: 10.1038/s41569-020-0360-5.
  24. Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol. 2006;6(3):271-6. doi: 10.1016/j.coph.2006.03.001.
  25. Abassi ZA, Skorecki K, Heyman SN, Kinaneh S, Armaly Z. Covid-19 infection and mortality: a physiologist's perspective enlightening clinical features and plausible interventional strategies. Am J Physiol Lung Cell Mol Physiol. 2020;318(5):L1020-2. doi: 10.1152/ajplung.00097.2020.
  26. Marshall RP, Gohlke P, Chambers RC, Howell DC, Bottoms SE, Unger T, McAnulty RJ, Laurent GJ. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004;286(1):L156-64. doi: 10.1152/ajplung.00313.2002.
  27. Кильдюшевский АВ, Молочков ВА, Митина ТА, Мойсюк ЯГ, Молочков АВ. Экстракорпоральный фотоферез - неспецифический метод иммунотерапии аутоиммунных заболеваний и Т-клеточной лимфомы кожи (обзор литературы и собственные исследования). Альманах клинической медицины. 2019;47(5):419-34. doi: 10.18786/2072-0505-2019-47-061.
  28. Федулкина ВА, Кофиади ИА, Ватазин АВ, Кильдюшевский АВ, Чуксина ЮЮ, Зуль-карнаев АБ. Разработка метода оценки уровня экспрессии генов, ответственных за активацию и ингибирование Т-клеточно-го ответа у реципиентов почечного трансплантата при проведении экстракорпоральной фотохимиотерапии. Клиническая лабораторная диагностика. 2018;63(3):173-8. doi: 10.18821/0869-2084-2018-63-3-173-178.
  29. Козлов ИБ, Ватазин АВ, Кильдюшевский АВ, Зулькарнаев АБ, Федулкина ВА, Фаенко АП, Яздовский ВВ, Гудима ГО, Кофиади ИА. Анализ экспрессии генов иммунной системы, ответственных за активацию и ингибирование Т-клеточного иммунного ответа, у реципиентов почечного трансплантата после ЭКФ. Иммунология. 2020;41(1):20-30. doi: 10.33029/0206-4952-2020-41-1-20-30.
  30. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. doi: 10.1016/S0140-6736(20)30628-0.
  31. Zha L, Li S, Pan L, Tefsen B, Li Y, French N, Chen L, Yang G, Villanueva EV. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Med J Aust. 2020;212(9):416-20. doi: 10.5694/mja2.50577.
  32. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-5. doi: 10.1016/S0140-6736(20)30317-2.
  33. Manjili RH, Zarei M, Habibi M, Manjili MH. COVID-19 as an Acute Inflammatory Disease. J Immunol. 2020;205(1):12-9. doi: 10.4049/jim-munol.2000413.
  34. Berger CL, Hanlon D, Kanada D, Girardi M, Edel-son RL. Transimmunization, a novel approach for tumor immunotherapy. Transfus Apher Sci. 2002;26(3):205-16. doi: 10.1016/s1473-0502(02)00014-9.
  35. O'Brien CB, Mclaughlin SN, Stouch BC, inventors and assignees. Photopheresis treatment of chronic HCV infections. United States Patent Application 20040062754, А1.2004 Apr 1.

Supplementary files

There are no supplementary files to display.


Copyright (c) 2020 Kildyushevsky A.V., Molochkov A.V., Zhuravlev O.R., Mitina T.A., Belousov K.A., Zakharov S.G., Stepanova E.A., Semenov D.Y.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies