Opportunities for correction of immunosuppression in patients with COVID-19

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Abstract

Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 1997–2022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity — the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor-α (TNFα), interferon-γ (IFNγ) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at “training” effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.

About the authors

Mikhail V. Kiselevskiy

N.N. Blokhin National Medical Research Center of Oncology; National University of Science and Technology “MISIS”

Author for correspondence.
Email: kisele@inbox.ru
ORCID iD: 0000-0002-0132-167X

PhD, MD (Medicine), Professor, Head of the Laboratory of Cell Immunity, Professor, Biomedical Engineering Research and Education Center

Russian Federation, Moscow; Moscow

H. M. Treshalina

N.N. Blokhin National Medical Research Center of Oncology

Email: treshalina@yandex.ru
ORCID iD: 0000-0002-3878-3958

PhD, MD (Medicine), Professor, Leading Researcher, Laboratory of Cell Immunity, Research Institute of Experimental Diagnostics and Therapy of Tumors

Russian Federation, Moscow

I. N. Mikhailova

N.N. Blokhin National Medical Research Center of Oncology

Email: irmikhaylova@gmail.com
ORCID iD: 0000-0002-7659-6045

PhD, MD (Medicine), Leading Researcher, Department of Biotherapy, N.N. Trapeznikov Research Institute of Clinical Oncology

Russian Federation, Moscow

D. V. Martirosyan

Pirogov Russian National Research Medical University

Email: 16710@list.ru

Medical Student

Russian Federation, Moscow

I. V. Manina

Institute of Allergology and Clinical Immunology

Email: irina.v.manina@gmail.com
ORCID iD: 0000-0002-4674-5484

PhD (Medicine), Chief Physician

Russian Federation, Moscow

V. V. Reshetnikova

N.N. Blokhin National Medical Research Center of Oncology

Email: veravr@gmail.ru
ORCID iD: 0000-0002-2821-3425

PhD (Engineering Science), Researcher, Laboratory of Cell Immunity, Research Institute of Experimental Diagnostics and Therapy of Tumors

Russian Federation, Moscow

I. G. Kozlov

Sechenov First Moscow State Medical University; Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Email: immunopharmacology@yandex.ru
ORCID iD: 0000-0002-9694-5687

PhD, MD (Medicine), Professor of Department of Organization and Management in the Sphere of Medicines Circulation, Chief of the Laboratory of Experimental and Clinical Pharmacology

Russian Federation, Moscow; Moscow

References

  1. Киселевский М.В., Ситдикова С.М., Абдуллаев А.Г., Шляпников С.А., Чикилева И.О. Иммуносупрессия при сепсисе и возможности ее коррекции // Вестник хирургии им. И.И. Грекова. 2018. Т. 177, № 5. С. 105–107. [Kiselevskiy M.V., Sitdikova S.M., Abdullaev A.G., SHlyapnikov S.A., Chikileva I.O. Immunosuppression in sepsis and possibility of its correction. Vestnik hirurgii im. I.I. Grekova = Grekov’s Bulletin of Surgery, 2018, vol. 177, no. 5, pp. 105–107. (In Russ.)] doi: 10.24884/0042-4625-2018-177-5-105-107
  2. Лебедев В.Ф., Гаврилин С.В., Киров М.Ю., Неймарк М.И., Левит А.Л., Малкова О.Г., Останин А.А., Черных Е.Р., Стрельцова Е.И., Конь Е.М., Николенко А.В., Лебедев М.Ф., Чернышкова М.В., Ващенков В.В., Рудь А.А. Результаты многоцентрового проспективного контролируемого исследования эффективности препарата рекомбинантного интерлейкина-2 человека (ронколейкина) в комплексной интенсивной терапии тяжелого сепсиса // Интенсивная терапия. 2007. № 3. [Lebedev V.F., Gavrilin S.V., Kirov M.YU., Nejmark M.I., Levit A.L., Malkova O.G., Ostanin A.A., CHernyh E.R., Strel’cova I., Kon’ E.M., Nikolenko A.V., Lebedev M.F., CHernyshkova M.V., Vashchenkov V.V., Rud’ A.A. Results of a multicenter prospective controlled study of the efficacy of recombinant human interleukin-2 (Roncoleukin) in the complex intensive therapy of severe sepsis. Intensivnaya terapiya = Intensive Care, 2007, no. 3. (In Russ.)] URL: http://icj.ru/journal/number-3-2007/119-rezultaty-mnogocentrovogo-prospektivnogo-kontroliruemogo-issledovaniya-effektivnosti-preparata-rekombinantnogo-interleykina-2-cheloveka-ronkoleykina-v-kompleksnoy-intensivnoy-terapii-tyazhelogo.html (04.03.2022)
  3. Azkur Ah.K., Akdis M., Azkur D., Sokolowska M., van de Veen W., Brüggen M.-Ch., O’Mahony L., Gao Y., Nadeau K., Akdis C.A. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy, 2020, vol. 75, no. 7, pp. 1564–1581. doi: 10.1111/all.14364
  4. Bluestone J.A., Trotta E., Xu D. The therapeutic potential of regulatory T cells for the treatment of autoimmune disease. Expert. Opin. Ther. Tar., 2015, vol. 19, no. 8, pp. 1091–110. doi: 10.1517/14728222.2015.1037282
  5. Chahroudi A., Silvestri G. Interleukin-7 in HIV pathogenesis and therapy. Eur. Cytokine Netw., 2010, vol. 21, no. 3, pp. 202–207. doi: 10.1684/ecn.2010.0205
  6. Chen L., Qu J., Kalyani F.S., Zhang Q., Fan L., Fang Y., Li Y., Xiang C. Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell. Mol. Life Sci., 2022, vol. 79, no. 3: 142. doi: 10.1007/s00018-021-04096-y
  7. Conlon K.C., Lugli E., Welles H.C., Rosenberg S.A., Fojo A.T.,. Morris J.C., Fleisher T.A., Dubois S.P., Perera L.P., Stewart D.M., Goldman C.K., Bryant B.R., Decker J.M., Chen J., Worthy T.A., Figg W.D., Peer C.J., Sneller M.C., Lane H.C., Yovandich J.L., Creekmore S.P., Roederer M., Waldmann T.A. Redistribution hyperproliferation activation of natural killer cells CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Сlin. Oncol., 2015, vol. 33, no. 1, pp. 74–82. doi: 10.1200/JCO.2014.57.3329
  8. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7). Chin. Med. J., 2020, vol. 133, pp. 1087–1095. doi: 10.1097/CM9.0000000000000819
  9. Docke W.D., Randow F., Syrbe U., Krausch D., Asadullah K., Reinke P., Volk H.D., Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nature Medicine, 1997, vol. 3, no. 6, pp. 678–681. doi: 10.1038/nm0697-678
  10. Fathi N., Rezaei N. Lymphopenia in COVID-19: therapeutic opportunities. Cell. Biol. Int., 2020, vol. 44, no. 9, pp. 1792–1797. doi: 10.1002/cbin.11403
  11. François B., Jeannet R., Daix T. Francois B., Jeannet R., Daix T., Walton A.H., Shotwell M.S., Unsinger J., Monneret G., Rimmelé T., Blood T., Morre M., Gregoire A., Mayo G.A., Blood J., Durum S.K., Sherwood E.R., Hotchkiss R.S. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight., 2018, vol. 3, no. 5: e98960. doi: 10.1172/jci.insight.98960
  12. Frasca L., Piazza C., Piccolella E. CD4+ T cells orchestrate both amplification and deletion of CD8+ T cells. Crit. Rev. Immunol., 1998, vol. 18, no. 6, pp. 569–594. doi: 10.1615/CritRevImmunol.v18.i6.50
  13. Garvin M.R., Alvarez Ch., Prates E.T., Walker A.M., Amos B.K., Mast A.E., Justice A., Aronow B., Jacobson D.A. Mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife, 2020, vol. 9: e59177 doi: 10.7554/eLife.59177
  14. Gendelman O., Amital H., Bragazzi N.L., Watad A., Chodick G. Continuous hydroxychloroquine or colchicine therapy does not prevent infection with SARS-CoV-2: insights from a large healthcare database analysis. Autoimmun. Rev., 2020, vol. 19, no. 7: 102566. doi: 10.1016/j.autrev.2020.1025662020
  15. Ghizlane E.A., Manal M., Abderrahim E.K., Abdelilah E., Mohammed M., Rajae A., Amine B.M., Houssam B., Naima A., Brahim H. Lymphopenia in Covid-19: a single center retrospective study of 589 cases. Ann. Med. Surg. (Lond.), 2021, vol. 69: 102816. doi: 10.1016/j.amsu.2021.102816
  16. Giles A.J., Hutchinson M.-K.N., Sonnemann H.M., Jung J., Fecci P.E., Ratnam N.M., Zhang W., Song H., Bailey R., Davis D. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J. Immunother. Cancer, 2018, vol. 6, no. 1, pp. 1–13. doi: 10.1186/s40425-018-0371-5
  17. Gladstone D.E., Kim B.S., Mooney K., Karaba A.H., D’Alessio F.R. Regulatory T cells for treating patients with COVID-19 and acute respiratory distress syndrome: two case reports. Ann. Intern. Med., 2020, vol. 173, pp. 852–853. doi: 10.7326/L20-0681
  18. Gulati K., Guhathakurta S., Joshi J., Rai N., Ray A. Cytokines and their role in health and disease: a brief overview. MOJ Immunol., 2016, vol. 4, iss. 2: 00121
  19. Guo Y., Luan L., Rabacal W., Bohannon J.K., Fensterheim B.A., Hernandez A., Sherwood E.R. IL-15 superagonist-mediated immunotoxicity: role of NK cells and IFN-gamma. J. Immunology, 2015, vol. 195, no. 5, pp. 2353–2364. doi: 10.4049/jimmunol.1500300
  20. Helal M.A., Shouman S., Abdelwaly A., Elmehrath A.O., Essawy M., Sayed S.M., Saleh A.H., El-Badri N. Molecular basis of the potential interaction of SARS-CoV-2 spike protein to CD147 in COVID-19 associated-lymphopenia. J. Biomol. Struct. Dyn., 2022, vol. 40, no. 3, pp. 1109–1119. doi: 10.1080/07391102.2020.1822208
  21. Henderson L.A., Canna S.W., Schulert G.S., Volpi S., Lee P.Y., Kernan K.F., Caricchio R., Mahmud Sh., Hazen M.M., Halyabar O., Hoyt K.J., Han J., Grom A.A., Gattorno M., Ravelli A., De Benedetti F., Behrens E.M., Cron R.Q., Nigrovic P.A. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol., 2020, vol. 72, pp. 1059–1063. doi: 10.1002/art.41285
  22. Kiselevskiy M., Shubina I., Chikileva I., Sitdikova S., Samoylenko I., Anisimova N., Kirgizov K., Suleimanova A., Gorbunova T., Varfolomeeva S. Immune pathogenesis of COVID-19 intoxication: storm or silence? Pharmaceuticals, 2020, vol. 13, no. 8: 166. doi: 10.3390/ph13080166
  23. Kiselevskiy M.V., Vlasenko R., Reshetnikova V., Chikileva I., Shubina I., Osmanov E., Valiev T., Sidorova N., Batmanova N., Stepanyan N., Kirgizov K., Varfolomeeva S. Mesenchymal multipotent cells for hemopoietic stem cell transplantation: pro and contra. J. Pediatr. Hematol. Oncol., 2021, vol. 43, no. 3, pp. 90–94. doi: 10.1097/MPH.0000000000002065
  24. Laterre P.F., François B., Collienne C., Hantson Ph., Jeannet R., Remy K.E., Hotchkiss R.S. Association of interleukin 7 immunotherapy with lymphocyte counts among patients with severe coronavirus disease 2019 (COVID-19). JAMA Netw Open, 2020, vol. 3, no. 7: e2016485. doi: 10.1001/jamanetworkopen.2020.16485
  25. Liu J., Li S., Liu J., Liang B., Wang X., Wang H., Li W., Tong Q., Yi J., Zhao L., Xiong Li., Guo Ch., Tian J., Luo J., Yao J., Pang R., Shen H., Peng Ch., Liu T., Zhang Q., Wu J., Xu Li., Lu S., Wang B., Weng Zh., Han Ch., Zhu H., Zhou R., Zhou H., Chen X., Ye P., Zhu B., Wang L., Zhou W., He Sh., He Y., Jie Sh., Wei P., Zhang J., Lu Y., Wang W., Zhang L., Li L., Zhou F., Wang J., Dittmer Ulf., Lu M., Hu Yu., Yang D., Zheng X. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. eBioMedicine, 2020, vol. 55: 102763 doi: 10.1016/j.ebiom.2020.102763
  26. Liu X., Shen Y., Wang H., Ge Q., Fei A., Pan S. Prognostic significance of neutrophil to lymphocyte ratio in patients with sepsis: a prospective observational study. Mediators Inflamm., 2016, vol. 2016: 8191254. doi: 10.1155/2016/8191254
  27. Lu L., Lan Q., Li Z., Zhou X., Gu J., Li Q., Wang J., Chen M., Liu Y., Shen Y., Brand D.D., Ryffel B., Horwitz D.A., Quismorio F.P., Liu Zh., Li B., Olsen N.J., Zheng S.G. Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc. Natl. Acad. Sci. USA, 2014, vol. 111, no. 33, pp. E3432–E3440. doi: 10.1073/pnas.1408780111
  28. Lu L., Zhou X., Wang J., Zheng S.G., Horwitz D.A. Characterization of protective human CD4CD25 FOXP3 regulatory T cells generated with IL-2, TGF-beta and retinoic acid. PLoS One, 2010, vol. 5, no. 12: e15150. doi: 10.1371/journal.pone.0015150
  29. Ma M., Badeti S., Chen C.H., Pinter A., Jiang Q., Shi L., Zhou R., Xu H., Li Q., Gause W., Liu D. CAR-NK Cells effectively target the D614 and G614 SARS-CoV-2-infected cells. bioRxiv, 2021: 426742. doi: 10.1101/2021.01.14.426742
  30. Ma M., Badeti S., Geng K., Liu D. Efficacy of targeting SARS-CoV-2 by CAR-NK cells. bioRxiv, 2020, vol. 8, no. 11: 247320. doi: 10.1101/2020.08.11.247320
  31. Mehrabadi A.Z., Ranjbar R., Farzanehpour M., Shahriary A., Dorostkar R., Hamidinejad M.A., Ghaleh H.E.G. Therapeutic potential of CAR T cell in malignancies: a scoping review. Biomed. Pharmacother., 2022, vol. 146: 112512. doi: 10.1016/j.biopha.2021.112512
  32. Nalos M., Santner-Nanan B., Parnell G., Tang B., McLean A.S., Nanan R. Immune effects of interferon gamma in persistent staphylococcal sepsis. Am. J. Respir. Crit. Care Med, 2012, vol. 185, no. 1, pp. 110–112 doi: 10.1164/ajrccm.185.1.110
  33. Qin C., Zhou L., Hu Z., Zhang S., Yang S., Tao Y., Xie C., Ma K., Shang K., Wang W., Tian D.S. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis., 2020, vol. 71, no. 15, pp. 762–768. doi: 10.1093/cid/ciaa248
  34. Rommasi F., Nasiri M.J., Mirsaeidi M. Immunomodulatory agents for COVID-19 treatment: possible mechanism of action and immunopathology features. Mol. Cell. Biochem., 2022, vol. 477, no. 3, pp. 711–726. doi: 10.1007/s11010-021-04325-9
  35. Rommasi А., Nasiri M.J., Mirsaeidi M. Immunomodulatory agents for COVID-19 treatment: possible mechanism of action and immunopathology features. Mol. Cell. Biochem., 2022, vol. 11, pp. 1–16. doi: 10.1007/s11010-021-04325-9
  36. Saha A., Sharma A.R., Bhattacharya M., Sharma G., Lee S.S., Chakraborty C. Tocilizumab: a therapeutic option for the treatment of cytokine storm syndrome in COVID-19. Arch. Med. Res., 2020, vol. 51, no. 6, pp. 595–597. doi: 10.1016/j.arcmed.2020.05.009
  37. Sakaguchi S., Miyara M., Costantino C.M., Hafler D.A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol., 2010, vol. 10, no. 7, pp. 490–500. doi: 10.1038/nri2785
  38. Shah V.K., Firmal P., Alam A., Ganguly D., Chattopadhyay S. Overview of immune response during SARS-CoV-2 infection: lessons from the past. Front. Immunol., 2020, vol. 7, no. 11: 1949. doi: 10.3389/fimmu.2020.01949
  39. Smolen J., Han C., Bala M., Maini R.N., Kalden J.R., van der Heijde D., Breedveld F.C., Furst D.E., Lipsky P.E. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti–tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum., 2005, vol. 52, no. 4, pp. 1020–1030. doi: 10.1002/art.20982
  40. Sohail A., Yu Z., Arif R., Nutini A., Nofal T.A. Piecewise differentiation of the fractional order CAR-T cells-SARS-2 virus model. Results Phys, 2022, vol. 33: 10504. doi: 10.1016/j.rinp.2021.105046
  41. Tan L., Wang Q., Zhang D., Ding J., Huang Q., Tang Y.Q., Wang Q. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct. Target. Ther., 2020, vol. 5, no. 1: 33. doi: 10.1038/s41392-020-0148-4
  42. Theoharides T., Conti P. Dexamethasone for COVID-19? Not so fast. J. Biol. Regul. Homeost. Agents, 2020, vol. 34, no. 3, pp. 1241–1243. doi: 10.23812/20-EDITORIAL_1-5
  43. Vanni G., Materazzo M., Dauri M., Farinaccio A., Buonomo C., Portarena I., Pellicciaro M., Legramante J.M., Rizza S., Chiaramonte C., Bellia A., Grande M., Potenza S., Sbordone F.P., Perrone M.A., Grimaldi F., Chiocchi M., Buonomo O.C. Lymphocytes, interleukin 6 and D-dimer cannot predict clinical outcome in coronavirus cancer patients: LyNC1.20 Study. Anticancer Res., 2021, vol. 41, no. 1, pp. 307–316. doi: 10.21873/anticanres.1
  44. Wang L., Chen J., Zhao J., Li F., Lu Sh., Liu P., Liu X., Huang Q., Wang H., Xu Q., Liu X., Yu Sh., Liu L., Lu H. The predictive role of lymphocyte subsets and laboratory measurements in COVID-19 disease: a retrospective study. Ther. Adv. Respir. Dis., 2021, vol. 15: 17534666211049739. doi: 10.1177/17534666211049739
  45. Wang Y., Zheng J., Islam Md S., Yang Y., Hu Y., Chen X. The role of CD4+FoxP3+ regulatory T cells in the immunopathogenesis of COVID-19: implications for treatment. Int. J. Biol. Sci., 2021, vol. 17, no. 6, pp. 1507–1520. doi: 10.7150/ijbs.59534
  46. Wen W., Su W., Tang H., Le W., Zhang X., Zheng Y., Liu X., Xie L., Li J., Ye J., Dong L., Cui X., Miao Y., Wang D., Dong J., Xiao C., Chen W., Wang H. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell. Discov., 2020, vol. 6: 31. doi: 10.1038/s41421-020-0168-9
  47. Xu X., Gao X. Immunological responses against SARS-coronavirus infection in humans. Cell. Mol. Immunol., 2004, vol. 1, no. 2, pp. 119–122.
  48. Yang X., Yu Y., Xu J., Shu H., Xia J., Liu H., Wu Y., Zhang L., Yu Z., Fang M., Yu T., Wang Y., Pan Sh., Zou X., Yuan Sh., Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet, 2020, vol. 8, no. 5, pp. 475–481. doi: 10.1016/S2213-2600(20)30079-5
  49. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Zh., Xiang J., Wang Y., Song B., Gu X., Guan L., Wei Y., Li H., Wu X., Xu J., Tu Sh., Zhang Y., Chen H., Cao B. Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, 2020, vol. 395, pp. 1054–1062. doi: 10.1016/S0140-6736(20)30566-3
  50. Zhou X., Kong N., Wang J., Fan H., Zou H., Horwitz D., Brand D., Liu Zh., Zheng S.G. Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J. Immunol., 2010, vol. 185, no. 5, pp. 2675–2679. doi: 10.4049/jimmunol.1000598

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