Progress in medical treatment of echinococcosis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HE Da ¹ , WU Jianli ² ,  LÜ Xiaoju ¹

1. Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Department of Cardiology, The First People’s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University), Chengdu 610200, P. R. China;

Corresponding author：

LÜ Xiaoju, Email: lvxj@scu.edu.cn

Keywords：

echinococcosis; hydatid disease; cystic echinococcosis; alveolar echinococcosis; albendazole; praziquantel; antiparasitic chemotherapy

DOI：

10.7507/1007-9424.202408118

Video：

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Echinococcosis was a zoonotic disease that seriously threatened human health. The disease was widely distributed in China, and was distributed in Tibet Autonomous Region, Qinghai Province, Xinjiang Uygur Autonomous Region, Sichuan Province, and other places, which had become a social and economic burden in China. Human beings were mainly infected with alveolar echinococcosis (AE) and cystic echinococcosis (CE), which mainly involved liver, lung, brain, bone and other organs or tissues. The surgical resection was the first line treatment, and antiparasitic agents therapy was the main supplementary or salvage treatment methods. Currently, classic drugs mainly included Albendazole and Praziquantel, which used alone or in combination. There were also some attempts to treat echinococcosis, including broad-spectrum anti infective drugs such as nitrozotocin, cell proliferation inhibiting drugs such as bortezomib, metabolic drugs such as metformin, or traditional medicines such as Artemisinin. It wss also suggested to adopt a cancer management model for echinococcosis, and the imaging follow-up time for CE after antiparasitic chemotherapy should be at least 3 years, and for AE should be at least 10 years. More importantly, measures such as education and vaccine inoculation should be taken to actively prevent and control the occurrence and spread of echinococcosis.

1.	Wen H, Vuitton L, Tuxun T, et al. Echinococcosis: advances in the 21st century. Clin Microbiol Rev, 2019, 32(2): e00075-e00018. doi: 10.1128/CMR.00075-18.
2.	Fu MH, Wang X, Han S, et al. Advances in research on echinococcoses epidemiology in China. Acta Trop, 2021, 219: 105921. doi: 10.1016/j.actatropica.2021.105921.
3.	Torgerson PR, Keller K, Magnotta M, et al. The global burden of alveolar echinococcosis. PLoS Negl Trop Dis, 2010, 4(6): e722. doi: 10.1371/journal.pntd.0000722.
4.	Horton J. Albendazole for the treatment of echinococcosis. Fundam Clin Pharmacol, 2003, 17(2): 205-212.
5.	WHO Informal Working Group on Echinococcosis. Guidelines for treatment of cystic and alveolar echinococcosis in humans. Bull World Health Organ, 1996, 74(3): 231-242.
6.	Brunetti E, Kern P, Vuitton DA, et al. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop, 2010, 114(1): 1-16.
7.	Whittaker C, Chesnais CB, Pion SDS, et al. Factors associated with variation in single-dose albendazole pharmacokinetics: A systematic review and modelling analysis. PLoS Negl Trop Dis, 2022, 16(10): e0010497. doi: 10.1371/journal.pntd.0010497.
8.	Chiodini PL. Medical management of cystic echinococcosis. Curr Opin Infect Dis, 2023, 36(5): 303-307.
9.	Richter J, Lindner AK, Geisel D, et al. Treatment of a giant hepatic echinococcal cyst with percutaneous drainage and in vivo assessment of the protoscolicidal effect of praziquantel. Clin J Gastroenterol, 2021, 14: 888-892.
10.	Hemphill A, Stadelmann B, Scholl S, et al. Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes. Parasitology, 2010, 137(3): 569-587.
11.	Stettler M, Rossignol JF, Fink R, et al. Secondary and primary murine alveolar echinococcosis: combined albendazole/nitazoxanide chemotherapy exhibits profound anti-parasitic activity. Int J Parasitol, 2004, 34(5): 615-624.
12.	Tappe D, Müller A, Frosch M, et al. Limitations of amphotericin B and nitazoxanide in the treatment of alveolar echinococcosis. Ann Trop Med Parasitol, 2009, 103(2): 177-181.
13.	Pérez-Molina JA, Díaz-Menéndez M, Gallego JI, et al. Evaluation of nitazoxanide for the treatment of disseminated cystic echinococcosis: report of five cases and literature review. Am J Trop Med Hyg, 2011, 84(2): 351-356.
14.	Reuter S, Merkle M, Brehm K, et al. Effect of amphotericin B on larval growth of Echinococcus multilocularis. Antimicrob Agents Chemother, 2003, 47(2): 620-625.
15.	Stadelmann B, Rufener R, Aeschbacher D, et al. Screening of the open source malaria box reveals an early lead compound for the treatment of alveolar echinococcosis. PLoS Negl Trop Dis, 2016, 10(3): e0004535. doi: 10.1371/journal.pntd.0004535.
16.	Autier B, Verger A, Plaisse C, et al. PLGA-PEG-COOH nanoparticles are efficient systems for delivery of mefloquine to Echinococcus multilocularis metacestodes. Exp Parasitol, 2024, 265: 108811. doi: 10.1016/j.exppara.2024.108811.
17.	Haby MM, Sosa Leon LA, Luciañez A, et al. Systematic review of the effectiveness of selected drugs for preventive chemotherapy for Taenia solium taeniasis. PLoS Negl Trop Dis, 2020, 14(1): e0007873. doi: 10.1371/journal.pntd.0007873.
18.	Yuan M, Luo Y, Xin Q, et al. Efficacy of osthole for Echinococcus granulosus in vitro and Echinococcus multilocularis in vivo. Vet Parasitol, 2016, 226: 38-43.
19.	Huang X, Wiehr S, Wild AM, et al. The effects of taxanes, vorinostat and doxorubicin on growth and proliferation of Echinococcus multilocularis metacestodes assessed with magnetic resonance imaging and simultaneous positron emission tomography. Oncotarget, 2018, 9(10): 9073-9087.
20.	Pensel PE, Albani C, Gamboa GU, et al. In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells. Acta Trop, 2014, 140: 1-9.
21.	Loos JA, Negro P, Cumino AC. In vitro anti-echinococcal activity of octreotide: Additive effect of metformin linked to autophagy. Acta Trop, 2020, 203: 105312. doi: 10.1016/j.actatropica.2019.105312.
22.	Enkai S, Inaoka DK, Kouguchi H, et al. Mitochondrial complex Ⅲ in larval stage of Echinococcus multilocularis as a potential chemotherapeutic target and in vivo efficacy of atovaquone against primary hydatid cysts. Parasitol Int, 2020, 75: 102004. doi: 10.1016/j.parint.2019.102004.
23.	Stadelmann B, Aeschbacher D, Huber C, et al. Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes. PLoS Negl Trop Dis, 2014, 8(12): e3352. doi: 10.1371/journal.pntd.0003352.
24.	Vaca HR, Celentano AM, Toscanini MA, et al. The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. PLoS Negl Trop Dis, 2021, 15: e0009226. doi: 10.1371/journal.pntd.0009226.
25.	Gao HJ, Sun XD, Luo YP, et al. Anti-echinococcal effect of verapamil involving the regulation of the calcium/calmodulin-dependent protein kinase Ⅱresponse in vitro and in a murine infection model. Parasit Vectors, 2021, 14(1): 108. doi: 10.1186/s13071-021-04618-4.
26.	Shiee MR, Kia EB, Zahabiun F, et al. In vitro effects of tropisetron and granisetron against Echinococcus granulosus (s.s.) protoscoleces by involvement of calcineurin and calmodulin. Parasit Vectors, 2021, 14(1): 197. doi: 10.1186/s13071-021-04691-9.
27.	Loos JA, Dávila VA, Brehm K, et al. Metformin suppresses development of the Echinococcus multilocularis larval stage by targeting the TOR pathway. Antimicrob Agents Chemother, 2020, 64(9): e01808-e01819. doi: 10.1128/AAC.01808-19.
28.	Loos JA, Churio MS, Cumino AC. Anthelminthic activity of glibenclamide on secondary cystic echinococcosis in mice. PLoS Negl Trop Dis, 2017, 11(11): e0006111. doi: 10.1371/journal.pntd.0006111.
29.	袁庆, 夏先明, 多吉, 等. 传统医学治疗棘球蚴病的研究进展. 西南军医, 2012, 14(2): 317-319.
30.	杨筱婉. 中西医结合治疗包虫病临床研究. 中医学报, 2016, 31(8): 1199-1202.
31.	Spicher M, Roethlisberger C, Lany C, et al. In vitro and in vivo treatments of echinococcus protoscoleces and metacestodes with artemisinin and artemisinin derivatives. Antimicrob Agents Chemother, 2008, 52(9): 3447-3450.
32.	Jafari A, Moazeni M, Hosseini SV, et al. Evaluation of the efficacy of Zataria multiflora essential oil versus albendazole in patients infected with liver cystic echinococcosis: A nonrandomized clinical trial. J Res Med Sci, 2021, 26: 120. doi: 10.4103/jrms.JRMS_950_19.
33.	Moghadaszadeh M, Khayyati M, Spotin A, et al. Scolicidal and apoptotic activities of 5-hydroxy-1, 4-naphthoquinone as a potent agent against Echinococcus granulosus protoscoleces. Pharmaceuticals (Basel), 2021, 14(7): 623. doi: 10.3390/ph14070623.
34.	崔紫烟, 冶赓博, 于文昊, 等. 阿苯达唑治疗多房棘球蚴病研究进展. 中国血吸虫病防治杂志, 2023, 35(1): 104-110.
35.	Pensel PE, Elissondo N, Gambino G, et al. Experimental cystic echinococcosis therapy: In vitro and in vivo combined 5-fluorouracil/albendazole treatment. Vet Parasitol, 2017, 245: 62-70.
36.	Laura C, Celina E, Sergio SB, et al. Combined flubendazole-nitazoxanide treatment of cystic echinococcosis: Pharmacokinetic and efficacy assessment in mice. Acta Trop, 2015, 148: 89-96.
37.	Rahdar M, Rafiei A, Valipour-Nouroozi R. The combination of cytokines and albendazole therapy for prophylaxis and treatment of experimental/hydatid cyst. Acta Trop, 2020, 201: 105206.
38.	Küster T, Stadelmann B, Hermann C, et al. In vitro and in vivo efficacies of mefloquine-based treatment against alveolar echinococcosis. Antimicrob Agents Chemother, 2011, 55(2): 713-721.
39.	Galitza Z, Bazarsky E, Sneier R, et al. Repeated treatment of cystic echinococcosis in patients with a long-term immunological response after successful surgical cyst removal. Trans R Soc Trop Med Hyg, 2006, 100(2): 126-133.
40.	Larrieu E, Zanini F. Critical analysis of cystic echinococcosis control programs and praziquantel use in South America, 1974–2010. Rev Panam Salud Publica, 2012, 31(1): 81-87.
41.	Zhang W, McManus DP. Vaccination of dogs against Echinococcus granulosus: a means to control hydatid disease?. Trends Parasitol, 2008, 24(9): 419-424.
42.	Petavy AF, Hormaeche C, Lahmar S, et al. An oral recombinant vaccine in dogs against Echinococcus granulosus, the causative agent of human hydatid disease: a pilot study. PLoS Negl Trop Dis, 2008, 2(1): e125. doi: 10.1371/journal.pntd.0000125.
43.	Umhang G, Lahoreau J, Hormaz V, et al. Surveillance and management of Echinococcus multilocularis in a wildlife park. Parasitol Int, 2016, 65(3): 245-250.

1. Wen H, Vuitton L, Tuxun T, et al. Echinococcosis: advances in the 21st century. Clin Microbiol Rev, 2019, 32(2): e00075-e00018. doi: 10.1128/CMR.00075-18.
2. Fu MH, Wang X, Han S, et al. Advances in research on echinococcoses epidemiology in China. Acta Trop, 2021, 219: 105921. doi: 10.1016/j.actatropica.2021.105921.
3. Torgerson PR, Keller K, Magnotta M, et al. The global burden of alveolar echinococcosis. PLoS Negl Trop Dis, 2010, 4(6): e722. doi: 10.1371/journal.pntd.0000722.
4. Horton J. Albendazole for the treatment of echinococcosis. Fundam Clin Pharmacol, 2003, 17(2): 205-212.
5. WHO Informal Working Group on Echinococcosis. Guidelines for treatment of cystic and alveolar echinococcosis in humans. Bull World Health Organ, 1996, 74(3): 231-242.
6. Brunetti E, Kern P, Vuitton DA, et al. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop, 2010, 114(1): 1-16.
7. Whittaker C, Chesnais CB, Pion SDS, et al. Factors associated with variation in single-dose albendazole pharmacokinetics: A systematic review and modelling analysis. PLoS Negl Trop Dis, 2022, 16(10): e0010497. doi: 10.1371/journal.pntd.0010497.
8. Chiodini PL. Medical management of cystic echinococcosis. Curr Opin Infect Dis, 2023, 36(5): 303-307.
9. Richter J, Lindner AK, Geisel D, et al. Treatment of a giant hepatic echinococcal cyst with percutaneous drainage and in vivo assessment of the protoscolicidal effect of praziquantel. Clin J Gastroenterol, 2021, 14: 888-892.
10. Hemphill A, Stadelmann B, Scholl S, et al. Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes. Parasitology, 2010, 137(3): 569-587.
11. Stettler M, Rossignol JF, Fink R, et al. Secondary and primary murine alveolar echinococcosis: combined albendazole/nitazoxanide chemotherapy exhibits profound anti-parasitic activity. Int J Parasitol, 2004, 34(5): 615-624.
12. Tappe D, Müller A, Frosch M, et al. Limitations of amphotericin B and nitazoxanide in the treatment of alveolar echinococcosis. Ann Trop Med Parasitol, 2009, 103(2): 177-181.
13. Pérez-Molina JA, Díaz-Menéndez M, Gallego JI, et al. Evaluation of nitazoxanide for the treatment of disseminated cystic echinococcosis: report of five cases and literature review. Am J Trop Med Hyg, 2011, 84(2): 351-356.
14. Reuter S, Merkle M, Brehm K, et al. Effect of amphotericin B on larval growth of Echinococcus multilocularis. Antimicrob Agents Chemother, 2003, 47(2): 620-625.
15. Stadelmann B, Rufener R, Aeschbacher D, et al. Screening of the open source malaria box reveals an early lead compound for the treatment of alveolar echinococcosis. PLoS Negl Trop Dis, 2016, 10(3): e0004535. doi: 10.1371/journal.pntd.0004535.
16. Autier B, Verger A, Plaisse C, et al. PLGA-PEG-COOH nanoparticles are efficient systems for delivery of mefloquine to Echinococcus multilocularis metacestodes. Exp Parasitol, 2024, 265: 108811. doi: 10.1016/j.exppara.2024.108811.
17. Haby MM, Sosa Leon LA, Luciañez A, et al. Systematic review of the effectiveness of selected drugs for preventive chemotherapy for Taenia solium taeniasis. PLoS Negl Trop Dis, 2020, 14(1): e0007873. doi: 10.1371/journal.pntd.0007873.
18. Yuan M, Luo Y, Xin Q, et al. Efficacy of osthole for Echinococcus granulosus in vitro and Echinococcus multilocularis in vivo. Vet Parasitol, 2016, 226: 38-43.
19. Huang X, Wiehr S, Wild AM, et al. The effects of taxanes, vorinostat and doxorubicin on growth and proliferation of Echinococcus multilocularis metacestodes assessed with magnetic resonance imaging and simultaneous positron emission tomography. Oncotarget, 2018, 9(10): 9073-9087.
20. Pensel PE, Albani C, Gamboa GU, et al. In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells. Acta Trop, 2014, 140: 1-9.
21. Loos JA, Negro P, Cumino AC. In vitro anti-echinococcal activity of octreotide: Additive effect of metformin linked to autophagy. Acta Trop, 2020, 203: 105312. doi: 10.1016/j.actatropica.2019.105312.
22. Enkai S, Inaoka DK, Kouguchi H, et al. Mitochondrial complex Ⅲ in larval stage of Echinococcus multilocularis as a potential chemotherapeutic target and in vivo efficacy of atovaquone against primary hydatid cysts. Parasitol Int, 2020, 75: 102004. doi: 10.1016/j.parint.2019.102004.
23. Stadelmann B, Aeschbacher D, Huber C, et al. Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes. PLoS Negl Trop Dis, 2014, 8(12): e3352. doi: 10.1371/journal.pntd.0003352.
24. Vaca HR, Celentano AM, Toscanini MA, et al. The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. PLoS Negl Trop Dis, 2021, 15: e0009226. doi: 10.1371/journal.pntd.0009226.
25. Gao HJ, Sun XD, Luo YP, et al. Anti-echinococcal effect of verapamil involving the regulation of the calcium/calmodulin-dependent protein kinase Ⅱresponse in vitro and in a murine infection model. Parasit Vectors, 2021, 14(1): 108. doi: 10.1186/s13071-021-04618-4.
26. Shiee MR, Kia EB, Zahabiun F, et al. In vitro effects of tropisetron and granisetron against Echinococcus granulosus (s.s.) protoscoleces by involvement of calcineurin and calmodulin. Parasit Vectors, 2021, 14(1): 197. doi: 10.1186/s13071-021-04691-9.
27. Loos JA, Dávila VA, Brehm K, et al. Metformin suppresses development of the Echinococcus multilocularis larval stage by targeting the TOR pathway. Antimicrob Agents Chemother, 2020, 64(9): e01808-e01819. doi: 10.1128/AAC.01808-19.
28. Loos JA, Churio MS, Cumino AC. Anthelminthic activity of glibenclamide on secondary cystic echinococcosis in mice. PLoS Negl Trop Dis, 2017, 11(11): e0006111. doi: 10.1371/journal.pntd.0006111.
29. 袁庆, 夏先明, 多吉, 等. 传统医学治疗棘球蚴病的研究进展. 西南军医, 2012, 14(2): 317-319.
30. 杨筱婉. 中西医结合治疗包虫病临床研究. 中医学报, 2016, 31(8): 1199-1202.
31. Spicher M, Roethlisberger C, Lany C, et al. In vitro and in vivo treatments of echinococcus protoscoleces and metacestodes with artemisinin and artemisinin derivatives. Antimicrob Agents Chemother, 2008, 52(9): 3447-3450.
32. Jafari A, Moazeni M, Hosseini SV, et al. Evaluation of the efficacy of Zataria multiflora essential oil versus albendazole in patients infected with liver cystic echinococcosis: A nonrandomized clinical trial. J Res Med Sci, 2021, 26: 120. doi: 10.4103/jrms.JRMS_950_19.
33. Moghadaszadeh M, Khayyati M, Spotin A, et al. Scolicidal and apoptotic activities of 5-hydroxy-1, 4-naphthoquinone as a potent agent against Echinococcus granulosus protoscoleces. Pharmaceuticals (Basel), 2021, 14(7): 623. doi: 10.3390/ph14070623.
34. 崔紫烟, 冶赓博, 于文昊, 等. 阿苯达唑治疗多房棘球蚴病研究进展. 中国血吸虫病防治杂志, 2023, 35(1): 104-110.
35. Pensel PE, Elissondo N, Gambino G, et al. Experimental cystic echinococcosis therapy: In vitro and in vivo combined 5-fluorouracil/albendazole treatment. Vet Parasitol, 2017, 245: 62-70.
36. Laura C, Celina E, Sergio SB, et al. Combined flubendazole-nitazoxanide treatment of cystic echinococcosis: Pharmacokinetic and efficacy assessment in mice. Acta Trop, 2015, 148: 89-96.
37. Rahdar M, Rafiei A, Valipour-Nouroozi R. The combination of cytokines and albendazole therapy for prophylaxis and treatment of experimental/hydatid cyst. Acta Trop, 2020, 201: 105206.
38. Küster T, Stadelmann B, Hermann C, et al. In vitro and in vivo efficacies of mefloquine-based treatment against alveolar echinococcosis. Antimicrob Agents Chemother, 2011, 55(2): 713-721.
39. Galitza Z, Bazarsky E, Sneier R, et al. Repeated treatment of cystic echinococcosis in patients with a long-term immunological response after successful surgical cyst removal. Trans R Soc Trop Med Hyg, 2006, 100(2): 126-133.
40. Larrieu E, Zanini F. Critical analysis of cystic echinococcosis control programs and praziquantel use in South America, 1974–2010. Rev Panam Salud Publica, 2012, 31(1): 81-87.
41. Zhang W, McManus DP. Vaccination of dogs against Echinococcus granulosus: a means to control hydatid disease?. Trends Parasitol, 2008, 24(9): 419-424.
42. Petavy AF, Hormaeche C, Lahmar S, et al. An oral recombinant vaccine in dogs against Echinococcus granulosus, the causative agent of human hydatid disease: a pilot study. PLoS Negl Trop Dis, 2008, 2(1): e125. doi: 10.1371/journal.pntd.0000125.
43. Umhang G, Lahoreau J, Hormaz V, et al. Surveillance and management of Echinococcus multilocularis in a wildlife park. Parasitol Int, 2016, 65(3): 245-250.

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