A Review on the Toxic Effects of Medicines used in Corona Virus Disease 2019 (COVID-19) Treatment

Yıl 2022, Cilt: 2 Sayı: 1, 1 - 10, 29.01.2022

Aysegul Özlü , Gökçe Taner , Nizameddin Koca

Öz

The novel coronavirus disease 2019 pandemic is affecting all around the world, particularly healthcare systems. The most critical problem for the COVID-19 infection as an emerging acute respiratory disease is the lack of effective methods to control and treat the disease. To date, there is no specific therapeutic agent approved by the FDA, so treatment options are limited. There are more than 4034 interventional studies in progress listed in clinicaltrials.org (Access date: 21.12.2021). This number was 900 approximately in December 2020. These intensive studies, which have increased fourfold, are to find a safe and effective treatment method. Since absolute therapy has not been standardized globally, the treatment approach varies from country to country and even from hospital to hospital. In addition to the vaccine studies that have been finalized and the vaccines are available for use, additional studies are underway for existing drugs that can prevent this disease or improve outcomes for COVID patients. The potential toxicity of the drugs chosen for the treatment is one of the more critical limiting factors. Although the side effects of previously approved medicines are known, studies are needed to determine the side effect profiles for newly approved products such as remdesivir.
In this review, we gathered the adverse and toxic effects of medications used against COVID-19 treatment according to the COVID guideline published by the Scientific Advisory Board of the Ministry of Health of Turkey.

Anahtar Kelimeler

Coronavirus disease 2019 (COVID-19), SARS-CoV-2; medicines, remdesivir, anakinra, tocilizumab, favipiravir, hydroxychloroquine, convalescent plasma, toxic effects, adverse effects

Kaynakça

• 1. Ahn, J. Y., Sohn, Y., Lee, S. H., Cho, Y., Hyun, J. H., Baek, Y. J., Jeong, S. J., Kim, J. H., Ku, N. S., Yeom, J. S., Roh, J., Ahn, M. Y., Chin, B. S., Kim, Y. S., Lee, H., Yong, D., Kim, H. O., Kim, S., & Choi, J. Y. (2020). Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea. Journal of Korean medical science, 35(14), e149. https://doi.org/10.3346/jkms.2020.35.e149
• 2. Bakheit, A. H. H., Al-Hadiya, B. M. H., & Abd-Elgalil, A. A. (2014). Azithromycin. Profiles of Drug Substances, Excipients and Related Methodology (Vol. 39). https://doi.org/10.1016/B978-0-12-800173-8.00001-5
• 3. Baldo, B. A. (2014). Drugs that act on the immune system: Cytokines and monoclonal antibodies. Side Effects of Drugs Annual (Vol. 36). Elsevier. https://doi.org/10.1016/B978-0-444-63407-8.00037-X
• 4. Bartoletti, M., Azap, O., Barac, A., Bussini, L., Ergonul, O., Krause, R., Paño-Pardo, J. R., Power, N. R., Sibani, M., Szabo, B. G., Tsiodras, S., Verweij, P. E., Zollner-Schwetz, I., & Rodríguez-Baño, J. (2021). ESCMID COVID-19 Living guidelines: drug treatment and clinical management. Clinical Microbiology and Infection. https://doi.org/10.1016/j.cmi.2021.11.007
• 5. Blood and Blood Products Department, Ministry of Health of Turkey (2020). The Guide Of Immune Plasma Supply and Clinical Use, Retrived from; https://dosyamerkez.saglik.gov.tr/Eklenti/37341,covid-19-immun-konvalesan-plazma-tedarik-ve-klinik-kullanim-rehberi-guncel--r1-v1pdf.pdf?0
• 6. Browning DJ. Pharmacology of chloroquine and hydroxychloroquine. In: Hydroxychloroquine and Chloroquine Retinopathy. New York: Springer, 2014:35-63. https://doi.org/10.1007/978-1-49390597-3_2
• 7. Buxeda, A., Arias-Cabrales, C., Pérez-Sáez, M. J., Cacho, J., Cabello Pelegrin, S., Melilli, E., Aladrén, M. J., Galeano, C., Lorenzo, I., Mazuecos, A., Saura, I. M., Franco, A., Ruiz-Fuentes, M. del C., Sánchez-Cámara, L. A., Siverio, O., Martin, M. L., González-García, E., López, V., Martin-Moreno, P. L., … Crespo, M. (2021). Use and Safety of Remdesivir in Kidney Transplant Recipients With COVID-19. Kidney International Reports, 6(9), 2305–2315. https://doi.org/10.1016/j.ekir.2021.06.023
• 8. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M., Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L., Li, C., … Wang, C. (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. The New England Journal of Medicine, 1787–1799. https://doi.org/10.1056/NEJMoa2001282
• 9. Capra, R., Rossi, N. De, Mattioli, F., Romanelli, G., Scarpazza, C., Pia, M., & Cossi, S. (2020). Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. European Journal of Internal Medicine, April, 1–5. https://doi.org/10.1016/j.ejim.2020.05.009
• 10. Charest, D. M., Krogsgard, E. S., & Thomason, A. R. (2010). A Patient Case: Intravenous Azithromycin-Induced Hepatotoxicity. Hospital Pharmacy, 45(7), 545–548. https://doi.org/10.1310/hpj4507-545
• 11. Chary, M. A., Barbuto, A. F., Izadmehr, S., Hayes, B. D., & Burns, M. M. (2020). COVID-19: Therapeutics and Their Toxicities. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 1–11. Advance online publication. https://doi.org/10.1007/s13181-020-00777-5
• 12. Chen, L., Xiong, J., Bao, L., & Shi, Y. (2020). Convalescent plasma as a potential therapy for COVID-19. The Lancet. Infectious diseases, 20(4), 398–400. https://doi.org/10.1016/S1473-3099(20)30141-9
• 13. Chong, Y. P., Song, J. Y., Seo, Y. Bin, Choi, J. P., Shin, H. S., Yoon, H. J., Choi, J. Y., Kim, T. H., Choi, Y. H., Kim, H. Bin, Yoon, J. H., Lee, J., Eom, J. S., Song, J. Y., Lee, S. O., Oh, W. S., Cheong, H. J., Song, Y. G., Choi, J. H., & Kim, W. J. (2015). Antiviral treatment guidelines for middle east respiratory syndrome. Infection and Chemotherapy, 47(3), 212–222. https://doi.org/10.3947/ic.2015.47.3.212
• 14. Colson, P., Rolain, J. M., & Raoult, D. (2020). Chloroquine for the 2019 novel coronavirus SARS-CoV-2. International Journal of Antimicrobial Agents, 55(3), 105923. https://doi.org/10.1016/j.ijantimicag.2020.105923
• 15. Colson, P., Rolain, J. M., Lagier, J. C., Brouqui, P., & Raoult, D. (2020). Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. International Journal of Antimicrobial Agents, 55(4), 105932. https://doi.org/10.1016/j.ijantimicag.2020.105932
• 16. Cristina de la Calle, C., López-Medrano, F., Pablos, J. L., Lora-Tamayo, J., Maestro-de la Calle, G., Sánchez-Fernández, M., Fernández-Ruiz, M., Pérez-Jacoiste Asín, M. A., Caro-Teller, J. M., García-García, R., Catalán, M., Martínez-López, J., Sevillano, Á., Origüen, J., Ripoll,… Aguado, J. M. (2021). Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: A single-centre retrospective comparative study. International Journal of Infectious Diseases, 105, 319–325. https://doi.org/10.1016/j.ijid.2021.02.041
• 17. Crouch, M., Limon, L., & Cassano, A. (2002). Clinical relevance and management of drug-related QT interval prolongation. Pharmacotherapy, 23:881-908.
• 18. Cunningham, A.C., Goh, H.P. & Koh, D. Treatment of COVID-19: old tricks for new challenges. Critical Care 24, 91 (2020). https://doi.org/10.1186/s13054-020-2818-6
• 19. Cvetkovic, RS, Goa, KL Lopinavir/Ritonavir. Drugs 63, 769–802 (2003). https://doi.org/10.2165/00003495-200363080-00004
• 20. Devaux, C. A., Rolain, J. M., Colson, P., & Raoult, D. (2020). New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. International Journal of Antimicrobial Agents, 105938. Advance online publication. https://doi.org/10.1016/j.ijantimicag.2020.105938
• 21. Drug Information Database. (2020, April 24). Lopinavir/ritonavir Drug Monograph. https://www.elsevier.com/tr-tr/solutions/drug-database
• 22. Drug Information Database. (2020, April 24). Tocilizumab Drug Monograph. https://www.elsevier.com/tr-tr/solutions/drug-database
• 23. Dzik S. (2020). COVID-19 Convalescent Plasma: Now Is the Time for Better Science. Transfusion Medicine Reviews, S0887-7963(20)30026-2. Advance online publication. https://doi.org/10.1016/j.tmrv.2020.04.002
• 24. Easterbrook, M., (1993). The ocular safety of hydroxychloroquine. Seminars in Arthritis and Rheumatism (Vol. 23, No. 2, pp. 62-67). https://doi.org/10.1016/S0049-0172(10)80009-5
• 25. FDA / CDER. (2017). Plaquenil ® Hydroxychloroquine Sulfate Tablets, USP Description. FDA. Retrieved from http://www.cdc.gov/malaria
• 26. FDA. (2020, May 1). FDA News Release: (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment).
• 27. FDA. (2021). FDA. Kineret Prescribing Information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf
• 28. Furuta, Y., Komeno, T., & Nakamura, T. (2017). Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 93(7), 449–463. https://doi.org/10.2183/pjab.93.027
• 29. Gabay, C (2012), Biologic Agents, Goldman's Cecil Medicine (Twenty Fourth Edition), W.B. Saunders, Pages 165-168, https://doi.org/10.1016/B978-1-4377-1604-7.00035-X.
• 30. Gautret, P., Lagier, J. C., Parola, P., Hoang, V. T., Meddeb, L., Mailhe, M., Doudier, B., Courjon, J., Giordanengo, V., Vieira, V. E., Dupont, H. T., Honoré, S., Colson, P., Chabrière, E., La Scola, B., Rolain, J. M., Brouqui, P., & Raoult, D. (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents, 105949. Advance online publication. https://doi.org/10.1016/j.ijantimicag.2020.105949
• 31. Gold Standart. (2021). Remdesivir Drug Monograph
• 32. González-Requena, D., Núñez, M., Jiménez-Nacher, I., González-Lahoz, J., & Soriano, V. (2004). Liver toxicity of lopinavir-containing regimens in HIV-infected patients with or without hepatitis C coinfection. AIDS Research and Human Retroviruses, 20(7), 698-700.
• 33. Jean, S.-S., Lee, P.-I., & Hsueh, P.-R. (2020). Treatment options for COVID-19: the reality and challenges. Journal of Microbiology, Immunology and Infection, xxxx. https://doi.org/10.1016/j.jmii.2020.03.034
• 34. Jin, Z., Tucker, K., Lin, X., Kao, C. C., Shaw, K., Tan, H., Symons, J., Behera, I., Rajwanshi, V. K., Dyatkina, N., Wang, G., Beigelman, L., & Deval, J. (2015). Biochemical Evaluation of the Inhibition Properties of Favipiravir and 2'-C-Methyl-Cytidine Triphosphates against Human and Mouse Norovirus RNA Polymerases. Antimicrobial Agents and Chemotherapy, 59(12), 7504–7516. https://doi.org/10.1128/AAC.01391-15
• 35. Kapoor, A., Pandurangi, U., Arora, V., Gupta, A., Jaswal, A., Nabar, A., Naik, A., Naik, N., Namboodiri, N., Vora, A., Yadav, R., & Saxena, A. (2020). Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society. Indian Pacing and Electrophysiology Journal. https://doi.org/10.1016/J.IPEJ.2020.04.003
• 36. Kyriazopoulou, E., Huet, T., Cavalli, G., Gori, A., Kyprianou, M., Pickkers, P., Eugen-Olsen, J., Clerici, M., Veas, F., Chatellier, G., Kaplanski, G., Netea, M. G., Pontali, E., Gattorno, M., Cauchois, R., Kooistra, E., Kox, M., Bandera, A., Beaussier, H., … Selmi, C. (2021). Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis. The Lancet Rheumatology, 3(10), e690–e697. https://doi.org/10.1016/S2665-9913(21)00216-2
• 37. L. Delang, R. Abdelnabi, J. Neyts. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Research, 153 (2018), pp. 85-94, https://doi.org/10.1016/j.antiviral.2018.03.003.
• 38. Lane, J. C., Weaver, J., Kostka, K., Duarte-Salles, T., Abrahao, M. T. F., Alghoul, H., ... & Casajust, P. (2020). Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study medRxiv 2020.04.08.20054551. https://doi.org/10.1101/2020.04.08.20054551
• 39. Leung, L.-S. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., & Marmor, M. F. (2015). Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American Journal of Ophthalmology, 160(4), 799-805.e1. https://doi.org/10.1016/J.AJO.2015.07.012
• 40. Li, H., Liu, D., Chen, L., Zhao, Q., Yu, Y., Ding, J., Miao, L., Xiao, Y., & Cai, H. (2014). Meta-Analysis of the Adverse Effects of Long-Term Azithromycin Use in Patients with Chronic Lung Diseases. 58(1), 511–517. https://doi.org/10.1128/AAC.02067-13
• 41. Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment. Annals of Internal Medicine 2006;145(8):599–609. https://doi.org/10.7326/0003-4819-145-8-200610170-00139
• 42. MacLennan S, Barbara JA. Risks and side effects of therapy with plasma and plasma fractions. Best Practice & Research Clinical Haematology 2006;19(1):169–189. https://doi.org/10.1016/j.beha.2005.01.033
• 43. Marquardt, K., & Albertson, T. E. (2001). Treatment of hydroxychloroquine overdose. The American Journal of Emergency Medicine, 19(5), 420–424. https://doi.org/10.1053/AJEM.2001.25774
• 44. Martinez, M. A., Vuppalanchi, R., Fontana, R. J., Stolz, A., Kleiner, D. E., Hayashi, P. H., Gu, J., Hoofnagle, J. H., & Chalasani, N. (2015). Clinical and histologic features of azithromycin-induced liver injury. Clinical Gastroenterology and Hepatology 13(2), 369–376.e3. https://doi.org/10.1016/j.cgh.2014.07.054
• 45. Mavrikakis, M., Papazoglou, S., Sfikakis, P. P., Vaiopoulos, G., & Rougas, K. (1996). Retinal toxicity in long term hydroxychloroquine treatment. Annals of the Rheumatic Diseases, 55(3), 187–189. https://doi.org/10.1136/ard.55.3.187
• 46. McMullan, B. J., & Mostaghim, M. (2015). Prescribing azithromycin. Australian Prescriber, 38(3), 87–89. https://doi.org/10.18773/austprescr.2015.030
• 47. Morrison, A. R., Johnson, J. M., Ramesh, M., Bradley, P., Jennings, J., & Smith, Z. R. (2020). Letter to the Editor: Acute hypertriglyceridemia in patients with COVID‐19 receiving tocilizumab. Journal of Medical Virology. https://doi.org/10.1002/jmv.25907
• 48. Nagata, T., Lefor, A., Hasegawa, M., & Ishii, M. (2015). Favipiravir: A New Medication for the Ebola Virus Disease Pandemic. Disaster Medicine and Public Health Preparedness, 9(1), 79-81. https://doi.org/10.1017/dmp.2014.151
• 49. National Institute of Health. (2021). https://clinicaltrials.gov/ct2/show/NCT04600895
• 50. Parnham, M. J., Haber, V. E., Giamarellos-Bourboulis, E. J., Perletti, G., Verleden, G. M., & Vos, R. (2014). Azithromycin: Mechanisms of action and their relevance for clinical applications. Pharmacology and Therapeutics, 143(2), 225–245. https://doi.org/10.1016/j.pharmthera.2014.03.003
• 51. Pasin, L., Cavalli, G., Navalesi, P., Sella, N., Landoni, G., Yavorovskiy, A. G., Likhvantsev, V. V., Zangrillo, A., Dagna, L., & Monti, G. (2021). Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies. European Journal of Internal Medicine, 86(February), 34–40. https://doi.org/10.1016/j.ejim.2021.01.016
• 52. Qianqian Fan, B. Z. J. M. S. Z. (2020). Safety profile of the antiviral drug remdesivir: An update. Biomedicine & Pharmacotherapy, 130(January), 1–3.
• 53. Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. New England Journal of Medicine. 1988 January 7;318(1):1–6. DOI: 10.1056/NEJM198801073180101
• 54. Roden, D. (2004). Drug-induced prolongation of the QT interval. New Engl J Med, 350:1013-22.
• 55. Sanders, J. M., Monogue, M. L., Jodlowski, T. Z., & Cutrell, J. B. (2020). Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA Journal of the American Medical Association, 2019. https://doi.org/10.1001/jama.2020.6019
• 56. Schroeder, R. L., & Gerber, J. P. (2014). Chloroquine and hydroxychloroquine binding to melanin: Some possible consequences for pathologies. Toxicology Reports, 1, 963–968. https://doi.org/10.1016/J.TOXREP.2014.10.019
• 57. Scientific Advisory Board, Ministry of Health of Turkey (2021). 2019-nCoV Disease Guide,
• 58. Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. https://doi.org/10.1016/S2213-2600(13)70038-9 59. Shah, S., Ackley, T. W., & Topal, J. E. (2021). Renal and hepatic toxicity analysis of remdesivir formulations: Does what is on the inside really count? Antimicrobial Agents and Chemotherapy, 65(10), 1–5. https://doi.org/10.1128/AAC.01045-21
• 60. Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., … Liu, L. (2020). Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. JAMA - Journal of the American Medical Association, 323(16), 1582–1589. https://doi.org/10.1001/jama.2020.4783
• 61. Silva-Vergara, Mario León, Silva, Luciana de Almeida, Maneira, Frederico Ricardo Zago, Silva, Achilles Gustavo da, & Prata, Aluízio. (2004). Azithromycin in the treatment of mucosal leishmaniasis. Revista do Instituto de Medicina Tropical de São Paulo, 46(3), 175-177. https://dx.doi.org/10.1590/S0036-46652004000300011
• 62. Silvergleid, A., Kleinman, S., & Tirnauer, J. (2020, May 2). Clinical use of plasma components. UptoDate: https://www.uptodate.com/contents/clinical-use-of-plasma-components
• 63. Smither, S. J., Eastaugh, L. S., Steward, J. A., Nelson, M., Lenk, R. P., & Lever, M. S. (2014). Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Research, 104, 153-155. https://doi.org/10.1016/j.antiviral.2014.01.012
• 64. Somagutta, M. K. R., Pormento, M. K. L., Hamid, P., Hamdan, A., Khan, M. A., Desir, R., Vijayan, R., Shirke, S., Jeyakumar, R., Dogar, Z., Makkar, S. S., Guntipalli, P., Ngardig, N. N., Nagineni, M. S., Paul, T., Luvsannyam, E., Riddick, C., & Sanchez-Gonzalez, M. A. (2021). The safety and efficacy of anakinra, an interleukin-1 antagonist in severe cases of covid-19: A systematic review and meta-analysis. Infection and Chemotherapy, 53(January), 221–237. https://doi.org/10.3947/IC.2021.0016
• 65. Takashita, E., Ejima, M., Ogawa, R., Fujisaki, S., Neumann, G., Furuta, Y., ... & Odagiri, T. (2016). Antiviral susceptibility of influenza viruses isolated from patients pre-and post-administration of favipiravir. Antiviral Research, 132, 170-177. https://doi.org/10.1016/j.antiviral.2016.06.007
• 66. Tutuncu, Z., & Kavanaugh, A. (2017). Anti-cytokine Therapies. Kelley and Firestein's Textbook of Rheumatology (Tenth Edit). Elsevier Inc. https://doi.org/10.1016/b978-0-323-31696-5.00063-2
• 67. Wang LS, Wang YR, Ye DW, Liu QQ. (2020) A review of the 2019 Novel Coronavirus (COVID-19) based on current evidence. International Journal of Antimicrobial Agents. https://doi.org/10.1016/j.ijantimicag.2020.105948
• 68. Wang, Y., Zhang, D., Du, P. G., Du, P. R., Zhao, P. J., Jin, P. Y., Fu, P. S., Gao, P. L., Cheng, P. Z., Lu, P. Q., Hu, P. Y., Luo, P. G., Wang, P. K., Lu, P. Y., Li, H., Ms, S. W., Ms, S. R., Yang, C., Mei, C., … Wang, P. C. (2020). Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet, 6736(20), 1–10. https://doi.org/10.1016/S0140-6736(20)31022-9
• 69. Yao, T. T., Qian, J. D., Zhu, W. Y., Wang, Y., & Wang, G. Q. (2020). A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus—A possible reference for coronavirus disease-19 treatment option. Journal of Medical Virology, 92(6), 556–563. https://doi.org/10.1002/jmv.25729
• 70. Ye, Q., Wang, B., & Mao, J. (2020). The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. Journal of Infection. https://doi.org/10.1016/J.JINF.2020.03.037
• 71. Young, B., Tan, T. T., & Leo, Y. S. (2021). The place for remdesivir in COVID-19 treatment. The Lancet Infectious Diseases, 21(1), 20–21. https://doi.org/10.1016/S1473-3099(20)30911-7
• 72. Zhang, B., Liu, S., Tan, T., Huang, W., Dong, Y., Chen, L., Chen, Q., Zhang, L., Zhong, Q., Zhang, X., Zou, Y., & Zhang, S. (2020). Treatment With Convalescent Plasma for Critically Ill Patients With SARS-CoV-2 Infection. Chest, S0012-3692(20)30571-7. Advance online publication. https://doi.org/10.1016/j.chest.2020.03.039
• 73. Zhou, M., Zhang, X., & Qu, J. (2020). Coronavirus disease 2019 (COVID-19): a clinical update. Frontiers of medicine, 14(2), 126–135. https://doi.org/10.1007/s11684-020-0767-8