COVID-19 medical therapy: Difference between revisions
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[[COVID-19]] is an inflammatory [[hypercytokinemia]] disease. The aim of therapy is prevention of [[viral replication]] and controlling the [[inflammatory]] process. <br /> | [[COVID-19]] is an inflammatory [[hypercytokinemia]] disease. The aim of therapy is prevention of [[viral replication]] and controlling the [[inflammatory]] process. <br /> | ||
== | == Antiviral Agents == | ||
=== Remdesivir === | === Remdesivir === | ||
| Line 74: | Line 74: | ||
* A clinical trial is investigating the efficacy of combination between [[Oseltamivir]] with [[chloroquine]] and [[favipiravir]] .<ref name="pmid32256547">{{cite journal |vauthors=Rosa SGV, Santos WC |title=Clinical trials on drug repositioning for COVID-19 treatment |journal=Rev. Panam. Salud Publica |volume=44 |issue= |pages=e40 |date=2020 |pmid=32256547 |pmc=7105280 |doi=10.26633/RPSP.2020.40 |url=}}</ref> | * A clinical trial is investigating the efficacy of combination between [[Oseltamivir]] with [[chloroquine]] and [[favipiravir]] .<ref name="pmid32256547">{{cite journal |vauthors=Rosa SGV, Santos WC |title=Clinical trials on drug repositioning for COVID-19 treatment |journal=Rev. Panam. Salud Publica |volume=44 |issue= |pages=e40 |date=2020 |pmid=32256547 |pmc=7105280 |doi=10.26633/RPSP.2020.40 |url=}}</ref> | ||
== | == Supportive Agents == | ||
===[[Azithromycin]]=== | ===[[Azithromycin]]=== | ||
Revision as of 12:26, 30 July 2020
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COVID-19 medical therapy On the Web |
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American Roentgen Ray Society Images of COVID-19 medical therapy |
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Risk calculators and risk factors for COVID-19 medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Sabawoon Mirwais, M.B.B.S, M.D.[3] Sara Zand, M.D.[4]
Overview
COVID-19 is an inflammatory hypercytokinemia disease. The aim of therapy is prevention of viral replication and controlling the inflammatory process.
Antiviral Agents
Remdesivir
- Remdesivir is a prodrug and inhibits viral RNA polymerase when intracellularly metabolized to an ATP analog.
- Effects of remdesivir in COVID-19 include :[2] 1.Significant reduction in viral load in bronchoaleolar lavage 2.Inhibition of SARS-COV-2 replication in nasal and bronchial airway epithelial cells.
- Remdesivir Indicates only for in-hospital setting in Severe COVID-19 disease.
Contraindications of remdesivir include :
- Severe renal impairment (eGFR <30 ml/min)
- Severe hepatic dysfunction or alanin transferase (ALT)ᐳ 5-times upper limit
Hydroxychloroquine and Chloroquine
- Hydroxychloroquine has been effective in graft versus host disease ,lupus erythematosus, rheumatoid arthritis, and malaria
- In the begining of COVID-19 pandemic ,Hydroxychloroquine was used due to inhibition of the entry of SARS-COV-2 and prevention of the fusion of viral spike protein to ACE2 receptor and reduction of cytokine storm.
- Intracellular uptake of hydroxychloroquine was enhanced with combination with Zinc.[3]
- Hydroxychloroquine has cardiac side effects due to QT prolongation effect.
- Efficacy of remdesivir is reduced in combination with hydroxychroroquine.
- Due to cardiac side effects, Recently FDA dissapproved the emergency use authorization of hydroxychloroquine if clinical trials are unavailable.
- Lopinavir-Ritonavir Inhibits the activity of the HIV-1 protease.
- There is no benefit in the administration of lopinavir-ritonavir in COVID-19.
- In an open-label randomized controlled trial, the comparison between patients with COVID-19 received either lopinavir-ritonavir 400/100 mg, orally twice daily plus standard of care or standard care alone showed no benefit of administration of lopinavir-ritonavir[4]
- Only one study in Korea in the initial phase of outbreak accepted using this combination.[5]
- Side effects: Diarrhea, nausea, asthenia
Umifenovir (Arbidol)
- Umifenovir has been used in treatment of Ebola virus, human herpesvirus 8 (HHV-8), hepatitis C virus (HCV), and Tacaribe arenavirus, influenza A,B [6]
- Mechanism of action: inhibition of the virus fusion to the cell membrane and hydrogen binding to membrance phospholipids.[7]
- In a retrospective cohort study showed improvement in chest ct scan of COVID-19 patients received a combination of umifenovir and lopinavir-ritonavir.[8]
- In prospective study, umifenovir had inferior outcomes in clinical recovery rate and relief of fever and cough compared with favipiravir[9]
- Safety and efficacy in COVID-19 is under investigation in china with two randomized open trials.
Favipiravir (Avigan)
- Favipiravir has been used in 2014 in Japan for the treatment of influenza resistant to neuraminidase inhibitors and has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, and norovirus [10] [11]
- Mechanism of action: after entering the infected cells and being phosphorylated, inhibits viral RNA replication.
- SARS-CoV-2 is an enveloped, positive-sense, single-strand RNA virus and studies showed the efficacy of favipiravir on SARS-COV-2.
- A randomized control trial has shown that COVID-19 patients treated with favipiravir have superior recovery rate (71.43%) than that treated with umifenovir (55.86%), and the duration of fever and cough relief time are significantly shorter in favipiravir group than in umifenovir group [9]
- Two randomized and nonrandomized controlled trials are evaluating the safety and efficacy of favipiravir for treatment of COVID-19 disease.
Oseltamivir (Tamiflu)
- Oseltamivir has been approved for the treatment of influenza A,B viruses and inhibits neuraminidase glygoprotein which is essential for replication of influenza A and B viruses[12]
- The study in wohan showed no positive outcomes were observed in COVID-19 patients after recieving osetamivir[13]
- A clinical trial is investigating the efficacy of combination between Oseltamivir with chloroquine and favipiravir .[14]
Supportive Agents
Azithromycin
- Azithromycin has been effective in the treatment of Zika and Ebola viruses and prevented severe respiratory tract infection[15]
- Mechanism of action is binding to 50S subunit of the bacteria ribosom,then inhibition of translation of mRNA.
- Effects of azithromycin in treatment of viral respiratory tract infection include:1. antibacterial coverage 2.immunomodulatory and anti-inflammatory effects. [16]
- Many trials in COVID-19 patients showed the effectiveness of azithromycin combined with hydroxychloroquine.
- A trial in france reported %100 viral clearance in nasopharengeal swap after recieving hydroxychloroquine with azithromycin [16]
- Data about benefits of azithromycin in COVID-19 disease is still inadequate and needs further evaluation.
Vitamin C (Ascorbic Acid)
Effects of Vitamin C in viral agents include:[17]
- Maturation of T lymphocytes and NK( natural killer) cells which are involved in the immune response to viral agents.
- Inhibition of reactive oxygen species (ROS) production
- Remodulation of the cytokine network in systemic inflammatory syndrome.
Study in COVID-19 patients in china showed administration of high dose IV,Vitamin C (1500mg per day) in moderate and severe cases was correlated with improvement in oxygenation indexes and recovery .[18]
Corticosteroids
- Effects of Low doses of methylprednisolone in COVID-19 include:[19][20]
- Controlled of hypercytokinemia
- Anti-inflammatory effect in superimposed infection in COVID-19
- Increased blood pressure when it is low
2.Effects of dexamethason in ARDS related COVID-19 include:[22] [20]
- Decreased days of intubation
- Decreased mortality
3.Due to suppression of immune system, the role of corticosteroid in COVID-19 would be evaluated by further investigation.
Niclosamide and Ivermectin
- Mechanism of action is Inhibition of binding of coronavirus onto the cells.[23]
- Niclosamid inhibits replication of MERS-COV AND SARS-COV-2.[24]
- Ivermectin inhibits viral replication in dengue virus, flavivirus,influenza. [24]
- FDA approved Ivermectin for treatment of SARS-COV-2. Study showed Ivermectin inhibited SARS-COV-2 replication up to 5000 fold at 48 h in vitro. [25]
Convalescent Plasma
- Convalescent Plasma is Transfusion of plasma loaded with antibodies after improvement from COVID-19.
- Studies in Taiwan and South Korea showed clinical benefits in severe cases of SARS-COV and MERS[26]
- Pilot study in COVID19 showed symptoms improvement including fever, cough, tightness of breath,chest pain.[27]
- Serious side effects were not reported.[27]
Anticoagulation
- In COVID-19 hypercoagulable state induces micro-macro-vascular thrombosis.
- Predictors of poor outcome in COVID-19 include: Disseminated intravascular coagulation , high level of D-dimer.[28]
- Mortality with anticoagulant therapy was decreased in COVID-19.
- Efficacy of heparin in COVID-19 includes : 1.anti inflammatory properties,2. prevention of viral attachment via changing in covid 19 spike protein [29]3.anticoagulation effect.
- Efficacy of low molecular weight heparin in COVID-19 includes:1. reduction in level of IL-6 and cytokine storm.[30]2.anticoagulation effect.
- Prophylactic anticoagulant therapy is necessary for all hospitalized COVID-19 patients.
- In patients with rapidly progressing respiratory distress and the probability of thrombosis, treatment doses of anticoagulant is considered.
Ibuprofen
- Ibuprofen is an anti-inflammatory drug (NSAID) and blocks the renin-angiotensin pathway.
- Ibuprofen is Activator of ACE2 receptor. [31]
- There is No strong evidence between intake of NSAID and worsening COVID-19.
- Ibuprofen approved by FDA for treatment of COVID-19.
Tucilizumab (Actemra)
- Tucilizumab is a monocolonal antibody that binds to IL-6 receptor on the cells and prevents inflammatory response.[32]
- Tucilizumab has been used for treatment of RA and juvenile ideopathic artheritis.
- Hypoxia
- Lung infiltration on CXR
- High inflammatory markers(CRP>3g/dl,ferritin>400ng/dl
- Clinical deterioration
- Contraindications of tucilizumab include as followings:
- Confirmed bacterial or fungal infection
- Platelet count<100000/cc
- Neutrophil count<2000/cc
- Alanin aminotrasferase or aspartat aminotransferase >5times upper limit normal
References
- ↑ Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, Neville S, Carra E, Lew W, Ross B, Wang Q, Wolfe L, Jordan R, Soloveva V, Knox J, Perry J, Perron M, Stray KM, Barauskas O, Feng JY, Xu Y, Lee G, Rheingold AL, Ray AS, Bannister R, Strickley R, Swaminathan S, Lee WA, Bavari S, Cihlar T, Lo MK, Warren TK, Mackman RL (March 2017). "Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses". J. Med. Chem. 60 (5): 1648–1661. doi:10.1021/acs.jmedchem.6b01594. PMC 7202039 Check
|pmc=value (help). PMID 28124907. - ↑ Grein, Jonathan; Ohmagari, Norio; Shin, Daniel; Diaz, George; Asperges, Erika; Castagna, Antonella; Feldt, Torsten; Green, Gary; Green, Margaret L.; Lescure, François-Xavier; Nicastri, Emanuele; Oda, Rentaro; Yo, Kikuo; Quiros-Roldan, Eugenia; Studemeister, Alex; Redinski, John; Ahmed, Seema; Bernett, Jorge; Chelliah, Daniel; Chen, Danny; Chihara, Shingo; Cohen, Stuart H.; Cunningham, Jennifer; D’Arminio Monforte, Antonella; Ismail, Saad; Kato, Hideaki; Lapadula, Giuseppe; L’Her, Erwan; Maeno, Toshitaka; Majumder, Sumit; Massari, Marco; Mora-Rillo, Marta; Mutoh, Yoshikazu; Nguyen, Duc; Verweij, Ewa; Zoufaly, Alexander; Osinusi, Anu O.; DeZure, Adam; Zhao, Yang; Zhong, Lijie; Chokkalingam, Anand; Elboudwarej, Emon; Telep, Laura; Timbs, Leighann; Henne, Ilana; Sellers, Scott; Cao, Huyen; Tan, Susanna K.; Winterbourne, Lucinda; Desai, Polly; Mera, Robertino; Gaggar, Anuj; Myers, Robert P.; Brainard, Diana M.; Childs, Richard; Flanigan, Timothy (2020). "Compassionate Use of Remdesivir for Patients with Severe Covid-19". New England Journal of Medicine. 382 (24): 2327–2336. doi:10.1056/NEJMoa2007016. ISSN 0028-4793.
- ↑ Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ (2014). "Chloroquine is a zinc ionophore". PLoS ONE. 9 (10): e109180. doi:10.1371/journal.pone.0109180. PMC 4182877. PMID 25271834.
- ↑ Cao, Bin; Wang, Yeming; Wen, Danning; Liu, Wen; Wang, Jingli; Fan, Guohui; Ruan, Lianguo; Song, Bin; Cai, Yanping; Wei, Ming; Li, Xingwang; Xia, Jiaan; Chen, Nanshan; Xiang, Jie; Yu, Ting; Bai, Tao; Xie, Xuelei; Zhang, Li; Li, Caihong; Yuan, Ye; Chen, Hua; Li, Huadong; Huang, Hanping; Tu, Shengjing; Gong, Fengyun; Liu, Ying; Wei, Yuan; Dong, Chongya; Zhou, Fei; Gu, Xiaoying; Xu, Jiuyang; Liu, Zhibo; Zhang, Yi; Li, Hui; Shang, Lianhan; Wang, Ke; Li, Kunxia; Zhou, Xia; Dong, Xuan; Qu, Zhaohui; Lu, Sixia; Hu, Xujuan; Ruan, Shunan; Luo, Shanshan; Wu, Jing; Peng, Lu; Cheng, Fang; Pan, Lihong; Zou, Jun; Jia, Chunmin; Wang, Juan; Liu, Xia; Wang, Shuzhen; Wu, Xudong; Ge, Qin; He, Jing; Zhan, Haiyan; Qiu, Fang; Guo, Li; Huang, Chaolin; Jaki, Thomas; Hayden, Frederick G.; Horby, Peter W.; Zhang, Dingyu; Wang, Chen (2020). "A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19". New England Journal of Medicine. 382 (19): 1787–1799. doi:10.1056/NEJMoa2001282. ISSN 0028-4793.
- ↑ Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, Choe KW, Kang YM, Lee B, Park SJ (February 2020). "Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR". J. Korean Med. Sci. 35 (6): e79. doi:10.3346/jkms.2020.35.e79. PMC 7025910 Check
|pmc=value (help). PMID 32056407 Check|pmid=value (help). - ↑ Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ (January 2016). "The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses". J. Virol. 90 (6): 3086–92. doi:10.1128/JVI.02077-15. PMC 4810626. PMID 26739045.
- ↑ Villalaín J (July 2010). "Membranotropic effects of arbidol, a broad anti-viral molecule, on phospholipid model membranes". J Phys Chem B. 114 (25): 8544–54. doi:10.1021/jp102619w. PMID 20527735.
- ↑ Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, Hong Z, Xia J (July 2020). "Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study". J. Infect. 81 (1): e1–e5. doi:10.1016/j.jinf.2020.03.002. PMC 7156152 Check
|pmc=value (help). PMID 32171872 Check|pmid=value (help). - ↑ 9.0 9.1 Chen, Chang; Zhang, Yi; Huang, Jianying; Yin, Ping; Cheng, Zhenshun; Wu, Jianyuan; Chen, Song; Zhang, Yongxi; Chen, Bo; Lu, Mengxin; Luo, Yongwen; Ju, Lingao; Zhang, Jingyi; Wang, Xinghuan (2020). doi:10.1101/2020.03.17.20037432. Missing or empty
|title=(help) - ↑ Furuta Y, Komeno T, Nakamura T (2017). "Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase". Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 93 (7): 449–463. doi:10.2183/pjab.93.027. PMC 5713175. PMID 28769016.
- ↑ De Clercq E (November 2019). "New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections". Chem Asian J. 14 (22): 3962–3968. doi:10.1002/asia.201900841. PMC 7159701 Check
|pmc=value (help). PMID 31389664. - ↑ McClellan K, Perry CM (2001). "Oseltamivir: a review of its use in influenza". Drugs. 61 (2): 263–83. doi:10.2165/00003495-200161020-00011. PMID 11270942.
- ↑ Wang, Dawei; Hu, Bo; Hu, Chang; Zhu, Fangfang; Liu, Xing; Zhang, Jing; Wang, Binbin; Xiang, Hui; Cheng, Zhenshun; Xiong, Yong; Zhao, Yan; Li, Yirong; Wang, Xinghuan; Peng, Zhiyong (2020). "Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China". JAMA. 323 (11): 1061. doi:10.1001/jama.2020.1585. ISSN 0098-7484.
- ↑ Rosa S, Santos WC (2020). "Clinical trials on drug repositioning for COVID-19 treatment". Rev. Panam. Salud Publica. 44: e40. doi:10.26633/RPSP.2020.40. PMC 7105280 Check
|pmc=value (help). PMID 32256547 Check|pmid=value (help). Vancouver style error: initials (help) - ↑ Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, Mancia Leon WR, Krencik R, Ullian EM, Spatazza J, Pollen AA, Mandel-Brehm C, Nowakowski TJ, Kriegstein AR, DeRisi JL (December 2016). "Zika virus cell tropism in the developing human brain and inhibition by azithromycin". Proc. Natl. Acad. Sci. U.S.A. 113 (50): 14408–14413. doi:10.1073/pnas.1618029113. PMC 5167169. PMID 27911847.
- ↑ 16.0 16.1 Gautret, Philippe; Lagier, Jean-Christophe; Parola, Philippe; Hoang, Van Thuan; Meddeb, Line; Mailhe, Morgane; Doudier, Barbara; Courjon, Johan; Giordanengo, Valérie; Vieira, Vera Esteves; Dupont, Hervé Tissot; Honoré, Stéphane; Colson, Philippe; Chabrière, Eric; La Scola, Bernard; Rolain, Jean-Marc; Brouqui, Philippe; Raoult, Didier (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. doi:10.1016/j.ijantimicag.2020.105949. ISSN 0924-8579.
- ↑ van Gorkom G, Klein Wolterink R, Van Elssen C, Wieten L, Germeraad W, Bos G (March 2018). "Influence of Vitamin C on Lymphocytes: An Overview". Antioxidants (Basel). 7 (3). doi:10.3390/antiox7030041. PMC 5874527. PMID 29534432. Vancouver style error: initials (help)
- ↑ Cheng RZ (March 2020). "Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?". Med Drug Discov. 5: 100028. doi:10.1016/j.medidd.2020.100028. PMC 7167497 Check
|pmc=value (help). PMID 32328576 Check|pmid=value (help). - ↑ Lamontagne F, Rochwerg B, Lytvyn L, Guyatt GH, Møller MH, Annane D, Kho ME, Adhikari N, Machado F, Vandvik PO, Dodek P, Leboeuf R, Briel M, Hashmi M, Camsooksai J, Shankar-Hari M, Baraki MK, Fugate K, Chua S, Marti C, Cohen D, Botton E, Agoritsas T, Siemieniuk R (August 2018). "Corticosteroid therapy for sepsis: a clinical practice guideline". BMJ. 362: k3284. doi:10.1136/bmj.k3284. PMC 6083439. PMID 30097460. Vancouver style error: initials (help)
- ↑ 20.0 20.1 Russell CD, Millar JE, Baillie JK (February 2020). "Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury". Lancet. 395 (10223): 473–475. doi:10.1016/S0140-6736(20)30317-2. PMC 7134694 Check
|pmc=value (help). PMID 32043983 Check|pmid=value (help). - ↑ Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y (March 2020). "Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China". JAMA Intern Med. doi:10.1001/jamainternmed.2020.0994. PMC 7070509 Check
|pmc=value (help). PMID 32167524 Check|pmid=value (help). - ↑ Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM (March 2020). "Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial". Lancet Respir Med. 8 (3): 267–276. doi:10.1016/S2213-2600(19)30417-5. PMID 32043986 Check
|pmid=value (help). - ↑ Wu CJ, Jan JT, Chen CM, Hsieh HP, Hwang DR, Liu HW, Liu CY, Huang HW, Chen SC, Hong CF, Lin RK, Chao YS, Hsu JT (July 2004). "Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide". Antimicrob. Agents Chemother. 48 (7): 2693–6. doi:10.1128/AAC.48.7.2693-2696.2004. PMC 434198. PMID 15215127.
- ↑ 24.0 24.1 Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, Hafner K, Papies J, Mösbauer K, Zellner A, Zannas AS, Herrmann A, Holsboer F, Brack-Werner R, Boshart M, Müller-Myhsok B, Drosten C, Müller MA, Rein T (December 2019). "SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection". Nat Commun. 10 (1): 5770. doi:10.1038/s41467-019-13659-4. PMC 6920372 Check
|pmc=value (help). PMID 31852899. - ↑ Caly, Leon; Druce, Julian D.; Catton, Mike G.; Jans, David A.; Wagstaff, Kylie M. (2020). "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro". Antiviral Research. 178: 104787. doi:10.1016/j.antiviral.2020.104787. ISSN 0166-3542.
- ↑ Yeh KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, Lu JJ, Chang FY (November 2005). "Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital". J. Antimicrob. Chemother. 56 (5): 919–22. doi:10.1093/jac/dki346. PMC 7110092 Check
|pmc=value (help). PMID 16183666. - ↑ 27.0 27.1 Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X (April 2020). "Effectiveness of convalescent plasma therapy in severe COVID-19 patients". Proc. Natl. Acad. Sci. U.S.A. 117 (17): 9490–9496. doi:10.1073/pnas.2004168117. PMC 7196837 Check
|pmc=value (help). PMID 32253318 Check|pmid=value (help). - ↑ Tang N, Li D, Wang X, Sun Z (April 2020). "Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia". J. Thromb. Haemost. 18 (4): 844–847. doi:10.1111/jth.14768. PMC 7166509 Check
|pmc=value (help). PMID 32073213 Check|pmid=value (help). - ↑ Mycroft-West, Courtney; Su, Dunhao; Elli, Stefano; Li, Yong; Guimond, Scott; Miller, Gavin; Turnbull, Jeremy; Yates, Edwin; Guerrini, Marco; Fernig, David; Lima, Marcelo; Skidmore, Mark (2020). doi:10.1101/2020.02.29.971093. Missing or empty
|title=(help) - ↑ Shi, Chen; Wang, Cong; Wang, Hanxiang; Yang, Chao; Cai, Fei; Zeng, Fang; Cheng, Fang; Liu, Yihui; Zhou, Taotao; Deng, Bin; Vlodavsky, Israel; Li, Jinping; Zhang, Yu (2020). doi:10.1101/2020.03.28.20046144. Missing or empty
|title=(help) - ↑ Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM (August 2005). "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury". Nat. Med. 11 (8): 875–9. doi:10.1038/nm1267. PMC 7095783 Check
|pmc=value (help). PMID 16007097. - ↑ Fu B, Xu X, Wei H (April 2020). "Why tocilizumab could be an effective treatment for severe COVID-19?". J Transl Med. 18 (1): 164. doi:10.1186/s12967-020-02339-3. PMC 7154566 Check
|pmc=value (help). PMID 32290839 Check|pmid=value (help). - ↑ Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H (May 2020). "Effective treatment of severe COVID-19 patients with tocilizumab". Proc. Natl. Acad. Sci. U.S.A. 117 (20): 10970–10975. doi:10.1073/pnas.2005615117. PMC 7245089 Check
|pmc=value (help). PMID 32350134 Check|pmid=value (help). - ↑ Kewan, Tariq; Covut, Fahrettin; Al–Jaghbeer, Mohammed J.; Rose, Lori; Gopalakrishna, K.V.; Akbik, Bassel (2020). "Tocilizumab for treatment of patients with severe COVID–19: A retrospective cohort study". EClinicalMedicine: 100418. doi:10.1016/j.eclinm.2020.100418. ISSN 2589-5370.