Introduction
Various treatments for COVID-19 are in clinical trials around the world.
Global coronavirus COVID-19 clinical trial tracker
external link opens in a new window There are several treatments being used off-label on a compassionate-use basis, or as part of a clinical trial.
WHO: off-label use of medicines for COVID-19
external link opens in a new window It is important to note that there may be serious adverse effects associated with these drugs, and that these adverse effects may overlap with the clinical manifestations of COVID-19. These drugs may also increase the risk of death in an older patient or a patient with an underlying health condition (e.g., drugs that prolong the QT interval may increase the risk of cardiac death).[694]Kalil AC. Treating COVID-19: off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA Mar 24 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2763802
http://www.ncbi.nlm.nih.gov/pubmed/32208486?tool=bestpractice.com
Drug-drug interactions with the patient’s existing medication(s), and drug-disease interactions (e.g., impact of inflammation on drug metabolism in COVID-19 patients), must also be considered.[695]Marzolini C, Battegay M, Sendi P, et al. Prescribing in COVID-19 patients: should we take into account inflammation? Br J Clin Pharmacol. 2020 Aug 20 [Epub ahead of print].
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.14524
http://www.ncbi.nlm.nih.gov/pubmed/32820554?tool=bestpractice.com
International trials to identify treatments that may be beneficial, such as the World Health Organization’s (WHO) Solidarity trial and the UK’s randomised evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing.
WHO: “Solidarity” clinical trial for COVID-19 treatments
external link opens in a new window
RECOVERY trial
external link opens in a new window
Remdesivir
A novel intravenous nucleoside analogue with broad antiviral activity that shows in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the US, the Food and Drug Administration (FDA) has issued an emergency-use authorisation for remdesivir for the treatment of suspected or confirmed COVID-19 in adults and children who are hospitalised, regardless of disease severity.[696]US Food and Drug Administration. COVID-19 update: FDA broadens emergency use authorization for veklury (remdesivir) to include all hospitalized patients for treatment of COVID-19. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/covid-19-update-fda-broadens-emergency-use-authorization-veklury-remdesivir-include-all-hospitalized
The authorisation is based on results from a randomised, placebo-controlled trial of remdesivir in 1063 patients hospitalised with severe COVID-19 run by the National Institute of Allergy and Infectious Disease (NIAID). The study found that patients taking a 10-day course of remdesivir had a faster time to recovery (i.e., defined as a patient no longer requiring hospitalisation, or hospitalisation no longer requiring oxygen or ongoing medical care) compared with placebo, with a median recovery time of 11 days versus 15 days. Results were significant only among patients who received oxygen. The mortality rate was 7.1% with remdesivir compared with 11.9% with placebo, although the difference was not statistically significant. The incidence of adverse effects was not significantly different between the two groups. Even though the trial was ongoing, the data and safety monitoring board made the recommendation to unblind the results to the trial team members from NIAID, who subsequently decided to make the results public.[697]Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19: preliminary report. N Engl J Med. 2020 May 22 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
http://www.ncbi.nlm.nih.gov/pubmed/32445440?tool=bestpractice.com
The National Institutes of Health guidelines recommend prioritising remdesivir in hospitalised patients with COVID-19 who require supplemental oxygen, but who are not on high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation. The guidelines panel recommends that patients should receive treatment for 5 days or until hospital discharge, whichever comes first (patients who have not shown clinical improvement after 5 days can receive treatment for up to 10 days). The guidelines panel does not recommend for or against remdesivir for the treatment of patients with severe disease who require high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, as there are insufficient data.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America recommends remdesivir over no antiviral treatment among hospitalised patients with severe COVID-19, with the same treatment duration as recommended above.[545]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 infection. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
A UK National Institute for Health and Care Excellence review suggests there is some benefit with remdesivir compared with placebo for reducing supportive measures including mechanical ventilation and reducing time to recovery in patients who are on oxygen therapy. However, no statistically significant differences were found for mortality and serious adverse events.[698]National Institute for Health and Care Excellence. COVID 19 rapid evidence summary: remdesivir for treating hospitalised patients with suspected or confirmed COVID-19. 2020 [internet publication].
https://www.nice.org.uk/advice/es27/chapter/Key-messages
An expert guideline panel makes a weak recommendation for the use of remdesivir in severe disease, and supports more randomised trials as the quality of the evidence is low.
BMJ rapid recommendations: remdesivir for severe covid-19 – a clinical practice guideline
external link opens in a new window A network meta-analysis found that both 5-day and 10-day remdesivir regimens were associated with higher odds of clinical improvement in hospitalised patients compared with placebo.[699]Jiang Y, Chen D, Cai D, et al. Effectiveness of remdesivir for the treatment of hospitalized Covid-19 persons: a network meta-analysis. J Med Virol. 2020 Aug 19 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/32813283?tool=bestpractice.com
There are little data available to support the use of remdesivir in patients with mild or moderate disease. Hospitalised patients with moderate disease had a statistically significantly better clinical status after 5 days of treatment (but not 10 days of treatment) compared with those who received standard care at 11 days after initiation of treatment, but the difference was of uncertain clinical importance.[700]Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020 Aug 21 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2769871
http://www.ncbi.nlm.nih.gov/pubmed/32821939?tool=bestpractice.com
The National Institutes of Health guidelines panel does not recommend for or against remdesivir for the treatment of mild or moderate disease as there are insufficient data.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Remdesivir appears to be safe to use in pregnancy.[701]Dashraath P, Jing Lin Jeslyn W, Mei Xian Karen L, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol. 2020 Jun;222(6):521-31.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270569/
http://www.ncbi.nlm.nih.gov/pubmed/32217113?tool=bestpractice.com
Possible adverse effects include elevated liver enzymes and infusion-related reactions (e.g., hypotension, nausea, vomiting, sweating, shivering). The FDA recommends against the concomitant use of remdesivir with chloroquine or hydroxychloroquine due to a drug interaction that may result in reduced antiviral activity of remdesivir, although this has not been observed in practice.[702]US Food and Drug Administration. Coronavirus (COVID-19) update: FDA warns of newly discovered potential drug interaction that may reduce effectiveness of a COVID-19 treatment authorized for emergency use. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-warns-newly-discovered-potential-drug-interaction-may-reduce
The European Medicines Agency has granted a conditional marketing authorisation to remdesivir for the treatment of COVID-19 in adults and children 12 years of age and older with pneumonia who require supplemental oxygen.[703]European Medicines Agency. First COVID-19 treatment recommended for EU authorisation. 2020 [internet publication].
https://www.ema.europa.eu/en/news/first-covid-19-treatment-recommended-eu-authorisation
An interim clinical commissioning policy has been put in place to define routine access to remdesivir in the treatment of COVID-19 across the UK from 3 July.[704]Medicines and Healthcare products Regulatory Agency. Update: publication of an interim clinical commissioning policy – remdesivir for patients hospitalised with COVID-19 (adults and children aged 12 years and older). 2020 [internet publication].
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103091
Clinical trials of inhaled remdesivir, and remdesivir plus interferon beta-1a, have started.[705]National Institutes of Health. NIH clinical trial testing remdesivir plus interferon beta-1a for COVID-19 treatment begins. 2020 [internet publication].
https://www.nih.gov/news-events/news-releases/nih-clinical-trial-testing-remdesivir-plus-interferon-beta-1a-covid-19-treatment-begins
Convalescent plasma
Clinical trials to determine the safety and efficacy of convalescent plasma that contains antibodies to SARS-CoV-2 in patients with COVID-19 are ongoing. In the US, the Food and Drug Administration has issued an emergency-use authorisation for convalescent plasma for the treatment of COVID-19 in hospitalised patients.[706]US Food and Drug Administration. FDA issues emergency use authorization for convalescent plasma as potential promising COVID–19 treatment, another achievement in administration’s fight against pandemic. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
This follows publication of a preprint (not peer reviewed) of an open-label, multicentre, expanded access programme study of over 35,000 patients that found convalescent plasma lowered 7-day mortality by 9% in hospitalised patients when given within 3 days of diagnosis, and by 12% when given 4 or more days later.[707]Joyner MJ, Senefeld JW, Klassen SA, et al; medRxiv. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. 2020 [internet publication].
https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1
A meta-analysis and systematic review with a total of 5444 patients found that the use of convalescent plasma reduced mortality, increased viral clearance, and resulted in clinical improvement in patients with COVID-19; however, the evidence is of low quality and further randomised controlled trials are required.[708]Sarkar S, Soni KD, Khanna P. Convalescent plasma a clutch at straws in COVID-19 management! A systematic review and meta-analysis. J Med Virol. 2020 Aug 10 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26408
http://www.ncbi.nlm.nih.gov/pubmed/32776573?tool=bestpractice.com
The authors of a Cochrane rapid review were uncertain as to whether convalescent plasma is beneficial for hospitalised patients with COVID-19. The completed studies were of poor quality, and the results could be related to natural progression of the disease or to other treatments the patient receives. The currently available evidence on the safety and efficacy of convalescent plasma for the treatment of hospitalised patients is of very low certainty.[709]Piechotta V, Chai KL, Valk SJ, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2020 Jul 10;7:CD013600.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013600.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/32648959?tool=bestpractice.com
The National Institutes of Health guidelines panel says that there is currently insufficient evidence to recommend either for or against the use of convalescent plasma for the treatment of COVID-19.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America recommends convalescent plasma only in the context of a clinical trial.[545]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 infection. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
Hydroxychloroquine/chloroquine
Hydroxychloroquine and chloroquine are oral drugs that are indicated for the prophylaxis and treatment of malaria, as well as the treatment of some autoimmune conditions. Both drugs show in vitro activity against SARS-CoV-2; however, hydroxychloroquine has been used more commonly in trials due to its better adverse-effect profile.[710]Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-71.
https://www.nature.com/articles/s41422-020-0282-0
http://www.ncbi.nlm.nih.gov/pubmed/32020029?tool=bestpractice.com
[711]Cortegiani A, Ingoglia G, Ippolito M, et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020 Jun;57:279-83.
https://www.sciencedirect.com/science/article/pii/S0883944120303907
http://www.ncbi.nlm.nih.gov/pubmed/32173110?tool=bestpractice.com
Initial data from clinical trials of hydroxychloroquine seemed promising.[712]Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949.
https://www.sciencedirect.com/science/article/pii/S0924857920300996
http://www.ncbi.nlm.nih.gov/pubmed/32205204?tool=bestpractice.com
[713]Chen Z, Hu J, Zhang Z, et al; medRxiv. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. 2020 [internet publication].
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.full.pdf
[714]Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020 May 14;369:m1849.
https://www.bmj.com/content/369/bmj.m1849
http://www.ncbi.nlm.nih.gov/pubmed/32409561?tool=bestpractice.com
However, a living systematic review of current evidence (as of 27 August) concludes that there is low-strength evidence from trials and cohort studies that hydroxychloroquine has no positive effect on all-cause mortality or the need for mechanical ventilation. Trials show low strength of evidence for no positive effect on intubation or death and discharge from the hospital, whereas evidence from cohort studies about these outcomes remains insufficient. Data are insufficiently strong to support a treatment benefit of hydroxychloroquine for other outcomes.[715]Hernandez AV, Roman YM, Pasupuleti V, et al. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann Intern Med. 2020 May 27 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-2496
http://www.ncbi.nlm.nih.gov/pubmed/32459529?tool=bestpractice.com
[716]Hernandez AV, Roman YM, Pasupuleti V, et al. Update alert 2: hydroxychloroquine or chloroquine for the treatment or prophylaxis of COVID-19. Ann Intern Med. 2020 Aug 27 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/L20-1054
http://www.ncbi.nlm.nih.gov/pubmed/32853033?tool=bestpractice.com
A meta-analysis of randomised controlled trials found that hydroxychloroquine showed no benefit in the treatment of mild to moderate disease also.[717]Pathak DSK, Salunke DAA, Thivari DP, et al. No benefit of hydroxychloroquine in COVID-19: results of systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Syndr. 2020 Sep 1;14(6):1673-80.
https://www.sciencedirect.com/science/article/pii/S1871402120303362?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/32905939?tool=bestpractice.com
The WHO and the National Institutes of Health have prematurely discontinued their clinical trials of hydroxychloroquine citing a lack of efficacy; however, results are yet to be published. Preliminary results from the UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of dying or improve other outcomes in hospitalised patients, and investigators have stopped enrolling participants into the hydroxychloroquine arm of the trial.[718]Torjesen I. Covid-19: hydroxychloroquine does not benefit hospitalised patients, UK trial finds. BMJ. 2020 Jun 8;369:m2263.
https://www.bmj.com/content/369/bmj.m2263
http://www.ncbi.nlm.nih.gov/pubmed/32513810?tool=bestpractice.com
The National Institutes of Health guideline panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 in hospitalised patients. The panel recommends against the use of both drugs in non-hospitalised patients except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America strongly recommends against the use of hydroxychloroquine or chloroquine (with or without azithromycin) for the treatment of COVID-19 in hospitalised patients based on moderate-quality evidence.[545]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 infection. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
The FDA has revoked its emergency-use authorisation for hydroxychloroquine and chloroquine as it believes the potential benefits no longer outweigh the known and potential risks.[539]Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020 Jun 2 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265858/
http://www.ncbi.nlm.nih.gov/pubmed/32502594?tool=bestpractice.com
If used, hydroxychloroquine and chloroquine should be used with caution in patients with pre-existing cardiovascular disease due to the risk of arrhythmias, and a baseline echocardiogram is recommended before treatment, particularly in patients who are critically ill.[719]Roden DM, Harrington RA, Poppas A, et al. Considerations for drug interactions on QTc in exploratory COVID-19 (coronavirus disease 2019) treatment. Circulation. 2020 Jun 16;141(24):e906-7.
https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.120.047521
http://www.ncbi.nlm.nih.gov/pubmed/32267732?tool=bestpractice.com
[720]Kamp TJ, Hamdan MH, January CT. Chloroquine or hydroxychloroquine for COVID-19: is cardiotoxicity a concern? J Am Heart Assoc. 2020 May 28:e016887.
https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.016887
http://www.ncbi.nlm.nih.gov/pubmed/32463308?tool=bestpractice.com
Caution is recommended when using these drugs with other drugs that prolong the QT interval (e.g., azithromycin) due to an increased risk of QT interval prolongation and/or ventricular tachycardia (including Torsades de Pointes).[721]Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. 2020 May 1 [Epub ahead of print].
https://jamanetwork.com/journals/jamacardiology/fullarticle/2765633
http://www.ncbi.nlm.nih.gov/pubmed/32356858?tool=bestpractice.com
[722]Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020 May 1 [Epub ahead of print].
https://jamanetwork.com/journals/jamacardiology/fullarticle/2765631
http://www.ncbi.nlm.nih.gov/pubmed/32356863?tool=bestpractice.com
[723]Nguyen LS, Dolladille C, Drici MD, et al. Cardiovascular toxicities associated with hydroxychloroquine and azithromycin: an analysis of the World Health Organization pharmacovigilance database. Circulation. 2020 May 22 [Epub ahead of print].
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048238
http://www.ncbi.nlm.nih.gov/pubmed/32442023?tool=bestpractice.com
Lopinavir/ritonavir
An oral antiretroviral protease inhibitor currently approved for the treatment of HIV Infection. Lopinavir/ritonavir has been used in clinical trials for the treatment of COVID-19. Results from one small case series found that evidence of clinical benefit with lopinavir/ritonavir was equivocal.[724]Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA. 2020 Mar 3;323(15):1488-94.
https://jamanetwork.com/journals/jama/fullarticle/2762688
http://www.ncbi.nlm.nih.gov/pubmed/32125362?tool=bestpractice.com
A randomised controlled trial of 200 patients with severe disease found that treatment with lopinavir/ritonavir plus standard care (i.e., oxygen, non-invasive and invasive ventilation, antibiotics, vasopressors, renal replacement therapy, and extracorporeal membrane oxygenation, as necessary) was not associated with an decreased time to clinical improvement compared with standard care alone, and 28-day mortality was similar in both groups.[725]Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020 May 7;382(19):1787-99.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121492/
http://www.ncbi.nlm.nih.gov/pubmed/32187464?tool=bestpractice.com
Preliminary results from the UK RECOVERY trial found that there is no beneficial effect of lopinavir/ritonavir in hospitalised patients with COVID-19. There was no significant difference in 28-day mortality, risk of progression to mechanical ventilation, or duration of hospital stay between the two treatment arms (lopinavir/ritonavir versus usual care alone), and the results were consistent in different subgroups of patients.[726]RECOVERY Trial. No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY. 2020 [internet publication].
https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery
Interim data from the WHO Solidarity trial found that lopinavir/ritonavir has little or no reduction in the mortality of hospitalised COVID-19 patients when compared with standard of care.[727]World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. 2020 [internet publication].
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
Lopinavir/ritonavir causes QT interval prolongation and may increase the risk of bradycardia, especially in older, critically ill patients.[728]Beyls C, Martin N, Hermida A, et al. Lopinavir-ritonavir treatment for COVID-19 infection in intensive care unit: risk of bradycardia. Circ Arrhythm Electrophysiol. 2020 Aug;13(8):e008798.
https://www.ahajournals.org/doi/10.1161/CIRCEP.120.008798
http://www.ncbi.nlm.nih.gov/pubmed/32809882?tool=bestpractice.com
The National Institutes of Health guidelines panel recommends against the use of lopinavir/ritonavir for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Centre for Evidence-Based Medicine: lopinavir/ritonavir – a rapid review of effectiveness in COVID-19
external link opens in a new window
Intravenous immunoglobulin
Intravenous immunoglobulin (IVIG) is being trialled in some patients with COVID-19.[32]Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-13.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30211-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/32007143?tool=bestpractice.com
[729]Jawhara S. Could intravenous immunoglobulin collected from recovered coronavirus patients protect against COVID-19 and strengthen the immune system of new patients? Int J Mol Sci. 2020 Mar 25;21(7).
https://www.mdpi.com/1422-0067/21/7/2272/htm
http://www.ncbi.nlm.nih.gov/pubmed/32218340?tool=bestpractice.com
A retrospective study of 58 patients with severe COVID-19 found that IVIG, when used as an adjuvant treatment within 48 hours of admission, may reduce the use of mechanical ventilation, reduce hospital/intensive care unit stay, and reduce 28-day mortality; however, this study had several limitations.[730]Xie Y, Cao S, Li Q, et al. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect. 2020 Apr 10 [Epub ahead of print].
https://www.journalofinfection.com/article/S0163-4453(20)30172-9/pdf
http://www.ncbi.nlm.nih.gov/pubmed/32283154?tool=bestpractice.com
There is currently insufficient evidence to recommend IVIG for the treatment of COVID-19.[731]Zhang J, Yang Y, Yang N, et al. Effectiveness of intravenous immunoglobulin for children with severe COVID-19: a rapid review. Ann Transl Med. 2020 May;8(10):625.
http://atm.amegroups.com/article/view/43600/html
http://www.ncbi.nlm.nih.gov/pubmed/32566562?tool=bestpractice.com
The National Institutes of Health guidelines panel recommends against the use of non-SARS-CoV-2-specific IVIG for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Monoclonal antibody treatments
SARS-CoV-2 monoclonal antibodies have the potential to be used for prophylaxis and treatment of COVID-19.[732]Marovich M, Mascola JR, Cohen MS. Monoclonal antibodies for prevention and treatment of COVID-19. JAMA. 2020 Jun 15 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2767383
http://www.ncbi.nlm.nih.gov/pubmed/32539093?tool=bestpractice.com
Recombinant, fully human monoclonal neutralising antibodies, such as JS016 and LY-COV555, are in development. These antibodies bind to the SARS-CoV-2 surface spike protein receptor binding domain, which blocks the binding of the virus to the angiotensin-converting enzyme-2 (ACE2) host cell surface receptor. Both antibody treatments have started phase 1 studies.[733]Eli Lilly and Company. Lilly announces start of a phase 1 study for its second potential COVID-19 antibody treatment. 2020 [internet publication].
https://investor.lilly.com/news-releases/news-release-details/lilly-announces-start-phase-1-study-its-second-potential-covid
[734]Eli Lilly and Company. Lilly begins world's first study of a potential COVID-19 antibody treatment in humans. 2020 [internet publication].
https://investor.lilly.com/news-releases/news-release-details/lilly-begins-worlds-first-study-potential-covid-19-antibody
Novel multi-antibody cocktail therapies (e.g., REGN-COV2) are also in clinical trials for prophylaxis or treatment.[735]Regeneron. Regeneron announces important advances in novel COVID-19 antibody program. 2020 [internet publication].
https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-important-advances-novel-covid-19-antibody
The UK RECOVERY trial is investigating whether adding REGN-COV2 to usual standard of care (versus standard care alone) has any impact on all-cause 28-day mortality.[736]Mahase E. Covid-19: RECOVERY trial will evaluate "antiviral antibody cocktail". BMJ. 2020 Sep 15;370:m3584.
https://www.bmj.com/content/370/bmj.m3584
http://www.ncbi.nlm.nih.gov/pubmed/32933902?tool=bestpractice.com
Interleukin-6 (IL-6) inhibitors
IL-6 inhibitors (e.g., tocilizumab, siltuximab) are being trialled in COVID-19 patients for the treatment of virus-induced cytokine release syndrome. These drugs are already approved in some countries for other indications. A meta-analysis of 23 observational studies found that tocilizumab plus standard of care may reduce mortality and the need for mechanical ventilation in patients with severe disease.[737]Aziz M, Haghbin H, Sitta EA, et al. Efficacy of tocilizumab in COVID-19: a systematic review and meta-analysis. J Med Virol. 2020 Sep 12 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26509
http://www.ncbi.nlm.nih.gov/pubmed/32918755?tool=bestpractice.com
However, the randomised controlled COVACTA trial failed to meet its primary end point of clinical status, and found that tocilizumab did not improve mortality. Full results are yet to be published.[738]Furlow B. COVACTA trial raises questions about tocilizumab's benefit in COVID-19. Lancet Rheumatol. 2020 Sep 9 [Epub ahead of print].
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30313-1/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/32929415?tool=bestpractice.com
The National Institutes of Health guidelines panel recommends against the use of IL-6 inhibitors for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Anakinra
Anakinra, an interleukin-1 inhibitor, is being trialled in COVID-19 patients for the treatment of virus-induced cytokine release syndrome. It is already approved in some countries for other indications. Addition of high-dose intravenous anakinra to non-invasive ventilation and standard care (which included hydroxychloroquine and lopinavir/ritonavir) in COVID-19 patients with moderate to severe acute respiratory distress syndrome and hyperinflammation was associated with a higher survival rate at 21 days in a small retrospective study.[739]Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020 Jun;2(6):e325-31.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252085/
http://www.ncbi.nlm.nih.gov/pubmed/32501454?tool=bestpractice.com
A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[740]Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020 Jul;2(7):e393-400.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259909/
http://www.ncbi.nlm.nih.gov/pubmed/32835245?tool=bestpractice.com
A small retrospective case series found that anakinra could be beneficial in patients with cytokine release syndrome when initiated early after the onset of acute hypoxic respiratory failure.[741]Navarro-Millán I, Sattui SE, Lakhanpal A, et al. Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series. Arthritis Rheumatol. 2020 Jun 30 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/abs/10.1002/art.41422
http://www.ncbi.nlm.nih.gov/pubmed/32602262?tool=bestpractice.com
The National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The National Institute for Health and Care Excellence in the UK states that there is no evidence available to determine whether anakinra is effective, safe, or cost-effective for treating adults and children with secondary haemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[742]National Institute for Health and Care Excellence. COVID 19 rapid evidence summary: anakinra for COVID-19 associated secondary haemophagocytic lymphohistiocytosis. 2020 [internet publication].
https://www.nice.org.uk/advice/es26/chapter/Key-messages
Antigranulocyte–macrophage colony-stimulating factor (GM-CSF) monoclonal antibodies
Mavrilimumab was associated with improved clinical outcomes compared with standard care in non-mechanically ventilated patients with severe disease and systemic hyperinflammation in a single-centre prospective cohort study.[743]De Luca G, Cavalli G, Campochiaro C, et al. GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol. 2020 Aug;2(8):e465-73.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430344/
http://www.ncbi.nlm.nih.gov/pubmed/32835256?tool=bestpractice.com
Lenzilumab was associated with a reduction in the relative risk of progression to invasive mechanical ventilation and/or death in high-risk COVID-19 patients with severe pneumonia compared with a matched control cohort of patients who received standard care alone in a small study of 39 patients.[744]Temesgen Z, Assi M, Shweta FNU, et al. GM-CSF neutralization with lenzilumab in severe COVID-19 pneumonia: a case-control study. Mayo Clin Proc. 2020 Aug [Epub ahead of print].
https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_8_7.pdf
[745]Temesgen Z, Assi M, Vergidis P, et al. First clinical use of lenzilumab to neutralize GM-CSF in patients with severe COVID-19 pneumonia. medRxiv. 2020 Jun 14 [Epub ahead of print].
https://www.medrxiv.org/content/10.1101/2020.06.08.20125369v2
http://www.ncbi.nlm.nih.gov/pubmed/32587983?tool=bestpractice.com
Janus kinase inhibitors
Janus kinase inhibitors (e.g., fedratinib, ruxolitinib, baricitinib) are currently in clinical trials for the treatment of COVID-19-associated cytokine release syndrome.[746]Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib. J Microbiol Immunol Infect. 2020 Jun;53(3):368-70.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156211/
http://www.ncbi.nlm.nih.gov/pubmed/32205092?tool=bestpractice.com
[747]Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020 Jul;146(1):137-46.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250105/
http://www.ncbi.nlm.nih.gov/pubmed/32470486?tool=bestpractice.com
[748]Titanji BK, Farley MM, Mehta A, et al. Use of baricitinib in patients with moderate and severe COVID-19. Clin Infect Dis. 2020 Jun 29 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337637/
http://www.ncbi.nlm.nih.gov/pubmed/32597466?tool=bestpractice.com
The National Institutes of Health guidelines panel recommends against the use of Janus kinase inhibitors for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Stem cell therapy
Stem cell therapy is being investigated to treat patients with COVID-19 in clinical trials. It is thought that mesenchymal stem cells can reduce the pathological changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[749]ClinicalTrials.gov. Mesenchymal stem cell treatment for pneumonia patients infected with 2019 novel coronavirus. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04252118
The National Institutes of Health guidelines panel recommends against the use of mesenchymal stem cells for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Adipose-derived mesenchymal stem cells have been approved by the FDA for the treatment of severe COVID-19.
Granulocyte colony-stimulating factor (G-CSF)
Recombinant G-CSF plus usual care did not accelerate clinical improvement compared with usual care alone according to preliminary findings from a randomised clinical trial in patients with lymphopenia and no comorbidities. Larger studies are needed to determine whether G-CSF, which increases peripheral blood leukocyte and lymphocyte cell counts, is beneficial in COVID-19 patients.[750]Cheng LL, Guan WJ, Duan CY, et al. Effect of recombinant human granulocyte colony-stimulating factor for patients with coronavirus disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. JAMA Intern Med. 2020 Sep 10 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2770680
http://www.ncbi.nlm.nih.gov/pubmed/32910179?tool=bestpractice.com
Bacille Calmette-Guerin (BCG) vaccine
The BCG vaccine is being trialled in some countries for the prevention of COVID-19, including in healthcare workers. There is some evidence that BCG vaccination prevents other respiratory tract infections in children and older people mediated by induction of innate immune memory.[751]Centre for Evidence-Based Medicine; Soliman R, Brassey J, Plüddemann A, et al. Does BCG vaccination protect against acute respiratory infections and COVID-19? A rapid review of current evidence. 2020 [internet publication].
https://www.cebm.net/covid-19/does-bcg-vaccination-protect-against-acute-respiratory-infections-and-covid-19-a-rapid-review-of-current-evidence/
However, there is no evidence to support its use in COVID-19, and the WHO does not recommend it for the prevention of COVID-19.[752]World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19: scientific brief. 2020 [internet publication].
https://www.who.int/news-room/commentaries/detail/bacille-calmette-guérin-(bcg)-vaccination-and-covid-19
Bemcentinib
An experimental small molecule that inhibits AXL kinase. Bemcentinib has previously demonstrated a role in the treatment of cancer, but has also been reported to have antiviral activity in preclinical models, including activity against SARS-CoV-2. It was the first candidate to be selected as part of the UK’s Accelerating COVID-19 Research and Development (ACCORD) study.[753]Department of Health and Social Care. COVID-19 treatments could be fast-tracked through new national clinical trial initiative. 2020 [internet publication].
https://www.gov.uk/government/news/covid-19-treatments-could-be-fast-tracked-through-new-national-clinical-trial-initiative
The study has stopped recruiting new patients into the trial due to the reduction of new COVID-19 cases in the UK. Patients already recruited will continue on treatment as per the study protocol.
Angiotensin-II receptor antagonists
Angiotensin-II receptor antagonists such as losartan are being investigated as a potential treatment because it is thought that the angiotensin-converting enzyme-2 (ACE2) receptor is the main binding site for the virus.[754]Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020 Mar 4 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.21656
http://www.ncbi.nlm.nih.gov/pubmed/32129518?tool=bestpractice.com
[755]ClinicalTrials.gov. Losartan for patients with COVID-19 requiring hospitalization. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04312009
[756]ClinicalTrials.gov. Losartan for patients with COVID-19 not requiring hospitalization. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04311177
However, some experts believe that these drugs may worsen COVID-19 due to overexpression of ACE2 in people taking these drugs.
Other antivirals
Various other antiviral drugs (monotherapy and combination therapy) are being trialled in patients with COVID-19 (e.g., oseltamivir, darunavir, ganciclovir, favipiravir, baloxavir marboxil, umifenovir, ribavirin, interferon, leronlimab).[757]Chinese Clinical Trial Registry. A randomized, open-label, blank-controlled trial for the efficacy and safety of lopinavir-ritonavir and interferon-alpha 2b in hospitalization patients with 2019-nCoV pneumonia (novel coronavirus pneumonia, NCP). 2020 [internet publication].
http://www.chictr.org.cn/com/25/showprojen.aspx?proj=48684
[758]Chinese Clinical Trial Registry. Clinical study for safety and efficacy of favipiravir in the treatment of novel coronavirus pneumonia (COVID-19). 2020 [internet publication].
http://www.chictr.org.cn/showprojen.aspx?proj=49042
[759]Chinese Clinical Trial Registry. Clinical study of arbidol hydrochloride tablets in the treatment of novel coronavirus pneumonia (COVID-19). 2020 [internet publication].
http://www.chictr.org.cn/showprojen.aspx?proj=49165
[760]Chinese Clinical Trial Registry. Randomized, open-label, controlled trial for evaluating of the efficacy and safety of baloxavir marboxil, favipiravir, and lopinavir-ritonavir in the treatment of novel coronavirus pneumonia (COVID-19) patients. 2020 [internet publication].
http://www.chictr.org.cn/showprojen.aspx?proj=49015
[761]Zeng YM, Xu XL, He XQ, et al. Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus pneumonia. Chin Med J (Engl). 2020 May 5;133(9):1132-4.
https://journals.lww.com/cmj/FullText/2020/05050/Comparative_effectiveness_and_safety_of_ribavirin.24.aspx
http://www.ncbi.nlm.nih.gov/pubmed/32149772?tool=bestpractice.com
[762]Li H, Wang YM, Xu JY, et al. Potential antiviral therapeutics for 2019 novel coronavirus [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):170-2.
http://www.ncbi.nlm.nih.gov/pubmed/32164080?tool=bestpractice.com
[763]Deng L, Li C, Zeng Q, et al. Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study. J Infect. 2020 Jul;81(1):e1-5.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156152/
http://www.ncbi.nlm.nih.gov/pubmed/32171872?tool=bestpractice.com
[764]ClinicalTrials.gov. Efficacy and safety of darunavir and cobicistat for treatment of pneumonia caused by 2019-nCoV (DACO-nCoV). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04252274
[765]Synairgen. COVID-19. 2020 [internet publication].
https://www.synairgen.com/covid-19/
[766]CytoDyn Inc. Leronlimab used in seven patients with severe COVID-19 demonstrated promise with two intubated patients in ICU, removed from ICU and extubated with reduced pulmonary inflammation. 2020 [internet publication].
https://www.cytodyn.com/newsroom/press-releases/detail/399/leronlimab-used-in-seven-patients-with-severe-covid-19
There is no evidence to support the use of umifenovir.[767]Huang D, Yu H, Wang T, et al. Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. J Med Virol. 2020 Jul 3 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26256
http://www.ncbi.nlm.nih.gov/pubmed/32617989?tool=bestpractice.com
Triple therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin has been tested in hospitalised COVID-19 patients in a small open-label randomised phase 2 trial. Patients who received triple therapy had a significantly shorter median time to a negative nasopharyngeal swab result compared with the control group (lopinavir/ritonavir only). Patients had mild to moderate disease at the time of enrollment.[768]Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-704.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211500/
http://www.ncbi.nlm.nih.gov/pubmed/32401715?tool=bestpractice.com
The National Institutes of Health guidelines panel recommends against the use of interferons for the treatment of severe or critically ill patients, except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Antibiotics
The PRINCIPLE trial in the UK is currently evaluating three treatment strategies in older people (people aged over 65 years, or people aged over 50 years with an underlying health condition): usual care alone; usual care plus azithromycin; and usual care plus doxycycline.[769]University of Oxford. PRINCIPLE trial. 2020 [internet publication].
https://www.principletrial.org
Ivermectin
Ivermectin, a broad-spectrum antiparasitic agent, has been shown to be effective against SARS-CoV-2 in vitro.[770]Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787.
https://www.sciencedirect.com/science/article/pii/S0166354220302011
http://www.ncbi.nlm.nih.gov/pubmed/32251768?tool=bestpractice.com
It is unclear whether the doses necessary to achieve antiviral activity against SARS-CoV-2 are attainable in humans.[771]Momekov G, Momekova D; medRxiv. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens. 2020 [internet publication].
https://www.medrxiv.org/content/10.1101/2020.04.11.20061804v2
Numerous registered clinical studies of ivermectin, either alone or in combination with other drugs (e.g., doxycycline, hydroxychloroquine), are ongoing in many countries for the treatment or prevention of COVID-19. Further research in randomised controlled trials is necessary. The National Institutes of Health guidelines panel recommends against the use of ivermectin for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Vitamin C
Vitamin C supplementation has shown promise in the treatment of viral infections.[772]Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition. 2020 Apr 21:100190.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172861/
http://www.ncbi.nlm.nih.gov/pubmed/32322486?tool=bestpractice.com
High-dose intravenous vitamin C is being trialled in some centres for the treatment of severe COVID-19.[773]ClinicalTrials.gov. Vitamin C infusion for the treatment of severe 2019-nCoV infected pneumonia. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04264533
There is no evidence to support or refute the use of vitamin C in the treatment of patients with COVID-19; however, a substantial number of trials are ongoing.[774]Baladia E, Pizarro AB, Ortiz-Muñoz L, et al. Vitamin C for COVID-19: a living systematic review. Medwave. 2020 Jul 28;20(6):e7978.
https://www.medwave.cl/link.cgi/English/Original/SystReviews/7978.act
http://www.ncbi.nlm.nih.gov/pubmed/32759894?tool=bestpractice.com
The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin C.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Vitamin D
Vitamin D supplementation has been associated with a reduced risk of respiratory infections such as influenza in some studies.[775]Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020 Apr 2;12(4).
https://www.mdpi.com/2072-6643/12/4/988/htm
http://www.ncbi.nlm.nih.gov/pubmed/32252338?tool=bestpractice.com
[776]McCartney DM, Byrne DG. Optimisation of vitamin D status for enhanced immuno-protection against Covid-19. Ir Med J. 2020 Apr 3;113(4):58.
http://imj.ie/optimisation-of-vitamin-d-status-for-enhanced-immuno-protection-against-covid-19/
http://www.ncbi.nlm.nih.gov/pubmed/32268051?tool=bestpractice.com
[777]Jakovac H. COVID-19 and vitamin D: is there a link and an opportunity for intervention? Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E589.
https://journals.physiology.org/doi/full/10.1152/ajpendo.00138.2020
http://www.ncbi.nlm.nih.gov/pubmed/32297519?tool=bestpractice.com
Vitamin D is being trialled in patients with COVID-19.[778]ClinicalTrials.gov. Vitamin D on prevention and treatment of COVID-19 (COVITD-19). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04334005
[779]ClinicalTrials.gov. COVID-19 and vitamin D supplementation: a multicenter randomized controlled trial of high dose versus standard dose vitamin D3 in high-risk COVID-19 patients (CoVitTrial). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04344041
However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[780]Centre for Evidence-Based Medicine; Lee J, van Hecke O, Roberts N. Vitamin D: a rapid review of the evidence for treatment or prevention in COVID-19. 2020 [internet publication].
https://www.cebm.net/covid-19/vitamin-d-a-rapid-review-of-the-evidence-for-treatment-or-prevention-in-covid-19/
A pilot randomised controlled trial found that high-dose calcifediol, a vitamin D3 analogue, significantly reduced the need for intensive care unit treatment in hospitalised patients, and may improve clinical outcomes.[781]Castillo ME, Entrenas Costa LM, Vaquero Barrios JM, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020 Aug 29;105751.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456194/
http://www.ncbi.nlm.nih.gov/pubmed/32871238?tool=bestpractice.com
The UK National Institute for Health and Care Excellence states that while there is no evidence to support taking vitamin D specifically to prevent or treat COVID-19, it does recommend that all people should take a vitamin D supplement daily as per UK government advice to maintain bone and muscle health during the pandemic, especially if they are not getting enough sun exposure due to shielding or self-isolating.[782]National Institute for Health and Care Excellence. COVID-19 rapid evidence summary: vitamin D for COVID-19. 2020 [internet publication].
https://www.nice.org.uk/advice/es28/chapter/Key-messages
The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin D.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Probiotics
There is emerging evidence that gut dysbiosis may have a role in the pathogenesis of COVID-19.[315]Dhar D, Mohanty A. Gut microbiota and Covid-19- possible link and implications. Virus Res. 2020 May 13;285:198018.
https://www.sciencedirect.com/science/article/pii/S0168170220304603?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/32430279?tool=bestpractice.com
[316]Zuo T, Zhang F, Lui GCY, et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology. 2020 May 19 [Epub ahead of print].
https://www.gastrojournal.org/article/S0016-5085(20)34701-6/pdf
http://www.ncbi.nlm.nih.gov/pubmed/32442562?tool=bestpractice.com
[317]Gu S, Chen Y, Wu Z, et al. Alterations of the gut microbiota in patients with COVID-19 or H1N1 influenza. Clin Infect Dis. 2020 Jun 4 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/32497191?tool=bestpractice.com
Probiotics may represent a complementary approach for the prevention or treatment of mucosal damage or inflammation through the modulation of gut microbiota; however, further research is required.[783]Mak JWY, Chan FKL, Ng SC. Probiotics and COVID-19: authors' reply. Lancet Gastroenterol Hepatol. 2020 Aug;5(8):722-3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357987/
http://www.ncbi.nlm.nih.gov/pubmed/32673605?tool=bestpractice.com
Traditional Chinese medicine
Traditional Chinese medicine is being used in patients with COVID-19 in China according to local guidelines and as part of clinical trials.[784]Yang Y, Islam MS, Wang J, et al. Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. Int J Biol Sci. 2020 Mar 15;16(10):1708-17.
https://www.ijbs.com/v16p1708.htm
http://www.ncbi.nlm.nih.gov/pubmed/32226288?tool=bestpractice.com
Hyperbaric oxygen
Preliminary evidence suggests that hyperbaric oxygen treatment has been successfully used to treat deteriorating, severely hypoxaemic patients with severe COVID-19.[785]Harch PG. Hyperbaric oxygen treatment of novel coronavirus (COVID-19) respiratory failure. Med Gas Res. Apr-Jun 2020;10(2):61-2.
http://www.ncbi.nlm.nih.gov/pubmed/32541128?tool=bestpractice.com
[786]Thibodeaux K, Speyrer M, Raza A, et al. Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series. J Wound Care. 2020 May 1;29(sup5a):S4-8.
http://www.ncbi.nlm.nih.gov/pubmed/32412891?tool=bestpractice.com
Clinical trials are currently recruiting.[787]ClinicalTrials.gov. Hyperbaric oxygen for COVID-19 patients. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04332081
[788]ClinicalTrials.gov. Safety and efficacy of hyperbaric oxygen for ARDS in patients with COVID-19 (COVID-19-HBO). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04327505
Nitric oxide
Studies indicate that nitric oxide may help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.[789]Martel J, Ko YF, Young JD, et al. Could nasal nitric oxide help to mitigate the severity of COVID-19? Microbes Infect. 2020 May 6 [Epub ahead of print].
https://www.sciencedirect.com/science/article/pii/S1286457920300800?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/32387333?tool=bestpractice.com
The FDA has approved an investigational drug application for inhaled nitric oxide to be studied in a phase 3 study of up to 500 patients with COVID-19. Other studies are currently recruiting.
Aviptadil
A synthetic form of vasoactive intestinal peptide (also known as RLF-100) has been granted an expanded access protocol (which makes the treatment available to patients who have exhausted approved therapies and who are not eligible for the current clinical trial of aviptadil) for the treatment of respiratory failure in patients with COVID-19. Intravenous and inhaled formulations are currently in phase 2 and 3 clinical trials in the US.[790]ClinicalTrials.gov. Intravenous aviptadil for critical COVID-19 with respiratory failure (COVID-AIV). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04311697
[791]ClinicalTrials.gov. Inhaled aviptadil for the treatment of non-acute lung injury in COVID-19 (AVINALI). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04360096
Icatibant
A selective bradykinin B2 receptor antagonist. A small exploratory case-control study of 9 people found an association between the administration of icatibant and improved oxygenation, suggesting that administration in the early stages of disease when patients are hypoxic may be beneficial. Treatment strategies that target the kallikrein-kinin system require further investigation in randomised trials for patients with COVID-19.[792]van de Veerdonk FL, Kouijzer IJE, de Nooijer AH, et al. Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19. JAMA Netw Open. 2020 Aug 3;3(8):e2017708.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2769237
http://www.ncbi.nlm.nih.gov/pubmed/32789513?tool=bestpractice.com
Tradipitant
A neurokinin 1 antagonist that is being trialled for the treatment of neurogenic inflammation of the lung secondary to SARS-CoV-2 infection. Interim analysis of the ODYSSEY study found that hospitalised patients improved sooner when treated with tradipitant compared with placebo. The trial is ongoing.[793]Vanda Pharmaceuticals Inc. Vanda Pharmaceuticals' interim analysis from ODYSSEY study shows tradipitant may accelerate clinical improvement in patients with COVID-19 pneumonia. 2020 [internet publication].
https://vandapharmaceuticalsinc.gcs-web.com/node/14256/pdf
[794]ClinicalTrials.gov. ODYSSEY: a study to investigate the efficacy of tradipitant in treating severe or critical COVID-19 infection. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04326426