THERAPEUTICS

What are possible viral targets for SARS-CoV-2 and how are novel antivirals identified?

Answered in May 10, 2020 Newsletter

  • Novel drug development can generally take upwards of a decade. Given the urgency to have treatments for COVID-19, the first wave of drug discovery has focused on repurposing existing medications. This reduces time and cost to bring a drug to market as the safety and side-effect profiles are known, and production/ distribution are already established.(1) Repurposing of existing therapies may be done using knowledge from existing coronaviruses (e.g.: remdesivir).(2)

  • The development of novel agents against SARS-CoV-2 may take the form of monoclonal antibodies, peptides, interferon therapies, or small-molecule drugs.

  • Several proteins in SARS-CoV-2 have been considered for development of novel small molecule drugs including spike, envelope, membrane, nucleocapsid, protease, hemagglutinin esterase, helicase, and other non-structural proteins.(3)

  • Monoclonal antibodies for novel therapy development against SARS-CoV-2 is an attractive option as they may be produced more quickly.(4) This strategy is being adopted by several groups, including Vancouver company AbCellera who has identified 500 antibodies as potential therapeutic candidates for COVID-19 and thus received $175 million in funding from the Canadian Government for this purpose.(5)

  1. Ekins S, Mottin M, Ramos PRPS, et al. Déjà vu: Stimulating open drug discovery for SARS-CoV-2. Drug Discovery Today. Published online April 19, 2020. doi:10.1016/j.drudis.2020.03.019 

  2. Beck BR, Shin B, Choi Y, et al. Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model. Comput Struct Biotechnol J. 2020; 18:784–79. doi:10.1016/j.csbj.2020.03.025 

  3. Bhatia R, Narang RK, Rawal RK. A Summary of Viral Targets and Recently Released PDB IDs of SARS-CoV-2. The Open Virology Journal. 2020;14(1). doi:10.2174/1874357902014010007 

  4. Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol. 2020 Mar; 38(1):10-18. doi:10.12932/AP-200220-0773

What is the evidence for non-invasive ventilation strategies in COVID-19?

Answered in May 10, 2020 Newsletter

  • There is currently no robust published evidence looking at the risks of non-invasive ventilation in patients with COVID-19 or their health care providers. 

  • There is conflicting published evidence regarding the safety of non-invasive positive pressure ventilation in terms of room air contamination and risk to staff.(1,2) The current guidelines from the WHO recommend using high flow oxygen and non-invasive ventilation with airborne precautions.(3)

  • Non-invasive ventilation has a role in the treatment of COVID-19 by reducing the need for intubation in certain patients. However, further research is needed to weigh the risks and benefits to healthcare workers and patients.(4,5)

  1. Arulkumaran N, Brealey D, Howell D, Singer M. Use of non-invasive ventilation for patients with COVID-19: a cause for concern? The Lancet Respiratory medicine. 2020. PMID: 32325017. 10.1016/s2213-2600(20)30181-8. 

  2. Heffernan DS, Evans HL, Huston JM, et al. Surgical infection society guidance for operative and peri-operative care of adult patients infected by the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2). Surgical Infections. 2020;21(4):301-308. doi:10.1089/sur.2020.101 

  3. World Health Organization. WHO Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Who [Internet]. 2020;2019(March):12.

  4. Radovanovic D, Rizzi M, Pini S, Saad M, Chiumello DA, Santus P. Helmet CPAP to Treat Acute Hypoxemic Respiratory Failure in Patients with COVID-19: A Management Strategy Proposal. Journal of clinical medicine. 2020; 9 (4). PMID: 32331217. 10.3390/jcm9041191 

  5. Winck JC, Ambrosino N. COVID-19 pandemic and non invasive respiratory management: Every Goliath needs a David. An evidence based evaluation of problems. Pulmonology. 2020.

What is the evidence for remdesivir in treating COVID-19?

Answered in May 1, 2020 Newsletter

  • Remdesivir (RDV) is an adenosine analog antiviral medication that was initially developed for the Ebola outbreak in 2016.(1) 

  • While RDV is not yet FDA approved for the treatment of SARS-CoV-2, promising preliminary research led to RDV being distributed by the manufacturer, Gilead Sciences, for compassionate use for COVID-19.(2,3) Due to high volume of requests and limited supply, Gilead Sciences ceased RDV distribution for compassionate use on March 22, 2020, to maintain availability for randomized controlled trials.(4)

  • A multinational observational study investigated patients treated with compassionate use RDV: 35 of 53 patients (68%) had clinical improvement.(5) However, this study is limited by lacking a control group, thereby significantly diminishing the quality of the evidence.

  • A randomized, double-blind, placebo-controlled trial of RDV found that of the 237 patients enrolled (158 given RDV and 79 placebo), RDV was not associated with time to clinical improvement (hazard ratio 1.23) in patients hospitalized with severe COVID-19.(6) In a subgroup analysis, they found that patients who received RVD within 10 days of symptom onset had a shorter time to clinical improvement, but this was not statistically significant.

  • Several other double-blinded, randomized, placebo-controlled trials are currently underway.(7,8,9,10)

  1. Amirian S, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health. 2020;9:100128.

  2. Choy K-T, Wong AY-L, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786.

  3. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. bioRxiv [preprint]. 2020. [posted 2020 April 22; accessed 2020 April 27].

  4. Hillaker E, Belfer JJ, Bondici A, et al. Delayed initiation of remdesivir in a covid-19 positive patient. Pharmacotherapy. 2020 April 13. [Epub ahead of print].

  5. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. New Engl J Med. 2020 April 10. [Epub ahead of print].

  6. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 [Epub ahead of print]

  7. National Institute of Allergy and Infectious Diseases (NIAID). A multicentre, adaptive, randomized blinded controlled trial of the safety and efficacy of investigational therapeutics for the treatment of COVID-19 in hospitalized adults. ClinicalTrials.gov. Published 21 February 2020. Last updated 27 April 2020. Accessed 27 April 2020.

  8. Gilead Sciences. A phase 3 randomized study to evaluate the safety and antiviral activity of remdesivir (GS-5734TM) in participants with severe coronavirus disease (COVID-19). Published 3 March 2020. Last updated 24 April 2020. Accessed 27 April 2020.

  9. Gilead Sciences. A phase 3 randomized study to evaluate the safety and antiviral activity of remdesivir (GS-5734TM) in participants with moderate coronavirus disease (COVID-19) compared to standard of care. Published 3 March 2020. Last updated 24 April 2020. Accessed 27 April 2020.

  10. Sunnybrook Health Sciences Centre Toronto. A Multi-centre, Adaptive, Randomized, Open-label, Controlled Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Patients. ClinicalTrials.gov. Published 01 April 2020. Accessed 08 April 2020.

Does the use of intranasal steroids (e.g.: for allergic rhinitis) influence the risk of acquiring COVID-19? What is the evidence for other respiratory viruses?

Answered in May 1, 2020 Newsletter

  • Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI) maintain that, in the current pandemic, intranasal steroid prescribing should be continued as per usual standard of care.(1) This recommendation is based on expert opinion and anecdotal evidence from Wuhan.  Proposed harms of avoiding intranasal steroids when indicated include increased sneezing which may perpetuate virus spread in asymptomatic carriers, as well as the risk of mistaking allergic rhinitis for COVID-19.

  • No other data exist in COVID-19 or other coronavirus outbreaks with regards to intranasal steroid use and susceptibility to infection.

  • Existing safety data for both acute and chronic use of intranasal steroids suggests no increased risk of infection and no significant systemic absorption.(2) 

  • In a trial of intranasal steroids for common cold symptoms in healthy young adults, intranasal steroid use was associated with prolonged shedding of viable rhinovirus as determined by growth in cell culture, but no difference in rhinovirus detection by PCR.(3) As well, intranasal steroid use did not significantly impact severity or duration of symptoms.

  1. Bousquet J, Akdis C, Jutel M, et al. Intranasal corticosteroids in allergic rhinitis in COVID-19 infected patients: An ARIA-EAACI statement. Allergy. March 2020.  

  2. Demoly P. Safety of intranasal corticosteroids in acute rhinosinusitis. Am J Otolaryngol. 2008. 29(6): 403–413.

  3. Puhakka T, Mäkelä MJ, Malmström K, Uhari M, Savolainen J, Terho EO, et al. The common cold: Effects of intranasal fluticasone propionate treatment. J Allergy Clin Immunol. 1998 Jun;101(6):726–31.

Is there any evidence regarding the use of inhaled bronchodilators for the management of COVID-19?

Answered in May 1, 2020 Newsletter

  • There is presently no published evidence regarding the use of inhaled bronchodilators for the management of SARS-CoV-2, MERS-CoV or SARS-CoV.

  • Limited evidence is published on the utility of inhaled or intravenous bronchodilators in patients with ARDS.(1) The BALTI-2 trial(2) (n=273) and the ALTA trial(3) (n=282) are randomized controlled trials studying the use of intravenous and inhaled bronchodilators respectively, for the treatment of ARDS. Despite biological plausibility, there was no mortality benefit and both trials were terminated early due to adverse effect or futility.(1,2,3)

  • Evidence for the use of bronchodilators in pneumonia is extrapolated from the treatment of acute cough or acute bronchitis with bronchodilators, which showed limited utility. The Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community acquired pneumonia do not mention the use of bronchodilators for treatment of pneumonia.(4)

  1. Bassford CR, Thickett DR, Perkins GD. The rise and fall of β-agonists in the treatment of ARDS. Crit Care. 2012;16(2):208.  

  2. Smith FG, Perkins GD, Gates S, et al. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet. 2012;379(9812):229-235.  

  3. Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, et al. Randomized, placebo-controlled clinical trial of an aerosolized β2-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184(5):561–8.  doi: 10.1164/rccm.201012-2090OC. 

  4. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med. 2019;200(7):E45–67.doi: 10.1164/rccm.201908-1581ST.

What is the evidence for vitamin D supplementation in preventing or treating COVID-19?

Answered in April 24, 2020 Newsletter

  • Vitamin D has been speculated to have protective effects against SARS-CoV-2 infection due to its immunomodulatory properties and potential antiviral effects.(1)

  • Recent epidemiological studies suggest that hypovitaminosis D is associated with higher rates of COVID-19 attributed morbidity and mortality.(2,3,4) However, the evidence from these studies is weak due to significant difficulties with case ascertainment and confounder bias.

  • Two randomized controlled trials in Europe will soon be investigating the role of vitamin D supplementation in mitigating COVID-19 attributed mortality and morbidity.(5,6,7) 

  • There is currently no recommendation for vitamin D supplementation in preventing or treating COVID-19. As part of good general health, it is recommended to supplement your diet with the daily recommended dose of vitamin D if you are at risk for deficiency.

  1. Hughes DA, Norton R. Vitamin D and respiratory health. Clinical and Experimental Immunology. 2009;158(1):20-25.

  2. Alipio MM. Do latitude and ozone concentration predict Covid-2019 cases in 34 countries? medRxiv [preprint]. 2020. medRxiv [preprint]. [posted 2020 April 14; accessed 2020 April 20]. 

  3. Braiman M. Latitude dependence of COVID-19 mortality rate - a possible relationship to vitamin D deficiency? SSRN [preprint]. 2020. SSRN. [posted 2020 March 26; accessed 2020 April 20]. 

  4. Ilie PC, Stefanescu S, Smith L. The role of Vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Research Square [preprint]. Research Square [posted 2020 April 08; accessed 2020 April 20]. 

  5. University Hospital, Angers. COVID-19 and vitamin D supplementation: a multicenter randomized controlled trial of high dose versus standard dose vitamin D3 in high-risk COVID-10 patients (CoVitTrial). ClinicalTrials.gov. Published 14 April 2020. Accessed 20 April 2020. 

  6. University Hospital, Lille. Impact of zinc and vitamin D3 supplementation on the survival of aged patients infected with COVID-19 (ZnD3-CoVici) ClinicalTrials.gov. Published 17 April 2020. Accessed 20 April 2020. 

  7. Universidad de Granada. Vitamin D on prevention and treatment of COVID-19 (COVITD-19). ClinicalTrials.gov. Published 3 April 2020. Accessed 20 April 2020.

Many COVID-19 investigational therapies are only available through clinical trials. What ethical issues should be considered for populations that face barriers to trial enrolment?

Answered in April 24, 2020 Newsletter

  • Randomized controlled trials (RCTs) are often organized through urban tertiary care centres with online support, thus excluding rural populations and those without reliable internet connection. Other perceived enrollment barriers include, but are not limited to, patient socioeconomic status and ethnicity.(1,2)

  • Research is expedited during outbreaks and this can create additional ethical difficulties, especially regarding community acceptability of randomization and placebo control. The West African Ebola epidemic reinforced the notion that local political will was essential for successful completion of clinical trials.(3)

  • Providing experimental medications on compassionate grounds to those unable to participate in controlled trials should not be done without consideration of risks including potential for drug adverse reactions and harm, lack of adequate monitoring, and the limitation of drug availability for formal trials.(4,5)

  1. Wong AR, Sun V, George K, Liu J, Padam S, Chen BA, et al. Barriers to Participation in Therapeutic Clinical Trials as Perceived by Community Oncologists. JCO Oncol Pract. 2020;JOP.19.00662. 

  2. Quinn SC, Kumar S. Health inequalities and infectious disease epidemics: A challenge for global health security. Biosecurity and Bioterrorism. 2014;12(5):263–73.doi: 10.1089/bsp.2014.0032 

  3. Beavogui AH, Delamou A, Yansane ML, Konde MK, Diallo AA, Aboulhab J, et al. Clinical research during the Ebola virus disease outbreak in Guinea: Lessons learned and ways forward. Clin Trials. 2016;13(1):73–8. 

  4. Raus K. An analysis of common ethical justifications for compassionate use programs for experimental drugs. BMC Med Ethics [Internet]. 2016;17(1):1–9. 

  5. Rosenblatt M, Kuhlik B. Principles and challenges in access to experimental medicines. JAMA. 2015;313(20):2023-2024.

How do COVID-19 guidelines address Advanced Care Planning and what resources are available?

Answered in April 24, 2020 Newsletter

  • Most COVID-19 treatment guidelines do not specifically address Advance Care Planning (ACP).

  • In general, outpatient ACP discussions increase concordance of patient preference with care received, increase Advance Directive completion, and improve patient and family perception of end-of-life discussions.(1,2,3)

  • The current pandemic reinforces the notion that ACP discussions are a fundamental aspect of outpatient family medicine, especially for patients with life-limiting conditions.

  • To facilitate ACP discussions over phone or videoconference, in the context of the SARS-CoV-2 pandemic, a two page handout is available here.  For additional ACP resources relating to COVID-19, please see Speak Up Canada and Virtual Hospice Canada. 

  1. Houben CHM, Spruit MA, Groenen MTJ, Wouters EFM, Janssen DJA. Efficacy of advance care planning: a systematic review and meta-analysis. J Am Med Dir Assoc. 2014 Jul;15(7):477–89.  

  2. Jimenez G, Tan WS, Virk AK, Low CK, Car J, Ho AHY. Overview of Systematic Reviews of Advance Care Planning: Summary of Evidence and Global Lessons. J Pain Symptom Manage. 2018 Sep 1;56(3):436-459.e25.  

  3. Sævareid TJL, Thoresen L, Gjerberg E, Lillemoen L, Pedersen R. Improved patient participation through advance care planning in nursing homes-A cluster randomized clinical trial. Patient Educ Couns. 2019;102(12):2183–91.

Does the BCG vaccine mitigate COVID-19?

Answered in April 17, 2020 Newsletter

  • The Bacille Calmette-Guérin (BCG) vaccine is speculated to have protective effects against SARS-CoV-2 infection due to its non-specific immune-boosting effects, termed “trained immunity”.(1)

  • Recent epidemiological studies in preprint have demonstrated a possible association between neonatal BCG vaccination and lower rates of COVID-19 attributable deaths.(2,3,4,5)

  • Currently the WHO does not recommend BCG vaccination for prophylaxis against SARS-CoV-2 because these studies are limited by possible confounder bias and case ascertainment bias. Caution is important since redistribution of the BCG vaccine could be detrimental to TB endemic countries.(6) 

  • The WHO is planning for further recommendations based on the findings of two ongoing randomized controlled trials investigating the efficacy of prophylactic BCG administration in healthcare workers exposed to COVID-19.(6,7,8)

  1. Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang Sy, Oosting M, et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe. 2018;23(1):89-100. 

  2. Berg MK, Yu Q, Salvador CE, Melani I, Kitayama S. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. medRxiv [preprint]. 2020. [posted 2020 April 7; cited 2020 April 15]. 

  3. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv [preprint] 2020. [posted 2020 March 28; cited 2020 April 15]. 

  4. Sala G, Miyakawa T. Association of BCG vaccination policy with prevalence and mortality of COVID-19. MedRxiv [preprint] 2020. [posted 2020 April 06; cited 2020 April 15]. 

  5. Shet A, Ray D, Malavige N, Santosham M, Bar-Zeev N. Differential COVID-19-Attributable Mortality and BCG Vaccine Use in Countries. MedRxiv [preprint] 2020. [posted 2020 April 06, cited 2020 April 15].

  6. World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19 [Internet]. WHO. Published 12 April 2020. Cited 15 April 2020.

  7. UMC Utrecht. Reducing health care workers absenteeism in COVID-19 pandemic through BCG vaccine (BCG-CORONA). ClinicalTrial.gov. Published 31 March 2020. Accessed 13 April 2020.

  8. Murdoch Childrens Research Institute. BCG vaccination to protect healthcare workers against COVID-19 (BRACE). ClinicalTrial.gov. Published 31 March 2020. Accessed 13 April 2020.

What is the evidence for heparin and other anticoagulants to prevent thrombotic complications of COVID-19? 

Answered in April 17, 2020 Newsletter

  • Current Canadian guidelines recommend VTE prophylaxis in hospitalized patients with COVID-19, as per standard of care, with preference for low molecular weight heparin (LMWH). LMWH is preferred over novel oral anticoagulants (NOACs) and warfarin due to superior outcomes among critically ill patients, less drug-drug interactions, and a hypothesized anti-inflammatory effect.(1,2) 

  • One group found rates of thrombotic complications in COVID-19 patients approaching 31% despite heparin prophylaxis. However, further research is needed to warrant a deviation from standard prophylaxis.(3) 

  • A retrospective review of 449 COVID-19 patients found no difference in mortality between patients taking heparin and those who did not. However, high-dose heparin was associated with mortality reduction among patients with significantly elevated D-dimer and signs of “sepsis-induced coagulopathy”. The latter includes alterations in prothrombin time, platelet count, and sequential organ failure assessment.(4) 

  • International guidelines suggest heparin or LMWH prophylaxis for all admitted COVID-19 patients, not just the critically ill.(5) 

  • No results are yet available from large RCTs that assess the efficacy of different therapeutic anticoagulation regimens in COVID-19.

  1. Public Health Agency of Canada. 7.3 Prevention of complications. Table 2 - prevention of complications in critically ill patients. In: Clinical Management of Patients with Moderate to Severe COVID-19 - Interim Guidance.; 2020.

  2. Hunt B, Retter A, McClintock C. Practice guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19. International Society on Thrombosis and Haemostasis. March 2020. 

  3. Klok et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. [In Press]. Thrombosis Research. 10 April 2020. 

  4. Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. April 2020.

  5. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. March 2020.

Over the last few weeks, new evidence has emerged on hydroxychloroquine in the treatment of COVID-19. What do these studies show?

Answered in April 17, 2020 Newsletter

  • A RCT involving 62 patients studied hydroxychloroquine for mild COVID-19 pneumonia and reported significant radiologic improvement, but only a small, albeit statistically significant, clinical benefit (one day reduction in duration of fever and cough).(1)

  • A retrospective chart review comparing outcomes of COVID-19 patients with or without hydroxychloroquine within 48 hours of hospitalization found no difference in mortality or critical illness.(2)

  • The high-dose chloroquine arm of a clinical trial that combined chloroquine with azithromycin in hospitalized COVID-19 patients was terminated early due to increased mortality (two deaths from ventricular tachycardia) and cardiac toxicity (QTc >500 ms in 25%).(3) 

  • A case series of patients treated with hydroxychloroquine and azithromycin failed to show improved viral clearance or clinical benefit.(4)

  1. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv [Preprint]. 2020 Apr 10;2020.03.22.20040758.

  2. Mahevas M, Tran V-T, Roumier M, Chabrol A, Paule R, Guillaud C, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. medRxiv [Preprint]. 2020 Apr 14;2020.04.10.20060699. 

  3. Borba M, Val F de A, Sampaio VS, Alexandre MA, Melo GC, Brito M, et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). medRxiv [Preprint]. 2020 Apr 11;2020.04.07.20056424.

  4. Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Médecine Mal Infect [Internet]. 2020 Mar 30 [cited 2020 Apr 14].

What clinical trials for treatment of COVID-19 are currently ongoing in Canada?

Answered in April 10, 2020 Newsletter

  • The Solidarity trial is a global initiative led by the World Health Organization to investigate four treatment options (remdesivir, lopinavir/ritonavir +/- interferon beta-1, and chloroquine or hydroxychloroquine) against standard of care to assess their effectiveness against COVID-19.(1) CATCO, the Canadian arm, will soon be recruiting hospitalized patients to evaluate lopinavir/ritonavir.

  • The REMAP-CAP trial is an international adaptive trial that evaluates numerous therapies (including steroids, monoclonal antibodies, antibiotics and antivirals) for the management of severe community-acquired pneumonia and was recently extended to include therapies for COVID-19.(3)

  • Canadian Blood Services announced earlier this April they will be launching a trial to study the use of convalescent plasma for the treatment of COVID-19, and are in the process of securing Health Canada approval.(4)

  1. Sunnybrook Health Sciences Centre Toronto. A Multi-centre, Adaptive, Randomized, Open-label, Controlled Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Patients. ClinicalTrials.gov. Published 01 April 2020. Accessed 8 April 2020.

  2. University of Minnesota. A Multi-centre, Adaptive, Randomized, Open-label, Controlled Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Patients. ClinicalTrials.gov. Published 16 March 2020. Accessed 8 April 2020.

  3. MJM Bonten. Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia. ClinicalTrials.gov. Published 13 April 2016. Accessed 8 April 2020. 

  4. Canadian Blood Services. COVID-19 convalescent plasma for patients [Internet]. CBS. Published 2 April 2020. Cited 8 April 2020.

Is there any evidence for zinc in the treatment of COVID-19?

Answered in April 10, 2020 Newsletter

  • In vitro, zinc inhibited SARS-CoV-1 RNA polymerase activity and viral replication.(1) The applicability of this study is limited by its use of likely supraphysiologic zinc concentrations and an ionophore to increase cellular zinc levels. It is not known if similar effects would be seen for SARS-CoV-2.

  • Zinc deficiency impairs immune response.(2) Low serum zinc correlated with all-cause mortality in an observational study of elderly patients living in a personal care home.(3) In areas of the developing world where zinc deficiency is endemic, supplementation has shown benefit in some situations such as decreasing childhood pneumonia incidence.(4,5) 

  • In the setting of critical illness, low serum zinc is frequently demonstrated without correlation to clinical outcome.(6,7) It is not known whether supplementation would confer benefit in cases of severe COVID-19.

  • Frequent zinc lozenges have been shown to reduce the duration of common cold symptoms in adults.(8,9) However, as coronavirus is only responsible for a minority of colds, the majority being due to rhinovirus, the efficacy of zinc supplementation in mild COVID-19 is unclear.

  1. Velthuis AJW te, Worm SHE van den, Sims AC, Baric RS, Snijder EJ, Hemert MJ van. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLOS Pathog. 2010 Nov 4;6(11):e1001176.

  2. Hojyo S, Fukada T. Roles of Zinc Signaling in the Immune System. J Immunol Res. 2016;2016:6762343.

  3. Meydani SN, Barnett JB, Dallal GE, Fine BC, Jacques PF, Leka LS, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. 2007 Oct;86(4):1167–73.

  4. Roth DE, Richard SA, Black RE. Zinc supplementation for the prevention of acute lower respiratory infection in children in developing countries: meta-analysis and meta-regression of randomized trials. Int J Epidemiol. 2010 Jun;39(3):795–808.

  5. Mayo-Wilson E, Junior JA, Imdad A, Dean S, Chan XHS, Chan ES, et al. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. Cochrane Database Syst Rev. 2014 May 15;(5):CD009384.

  6. Linko R, Karlsson S, Pettilä V, Varpula T, Okkonen M, Lund V, et al. Serum zinc in critically ill adult patients with acute respiratory failure. Acta Anaesthesiol Scand. 2011 May 1;55(5):615–21.

  7. Boudreault F, Pinilla-Vera M, Englert JA, Kho AT, Isabelle C, Arciniegas AJ, et al. Zinc deficiency primes the lung for ventilator-induced injury. JCI Insight. 2017 Jun 2;2(11).

  8. Science M, Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. CMAJ Can Med Assoc J. 2012 Jul 10;184(10):E551–61.

  9. Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage: JRSM Open [Internet]. 2017 May 2 [cited 2020 Apr 7].

What are the best management strategies for patients already on inhaled steroids or who need to start a short course of oral steroids for another indication (eg: asthma or COPD), in the setting of possible exposure to SARS-CoV-2 or confirmed COVID-19 infection?

Answered in April 10, 2020 Newsletter

  • There is presently no published evidence for the effects of inhaled or low dose oral steroids in patients with asthma or COPD in the presence of COVID-19.

 

  • Literature from SARS-COV1 and MERS, extrapolated to SARS-COV2, indicates that intravenous steroids may cause harm.(1) Of note, doses used to treat severe COVID-19 are much higher than what is typically used to treat asthma or COPD exacerbations.

  • Current guidelines by the Global Initiative for Asthma 2019 and the American Academy of Allergy, Asthma & Immunology suggest continuing inhaled corticosteroids and oral corticosteroids as indicated to treat asthma and asthma exacerbations.(2,3)

  • Reducing or stopping chronic inhaled corticosteroids increases the risk of an asthma exacerbation and severe infection (RR 2.35).(4) 

  • In the setting of suspected or confirmed COVID-19, it is recommended to avoid nebulized medications as there is the potential for increased transmission. Inhaled medications should preferentially be delivered via metered-dose inhaler with a spacer or a valved holding chamber.(5)

  1. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-475.

  2. Global Initiative for Asthma. Recommendations for inhaled asthma controller medications. Published March 19, 2020.

  3. American Academy of Allergy, Asthma & Immunology. COVID-19 and Asthma - What Patients Need to Know. Published March 23, 2020.

  4. Hartmann-Boyce J, Hobbs R. Inhaled Steroids in Asthma during the COVID-19 Outbreak. Oxford: University of Oxford; 2020. Accessed April 6, 2020.

  5. Shaker MS, Oppenheimer J, Grayson M, et al. COVID-19: pandemic contingency planning for the allergy and immunology clinic. The Journal of Allergy and Clinical Immunology: In Practice. March 2020:S2213219820302531.

What is Favipiravir and what is the evidence for its use in treating COVID-19?

Answered in April 3, 2020 Newsletter

  • Favipiravir (Avigan) is a novel RNA dependent RNA polymerase (RdRp) inhibitor that is used to treat influenza in China.(1)

  • In the preprint of a randomized study comparing Favipiravir to Umefenovir (also known as Arbidol, an influenza medication used in China and Russia), Favipiravir had a higher 7-day rate of recovery (71% vs. 56%), but did not alter mortality or need for intubation.(2)

  • Favipiravir adverse reactions include diarrhea, hepatitis, uricemia, and psychiatric symptoms.(2)

  • Results from large placebo-controlled trials are not yet available and Favipiravir is not widely available in North America.

  1. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCov) in vitro. Cell Res. 2020;30(3):269-271.

  2. Chen C, Huang J, Cheng Z, et al. Favipiravir versus arbidol for covid-19: a randomized clinical trial. medRxiv [preprint]. 2020. medRxiv 49192 [posted 2020 Mar 20; revised 2020 Mar 27; cited 30 Mar 2020].

What is the evidence for convalescent plasma in treating COVID-19?

Answered in April 3, 2020 Newsletter

  • The use of convalescent plasma for respiratory viral infections remains controversial.(1) Pooled data from SARS-CoV-1 and severe Influenza suggests that convalescent plasma decreases mortality.(2)

  • In SARS-CoV-2, two small observational studies of 5 and 10 critically-ill patients demonstrated clinical improvement and reduced viral loads after receiving convalescent plasma, with no patient deaths.(3,4)

  • Clinical trials are currently ongoing. Reasons for caution include transfusion reactions such as TRALI,(5) and theoretical risks such as antibody-dependent enhancement.(6)

  1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006 Sep;3(9):e343.

  2. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw F-M, Lim WS, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015 Jan 1;211(1):80–90.

  3. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA [Internet]. 2020 Mar 27 [cited 2020 Mar 29].

  4. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study. medRxiv. 2020 Mar 23;2020.03.16.20036145.

  5. Mora-Rillo M, Arsuaga M, Ramírez-Olivencia G, Calle F de la, Borobia AM, Sánchez-Seco P, et al. Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease contracted in Madrid, Spain. Lancet Respir Med. 2015 Jul 1;3(7):554–62.

  6. Casadevall A, Pirofski L. The convalescent sera option for containing COVID-19. J Clin Invest [Internet]. 2020 Mar 13 [cited 2020 Apr 1];130(4).

What is the evidence for pre- and post-exposure prophylaxis for preventing COVID-19?

Answered in April 3, 2020 Newsletter

  • No robust evidence is currently available for the use of any medication as pre- or post-exposure prophylaxis in COVID-19. 

  • Ongoing RCTs are examining the use of Lopinavir/Ritonavir, Hydroxychloroquine, and Arbidol in preventing COVID-19.(1,2,3)

  • Extrapolation from other coronaviruses such as MERS-CoV suggests possible benefit of antiviral prophylaxis, with one study citing 40% reduction in infection with Lopinavir/Ritonavir.(4)

  • Several articles highlight the potential for hydroxychloroquine to prevent COVID-19.(5) 

  1. Tan D. COVID-19 Ring-based prevention trial with lopinavir/ritonavir. ClinicalTrial.gov. Published March 25, 2020. Accessed March 31, 2020.

  2. Lee T, Zarychanski R, Schwartz I, Boulware D. Post-exposure prophylaxis and preemptive therapy for SARS-Coronavirus-2: A pragmatic randomized clinical trial. ClinicalTrial.gov. Published March 16, 2020. Accessed March 31, 2020. 

  3. Wang B. Clinical study of arbidol hydrochloride using for post-exposure prophylaxis of 2019-nCoV in high-risk population including medical staff. Chinese Clinical Trials Register. Published February 5, 2020. Accessed March 31, 2020

  4. Park SY, Lee JS, Son JS, Ko JH, Peck KR, Jung Y, et al. Post-exposure prophylaxis for Middle East respiratory syndrome in healthcare workers. J Hosp Infect. 2019;101(1):42–6. 

  5. Kapoor KM, Kapoor A. Role of chloroquine and hydroxychloroquine in the treatment of covid-19 infection- a systematic literature review. Pre-print. medRxiv. Published March 2020. Accessed April 1, 2020. 

What is the evidence regarding (hydroxy)chloroquine as treatment for COVID-19?

Answered in March 27, 2020 Newsletter

  • Chloroquine and hydroxychloroquine are antimalarial and anti-inflammatory agents with in vitro activity against SARS-CoV-2.(1,2)

  • Attention to these agents recently increased after Donald Trump tweeted about their potential use in treating COVID-19. His tweet referred to an open-label, non-randomized French study of 20 patients treated with hydroxychloroquine (6 patients also received azithromycin). The primary outcome was viral clearance as opposed to clinical outcome. While hydroxychloroquine was associated with improved viral clearance, this study was limited by the post-hoc exclusion of 6 treated patients with poor outcomes and the small sample size.(3)

  • Multiple large RCTs are currently ongoing worldwide and results are pending. 

  • This week, a Canadian RCT was launched in Manitoba, Quebec and Alberta looking at the use of hydroxychloroquine for post-exposure prophylaxis (PEP), and a Canadian pre-exposure prophylaxis and treatment RCT are also underway.

  1. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis [Internet]. 2020 [cited 2020 Mar 24]. 

  2. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269–71.

  3. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, 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.

Which high-yield critical care interventions are recommended in severe COVID-19 and associated acute respiratory distress syndrome (ARDS)?

Answered in March 27, 2020 Newsletter

  • Only a few retrospective studies with small sample sizes describe critical care and ventilation strategies in COVID-19.(1,2)

  • In the absence of more robust data, the Surviving Sepsis Campaign (SSC) and WHO COVID-19 guidelines support the use of ventilation with low tidal volumes (4-8 mL/kg predicted body weight), higher PEEP and plateau pressures below 30 cm H20 for COVID-19 related ARDS.(3,4)

  • Other SSC recommendations include: video-guided over direct laryngoscopy, conservative fluid strategy, norepinephrine as first-line vasopressor and target SPO2 92 to 96%.(5)

  1. Liu X, Liu X, Xu Y, et al. Ventilatory ratio in hypercapnic mechanically ventilated patients with COVID-19 associated ARDS. Am J Respir Crit Care Med. March 2020.

  2. Pan C, Chen L, Lu C, et al. Lung recruitability in SARS-CoV-2 associated acute respiratory distress syndrome: a single-center, observational study. Am J Respir Crit Care Med. March 2020.

  3. WHO. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected [Internet]. Interim Guidance. March 13, 2020. [cited 2020 Mar 25].

  4. ARDSnet. Mechanical ventilation protocol summary [Internet]. NIH NHLBI ARDS Clinical Network. 2008. [cited 2020 Mar 25].

  5. Alhazzani W, Hylander M, Arabi Y. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). [Internet]. Unedited accepted proof. Intensive Care Med. [cited 2020 Mar 25]. 

What is the evidence for interleukin-6 (IL-6) monoclonal antibodies for treating COVID-19?

Answered in March 27, 2020 Newsletter

  • Elevation of IL-6 correlates with COVID-19 severity and predicts clinical deterioration.(1)

  • Tocilizumab is an example of a recombinant humanized monoclonal antibody that binds to IL-6 receptors and inhibits IL-6 signalling.(2) It is approved for rheumatoid arthritis and cytokine release syndrome. 

  • In a recent case series of 21 patients with severe COVID-19, tocilizumab was associated with more rapid defervescence, decreased CRP, decreased oxygen requirements, and resolution of lung opacities.(3)

  • There are currently 4 clinical trials investigating anti-IL-6 monoclonal antibodies for treatment in COVID-19. No results are available yet. 

  1. Chen L, Liu H, Liu J, Liu K, Shang J, Deng Y, et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):203–8. 

  2. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome. Oncologist. 2018;23(8):943–7.DOI: 10.1634/theoncologist.2018-0028

  3. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. 2020 (pre-print). Cited March 26, 2020.

Do steroids help in the treatment of severe COVID-19?

Answered in March 21, 2020 Newsletter

  • Observational studies suggest that steroids do not provide morbidity or mortality benefit in severe COVID-19 and instead may cause harm and prolong viral shedding.(1,2,3)

  • Most guidelines recommend against the use of steroids in the management of COVID-19.(4,5)

  • Due to methodological limitations, these statements remain controversial and until large randomized controlled trials become available, certain physicians suggest that steroids may be considered exclusively among COVID-19 cases with ARDS.(6)

  1. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet Lond Engl. 2020 15;395(10223):473–5.

  2. Zhou W, Liu Y, Tian D, Wang C, Wang S, Cheng J, et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal Transduct Target Ther. 2020;5:18.

  3. [Pre-print] 2020. Impact of corticosteroid treatment in patients with coronavirus disease 2019. The Medical Journal of Australia [Internet]. [cited 2020 Mar 18].

  4. WHO. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected [Internet]. Interim Guidance. March 13, 2020. [cited 2020 Mar 17].

  5. CDC. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2020 Mar 17].

  6. Shang L, Zhao J, Hu Y, Du R, Cao B. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet Lond Engl. 2020 29;395(10225):683–4.

  7. China National Health Office Medical Letter. Notice on Issuing a New Coronavirus Pneumonia Diagnosis and Treatment Plan (Trial Implementation of Revised Fifth Edition) [Internet]. [cited 2020 Mar 19].

  8. Jin Y, Cai L, Cheng H, Deng T, Fan Y, Fang C, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Military Medical Research. 2020 [cited 2020 Mar 18]

Should patients taking ACE inhibitors (or ARBs) stop these agents and change to a new antihypertensive?

Answered in March 21, 2020 Newsletter

  • SARS-COV2 enters lung cells by binding to angiotensin-converting enzyme 2 (ACE2).(1)

  • Patients with hypertension, diabetes mellitus, and congestive heart failure are at increased risk for worse outcomes with COVID-19.(2) These conditions are indications for ACEi.

  • No studies have explicitly examined the clinical impact of ACEi on COVID-19. ACEi are theorized to increase levels of ACE2, based on preclinical and animal studies.(3,4) However, human studies do not show an increase in ACE2 with ACEi.(5)

  • Due to the lack of evidence that ACEi and ARBs change COVID-19 clinical outcomes, professional societies(6), including the Canadian Cardiovascular Society and Hypertension Canada(7) have recommended the continued use of these agents.

  1. Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV. Biochem Biophys Res Commun [Internet]. 2020;2.

  2. Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med [Internet]. 2020;1–13.

  3. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605–10.

  4. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of Angiotensin-Converting Enzyme 2 after Myocardial Infarction by Blockade of Angiotensin II Receptors. Hypertension. 2004;43(5):970–6.

  5. Walters TE, Kalman JM, Patel SK, Mearns M, Velkoska E, Burrell LM. Angiotensin converting enzyme 2 activity and human atrial fibrillation: Increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017;19(8):1280–7.

  6. Sparks M, Hiremath S. The Coronavirus Conundrum: ACE2 and Hypertension Edition [Internet]. NephJC. 2020 [cited 2020 Mar 19].

  7. Khan N. Hypertension Canada’s Statement on: Hypertension, ACE-Inhibitors and Angiotension Receptor Blockers and COVID-19 [Internet]. 2020 [cited 2020 Mar 13].

Should patients avoid NSAIDs for symptomatic management of COVID-19?

Answered in March 21, 2020 Newsletter

  • There is no published clinical evidence that NSAIDs worsen COVID-19.

  • Social media and the press have published articles advising patients to stop using NSAIDs based on anecdotal evidence from France.(1)

  • WHO officially clarified their recommendations: “WHO does not recommend against the use of ibuprofen”.(2)

  1.  Willsher K. Anti-inflammatories may aggravate Covid-19, France advises. The Guardian [Internet]. 2020.

  2.  WHO Official Twitter. Q: Could #ibuprofen worsen disease for people with #COVID19?. [Internet].

Does lopinavir-ritonavir (Kaletra) improve outcomes in patients with severe COVID-19?

Answered in March 21, 2020 Newsletter

  • To date, no therapeutics have been proven effective for treating COVID-19.

  • A RCT published in NEJM March 18 did not show any significant benefit of lopinavir-ritonavir over standard care for severe COVID-19 in time to clinical improvement (primary outcome). However, lopinavir-ritonavir was initiated a median of 12 days after onset of symptoms.(1)

  1. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalizedwith severe Covid-19. N Engl J Med. Published March 18, 2020.