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Frequently Asked Questions on COVID-19 Treatments

Arthur Kim, MD
Sharon R. Lewin, AO, FRACP, PhD, FAHMS
Jens D. Lundgren, MD, DMSc
Vikramjit Mukherjee, MD
Paul E. Sax, MD
Lynora Saxinger, MD, FRCPC, CTropMed
Leo Yee-Sin, MBBS, MPH, MRCP, FRCP, FAMS
Released: July 8, 2020

Questions & Answers

Do we have data on using tocilizumab with remdesivir in COVID-19?

Short Answer: Yes

Arthur Kim, MD (2/25/2021):

The REMAP-CAP trial found that a single injection of an IL-6 receptor antagonist, either tocilizumab or sarilumab, improved survival among critically ill patients with COVID-19 receiving organ support compared with receipt of usual care.[REMAP-CAP 2021] One third of patients in this study received remdesivir within 48 hours of randomization, and this proportion was similar across the control and immune modulation groups. Another recent study, the RECOVERY trial, reported that tocilizumab improved survival and other clinical outcomes in patients hospitalized with COVID-19 who had systemic inflammation and hypoxia.[RECOVERY 2020] Again, remdesivir use was equally distributed between the 2 study groups (27% tocilizumab vs 29% usual care).

In the ACTT-1 study of remdesivir vs placebo in hospitalized patients with COVID-19, remdesivir worked best in the subgroup of patients who were receiving oxygen (standard flow) but did not appear to benefit patients receiving high-flow oxygen or noninvasive mechanical ventilation.[Beigel 2020] The optimal stage of illness where one would use tocilizumab seems to be in those patients who are progressing with a high C-reactive protein (CRP) level and requiring high-flow oxygen.

Which patients are the best candidates for tocilizumab, given the cost and limited supply within the United States?

Short Answer: Guidance is evolving

Arthur Kim, MD (2/25/2021):

In the RECOVERY trial, patients hospitalized with COVID-19 were eligible to a secondary randomization to tocilizumab or usual care if they had oxygen saturation <92% on room air or were receiving oxygen, with CRP ≥75 mg/L.[RECOVERY 2020] As noted, this study found that tocilizumab improved survival. However, if we used tocilizumab in every hospitalized patient who met these criteria, we would run through our supply very quickly. I am sure many treatment centers in the United States and the United Kingdom are developing guidance on how tocilizumab should be used.

The Infectious Diseases Society of America recommends that tocilizumab may be used in hospitalized patients with either severe noncritical illness (oxygen saturation <94%) or those with critical disease (eg, on ventilation, with septic shock, or requiring extracorporeal membrane oxygenation).[Bhimraj 2021] Many patients receiving supplemental oxygen do get better on their own, and so deciding who should receive tocilizumab in that group is one of our biggest challenges. I would reserve tocilizumab for patients who appear to be progressing toward the intensive care unit (ICU) or toward needing high-flow oxygen.

Is there a role for augmented dosing of dexamethasone in patients with COVID-19 who have a high CRP level and worsening respiratory failure?

Short Answer: It is unclear

Arthur Kim, MD (2/25/2021):

Unfortunately, we do not have trial data in COVID-19 to support use of dexamethasone at a higher dose than that used in the RECOVERY dexamethasone study, which was 6 mg once daily for up to 10 days.[RECOVERY 2020 Many centers have increased the dexamethasone dose to 12 mg or higher for patients who are worsening, based on data from the DEXA-ARDS study that was conducted in patients with non–COVID-19 acute respiratory distress syndrome.[Villar 2020] This study evaluated a dexamethasone dose of 20 mg/day on Days 1-5 followed by 10 mg/day from Days 6-10 and found early use of this higher dose reduced the duration of ventilation and overall mortality.

Is there a role for serial CRP testing to assess rate of increase rather than a cutoff value in patients with worsening disease?

Short Answer: Possibly

Arthur Kim, MD (2/25/2021):

There are numerous reports from large hospital databases that have shown that large increases in CRP among patients hospitalized with COVID-19 can correlate with poor outcomes. The CRP cutoff of 75 mg/L used in the RECOVERY trial seems rather arbitrary,[RECOVERY 2021] but so does a doubling of CRP. A patient whose CRP level increases from 16 to 32 mg/L has experienced a doubling but would not represent the target population for tocilizumab use, for example. I would say that one should not rely entirely on baseline CRP for management decisions. If a patient’s baseline CRP is <75 mg/L but increases above that level, I would consider tocilizumab.

How long should treatment with dexamethasone and remdesivir be continued in appropriate patients with COVID-19?

Short Answer: Generally, 5-10 days

Arthur Kim, MD (2/25/2021):

Most patients treated with these agents will receive remdesivir for 5 days and dexamethasone for up to 10 days. In both the RECOVERY dexamethasone study and the ACTT-1 trial of remdesivir, treatment was given for up to 10 days.[RECOVERY 2020; Beigel 2020]

Treatment centers are not set up to provide outpatient administration of remdesivir at present, although studies are being designed to look at this issue.

We have extended remdesivir dosing for certain patients who are immune compromised, particularly patients with B-cell immunity defects in whom we have seen prolonged viral replication and even viral evolution. However, this is applied on a case-by-case basis in our institution; there is no rule of thumb for remdesivir extension.

At my center, we are seeing patients with a negative PCR test for SARS-CoV-2 but positive high-resolution CT scan of the lungs. Would you advise using remdesivir in such cases?

Short Answer: Depends on clinical judgement

Arthur Kim, MD (2/25/2021):

I think we have learned that testing for SARS-CoV-2 is not perfect. We have had cases at my own center where repeated swabs of the upper nasopharynx remained negative for COVID-19 even when the patient appeared to have COVID-19 and had a household contact who was positive for SARS-CoV-2 by polymerase chain reaction. Some of these patients eventually tested positive on a lower respiratory specimen. We have also had a patient who was admitted with a respiratory syndrome that we thought was COVID-19, treated with the protocol in use at that time, but turned out to have HIV infection and pneumocystis pneumonia.

I think management of these sorts of cases is highly dependent on clinical judgement. At my hospital, we require a COVID-19 diagnosis before remdesivir can be used, but perhaps exceptions can be made on a case-by-case basis.

Should dexamethasone be stopped abruptly in patients with COVID-19 or should dosing be tapered, and if so, on what schedule?

Short Answer: It varies

Arthur Kim, MD (2/25/2021):

At my center, we usually stop dexamethasone abruptly if it has been given at the 6-mg/day dose, but there are some cases where one might strongly consider a tapered discontinuation, particularly in patients with other comorbidities. For patients who are tapering back to their original dose of steroids or those who have lingering symptoms, there is a risk of adrenal insufficiency with abrupt discontinuation.

Are the currently available agents used to treat COVID-19 effective against the new SARS-CoV-2 variants?

Short Answer: It will likely depend on the type of treatment

Arthur Kim, MD (2/25/2021):

The circulation of new variants is a greater threat to the efficacy of monoclonal antibodies, particularly those that target the receptor binding domain. Some antibodies have been designed with these concerning mutations in mind,[Grand 2021] and so efficacy against circulating variants will vary depending on the product. However, new variants are a potential threat for these therapies[Wang 2021] and also possibly for use of convalescent plasma.

The emergence of new variants underlines the importance of rapid vaccine rollout in all countries and communities because reducing opportunities for this virus to be transmitted is central to controlling the evolution and spread of new mutant forms.

Roger Paredes, MD, PhD (1/14/2021):

Although there is a theoretical concern that these new variants containing multiple mutations may affect the efficacy of currently available agents to treat COVID-19, there is currently no evidence to suggest this in clinical practice. The main concern is that the monoclonal neutralizing antibodies that received emergency use authorization by the FDA may become ineffective if the mutations affect binding within the receptor-binding domain of the virus. Going forward, large monoclonal antibody trials should examine the efficacy of these agents against known circulating variants to help us fully answer this question.

Given that the WHO has issued a conditional recommendation against the use of remdesivir in hospitalized patients, are you still using remdesivir?

Short Answer: Yes

Roger Paredes, MD, PhD (1/14/2021):

Yes, we are still using remdesivir in a certain subset of patients. In my opinion, our best data for remdesivir comes from the ACTT-1 trial, which was a prospective, randomized, placebo-controlled trial.[Beigel 2020] This trial showed that patients who received remdesivir had a shorter time to recovery (the primary endpoint) than those who received placebo, and there was a trend toward reduced all-cause mortality. Of importance, the trial showed that remdesivir was most effective in the subgroup of patients with COVID-19 receiving low-flow oxygen, and thus, this is likely the subset of patients we want to target. The WHO Solidarity trial was not as powerful with its open-label study design, and it was not able to tease out the effect of remdesivir on patients receiving low-flow vs high-flow oxygen.[Dyer 2020] It is important to note, however, that remdesivir is not a magic bullet and certainly not the ultimate cure for COVID-19. In the future, we must really consider combination therapy, and it is likely that remdesivir will result in even greater efficacy when given in combination with immune modulators, such as baricitinib, and dexamethasone. Of note, the FDA issued an emergency use authorization for the combination of baricitinib and remdesivir for the treatment of COVID-19 in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.[FDA Drug Combination] In addition, recent data from the REMAP-CAP trial in the United Kingdom show that treatment with the IL-6 receptor antagonists tocilizumab or sarilumab improved outcomes, including survival, for critically ill patients with COVID-19 receiving organ support in intensive care.[REMAP-CAP] More than 80% of patients in the REMAP-CAP trial received corticosteroids, and more than 30% received remdesivir, as part of usual care. Therefore, combinations of different types of treatments are demonstrating benefit.

Vikramjit Mukherjee, MD (12/18/2020):

I understand why the WHO issued this recommendation. Data from the large, international phase III WHO SOLIDARITY trial found no benefit of remdesivir therapy in hospitalized patients, including no change in mortality, duration of hospitalization, or ventilation.[Pan 2021] As the WHO focuses on low to medium income countries, it makes sense to recommend against a medication such as remdesivir when resources may be better spent toward oxygen supplementation, steroid use, and supportive care.

However, in the US healthcare setting, I think the US-based phase III NIAID ACTT-1 trial is more relevant. Data from ACTT-1 showed that remdesivir treatment significantly improved the time to recovery and decreased the duration of hospitalization relative to placebo for hospitalized patients with COVID-19.[Beigel 2020] Here in New York City, this reduction in hospitalization was critically important when the hospitals were exceeding capacity; finding empty beds and getting people home quicker is invaluable. At my institution, we are still using remdesivir for patients who meet the ACTT-1 study criteria (SpO2 ≤ 94% on room air and admitted).

Is there a role for combination antiviral therapies with diverse viral targets in the treatment of COVID-19?

Short Answer: Unknown

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

Although this has been proposed based on treatment of HIV infection as a model, there are some important differences between an acute respiratory viral infection, such as COVID-19, and a chronic viral infection that integrates into your own cells, such as HIV. To oversimplify, with persistent infections that can relapse, the consequences of monotherapy can be severe. You might just be buying time for the pathogen to become resistant to therapy. This was observed with tuberculosis and then later with HIV. I would not anticipate the same issue with COVID-19, which is an acute, self-limiting infection.

We do not have many concerns about resistance development during the early phase of COVID-19 infection, probably because the active viral replication period is relatively short. Although it is possible that combination antiviral therapy may reduce viral load more quickly, I do not consider this approach to be the highest priority right now.

Would you recommend using tocilizumab in combination with steroids in more severe critical cases?

Short Answer: Tocilizumab should be used only in clinical trials

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

There were some promising data and many promising anecdotes for tocilizumab.[Dastan 2020; Perrone 2020; Stone 2020] At the moment, I think we are being cautious because of the possibility of more significant opportunistic infections in critically ill patients. The action of tocilizumab can be prolonged, so patients may present late with infective complications.[Morel 2017] Until we have a better understanding of the degree of benefit, it is probably best to use tocilizumab only in the context of a clinical trial because patients must be carefully monitored. The current NIH guidelines recommend against the use of IL-6 receptor antibodies, including tocilizumab, except in the context of a clinical trial.[NIH 2020]

Could early use of immunomodulators upon diagnosis in high-risk patients reduce the risk of progression to severe disease and death?

Short Answer: It depends whether the drug dampens/blocks or enhances the immune response

Sharon R. Lewin, AO, FRACP, FAHMS (10/13/2020):

In general, the first phase of COVID-19 illness is virally driven—most viral replication occurs in the first 7 days—and then if patients progress to moderate or severe disease, the pathogenesis is largely driven by immune dysfunction. Therefore, antivirals will work best early and immunomodulators that dampen or block aspects of the immune response likely provide the most benefit in the second and third weeks of infection or once a patient progresses to more severe disease.[Wiersinga 2020] This is the case for corticosteroids, such as dexamethasone. Other drugs, such as anti-IL-6 antibodies, also block aspects of the immune response.

Immunomodulatory drugs like interferon-β stimulate the immune system and function more like an antiviral; the hypothesis is that they should be given earlier. Because they activate the immune system, it could be harmful to give interferons in the setting of immune dysregulation. Therefore, when you use interferon might be very important. The data to date show benefits in terms of reduction in virus and a reduced time to symptoms. They do not show a mortality benefit for COVID-19 if administered in the first 7 days.[Rahmani 2020; Davoudi-Monfared 2020]

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

In the RECOVERY trial, dexamethasone was associated with a reduction in 28-day mortality in patients with symptoms for more than 7 days but not in those with a more recent symptom onset.[RECOVERY 2020] Whether this finding was a direct result of the steroid treatment or due to a related factor, such as an opportunistic infection, is unclear. These data suggest that in the later, inflammatory stage of the disease, the risk/benefit of steroids would appear to be most robust. If people are tempted to give steroids before the patient requires oxygen, that would not be supported by the data or current treatment guidelines.[NIH 2020]

Are high-dose steroids indicated for severe COVID-19?

Short Answer: No

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

In recent randomized trials and in the RECOVERY trial, the dexamethasone dose is relatively modest.[RECOVERY 2020] Some other trials evaluated high-dose vs lower-dose steroids, including a physiologic stress dose vs the pharmacologic dose of hydrocortisone.[Angus 2020] In the latter study, although both doses had an effect, the higher dose appeared more effective. Although we might see more data on dosing in the future, I think current data suggest that moderate dosing of corticosteroids is the best option. Dexamethasone 6 mg/day or equivalent is currently recommended.[NIH 2020]

Should convalescent plasma be screened for autoantibodies to interferon-α before being used to treat patients with COVID-19?

Short Answer: Should be considered

Sharon R. Lewin, AO, FRACP, FAHMS (10/13/2020):

Convalescent plasma is collected from people who have recovered from COVID-19, and it has an FDA Emergency Use Authorization in the United States.[FDA Convalescent Plasma] It remains under clinical evaluation in many clinical trials around the world. Theoretically, if you collected plasma from a person with type I autoantibodies to interferon and administered it to a patient with COVID-19, you may induce more severe disease.[Bastard 2020]

We do not know how long the type I autoantibodies persist yet. Currently, plasma is not widely evaluated for these type I autoantibodies. I think clinicians and researchers should consider screening convalescent plasma for autoantibodies prior to transfusion.

Which patients are indicated to receive monoclonal antibody treatments?

Short answer: Nonhospitalized patients at high risk for severe COVID-19 and/or hospitalization

Arthur Kim, MD (2/25/2021):

The neutralizing antibodies bamlanivimab and etesevimab have been studied in the phase II/III BLAZE-1 trial, which has previously reported that use of these drugs reduced SARS-CoV-2 viral load and COVID-19–related hospitalization in nonhospitalized patients with mild to moderate COVID-19.[Gottlieb 2021; Chen 2021] A second dual-antibody regimen, REGN-COV2 (casirivimab with imdevimab), was also shown to reduce viral load in nonhospitalized patients with COVID-19 in a phase I-III trial.[Weinreich 2021] Findings from a large phase III cohort of BLAZE-1 have since been reported by press release showing that bamlanivimab and etesevimab reduced hospitalization and deaths among 769 patients with mild to moderate COVID-19.[Lilly 2021]

Bamlanivimab and etesevimab received Emergency Use Authorizations (EUAs) from FDA and a positive scientific opinion from the European Medicines Agency, and casirivimab and imdevimab have also received EUAs from the FDA. However, it should be noted that neither regimen is authorized for patients with COVID-19 who are hospitalized or require oxygen therapy. A study of bamlanivimab plus remdesivir in hospitalized patients with COVID-19 was stopped early for futility.[ACTIV-3 2021]

One of the threats to the use of these antibodies is viral evolution.[Wang 2021] Monoclonal antibodies are being tested in a variety of clinical trials, so we will wait to see those data.

Jens D. Lundgren, MD, DMSc (11/19/20):

Both treatments have received Emergency Use Authorization from the FDA for use in patients with mild to moderate COVID-19 at high risk for progressing to severe COVID-19 and/or hospitalization.[FDA Bamlanivimab; FDA Casirivimab and Imdevimab] The Emergency Use Authorizations state specifically that these antibodies must not be used in hospitalized patients.

Bamlanivimab was not tested in hospitalized patients. By contrast, the casirivimab/imdevimab cocktail (REGN-COV2) was tested in hospitalized patients[NCT04426695; Regeneron REGN-COV2] and outpatients.[NCT04425629; Regeneron Outpatient] The phase II/III trial assessing REGN-COV2 in outpatients demonstrated significantly reduced viral load and patient medical visits. However, Regeneron announced in a press release at the end of October that their data and safety monitoring board recommended pausing further enrollment of hospitalized patients requiring high-flow oxygen or mechanical ventilation based on a potential safety signal and an unfavorable risk/benefit profile.[Regeneron REGN-COV2]

We do not know if this potential concern is specific to this antibody cocktail or if it is a broader problem related to monoclonal antibodies. For now, monoclonal antibodies are not recommended for hospitalized patients.

The NIH treatment guidelines are updated frequently as new research findings become available.[NIH 2020] The Guidelines Panel states that there are insufficient data to recommend either for or against the use of these monoclonal antibody treatments. Healthcare providers are encouraged to discuss participation in a clinical trial with appropriate patients. Because supplies are likely to be limited, only the patients most at risk for disease progression should receive these therapies through the Emergency Use Authorization.[NIH 2020; FDA Bamlanivimab; FDA Casirivimab and Imdevimab]

Why did the FDA broaden the Emergency Use Authorization for remdesivir to include all hospitalized patients if it was only beneficial in the subgroup of patients receiving supplemental oxygen?

Short Answer: Benefits some but not all

Paul E. Sax, MD (9/1/2020):

The subset analysis from the ACTT-1 preliminary report shows a forest plot of time to recovery according to subgroup with 127 patients in the group not receiving oxygen. The relative rate for recovery time was better with vs without remdesivir in that group, but the difference did not quite reach statistical significance (recovery rate: 1.38; 95% CI: 0.94-2.03).[Beigel 2020] The subgroup was small, which could have prevented the effect from reaching statistical significance. I think these results reflect what we think about the pathogenesis of COVID-19 and the efficacy of antiviral drugs—that earlier treatment is likely to be beneficial.

I actually favored this particular EUA expansion[FDA Remdesivir] and here is an example of why. A patient was admitted to our hospital recently who was being treated for cancer and so was immunocompromised from the chemotherapy. Although he did not require oxygen, he was SARS-CoV-2 positive and he did have infiltrates and a fever with no other clear cause. I agreed with my colleague who was managing the patient that remdesivir was appropriate in that case. I think this is the type of case where using remdesivir is justified. I do not know whether remdesivir would benefit all patients with COVID-19, but I think it is reasonable for those who are sick enough to be hospitalized.

Another phase III remdesivir study was recently published, and I will disclose that the senior author of the paper was Francisco Marti who is a colleague of mine.[Spinner 2020] Patients with moderate COVID-19 pneumonia who had decent oxygen saturations were randomized to 10 days of remdesivir (n = 197), 5 days of remdesivir (n = 199), or standard of care (n = 200). It was an open-label trial conducted at multiple hospitals in the United States, Europe, and Asia. The major positive finding was that patients assigned to 5 days of remdesivir showed a faster time to recovery compared with standard of care (odds ratio: 1.65; 95% CI: 1.09-2.48; P = .02), whereas patients assigned to 10 days of remdesivir did not (P = .18 ). It is not clear why the 10-day treatment course was not beneficial. The results of this study are supportive although not overwhelmingly favorable, and I agree with the authors who concluded that there was a statistically significant benefit in some patients who received remdesivir but not all.

Do we have data to inform combining dexamethasone and remdesivir for mechanically ventilated patients, and is that of any benefit?

Short Answer: Unknown

Paul E. Sax, MD (9/1/2020):

We currently do not know whether remdesivir augments the benefit that dexamethasone showed in mechanically ventilated patients. Remdesivir did not seem to be beneficial to that subgroup of patients in the ACTT-1 study,[Beigel 2020] but it might help if you are also giving it with dexamethasone. I think a lot of us are now actually doing that, so if you have someone who requires oxygen, and requires intubation, he or she is often receiving remdesivir and dexamethasone.

Are there any data or recommendations for the outpatient management of COVID-19? And when should one pursue more aggressive workups such as a CT angiography or transfer to the emergency department because so many patients have chest pain and shortness of breath?

Short Answer: Policy dependent

Leo Yee-Sin, MBBS, MPH, MRCP, FRCP, FAMS (8/17/20):

I think that the outpatient management of COVID-19 depends on the policies of the different healthcare settings. In Singapore, our policy is to admit every COVID-19 patient until they are either PCR negative twice, or they are completely asymptomatic up to Day 21 before we discharge them back into the community setting. I understand that some healthcare system policies only admit individuals if they require medical attention.

Chest pain is not an uncommon feature of COVID-19. We have experienced many patients with chest pain, and when we bring them into the acute care setting for ECG and other forms of testing, many have normal findings. However, I want to caution that this disease has demonstrated many phenomena about which we are still continuing to learn. From histopathology studies of postmortem cases, we learned that many patients have microthrombosis/microinfarct.[Ahmed 2020] We do not know whether these clinical symptoms of chest pain represent episodes of microinfarct. Therefore, I think it is worthwhile to monitor patients carefully.

What are your thoughts on some of the limitations of the RECOVERY trial, particularly in terms of allowing for clinician judgment on patient eligibility for the use of dexamethasone? Also, it appeared to have a higher mortality rate than we are seeing in many places in the United States.

Short Answer: Open-label, randomization valid

Jens D. Lundgren, MD, DMSc (8/4/20):

I agree with the questioner that the RECOVERY trial mortality rates were fairly high for patients receiving usual care (14% in the no oxygen group; 26% in the oxygen only group; and 41% in the invasive mechanical ventilation group).[RECOVERY 2020] There was a provision in the protocol that if physicians deemed that it was not in the best interest of the participant to be randomized into the dexamethasone arm, then they could defer away from that. However, that position was made prior to randomization, and such patients were not included in the comparison of outcomes with vs without dexamethasone; therefore, the randomization is still valid in terms of the comparison.

The RECOVERY trial was an open-label study, so that is one limitation. The benefit of the design is that it allowed many patients to be quickly randomized to usual care with (n = 2104) or without dexamethasone (n = 4321). I would like to see more information on the patients who received oxygen only, as this group includes patients ranging from those who received a few liters of supplemental oxygen to those who received high-flow oxygen. More data from other ongoing trials will further inform questions about COVID-19 treatment.

What are your thoughts on the potential efficacy or what is currently known about hydroxychloroquine or chloroquine for treating COVID-19?

Short Answer: No benefit, so let’s move on

Jens D. Lundgren, MD, DMSc (8/4/20):

I think the most balanced response to that would be that there have now been several randomized trials of hydroxychloroquine in COVID-19, ranging from prevention to early treatment to treating patients with severe disease, and none of them has shown benefit. Evidence-based medicine, therefore, indicates that hydroxychloroquine should not be used for COVID-19 outside of a clinical trial because there are no reliable data demonstrating any benefit to the patient. It is still okay to use as part of a randomized trial, if there is a specific question that remains unanswered.

At some point, we need to move on and start to focus on other opportunities. Today, the NIH launched 2 randomized trials, ACTIV-2 and ACTIV-3. ACTIV-2 will evaluate whether virus-specific monoclonal antibodies can moderate the disease course when given early in acute disease.[ACTIV-2] ACTIV-3 will evaluate several monoclonal antibodies as therapeutics for hospitalized patients with COVID-19.[ACTIV-3 2021] So maybe we want to invest our resources to get answers to these questions now rather than continue to debate hydroxychloroquine.

Do you continue dexamethasone beyond the recommended 10-day- dosing period in patients who remain hypoxic after 10 days?

Short Answer: No

Vikramjit Mukherjee, MD (7/8/2020):

I would stop dexamethasone in these circumstances. The dexamethasone dose studied in the RECOVERY trial was 6 mg/day PO or IV for 10 days or until discharge, whichever was sooner.[RECOVERY 2020] Steroids present significant risk of adverse events, including hyperglycemia, neuromuscular weakness, and delirium, which we see quite often in the ICU.[Dexamethasone PI; Warrington 2006] Dexamethasone can cause immunosuppression, putting patients at risk of secondary infections that may have significant consequences.

Are equivalent doses of other glucocorticoids such as prednisolone likely to be as effective as dexamethasone in this setting?

Short Answer: Probably

Vikramjit Mukherjee, MD (7/8/2020):

It looks like the effect of dexamethasone is a class effect. In theory, there is nothing specific about dexamethasone that other steroids do not offer as well. Dexamethasone has less to do with fluid and water retention, and that may have a benefit. But overall, there is not a huge amount of differences that dexamethasone really offers in terms of uniqueness compared with other steroids. If your hospital is running out of dexamethasone, you should consider using one of the other steroids such as prednisone or methylprednisolone or hydrocortisone in a dose-adjusted regimen.[IDSA]

Since dexamethasone has shown a benefit for patients with COVID-19, do you think other steroids like methylprednisolone or hydrocortisone might also work?

Short Answer: Still unknown, but likely

Sharon R. Lewin, AO, FRACP, FAHMS (6/23/2020):

The use of dexamethasone (6 mg once daily for up to 10 days) resulted in lower 28-day mortality in patients who were receiving either oxygen alone or with invasive mechanical ventilation (23.3% and 29.3% vs 26.2% and 41.4% with usual care, respectively).[RECOVERY 2020]

At the moment, this is the only randomized trial evidence we have regarding the use of steroids in patients with COVID-19. Although we do use steroids interchangeably, for example in the management of severe Pneumocystis pneumonia, the best practice is to follow the evidence and use the dose and duration that was shown to work in this trial. Additional studies will help us refine our approach over time.

Should dexamethasone be administered to all COVID-19 patients requiring oxygen ventilation?

Short Answer: Yes

Sharon R. Lewin, AO, FRACP, FAHMS (6/23/2020):

The use of dexamethasone (6 mg once daily for up to 10 days) resulted in lower 28-day mortality in patients who were receiving either oxygen alone or with invasive mechanical ventilation (23.3% and 29.3% vs 26.2% and 41.4% with usual care, respectively).[RECOVERY 2020] Of note, the same benefit was not observed in patients who were not receiving respiratory support.

Given this compelling evidence, I anticipate that treatment guidelines will be updated accordingly.

This result is reminiscent of Pneumocystis pneumonia, where steroids were found to play a major role only in patients with severe disease. It will be interesting to see in future studies if and how these interventions might be used in combination with antiviral drugs, for example.

What do you think about the use of ivermectin for the treatment of COVID-19?

Short Answer: Not a viable strategy at this time

Arthur Kim, MD (2/25/2021):

Earlier in the pandemic, an in vitro study showed that ivermectin inhibited replication of SARS-CoV-2,[Caly 2020] and this created a good deal of enthusiasm. Ivermectin is an antiparasitic drug used to prevent strongyloidiasis, and we did use it in patients from endemic areas who were receiving immune modulatory therapies such as dexamethasone.

Subsequent human studies have been difficult to interpret, and COVID-19 treatment guidelines from the Infectious Diseases Society of America and the National Institutes of Health agree that there is insufficient evidence to use ivermectin to treat COVID-19 at this time.[Bhimraj 2021; NIH] The manufacturer of ivermectin has also issued a statement to say that there is no evidence to support its use in patients with COVID-19 or any scientific basis for its use in this setting.[Merck]

Sharon R. Lewin, AO, FRACP, FAHMS (6/23/2020):

Ivermectin is an antiparasitic drug that is approved by the FDA for the prevention of heartworm and also has antiviral properties. Ivermectin is hypothesized to block entry of viruses like dengue and HIV into the nucleus or passaging through the cytoplasm.[Wagstaff 2012]

Investigators at Monash University and my institute, the Doherty Institute, partnered together to determine whether ivermectin could also block entry of COVID-19 in vitro and showed that ivermectin did have antiviral properties.[Caly 2020] These results were very exciting particularly given that ivermectin is so widely available due to its inclusion on the WHO list of essential medicines. Unfortunately, the dose used in these studies was a very high dose that is not feasible to achieve with current dosing strategies for ivermectin. Further study is needed to determine whether ivermectin has potent antiviral activity at lower doses or whether similar drugs may have greater potency at feasible dosing levels.

I would also like to address the preprint publication using the Surgisphere database that was released saying that ivermectin had a survival benefit. There is some question about this database, which has been involved in the retraction of articles on hydroxychloroquine from the Lancet and on ACE2 receptor blockers from the New England Journal of Medicine. I would ignore this clinical paper until is it properly peer reviewed and vetted.

Overall, I would be cautious about the role of ivermectin in the treatment of COVID-19 and would definitely not recommend using it in any form outside of clinical trial, which will not be possible until dosing is worked out.

What do you think about the use of umifenovir for the treatment of COVID-19?

Short Answer: Not a viable strategy at this time

Sharon R. Lewin, AO, FRACP, FAHMS (6/23/2020):

Influenza is an RNA virus that shares some common pathways with SARS-CoV-2, although the 2 viruses are from very different families and utilize different replication cycles.

Umifenovir is an anti-influenza drug licensed for the treatment of influenza infection in Russia and China. When COVID-19 hit China, there were several small studies evaluating any and all possible treatment options and some of those studies showed potential proof of concept that umifenovir might be effective for the treatment of COVID-19 patients.

Of importance, no randomized controlled studies have been conducted with umifenovir for the treatment of COVID-19. Use of umifenovir is, therefore, not recommended.

How do you manage asymptomatic cases?

Short Answer: Isolate and monitor

Jens D. Lundgren, MD, DMSc (6/9/2020):

If, for one reason or another, I have ordered a diagnostic test for a person who is not exhibiting symptoms of COVID-19 and the test results come back positive, then my initial step is to isolate that patient as a precaution in the case that he or she may be in the presymptomatic stage.

If the patient does not develop symptoms, I would plan a follow-up test 5-7 days later to determine whether the virus is still present.

Should patients with COVID-19 be given anticoagulation therapy (such as heparin) and for how long?

Short Answer: It’s complicated

Jens D. Lundgren, MD, DMSc (6/9/2020):

Unfortunately, there is no clear evidence on this topic. The occurrence of thromboembolic complications associated with COVID-19 is well documented and has been observed in people with moderate to serious COVID-19.[Marone 2020; Llitjos 2020; Cui 2020] In my professional experience with infectious disease, I have been very surprised to see this, particularly to such a great extent. We saw it with HIV,[Saif 2001] but it is a much more substantial feature of COVID-19.

For patients who are admitted to the hospital with moderate to severe COVID-19, we give them 1000 units of heparin if they are not in intensive care and a double dose if they are in intensive care, with a goal of preventing thromboembolic events. We do not know if that strategy is enough, but that is what we currently do in my clinic and there is a trial being designed to test this approach.

Are there data to support the efficacy of convalescent plasma?

Short Answer: No

Jens D. Lundgren, MD, DMSc (6/9/2020):

Unfortunately, we do not have a good study to inform us on the effectiveness of plasma therapy. Current approaches involve the infusion of plasma from persons who have recovered from SARS-CoV-2 infection. The issue we are seeing with this strategy is the variability in antibody response from one individual to another and even within the same individual. Plasma may have come from a person with high titers of neutralizing antibodies or someone with low titers. We have also seen that the levels from patients with high titers fluctuate over time. I, therefore, have my doubts about the broader usefulness of this strategy.

What seems more promising is the development of more standardized products that have a defined neutralizing titer. This approach will help us better understand whether passive immunization is useful in the management of acute COVID-19.

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

There have been several small trials, but they do not give a strong signal of benefit or harm.[Li 2020, Gharbharan 2020] I think there is certainly enough data to support a possible role for convalescent plasma. However, most of the data we have were done in an uncontrolled, observational fashion, so there are limits to the conclusions that can be drawn. I think that it is completely appropriate to continue studying it, but so far the data do not suggest that it will provide similar benefits to other available treatments, such as corticosteroids or early antiviral treatment. It remains a contender, but I think its role in the treatment repertoire remains uncertain.[NIH 2020]

Are there useful data on the efficacy and timing of systemic antibiotics (azithromycin, cephalosporin)?

Short Answer: No

Jens D. Lundgren, MD, DMSc (6/9/2020):

We do not have any formal data to rely on here, so I can really only speak to my own clinical experience.

With influenza, patients typically develop bacterial superinfection on Day 4-6 after symptom onset. When I saw my first COVID-19 patients, I thought they must have a bacterial superinfection like we see in influenza. Instead, we have found that the symptoms and pathology are really from SARS-CoV-2, and we do not usually find a bacterial superinfection.

In my critically ill patients, I often give systemic antibiotics empirically just in case we might have overlooked something, but each time I am surprised again to find it has no demonstrable benefit and all microbiology comes back negative.

Choice of antibacterial agent is difficult when given empirically, but I typically try to cover the Gram-positive cocci and give meropenem as the standard for patients who are admitted with serious disease. That being said, there could be arguments for alternative recommendations.

Have you heard anything about treatment in the outpatient or at-home setting?

Short Answer: Yes

Jens D. Lundgren, MD, DMSc (6/9/2020):

There is intense discussion regarding treatment in the outpatient setting for people who are early in the course of COVID-19 and may be at higher risk of hospitalization. One has to wonder if there is a window of opportunity to dampen viral replication, perhaps through passive immunization or other means, and therefore reduce the risk of developing marked COVID-19.

In terms of at-home treatment, there is some discussion about the use of anticoagulation therapy for patients who have recovered from moderate to serious COVID-19 and been discharged from the hospital. At discharge, we would typically discontinue anticoagulation, although it remains unknown whether this is the correct standard of care.

Are combination treatments using 2 or 3 drugs being investigated?

Short Answer: Yes

Vikramjit Mukherjee, MD (5/28/2020):

Despite the negative trial results using a combination of lopinavir and ritonavir to treat patients with COVID-19,[Cao 2020] results are expected from ongoing studies of 2- and 3-drug regimens that include combinations of protease inhibitors in conjunction with other treatments as well as other combinations of candidate drugs, both FDA approved and investigational.[Thorlund 2020]

Have you observed adverse events in patients treated with hydroxychloroquine and azithromycin?

Short Answer: Yes

Vikramjit Mukherjee, MD (5/28/2020):

Our hospital and one of our sister hospitals in the Bronx were trial sites for the hydroxychloroquine and azithromycin study. These data from New York are showing significant QT (Q wave to T wave) interval prolongation. We do not yet know the actual incidence of how prolonged and how frequent the arrhythmias are, but it is something to definitely watch out for.

A large retrospective, observational trial from New York showed negative results for the combination of hydroxychloroquine and azithromycin, so the risks might outweigh the benefits in this setting.[Rosenberg 2020]

Are promising therapies under investigation right now for COVID-19?

Short Answer: Yes

Vikramjit Mukherjee, MD (5/28/2020):

Remdesivir is promising, and it is the only drug we have right now to use in an evidence-based manner. It is good to have at least 1 antiviral drug that has shown some benefit. However, we need to use it carefully as you would not expect it to have a lot of benefit if it is used 2 or 3 weeks into the onset of disease. I think of remdesivir as likely similar to oseltamivir phosphate (an antiviral medicine for treatment of flu) in that it may help improve patient symptoms if used early in disease onset, but data on this are still developing.

I have a lot of interest in drugs that can blunt the immune response.[Ingraham 2020] In my practice, I see that the viral pneumonia affects patients early on in the disease, but as they stay in the ICU and go into Week 2 of their illness, the viral pneumonia becomes a silent player and the host immune response and subsequent cytokine storm causes death in many cases. A safe way to blunt that cytokine response either with an IL-6 or an IL-1 inhibitor, or more generally with steroids, would help us at the bedside.

Have you observed IV extravasations with remdesivir? Is there any information about a potential subcutaneous formulation of remdesivir in the future?

Short Answer: No.

Vikramjit Mukherjee, MD (5/28/2020):

So far, we have not noticed any infiltration and the adverse event profile has been tolerable for our patients. I think subcutaneous administration of remdesivir or another formulation that allow self-administration would greatly benefit care, as it could be used to treat patients who are not admitted to the hospital if the data show that it is beneficial in mild disease.

Do you have experience with using convalescent plasma?

Short Answer: Yes.

Vikramjit Mukherjee, MD (5/28/2020):

The use of convalescent plasma is under study. The logic is that if someone has recovered from COVID-19, the patient would have antibodies to COVID-19 and transfusing those antibodies into a suitable candidate might provide benefit to the patient with active disease. We have used it and have seen few adverse events. However, the use of convalescent plasma is off-label and there are no data yet demonstrating efficacy in COVID-19. It can only be used in the context of a clinical trial, expanded access, or a single patient emergency written request.

Do you have any thoughts on the 5-day vs 10-day regimens of remdesivir?

Short Answer: It depends

Vikramjit Mukherjee, MD (5/28/2020):

Results from the open-label, randomized phase III SIMPLE-Severe trial comparing 5-day and 10-day remdesivir regimens were recently published. The data demonstrated similar improvement in clinical status in patients with severe COVID-19 who received a 5-day or a 10-day treatment course (P = .14).[Goldman 2020] However, if a patient were critically ill in the ICU, I would prefer a 10-day course as long as there are no significant adverse events.

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

Current data suggest that 5 days is sufficient for most patients.[Spinner 2020; Goldman 2020] Whether the more severely ill patients will benefit from extending the course to 10 days remains unknown. There is no strong evidence to support extending remdesivir administration in more severely ill patients, but some clinicians may consider it if supply allows. With limited supply of remdesivir in so many places, it might make sense to provide a 5-day course for all patients based on the data. The NIH guidelines also support a 5-day course but state that it may be extended to 10 days in the absence of clinical improvement.[NIH 2020]

Are investigational therapies or biologics being studied for use in patients with COVID-19?

Short Answer: Yes.

Vikramjit Mukherjee, MD (5/28/2020):

There are more than 500 trials currently going on across the world, and we hope to have answers very soon. Biologics such as siltuximab and tocilizumab are being evaluated.[Thorlund 2020] We have used tocilizumab, which is directed against the IL-6R, on a compassionate use basis, and it is being evaluated in clinical trials. I think there will prove to be a substantial role for biologics in trying to suppress the cytokine storm.[Ingraham 2020]

I am unenthusiastic about hydroxychloroquine given the adverse event profile and the observational data coming out of New York. I hope that we will have some concrete answers on what works and what does not work before the second wave hits us.

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