Dexamethasone

On June 16th, researchers at the University of Oxford announced preliminary results from the RECOVERY trial, a large randomized open-label controlled trial, which showed that the common glucocorticoid steroid drug dexamethasone reduced mortality in COVID-19 patients requiring supplemental oxygen or mechanical ventilation.147 The results were subsequently summarized and published in the New England Journal of Medicine on July 17th.198

The trial randomized 2,104 patients to receive standard of care plus 6 mg dexamethasone daily (orally or via intravenous infusion) and 4,321 patients to receive standard care alone. Among patients receiving invasive mechanical ventilator support, dexamethasone reduced deaths by 36%, while the death rate was reduced by 18% in those who did not need a ventilator but needed supplemental oxygen. There was no mortality benefit among patients who did not need any respiratory support or supplemental oxygen.

The researchers remarked, “Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.”

The researchers went on to state, “Dexamethasone is the first drug to be shown to improve survival in COVID-19. This is an extremely welcome result. The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

An observational study published in late July suggested that levels of C-reactive protein (CRP) may help identify patients more likely to benefit from glucocorticoid therapy.176 The study found that hospitalized COVID-19 patients whose CRP level was > 20 mg/dL had significantly decreased odds of needing mechanical ventilation or dying when they were treated with glucocorticoids within 48 hours of hospital admission. In contrast, patients whose CRP level was <10 mg/dL were more likely to need mechanical ventilation or die when treated with glucocorticoids. These results derive from a retrospective observational study, which does not have the ability to prove causality. Therefore, prospective studies are needed to fully elucidate the potential of using CRP level to guide glucocorticoid treatment decisions.

Remdesivir

Remdesivir is an antiviral drug that showed promise against SARS-CoV-2 in preliminary studies. It is a prodrug of an adenosine analog that has potent antiviral activity against many RNA virus families.55 In late April, 2020, data began to emerge from controlled clinical trials testing the efficacy of remdesivir in the United States and elsewhere around the world.

In late May, results of a large randomized controlled trial (called ACTT-1) conducted by the U.S. National Institute of Allergy and Infectious Disease (NIAID) were published in The New England Journal of Medicine. The trial randomly assigned 1,059 COVID-19 patients to a 10-day course of remdesivir plus standard of care or standard of care plus placebo. The time to clinical recovery improved with remdesivir treatment: those who took remdesivir recovered in a median of 11 days, whereas those who received a placebo recovered in a median of 15 days. There was a suggestion of reduced mortality with remdesivir in the trends in the data, but there was no statistically significant reduction in mortality with remdesivir.134

Although remdesivir improved time to recovery in the ACTT-1 trial, overall mortality remained high. The researchers remarked, “… given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient. Future strategies should evaluate antiviral agents in combination with other therapeutic approaches or combinations of antiviral agents to continue to improve patient outcomes in Covid-19.”

Importantly, not all remdesivir trials have shown clear benefit. For instance, a smaller clinical trial conducted in China did not find a statistically significant effect of remdesivir on time to clinical recovery.57

At the same time the preliminary results from the ACTT-1 trial were announced via NIAID press release on April 29th, Gilead Sciences, Inc., the maker of remdesivir, announced the results of a trial that suggested a 5-day treatment course may deliver similar results as a 10-day treatment course in patients with severe COVID-19.58

Research is ongoing and will help clarify which patients may benefit most from remdesivir, and with which other drugs remdesivir should be co-administered.

Convalescent Plasma

When a person is exposed to viruses like SARS-CoV-2, their immune system responds by producing antibodies, which facilitate the recognition and elimination of the virus. After the patient recovers, antibodies typically remain in their blood and can help the immune system respond again if the patient is re-exposed to the virus in the future.

Researchers are currently investigating whether administering the antibody-rich blood plasma of people who have recovered from COVID-19 to patients who become ill with SARS-CoV-2 infection can improve their outcomes. This antibody-rich blood plasma is called convalescent plasma and may help the immune system of people with active COVID-19 respond to the virus. This approach has been used for many decades to combat infectious diseases—similar approaches were even used during the 1918 influenza pandemic.87,88

A randomized controlled trial published in early June found that convalescent plasma did not improve time to clinical improvement within 28 days overall. However, the trial did find that patients with severe (but not critical) disease experienced more frequent and faster clinical improvement compared with controls. This trial was limited by early termination, and the benefit in severe patients was derived from a secondary outcome analysis, so further trials are needed. Nevertheless, this preliminary evidence suggests that convalescent plasma administered earlier in the course of the disease may provide more benefit than if administered later when the patient is already in critical condition.154

Interim results of another study published in August provided additional support for the notion that convalescent plasma may provide a mortality benefit if administered early in the course of COVID-19 illness (ie, within 72 hours of hospital admission).199

The FDA has granted emergency use authorizations and expanded access programs for convalescent plasma.89

If you have recovered from confirmed COVID-19 and are interested in potentially donating plasma, you can contact a local hospital or visit the American Red Cross website.

Exogenous Interferon Treatment

Interferons (IFNs) are a class of cytokines released by cells, including immune cells, in response to viral infection. They induce an antiviral response and help activate and regulate antiviral immune activity.161 There are three main groups of interferons: types I, II, and III. Type I IFNs, mainly IFN-alpha [α] and IFN-beta [β], are crucial during early viral infection because they stimulate many key steps in the immune response against viral pathogens.162,163 A grossly inadequate type I IFN response to infection with SARS-CoV-2 has been observed in severe and critical patients, accompanied by persistent viral load and an exaggerated cytokine response.164

Evidence published in early 2020 showed that SARS-CoV-2 was susceptible to in vitro inhibition by treatment with recombinant type I IFNs α and β.165 An open-label trial in China in medical staff exposed to SARS-CoV-2 infection yielded some preliminary evidence that IFN-α nasal drops may be effective as a preventive therapy.166 Previous in vitro evidence suggested that the original SARS coronavirus is susceptible to treatment with IFN-β.167,168 Several studies have examined using type I IFN-based therapies, and particularly IFN-β-based targeting of SARS-CoV-2 in the hope that it can become a clinically effective treatment for COVID-19.169-173

In late July 2020, Synairgen, a UK-based biotech company, announced positive preliminary results from an early-stage clinical trial of a nebulized (inhaled into the lungs) IFN-β drug, SNG001.174,175 Results have not yet been published in a peer-reviewed journal, only announced via press release, so they should be interpreted with caution. Nevertheless, the company reported that treatment with SNG001 reduced the odds of developing severe disease by 79% compared with placebo treatment (although the 95% confidence interval was very broad: 0.04–0.97). Moreover, the study found that patients treated with SNG001 were more than twice as likely to recover during treatment than those given placebo. (Recovery was defined as “no limitation of activities" or "no clinical or virological evidence of infection.")

The study of SNG001 also found that the IFN-β-based treatment significantly reduced a measure of breathlessness compared with placebo. Median time to hospital discharge was six days among those treated with SNG001 and nine days for those who received a placebo. Patients treated with SNG001 also had nearly 4-fold greater odds of having recovered by day 28 compared with placebo-treated patients.

The completion of larger ongoing trials of IFN-based therapies is needed to bolster confidence in this treatment approach. Nevertheless, these early results are based in sound biological science and appear promising.

Immunotherapies and “Cytokine Storm” in COVID-19

As the COVID-19 pandemic unfolded around the globe, doctors and scientists suggested that an exaggerated immune response could play an important role in the pathology of severe and fatal SARS-CoV-2 infections. Subsequently, research was undertaken to investigate whether therapies targeting certain inflammatory mediators could mitigate the excessive immune response and improve the clinical course of advanced COVID-19.

When a person’s airways become infected with SARS-CoV-2, the body must mount a robust innate immune response to prevent rapid viral replication and prevent the infection from spreading to other organs and tissues. In some cases, however, the immune response to the virus may spiral out of control and do more harm than good. Evidence suggests that if the immune system does not detect SARS-CoV-2 infection early, it may respond instead in an exaggerated fashion once the virus has begun replicating in the body and the viral load is high.156 Too many immune cells infiltrate tissues where the virus is replicating and release too many pro-inflammatory signals called cytokines. These cytokines recruit even more immune cells, and the cycle propagates throughout the body. Ultimately, multiple organs and tissues become damaged or impaired due to the buildup of immune cells and their inflammatory detritus. This phenomenon is referred to as a “cytokine storm”—a fitting metaphor given the ominous and rapid clinical decline that typically accompanies this immunopathology.157

Previous studies have documented clinical manifestations of ARDS cytokine storm that resemble the progression seen in some COVID-19 cases. As of late July, the role of cytokine storm in COVID-19 is not entirely understood. Research has revealed differences in the inflammatory milieu between advanced COVID-19 and ARDS due to some other causes. One inflammatory mediator thought to contribute to cytokine storm is interleukin-6 (IL-6).59 Unfortunately, data available as of late July have suggested that targeting IL-6 may not be as effective as initially hoped.

Drugs that block IL-6 signaling received considerable attention for several months following the initial revelations that advanced COVID-19 patients experiencing cytokine storms typically had very elevated levels of this cytokine. Two drugs that target IL-6 signaling, tocilizumab (Actemra) and sarilumab (Kevzara), both of which target the IL-6 receptor, underwent extensive testing but unfortunately did not show benefit in randomized controlled trials despite promising results in early observational studies.

On July 29th, Roche, the pharmaceutical company that makes Actemra, announced preliminary results of a large Phase 3 randomized controlled trial that showed that the drug failed to improve clinical status or reduce mortality in patients hospitalized with severe COVID-19 pneumonia. 177 The results have yet to be published in a peer-reviewed journal, and Roche said they will continue to study Actemra in different settings, including in combination with antiviral drugs in patients with COVID-19.

Research on sarilumab has been similarly disappointing. A large clinical trial first showed in April that sarilumab did not benefit patients with severe (but not critical) COVID-19.159 That same trial was continued in patients with more severe disease until early July, when it was halted due to lack of efficacy. On July 2nd, Regeneron and Sanofi, the pharmaceutical companies sponsoring the study, announced that sarilumab did not significantly improve clinical status in patients with severe COVID-19 requiring mechanical ventilation.160 Other trials of sarilumab are ongoing.

The initial enthusiasm for these IL-6-targeted drugs early in the pandemic on the basis of observational studies was not borne out in more rigorous randomized controlled trials. These circumstances represent an important lesson in the context of COVID-19 and medicine in general: it is critical not to become over-enthusiastic about potential therapies on the basis of early studies with weak methodological quality. Observational studies cannot establish a causal link between an intervention and an outcome. They only establish correlations or associations. Randomized controlled trials, on the other hand, can establish causality, but they take longer to complete. As we continue to move forward through the pandemic, the medical community and the public in general must remember that good quality scientific studies take time and that we need reliable data to inform treatment decisions.

Hydroxychloroquine

The antimalarial drugs chloroquine and hydroxychloroquine received attention early in the pandemic when anecdotal reports and preclinical evidence suggested these drugs might benefit COVID-19 patients.62,63 However, as evidence continued to accumulate through May and June, enthusiasm waned and concern about side effects and lack of efficacy mounted.

On June 3rd, the first rigorous study testing whether hydroxychloroquine could prevent development of COVID-19 was published in The New England Journal of Medicine. The 821 trial participants were randomly assigned to either hydroxychloroquine or placebo and took their first dose within four days after exposure to someone known to have COVID-19. There was no statistically significant difference in incidence of COVID-19 illness in the two groups. In addition, among subjects in either group who chose to take vitamin C or zinc supplements after their exposure to someone infected with SARS-CoV-2, there was an increased risk of developing COVID-19 illness.138 Side effects were more common among those who took hydroxychloroquine, but there were no serious adverse reactions reported.135

On June 15th, the U.S. FDA revoked the emergency use authorization (EUA) it had earlier issued for hydroxychloroquine and chloroquine. The agency stated that “The totality of scientific evidence currently available indicate a lack of benefit,” and that “...in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”146

Subsequent trials have also shown that hydroxychloroquine does not provide clinical benefit in the context of COVID-19.200,201

Colchicine

Preliminary evidence published in late June 2020 suggested that colchicine, an older anti-inflammatory drug normally used to treat gout and inflammation of the tissue surrounding the heart, may improve time to clinical deterioration in hospitalized COVID-19 patients.153

Colchicine piqued the interest of doctors and scientists working in inflammation research after a 2019 study showed that, in low doses, it reduced the risk of cardiovascular events in people who had recently had a heart attack.73

Preliminary evidence suggests that SARS-CoV-2 infection may trigger inflammation in cardiac tissue. The virus is thought to damage the heart by other mechanisms as well, such as triggering endothelial dysfunction, promoting blood clotting, and impairing the lung’s ability to supply the oxygen demanded by the hard-working cardiac tissue. Some researchers think these events may be triggered in part by activation of inflammatory pathways that colchicine can inhibit, namely the NLRP3 inflammasome.74-76

As of late June 2020, several clinical trials are enrolling patients to test the effects of colchicine in COVID-19.72,74

Although colchicine is generally well tolerated, it may cause problems in people with kidney impairment. This is important in the context of COVID-19 because SARS-CoV-2 infection has been shown to cause kidney damage in some cases. This is a potential safety concern that will be clarified in the ongoing trials.

Camostat Mesylate

An enzyme called TMPRSS2 facilitates a necessary step in the process by which SARS-CoV-2 and other coronaviruses enter cells.77 Therefore, inhibitors of this enzyme have been suggested as potential modalities to limit the pathogenicity of SARS-CoV-2. Some preclinical evidence suggests the drug camostat mesylate, a TMPRSS2 inhibitor developed in Japan in the 1980s, blocks viral entry of SARS-CoV-2 and might be a viable therapeutic option.78,79

As of early May, at least three clinical trials are recruiting subjects with confirmed COVID-19 to test whether camostat mesylate can improve clinical status or time to recovery. Camostat mesylate is approved in Japan for the treatment of chronic pancreatitis and postoperative gastric reflux. It is generally well tolerated, but there have been rare reports of serious side effects.80

Other Medications

Because there are no proven medical treatments for COVID-19 or other human coronaviruses, scientists are looking to both old and new antiviral drugs in search of effective therapies. Several drugs are currently being evaluated in preliminary research. These include antiviral drugs used to treat human immunodeficiency virus (HIV) and hepatitis B and C, such as ribavirin (Ribasphere), lopinavir-ritonavir (Kaletra), and interferon beta-1b (Betaseron).62,81,82 An early-stage open-label clinical trial published in the New England Journal of Medicine on March 18th, 2020 failed to show benefit with lopinavir-ritonavir in patients with severe COVID-19.83

Another antiviral drug, favipiravir (Avigan), is also undergoing studies to determine if it is efficacious in COVID-19 patients.84,85 Preliminary results from a phase 3 trial conducted in India showed that favipiravir led to faster viral clearance and offered more clinical benefit for patients compared with standard of care. Moreover, subjects who deteriorated clinically despite taking favipiravir did not need oxygen support as soon as those not receiving favipiravir.202 However, some safety concerns have arisen related to potential for the drug to cause birth defects.86

Prone Positioning in Awake, Non-Intubated COVID-19 Patients

Although mechanical ventilation can be lifesaving in some COVID-19 patients suffering with ARDS, it is not a pleasant experience and most patients would prefer to avoid intubation if possible. One strategy that may delay or avert the need for mechanical ventilation in some COVID-19 patients is as simple as adjusting the position in which they lie on their hospital bed.

For some hospitalized but non-critical COVID-19 patients, switching from lying on their back to lying on their stomach may help their lungs absorb more oxygen and keep their blood oxygen saturation at sufficient levels to avoid intubation. The strategy calls for patients to lie on their stomachs for several hours daily while receiving supplemental oxygen via a nasal cannula. Patients lying on their stomach are said to be in the “prone position,” and those lying on their back are in the “supine position.”

Although rigorous evidence is not yet available to clarify to what extent awake prone positioning can help avert deterioration in COVID-19 patients, many hospitals now implement proning in COVID-19 patients. Early, anecdotal reports92 and observational data in ARDS due to other causes93 are encouraging. At least two clinical trials are underway to formally evaluate the potential benefit of prone positioning with high-flow nasal cannula in moderate-to-severe COVID-19 patients.94,8

Angiotensin-II Receptor Blockers (ARBs), ACE inhibitors, and COVID-19 The SARS-CoV-2 virus enters the human body by interacting with a receptor on the outside surface of cells called angiotensin converting enzyme 2 (ACE2). ACE2 is a component of the renin-angiotensin system, which plays a critical role in maintaining homeostasis. Popular blood pressure medications—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—modulate this system to control blood pressure. Examples of ACE inhibitors are lisinopril (Prinivil, Zestril) and enalapril (Vasotec); ARBs include losartan (Cozaar) and telmisartan (Micardis). When it became widely reported that ACE2 served as the receptor site for SARS-CoV-2, many people taking ACE inhibitors or ARBs grew concerned that these drugs could increase their risk of COVID-19. However, cardiology societies around the world have issued statements urging patients not to discontinue their blood pressure medications, and stating that there is no compelling evidence that these drugs increase risk of COVID-19.95,96 It is important to keep in mind that stopping a blood pressure medication does have known risks and is not advised. A systematic review published on May 15th, 2020 found that observational and retrospective data available as of mid-May did not suggest that ACE inhibitors or ARBs were associated with increased risk of infection with SARS-CoV-2 or more severe COVID-19.132 The analysis included data from two retrospective cohort studies, one case-control study, and 14 observational studies. The researchers concluded that “High-certainty evidence suggests that ACE inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients.” Emerging, preliminary evidence suggests ARBs may actually be linked with improved outcomes in COVID-19. While it is crucial to acknowledge that these findings are preliminary, a retrospective study presented (pre-peer review) in late March suggested that people who had been taking ARBs prior to developing COVID-19 were less likely to develop severe disease than people who had not been taking ARBs.97 Other preclinical and preliminary evidence supports the potential beneficial effects of ARBs in COVID-19 as well.98 As of mid-May, at least four randomized controlled trials are planned to evaluate the use of ACE inhibitors or ARBs in the treatment of COVID-19.132