May 2020 Update
Brett Moskowitz, Founder and President, Bowery Consulting
This is the second Covid-19 pandemic update from Bowery Consulting with updated information informing our understanding of the spread and effects of the disease, how to protect certain patient types from severe infection, and the direction of new drug and vaccine research. I’ve continued to monitor the news closely and to keep up with the latest scientific and medical research from experts. This includes my attendance on a Covid-19 update via virtual video conference May 12th at which a number of global medical experts spoke on public health, treatment research, and critical care management. Below is a detailed snapshot of where we are today.
Treatment Options for Covid-19
Most likely, combinations of antiviral and anti-inflammatory drugs are going to be required in order to achieve maximal benefit and provide the best outcome in patients with Covid-19
—Dan Kurtizkes, MD, PHD, Professor of Medicine Harvard Medical School
Vaccine research is ongoing and there are many candidates being studied. In the meantime, drug treatments for infected patients are a major focus since we don’t yet have proven therapies for severely ill individuals. We are beginning to understand how to attack the virus and many studies are underway looking at different options.
Antivirals
Antivirals are likely to be part of the solution here. One key to the use of antivirals is that they will need to be started soon after symptom onset (perhaps within the first 7 days or less), because once the virus begins to effect the function of the immune system, reducing virus won’t protect the lungs and other organs from the “cytokine storm” known to cause severe illness and death. There are a number of antiviral drugs being studied.
Hydroxychloroquine is already widely used for malaria, Lupus, and some auto-immune diseases. It has antiviral effects and anti-inflammatory effects in general, but has shown mixed results from small clinical trials in patients with Covid-19. And an FDA warning have been issued about the potentially dangerous effect of this drug on cardiac function. So while there is no clear info yet, randomized, placebo-controlled trials are still ongoing.
Favipiravir—a Japanese drug—is getting some attention. It is an RNA polymerase inhibitor, so it blocks one of the steps necessary for the virus to replicate in cells. A pilot study showed benefit, but larger studies are still just getting underway.
Remdesivir has shown the greatest benefit of any anti-Covid 19 drug to date and has been given a conditional approval by the FDA so can be given in the hospital setting. It is an RNA polymerase inhibitor manufactured by Gilead. In an NIH study (ACTT-1) remdesivir had a 31% reduction in time to recovery vs placebo—11 days vs 15 days. They halted the study because of the benefit. While there is no data on a potential survival advantage yet, the difference in time to recovery is significant and caused Anthony Fauci to note that this is a step forward and shows that the drug has some ability to stop the virus. The drug is being studied in moderate and severe Covid-19 patients. One drawback is that it is taken IV only—so it is only a hospital-based therapy. It has also been shown to be protective in monkeys as prophylaxis against virus. And it has shown benefit in uncontrolled studies of patients getting the drug in “compassionate use.” About 68% showed improvement with remdesivir vs 30% of similar “historical control” patients not on antiviral therapy in Wuhan. This is a difficult way to do a comparison and more studies are needed with a proper control arm. The level of effect remains in question as does the appropriate timing of treatment to maximize benefit and the potential benefit when used in combination with other drugs in development. Studies are ongoing. Also, note that remdesivir is not for patients with renal insufficiency—eGFR under 30 ml/min.
Anti-Inflammatory Drugs
The initial stage of disease is viral infection, followed by a hyperinflammatory phase that leads to and perpetuates lung injury requiring ventilation and often leading to death. This is characterized by a “cytokine storm” that is characterized by high levels of Interleuken 6 (IL-6; a protein produced by cells that acts to regulate an inflammatory response to an infection). An IL-6 receptor blocker, Tocilizumab, has shown some benefit at blocking IL-6. Another study showed no clinical benefit. Several larger studies are being done around the world. Sarilumab is another IL-6 receptor blocker. It showed potential benefit at reducing mortality. A flood of additional drugs targeting various aspects of the inflammatory cascade including several monoclonal antibodies, several JAK inhibitors, and other agents are in various stages of study.
Convalescent Serum
This promising method has been shown to have some benefit in Avian influena, H1N1 influenza and MERS. A study in JAMA showed that 4/5 patients getting serum were successfully weaned from a ventilator. Clinical trials are underway. There is some theoretical concern about a negative impact of potentially dangerous enhancing antibodies.
Targeting the Mechanisms of Disease Progression
Angiotensin converting enzyme 2 (ACE-2) is the primary receptor for the virus to invade healthy cells. When the virus binds to this receptor, it causes downregulation of receptor expression, leading to acute lung injury, adverse effects on the heart, and increased vascular issues. An increase in ACE2 expression (upregulation), on the other hand, may make things worse by allowing the virus more chances to invade cells. So while blocking this receptor is another drug target, there has to be a balance between expression and blockade of the receptor.
Data from China of about 1200 patients on an ACE inhibitor showed lower mortality among those who continued on these drugs after Covid-19 infection. In addition, a recent NEJM paper showed lower mortality in those getting an ACE inhibitor or statin and no benefit in those on ARBs (angiotensin receptor blockers). So the evidence suggests that patients should not stop taking their ACE inhibitors or statins if they are admitted to the hospital with Covid-19.
Androgens and Covid-19 in Men
In addition to ACE2, a protein called TMPRSS2 is responsible for the binding of the Covid-19 virus onto healthy cells. This protein also happens to be linked to the growth of prostate cancer cells and is regulated by the hormone called androgen which is responsible for the expression of male sex organs and other male characteristics like facial hair beginning at puberty. Much has been made of the higher percentage of severe illness and death in men compared to women of similar age and no prior health issues. New research that included more than 4000 Italian men suggests a potential relationship between higher androgen levels and Covid-19 infection or severity. The study found that males with prostate cancer being treated with androgen deprivation therapy (ADT) were less likely to become infected with COVID-19 and die from the disease than other groups, including other patients with cancer. The study investigators concluded that “cancer patients have an increased risk of SARS-CoV-2 infections than non-cancer patients. However, prostate cancer patients receiving ADT appear to be partially protected from SARS-CoV-2 infections.”
Critical Care Management of patients with Covid-19
In the ICU we were seeing mortality rates of 55% or 60%. Remember, there were relatively young people coming off the streets with barely any pre-existing comorbidities.
—Vikram Mukhurjee, MD, NYU School of Medicine, Bellevue Medical ICU, New York, NY
It is important to remember that most people infected with the virus experience only very minor symptoms or none at all—this could be as many as half of the people who are infected. We don’t have enough data to know the real numbers of asymptomatic patients, but among symptomatic patients, at least 80% have mild-to-moderate disease that does not require hospitalization. Hospitalized patients are generally (but not always) elderly and have underlying conditions. There also appears to be a 50% greater risk of severe illness for males vs females. Among patients admitted to the ICU at Bellevue in New York City, for instance, 72% were male.
Patients with severe disease usually present to the emergency department with shortness of breath (dyspnea). For those who are infected or experiencing early symptoms, it is worth considering daily monitoring of oxygen levels at home with a simple device called an Oximeter that provides results in just seconds (if oxygen <95% call your doctor or go to the emergency department). In a minority of hospitalized patients, admission to the ICU is required. In these severe cases, those with shortness of breath can progress to acute respiratory distress syndrome (ARDS), and a hyperinflammatory response from the immune system called a “cytokine storm” that can often cause lung damage, renal failure, and sometimes blood clots. Shock, renal replacement, and treacheostomy were also common in the ICU at Bellevue. These patients required ongoing ventilation and were heavily sedated. The inflammatory surge was identified by large increases in IL-6, D-Dimers (which is a marker for risk of clots), C-Reactive Protein, and ferritin. This “cytokine release syndrome” causes high fevers despite lack of infection. The type of pneumonia seen in these patients is different than the pneumonia seen with the flu where a secondary bacterial infection occurs. In the case of Covid-19, antibiotics do not appear to be effective and steroids aren’t working either. Anti IL-6 therapy has been used in New York on select patients but this treatment is not approved.
Multisystem Inflammatory Syndrome in Children
Not much is yet known about a rare multiorgan inflammatory syndrome that appears to be linked to children who have recently recovered from asymptomatic or mild Covid-19 infection. The CDC has issued information for pediatricians about the link between the syndrome and Covid-19 in children. Symptoms may begin with a persistent fever, rash, red eyes, and/or upset stomach, but they may have or develop other symptoms as well. Medical attention is required as the illness can cause inflammation of the heart and blood vessels. Treatment with steroids appears to show some benefit and the vast majority of children survive and recover quickly, but the evidence is only anecdotal at this point and no treatment has been FDA approved to treat this syndrome as of yet.
How might the pandemic end?
We need to have 2 out of 3 people already immune to see the transmission chain slow down.
— Yonatan Grad, Harvard T.H. Chan School of Public Health, Boston
There is reason to be optimistic that we will find treatments to fight the disease well before we have a vaccine. In the meantime, there is a lot we are absorbing about this infection in terms of its course and how we might stop it. We are past the point where we can eliminate the virus through case control and isolation measures. We will instead only see the end of the pandemic when we reach population immunity, which can only be done in one of two ways:
· the daunting prospect of reaching herd immunity through infection—having about 2/3 of the population acquire the infection and gain subsequent immunity in order to slow the spread considerably and effectively end the pandemic.
· We develop and widely administer a vaccine prior to reaching herd immunity.
The first option—herd immunity through widespread infection of most of the population—will cause a large number of deaths. It will collapse our healthcare infrastructure to the extent that in addition to Covid cases, people will die of other causes like heart attacks and strokes that will go untreated.
The much less damaging option is to flatten the infection curve until we have wide access to highly effective treatments and/or a proven vaccine. If we effectively implement a combination of strategies to slow the rate of infection, we will not overwhelm hospitals and other healthcare institutions while we buy more time for researchers to find the tools we need to neutralize the impact of the virus.
There is some belief that Covid-19 may be seasonal based on our experience with previous Coronaviruses. The idea is that the virus may spread at a slower rate in summer and speed back up in the fall/winter, as happened with the Spanish Flu pandemic one hundred years ago. If so, delaying the peak of new infections into winter if we stop physical distancing could make things worse since much of the population will remain susceptible to infection and the virus may spread more readily at that time. Therefore, continued monitoring of new cases, fastidious contact tracing, isolation of infected individuals, and 14-day self-quarantine of persons who have been in close contact with infected individuals will remain crucial to mitigation efforts.
I hope that this update has helped you to get a snapshot of where things stand today. In this ever-moving pandemic, there will be new discoveries on an ongoing basis. Thank you for reading and please feel free to drop me a line if you have any feedback.
Stay safe.
Brett Moskowitz
President, Bowery Consulting
May 18, 2020