“Necessity is the mother of invention.” English proverb
“primum non nocere.” (“first, do no harm.”) Thomas Sydenham, 1624-1689, “The English Hippocrates”
In the past several months there has been a flurry of activity among doctors, clinical researchers, and pharmaceutical companies trying to find a medical therapy for patients suffering with COVID-19. If you find yourself confused about what’s available and what’s promising you’ve got a pretty good grasp of the current situation—chaos.
The goal of this Germ Gem is to help clarify the current state of the art of medical therapy for COVID-19. When you consider that the pandemic that is overwhelming hospitals and precipitating panic worldwide began only a little over four months ago, it’s not too surprising that an effective treatment has yet to emerge.
This is an “all hands on deck” moment in clinical medicine. Impressive public-private partnerships between academia, governmental organizations, such as, the National Institutes of Health (NIH), the Center for Disease Control and Prevention, non-governmental organizations, along with the pharmaceutical industry are springing up and need to be encouraged further. As I discuss below, we have an urgent need now for more randomized clinical trials (RCTs), and in my view, we need a coordinating organization to facilitate patient enrollment into studies of the most promising therapies. Even as we are learning more, three things are crystal clear now: 1) currently, there are no FDA approved treatments for COVID-19; 2) finding safe and effective treatments absolutely requires carrying out RCTs; and 3) several promising therapies are on the horizon.
Amazingly, more than 300 active clinical trials are reported to be underway. In my 43 years as an infectious diseases physician, no infection—not even HIV/AIDS or Ebola—has generated anything near this level of intense interest in finding a cure. I’ve highlighted below only a select few therapeutic agents that have received the most attention.
As in the development of many treatments of infectious diseases, some drugs target the infectious agent itself—SARS-CoV-2 in the case of COVID-19—other medications aim at preventing tissue damage, and a third category of treatments are measures that support the function of vital organs. So far most of the drugs tested in the treatment of COVID-19 are repurposed medicines, that is, they are already FDA approved for use in other diseases. An advantage of using a repurposed medicine is that it has an established track record in a sizeable number of people and its safety profile has been fairly well established.
1. Antiviral agents. Chloroquine and hydroxychloroquine, drugs with a long-standing history in the prevention and treatment of malaria, block the entry of SARS-CoV-2 into cells. Both drugs have been shown to inhibit the growth of the virus in cell cultures in a research lab. Additionally, these agents have immunomodulatory properties, that is, they inhibit production of cytokines that are key mediators of inflammation. It is this activity that underlies their therapeutic role in rheumatoid arthritis and systemic lupus erythematosus. And it is this anti-inflammatory property that is thought by some to be important in preventing lung damage associated with COVID-19.
Based on the results of small studies showing efficacy of chloroquine in China, and then of hydroxychloroquine in France, a great deal of enthusiasm was generated for their use in fighting COVID-19. The researchers in the French study also reported that addition of azithromycin, an antibiotic with anti-inflammatory properties, resulted in superior viral clearance.
Despite these encouraging results, both of these studies were found to have major limitations. Upon further analyses concerns about cardiotoxicity especially with azithromycin, led experts to call for properly controlled RCTs before any of these drugs can be recommended for treatment of COVID-19. Since the early 1990s RCTs have been the gold standard for assessing the effectiveness and safety of a treatment. Randomization eliminates possible biases that can obscure the benefits or toxicities of new therapies.
Notwithstanding the recognized need for RCTs, the Food and Drug Administration (FDA) was pressured by an overly enthusiastic American president who issued an Emergency Use Authorization (EUA) on March 28 that allowed for use of the drugs to treat patients with COVID-19. Such outside influence is not only potentially dangerous, but it also undermines the fundamental integrity of the FDA. (Indeed, this issue was called out in mid-April both in the New England Journal of Medicine and in the Journal of the American Medical Association).
On April 20, the Swiss drugmaker Novartis AG announced it will test hydrochloroquine in a RCT to see if it is actually effective in treating COVID-19. And on April 21, results of a non-peer-reviewed study of hydrochloroquine in 368 patients at US Veterans Administration medical centers were reported. An association of increased mortality was found in patients treated with the drug, which highlights the importance of and need for RCTs before widespread adoption of these drugs.
To gain entry into cells of the lung SARS-CoV-2 is known to use the ACE2 receptor on the surface of host cells. This discovery stimulated discussions about whether ACE inhibitors (like lisinopril) and/or angiotensin receptor blockers (like losartan)—drugs that are widely used for a number of heart conditions and hypertension—may potentially treat COVID-19. On the other hand because they increase expression of ACE2 receptors on cells, the risk is that they might actually worsen the disease.
Another antiviral, remdesivir, an agent that had shown promise during the Ebola virus crisis, was found to have potent activity in cell cultures of SARS-CoV-2. This drug targets key enzymes of coronaviruses called polymerases. On April 16, a report from a University of Chicago Medicine trial of remdesivir stirred up great interest. The trial involved 125 COVID-19 patients (113 of whom had severe disease). At the time of the report, most of these patients had already been discharged from hospital and only two had died. Similar trials are being run at other institutions, and if the results of these studies show similar safety and efficacy, this could yield the first FDA-approved agent to treat COVID-19.
2. Immunomodulators. While the immune system plays a pivotal role in defending us against microbial invaders, it is a “double-edged sword.” Agents that target the immune system work on both edges of the sword. Those that inhibit the immune system are called immunosuppressives, whereas those that increase the immune response are called immunostimulators.
In the case of many serious infections, severe COVID-19 included, SARS-CoV-2 provokes an overactive or dysregulated immune response causing damage to vital organs, such as the lungs, sometimes culminating in death. In response to the virus, many protein mediators called cytokines are released from cells of the immune system (lymphocytes and macrophages) that play a key role in tissue damage. And when the condition is fulminant, it is referred to as a cytokine storm. (A variety of cytokines, including interleukins, tumor necrosis factors, and growth factors, may be found in the storm cloud.)
When I started my career as an infectious diseases researcher, the first cytokine called interleukin (IL) had just been discovered; it was appropriately named IL-1. At last count, we’re up to IL-38. A number of therapeutic agents have been developed that down- or up-regulate these cytokines in a variety of inflammatory diseases.
But IL-6 is the cytokine that has captured most attention in the treatment of severe COVID-19. Monoclonal antibodies that target the receptor on cells for IL-6 already existed in the form of medicines for the treatment of rheumatoid arthritis, and three of these medicines have shown promise in small studies of patients with COVID-19: tocilizumab (already approved in China to treat coronavirus patients), sarilumab, and sultiximab. Again, these preliminary results are very encouraging and point to the need for larger RCTs before their role in treatment of COVID-19 can be established.
Corticosteroids are potent immunosuppressive agents that have a long track record of value in the treatment of a variety of inflammatory diseases. These agents also have shown benefit in treatment of acute respiratory distress syndrome (ARDS), an often fatal complication of severe infections, including COVID-19. A retrospective observational study of methylprednisolone in ARDS patients in China showed apparent benefit. But based on biases in the design of this study and concern about potential harms, it is recommended that corticosteroids only be used within the context of RCTs. (One of the potential downsides of all immunosuppressive drugs is that their inhibition of immune mediators may significantly reduce the body’s ability to fight SARS-CoV-2.)
Small trials of plasma (immunoglobulin) therapy of patients with severe COVID-19 have shown promise, and recruitment of donors who recovered from COVID-19 for blood plasma (called convalescent plasma) is underway at the Mayo Clinic and by the blood donation company Vitalant in Arizona, Colorado, New Mexico and Pennsylvania. The rationale behind this treatment approach is that antibodies (immunoglobins) in the plasma of recovered COVID-19 patients when transfused into patients sickened by SARS-CoV-2 may theoretically neutralize the virus. While the idea to use plasma containing immunoglobulins that can neutralize an infectious agent isn’t new, the results of the small published trials in COVID-19 look very promising. And recruitment of plasma donors, which is no easy task, needs to be ramped up as soon as possible.
3. Supportive care. A crucial component in the management of patients with severe COVID-19 is the support of vital organs, such as the lungs, heart, and kidneys. The lungs take the biggest hit in patients with COVID-19 pneumonia, and as everyone knows from news reports, ventilators to support lung function (gas exchange) are in woefully short supply. Innovative measures are underway, however, through government programs to share ventilators, and newly designed, cost-effective ventilators are being added to the supply of ventilators.
Another form of respiratory support is ECMO, which stands for extracorporeal membrane oxygenation. The ECMO machine is similar to the heart-lung by-pass machine used in open-heart surgery. It pumps and oxygenates a patient's blood outside the body, allowing the heart and lungs to rest. When to place patients with severe COVID-19 lung disease on ECMO is under study in many centers.
The cause of death in COVID-19 is often cardiovascular, and thromboembolic disease (blood clots), kidney failure (requiring dialysis), and/or secondary bacterial infections (sepsis) also are contributory factors in fatal COVID-19. The management of many COVID-19 patients in intensive care units includes careful monitoring for all these conditions, in addition to testing experimental drugs that target the virus or the immune system.
Prospects for COVID-19 therapies. I hope this brief overview of therapeutic approaches to severe COVID-19 has left you not only with an appreciation of the complexity of the challenges of treating this infectious disease but also with admiration for clinical researchers and their associates who are in search for a cure.
Mindful of the extraordinary role that the NIH’s National Institute of Allergy and Infectious Diseases played in development of AIDS Clinical Trials Units throughout the United States, I’m hopeful that they will once again rise to a huge challenge. With their help and the untiring dedication of a large number of clinical investigators and researchers in academia and the pharmaceutical industry, I’m confident the race for a cure of COVID-19 will be won.
