Part 12 COVID-19 Knowledge Update V
One of the most important questions that we need to address as part of the ever-changing COVID-19 risk analysis is, “How well are our treatment options working?”
Therapies and Strategies: What is Working, and What We Should Explore
As new information emerges regarding the risks of mortality, long-term symptoms, transmission, and effectiveness of treatments, we need to alter our policies to account for the changing risk assessment. This is something that largely has been ignored, with positions based on predictions and assessments established early in the pandemic, before we had all the pertinent information, still holding strong.
Next, we need to critically assess our strategies on developing treatments and protocols to deal with the COVID-19 threat, rather than simply plowing forward down the same trajectory on which we started. Solving this multifactored riddle will take creative approaches — there will be no magic pill, at least not in the near future, that ends the threat entirely.
What Treatments are Effective?
A meta-analysis of seven clinical trials including 1,703 critically ill and hospitalized patients found that the administration of inexpensive, readily available corticosteroids could be effective in reducing mortality from COVID-19 (dexamethasone, hydrocortisone, or methylprednisolone). According to the results of the study, 32.7% of the critically ill patients receiving corticosteroids died compared to 41.5% of patients receiving placebo (p< 0.001).1 While it is clearly not a miraculous treatment, these relatively cheap and widely available drugs seem to be able to significantly reduce death rates. For context, the data shows that the use of corticosteroids is associated with a roughly 27% decrease in COVID-19–related deaths, which suggests that if used universally and early, this treatment could have saved tens of thousands of lives in the U.S. alone.
Notably, the treatment protocol given to President Trump included dexamethasone (as well as an experimental antibody treatment (Regeneron’s REGN-COV2), vitamin D, zinc, aspirin, melatonin, and famotidine).
Regeneron’s antibody therapy, REGN-COV2, has gained widespread media attention, especially after it was given to President Trump. Results of Regeneron’s ongoing clinical trial seem to indicate a greater, and faster, decrease in viral load and COVID-19–related symptoms, all in non-hospitalized patients.2
Regeneron is not the only antibody therapy being currently developed. Eli Lilly is also developing an antibody therapy and has released preliminary data on a placebo-controlled trial with 452 participants. This trial saw a rate of hospitalization in those receiving their treatment, named LY-CoV555, at just 1.7%, compared to 6% with placebo, which translates to a 72% reduction in hospitalizations.3 The trial also showed that viral clearance began earlier in patients receiving LY-CoV555, meaning the time the patients spent compromised to the virus was shorter.
Moreover, another lab at the University of California, San Francisco, has been developing an antibody analogous to an antibody class found in camelids, such as llamas and alpacas, which is showing to be the most potent anti-coronavirus compound tested in labs. The antibody, called a “nanobody,” is roughly one-quarter of the size of human antibodies. It is also more stable, and if proven to be effective in humans, would be far easier to administer than the antibody therapies used in late-stage human research and early clinical use. The team behind the development posted their findings on BioRxiv in August, a preprint server, meaning their findings have not yet undergone peer-review.4
As reported in Technology Networks in September, a team from the University of Pittsburgh has reported that another antibody component therapy, known as Ab8, completely neutralizes the novel coronavirus in wild-type mice. The molecule is even smaller than the llama-inspired antibody, being one-tenth the size of typical human antibodies. These research results were published in the peer-reviewed academic journal Cell.5
Blood Pressure Drugs and Heart Medications
Corticosteroids are not the only cheap and widely available drugs that have shown promise in treating COVID-19, at least for individuals already taking them for other indications. The use of blood pressure medications, specifically ACE inhibitors, has also demonstrated significant reductions in serious cases and death across a large (28,000-participant) retrospective analysis, as reported by Technology Networks.
"Covid-19 patients with high blood pressure who were taking ACEi/ARB medications were 0.67 times less likely to have a critical or fatal outcome than those not taking these medications.
"As the world braces itself for a potential second wave of the infection, it is particularly important that we understand the impact that these medications have in Covid-19 patients.
"Our research provides substantial evidence to recommend continued use of these medications if the patients were taking them already.
"However, we are not able to address whether starting such tablets acutely in patients with Covid-19 might improve their prognosis, as the mechanism of action might be different," said the lead researcher Dr. Vassilios Vassiliou.
Another Phase IV trial with ACEi meds including 659 patients from 29 sites in Brazil found that continuing prescribed doses of ACE inhibitors, opposed to discontinuing use, resulted in an additional day alive/out of hospital as compared to patients that stopped usage of their ACE inhibitors. This further establishes the safety and potential benefits of this medication for those who were already prescribed this treatment; however, it is still unknown whether the acute use of ACE inhibitor medications after infection with the novel coronavirus will result in any benefit.
Initially heralded as a potential treatment for COVID-19, due to slightly but significantly reducing patients’ time spent in the hospital in an open-label trial (meaning that there was no placebo control or blinding), Gilead Sciences generated PR claiming that they had established its beneficial effects.6 Of course, due to the nature of their trial designs, the fact that the trials were conducted privately by Gilead, and the questionable benefits from the results, these claims generated skepticism.
In a large study of 11,000 individuals with combined data from 405 hospitals in 30 countries, four potential drugs to treat COVID-19 were tested (remdesivir, hydroxychloroquine, lopinavir, and interferon-beta1a). None of these treatments demonstrated any improvement in outcomes, including death, hospitalization, length of hospitalization, or the need of ventilation.7 Although I did not intend to include drugs that “don’t work” in this article, the recency of the information regarding remdesivir trials swayed me to include it. Further, the FDA’s recent approval of remdesivir as an approved drug for COVID-19 necessitated its entry. Unfortunately, many are now touting remdesivir as a miracle cure due to this approval, when in reality the benefits of the drug for COVID-19 are questionable at best.
Hypothetical and Experimental Treatments
More research on other potential therapies is needed to explore treatment of COVID-19. A new large study, named the ACTIV-5 Big Effect Trial headed by the National Institute of Health (NIH), is currently being conducted at 40 U.S. sites and is testing multiple drugs in late development that show promise in treating COVID-19 to determine the drug candidates that should be fast tracked towards larger trials.
A team conducting microarray analysis at the Scripps Research Institute in Jupiter, Florida, has found that a small molecule, named compound 5 (CF), was able to reduce the efficiency by about 25% of the virus’s ability to translate its genes , by attacking a “hairpin” structure within the virus’ RNA. The team then sought to enhance the potency of C5 by attaching another molecule, RIBOTAC, which increased the potency of C5 by roughly 10 times.8
Notably, that there is still a long way to go before a safe drug can be developed using this strategy. That said, it shows significant promise for future drug development.
A research team from the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, published a paper in July identifying 21 drugs that work in cell cultures to stop viral replication of COVID-19.9 It is of note that one of the drugs tested was remdesivir, which has not shown convincing efficacy in humans. Moreover, four of the drugs tested seemed to work synergistically with remdesivir, so it is likely that Gilead will take heed of this and continue research on the potential use of its drug for treating COVID-19. In addition, 13 other drugs are still in clinical research for other conditions and have not yet been approved for use, with two of the drugs gaining FDA approval for other indications. These drugs include astemizole (for treatment of allergies) and clofazimine (for treatment of leprosy). Of course, results obtained using cell culture alone are insufficient to warrant the use of these drugs for COVID-19 treatment without accompanying evidence in humans; moreover, clinical research on these drugs should only be undertaken after careful consideration regarding their safety.
Another study aiming to identify potential drugs currently on the market that may be used to treat COVID-19 has concluded that amodiaquine, a malarial drug, may be as effective as remdesivir10 at a fraction of its cost. Of course, remdesivir does not seem to be as effective as a stand-alone therapy, but it may still hold promise when used in combination with other drugs.
As reported by Technology Networks, three separate teams from the University of Bristol, Technical University of Munich, Germany, and the University of Helsinki, Finland, have independently found that neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. This leads the way to potential antiviral therapies designed specifically for COVID-19 infection.
Selective Use of Autoimmune Medications
Further corroborating evidence of erratic immune and inflammatory responses to COVID-19 infection, researchers have identified that in some severe cases COVID-19 resembles lupus,11 which corresponds to previous research findings demonstrating that some serious cases of COVID-19 involve symptoms similar to those of autoimmune diseases.12 Of course, this certainly does not mean that medications used for treating lupus or other autoimmune diseases will automatically be beneficial for treatment of COVID-19.
We need to look no further than hydroxychloroquine, an antiviral drug that is also used to treat autoimmune diseases such as lupus and rheumatoid arthritis, which has been demonstrated to be ineffective against COVID-19. As discussed in Technology Networks, these new insights into the aberrant immune response in some serious cases of COVID-19 may pave the way to personalized treatment approaches, depending on how the patient is responding to the disease. In some cases, medications that have been shown to be ineffective in a broad sense may indeed be effective in certain cases. Of course, we would need more evidence of their efficacy.
Interestingly, baricitinib, a drug used to treat the autoimmune disease rheumatoid arthritis, was shown to reduce time to recovery in hospitalized COVID-19 patients, when used in combination with remdesivir.13
In one small open-label clinical trial conducted in China, hydrogen inhalation demonstrated improvements in the severity of COVID-19 symptoms.14 It seems that this study, as well as reports from physicians in China and several other ongoing clinical trials15 utilizing hydrogen inhalation, prompted China to add molecular hydrogen to their approved therapies for COVID-19 back in April.16 One of the main proponents of implementation of hydrogen inhalation for COVID-19 treatment is Dr. Nanshan Zhong, a world-renowned pulmonologist who managed the SARS crisis and who has served as a key advisor in China’s COVID-19 response. However, it is widely whispered in closed circles that he has ownership in the company that manufactures the inhalation units being sold. I cannot confirm the truthfulness of this rumor; however, the lack of clinical evidence and slow reporting of results, despite inclusion of hydrogen inhalation therapy in China’s official protocol for treatment of COVID-19, does make me suspicious and skeptical.
Molecular hydrogen has been proposed as a potential therapy for multiple organ dysfunction syndrome (MODS) caused by influenza and other viral strains,17 with a literature review also proposing it as a potential adjunct treatment for COVID-19.18 There is some justification behind the hypothesis of its effectiveness. Molecular hydrogen, administered both via inhalation and dissolved in water, has been associated with positive outcomes in survival through immune modulation in preclinical research,19,20 reduced immune dysfunction21 and neuroinflammation, and improved recovery following sickness in mice.22
Further, early small-scale human clinical research has shown potential for the use of hydrogen therapy for treatment of autoimmune diseases such as rheumatoid arthritis,23,24psoriasis,25 and psoriatic arthritis.26 Moreover, while Parkinson’s disease has not officially been classified as an autoimmune disease, despite some researchers suggesting otherwise,27,28,29 there has been some early human evidence to suggest hydrogen water having efficacy in its treatment.30 Finally, according to early human clinical evidence, hydrogen inhalation is associated with reduced effort required to breathe in patients with tracheal stenosis,31 a condition that causes narrowing of the windpipe, resulting in breathing difficulty.
It’s important to note that none of these results definitively suggest that hydrogen therapy will be effective in treating COVID-19; however, they warrant further reason for its investigation. Similar to prophylactic use of Vitamin D, I personally believe there is also sound rationale to explore prophylactic use of high-dose hydrogen water for its promising potential metabolic benefits. Various metabolic issues are some of the biggest risk factors for developing severe symptoms of COVID-19 and dying. If research continues to demonstrate the effectiveness of hydrogen water against these stressors, hydrogen water may play an important role in our fight against the coronavirus. I need to reiterate yet again — this is pure conjecture. I am simply arguing for further research to be conducted, and I’m in no way suggesting that hydrogen therapy will work — either in cases where COVID-19 develops, or prophylactically. Please, do not use the information contained in this article as justification to gain any sense of safety from the virus, or disregard advice from your health care practitioner.
I’ve previously written about the emerging and mounting evidence that vitamin D deficiency leads to worse COVID-19–related outcomes. Despite unfathomably abhorrent media reporting regarding the credibility of these findings, here is an excerpt from the editorial published in the reputable scientific journal The Lancet:
“Pending results of such trials, it would seem uncontroversial to enthusiastically promote efforts to achieve reference nutrient intakes of vitamin D, which range from 400 IU/day in the UK to 600–800 IU/day in the USA. These are predicated on benefits of vitamin D for bone and muscle health, but there is a chance that their implementation might also reduce the impact of COVID-19 in populations where vitamin D deficiency is prevalent; there is nothing to lose from their implementation, and potentially much to gain.” (my emphasis)
Some skeptics claim that vitamin D should only be taken when physician-confirmed lab tests demonstrate its deficiency, even in the winter. However, some medical guidelines and even the UK government recommends supplementation with vitamin D during the winter months, due to the lack of sunshine and inadequate dietary supplementation. Despite this advice, early unpublished data from a research team at the Queen Mary University of London shows that two of three study people are not following this advice, potentially due to the reluctance to buy and take a supplement without a test result that shows they are vitamin D–deficient. Since vitamin D deficiency is far more likely to occur than vitamin D toxicity, and most individuals are unlikely to have their blood levels of vitamin D tested, universal recommended use may be more prudent.
As more properly controlled trials roll out to investigate whether vitamin D can reduce the risk and severity of COVID-19 symptoms, including “CORONAVIT,” which seeks to enroll 5000 participants who will be given either 800 or 3200 International Units (IU) of vitamin D per day.
Bradykinin is a peptide that promotes inflammation, and mitigating a bradykinin storm, similar to a cytokine storm, which is largely reported as one of the leading causes of death in COVID-19, is emerging as a potential new target in our war on the virus. In fact, some researchers are proposing that the more serious symptoms of COVID-19 arise mostly due to bradykinin storms and not cytokine storms, as reported by MedPage Today. Moreover, some researchers have proposed that vitamin D can reduce or prevent bradykinin storms in COVID-19.32,33
So, how does vitamin D fit in with the bradykinin storm hypothesis? Vitamin D is one of the identified regulators of renin-angiotensin system (RAS)32 from the paper that described the bradykinin storm response in COVID-19. This may be based on many observational and a few interventional models demonstrating the role of vitamin D in regulating RAS function in the context of pathophysiology of diabetes, hypertension, and kidney disease.34
More research is certainly needed to determine whether vitamin D could be an effective tool in treatment or prevention of COVID-19, but for now, it seems prudent to supplement with vitamin D as a precautionary measure. The good news is, we will be providing vitamin D free of charge on all orders from now until the end of the winter, supply chain allowing. More information on this will follow in a dedicated newsletter article.
Coming next week: Part 6 of the knowledge update involving lifestyle strategies and potential policy changes to improve COVID-19 outcomes