May 2020

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Exploring treatment options for COVID-19


by Ellen Stodola Editorial Co-Director

Potential treatments for COVID-19 are being researched worldwide. One proposed option is hydroxychloroquine. EyeWorld reached out to ophthalmologists who discussed this and other treatment options being explored.
Gary Wortz, MD, said that before physicians can decide on treatment, it’s important to understand how this virus is affecting people, both young and old. One of the most interesting things about COVID-19 is the way it affects older patients. “That struck me as a reason to look at differences in the immune system responses between children and adults. If we can identify the differences and formulate a strategy for immune modulation, maybe there’s an opportunity to prevent morbidity and mortality in older patients.”
Dr. Wortz specifically looked at some of the differences between younger and older patients’ immune systems and recognized that there’s generally a difference in the balance between Th1 and Th2 immune responses.1 An ideal immune system has a balance between the two. However, children tend to be more Th2 shifted (resulting in more atopy and allergies), and adults tend to be more Th1 shifted (more prone to autoimmune diseases).2 Th1, the pro-inflammatory side of the adaptive immune system, is moderated by cytokines, like interferon gamma, as well as TNF alpha, IL-1, IL-6, and IL-18, among others. The Th2 system, he said, tends to be anti-inflammatory and produces cytokines IL-4, IL-5, IL-10, and IL-13.3
“For reasons that are not clear yet, children infected with COVID-19 mount a quicker immune response and resolve the infection efficiently. They tend not to get the cytokine storm as their Th2 system is more dominant. In adults, it seems the virus is replicating silently before the patient feels sick, allowing for asymptomatic spread of the disease,” Dr. Wortz said.
“To fight a virus, we have to rely on our Th1 adaptive immune responses,” he continued. “COVID-19 doesn’t seem to be allowing interferon gamma to be stimulated, and interferon gamma is perhaps the most important of all
of our cytokines in terms of blocking viral reproduction. This and other pro-inflammatory cytokines are what actually make us feel sick. So the virus replicates unchecked for a period of time, and it’s not until we reach a tipping point where the immune system wakes up. At that point, we are fighting a losing battle. In response, the Th1 mounts a blitzkrieg attack of pro-inflammatory cytokines. Rather than being helpful, in many cases this overexuberant cytokine response ends up causing more harm. This is called a cytokine storm, and it may be one of the most important and under-recognized aspects of the disease process. Since adults don’t have a well-developed Th2 system to calm the storm, it is important to be looking for this in patients who are declining. Elevated serum ferritin is the classic marker for cytokine storm. Given that the immune systems of older adults may be set up for failure, it is important that we aggressively pursue treatment and prevention options.”

Treatment options

There is a push from hospitals and doctors trying to understand how effective hydroxychloroquine is in different scenarios, with various studies being conducted, said William Trattler, MD. The University of Minnesota’s randomized, double-blinded study for post-exposure prophylaxis began enrolling a 3,000-subject study in late March. The Duke University study, which began in April, is a double-blind, placebo-controlled study with 15,000 healthcare workers at risk for COVID-19 exposure.
Prophylaxis with hydroxychloroquine, a drug commonly used to prevent and treat malaria, is a potential option that could address the issue before patients even start to feel sick or show signs.
“With any study, it’s going to depend on the entry criteria, who they’re enrolling, what the regimen is going to be,” Dr. Trattler said. “As we get more data points, it will help us with our treatment regimen for patients, both those exposed to COVID-19 as well as those with confirmed COVID-19.”
Some doctors have already been incorporating hydroxychloroquine in COVID-19 treatment regimens, and several have shared their outcome studies, he said. The biggest challenge in an outcome study is it’s hard to extrapolate how those treated would compare to untreated patients.
Dr. Trattler pointed to lab studies of hydroxychloroquine and chloroquine that found that these medications can prevent infection of cells and treat already infected cells. Additionally, he said that a number of clinics in China began to use hydroxychloroquine for COVID-19. A non-peer-reviewed study of 62 patients (31 patients on hydroxychloroquine and 31 controls) found those on the drug had reduced fever and cough and improvement in pneumonia measured by chest CT, Dr. Trattler said.4
In Europe, Didier Raoult, MD, performed a comparative study with 36 patients (16 on placebo, 20 on hydroxychloroquine).5 Six patients in the hydroxychloroquine group also received azithromycin. The researcher found this combination fared better than hydroxychloroquine alone. He treated an additional 74 patients with this combination (all patients received an EKG before and were monitored due to risks of this combination with arrhythmia).
“We know hydroxychloroquine is a generic drug that’s cheap to make in mass quantities,” Dr. Wortz said. “We’re seeing production ramping up across the world.”
The use of hydroxychloroquine, also a current treatment for rheumatoid arthritis and lupus, is putting pressure on pharmacies to get enough supply for patients with established prescriptions as well as new prescriptions coming in for COVID-19, Dr. Trattler said. Dr. Trattler noted that some experts have opined that there’s not enough data to support use of hydroxychloroquine for this indication—combined with the fact that you’re taking it away from people who need it for other conditions. Though it’s important to understand that treatment with hydroxychloroquine for patients with COVID-19 is short term, between 12 and 30 pills total for therapy, he said.
Dr. Wortz said zinc could be helpful for treating COVID-19, as it’s been shown to decrease duration and severity of viral colds. It has been shown to specifically inhibit the RNA dependent RNA polymerase of other coronaviruses, which is essential for viral replication.6 Additionally, hydroxychloroquine is a zinc ionophore, he said, and since zinc has a hard time getting inside of cells, it can aid in this.
“We also know that hydroxychloroquine is an immune modulator; that’s why it’s prescribed in patients who have lupus and other rheumatologic conditions, so there’s a theory that hydroxychloroquine is calming down the cytokine storm that happens in patients who are going on to be more critically ill,” Dr. Wortz said.
Dr. Wortz also advocated looking for antiviral medications that block viral transcription and reproduction. “Remdesivir is looking like a great candidate,” he said, adding that it was developed for Ebola a few years ago. Ebola, like COVID-19, is an RNA virus, seeming to share a lot of characteristics in some transcription factors. “Remdesivir seems to be doing a good job at actively inhibiting the virus,” he said. “Additionally, a recent study out of Germany showed that blocking the serine protease TMPRSS2 with the drug camostat mesylate (approved to treat pancreatic inflammation in Japan) effectively prevented SARS-CoV-2 from gaining intracellular entry into lung cells through the ACE2 receptor.7 This has great promise for both treatment and prevention.”
Dr. Wortz said it’s also important to “target our own immune response to COVID-19.” Studies from China have identified tocilizumab, an IL-6 blocker, as helpful. Anakinra blocks IL-1, which is one of the master control cytokines of the inflammatory system, Dr. Wortz said.
Vaccine development is also underway, but until then Dr. Wortz said we may see different phases of the disease, necessitating different strategies.
Those who have recovered might have antibodies against COVID-19, and evidence shows that plasma transfusions to those with current infection could be effective, Dr. Wortz said.
Additionally, Dr. Wortz said that there are some trials being done with BCG, an old tuberculosis vaccine that stimulates the immune system.
Dr. Wortz said mortality rates might go down once more data from all of these studies are available to better guide COVID-19 treatment.

About the doctors

William Trattler, MD
Center for Excellence in Eye Care
Miami, Florida

Gary Wortz, MD
Commonwealth Eye Surgery
Lexington, Kentucky

Relevant disclosures

Trattler
: None
Wortz: None

References

1. Simon AK, et al. Evolution of the immune system in humans from infancy to old age. Proc Biol Sci. 2015;282:20143085.
2. Chang WS, et al. Age-related changes in immunological factors and their relevance in allergic disease development during childhood. Allergy Asthma Immunol Res. 2016;8:338–345.
3. Berger A. Th1 and Th2
responses: what are they?
BMJ. 2000;321:424.
4. Chen Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv. 2020. Epub ahead of print.
5. Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. Epub ahead of print.
6. te Velthuis AJ, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6:e1001176.
7. Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280.

Contact

Trattler: wtrattler@gmail.com
Wortz: garywortzmd@gmail.com

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