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APRIL 27, 2020 — Welcome to Cases in Deprescribing. In this series, I present a clinical scenario drawn from my own practice. I will share with you what I plan to do, but I am more interested in crowdsourcing a response from all of you to collectively determine best practice.
Please answer the polling question and contribute to the comments section with your own thoughts, particularly if you disagree with me.
You are seeing a 53-year-old woman whose test came back positive for COVID-19 yesterday. She complains of 4 days of fever to 102.5˚ F and wet cough with some shortness of breath. Her respiratory rate, temperature, and physical examination are normal in the office, except for a pulse rate of 105 beats/minute. Her pulse oximetry reading is 95%. She is otherwise healthy and asks if you can give her a course of hydroxychloroquine and azithromycin to fight the infection.
The patient is accompanied by her partner, who is 50 years of age and feels well. She has no chronic medical conditions, but she started taking vitamin C at a dose of 4000 mg/day and black elderberry daily several days ago. Her partner wants to know if she should take these supplements to prevent getting infected.
What is the best course of action to recommend to this patient and her partner?
Start hydroxychloroquine and azithromycin and encourage vitamin C/elderberry as prevention
Start hydroxychloroquine and azithromycin but discourage vitamin C/elderberry as prevention
Recommend to continue vitamin C/elderberry as prevention but discourage the use of hydroxychloroquine and azithromycin
Discourage both vitamin C/elderberry as prevention and active treatment against SARS-CoV-2
My Recommendation — Do You Agree?
I choose the option of no treatment. There is far too little evidence to recommend medications in the treatment or prevention of COVID-19, although the knowledge surrounding COVID-19 increases daily. All of the treatments included in this question are currently under investigation, and those of us not directly involved in those studies can only pay attention and hope that there are positive results.
Chloroquine and hydroxychloroquine have previously been demonstrated to be effective in vitro against HIV and dengue viruses, and chloroquine was effective in the lab once again in inhibiting the growth of SARS-CoV-2. But chloroquine and hydroxychloroquine have been less successful in achieving clinical outcomes against viruses, and there is pessimism that they will effectively treat SARS-CoV-2. A small, randomized trial conducted in China examining use of hydroxychloroquine, without azithromycin, found no benefit, though the study was criticized for methodologic flaws.
A more recent retrospective analysis of older men treated for COVID-19 within the Veterans Health Administration system found that hydroxychloroquine was associated with a higher risk for death versus no treatment. That nonrandomized study, which has not yet been peer reviewed, concluded that neither hydroxychloroquine nor hydroxychloroquine/azithromycin decreased the risk for mechanical ventilation. Prospective clinical trials of hydroxychloroquine for both prevention and treatment are pending and will hopefully yield definitive results.
At this time, guidelines from both the Infectious Diseases Society of America and the National Institutes of Health (NIH) do not recommend use of either drug. NIH goes a bit further and discourages use of hydroxychloroquine in combination with azithromycin because of potential toxicities. Nonetheless, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization for use of chloroquine and hydroxychloroquine in patients hospitalized for COVID-19 in March 2020. That statement was reinforced with a second announcement on April 24, 2020, emphasizing that the combination of hydroxychloroquine and azithromycin should only be given when a patient is hospitalized and participation in a clinical trial is “not available” or “not feasible.”
The unknown efficacy of hydroxychloroquine must be balanced against its known risks for adverse events. Hydroxychloroquine can cause QT prolongation and should be used with caution among patients with cardiac disease. Moreover, azithromycin also can cause QT prolongation, so using both of these drugs together can be dangerous. There is no research, however, on the potential synergy of these agents in causing arrhythmia. There are also warnings regarding the use of hydroxychloroquine among individuals with diabetes, kidney disease, and liver dysfunction.
There is also the issue of stewardship in preventing the overuse of hydroxychloroquine so that persons who depend on it for the management of autoimmune disease can continue their chronic therapy. There are reports that hydroxychloroquine is already in short supply. There are also the well-recognized concerns for antibiotic overuse; in China, virtually all patients treated with hydroxychloroquine also received azithromycin. The Department of Defense has launched a study of secondary bacterial infections in COVID-19 patients treated with the combination.
Safety is less of a concern with potentially preventive therapies such as vitamin C and black elderberry. Still, high doses of vitamin C, as described in this case, can lead to nausea or diarrhea, and there may be some risk for formation of calcium oxalate stones. However, high doses of intravenous vitamin C are generally well tolerated in cancer patients with normal renal function and no history of glucose-6-phosphate dehydrogenase deficiency.
The use of vitamin C regularly may have small impacts on the incidence and severity of the common cold. But vitamin C failed to improve the risk for organ damage or measures of inflammation in a randomized, placebo-controlled trial of patients with acute respiratory distress syndrome, a condition that is well known to potentially accompany SARS-CoV-19. It is doubtful that vitamin C will be helpful among patients with severe infections with COVID-19.
Black elderberry has some track record of success in reducing the symptoms of upper respiratory infections, but these studies are small and have variable methodology. There are fewer data on using black elderberry in the prevention of infection.
Everyone is anxious, to put it mildly, regarding the risk for COVID-19, and it is natural to want to try just about anything to stay well. I engage in shared decision-making about these choices every day, and many of my patients continue to use treatments, most often those available over-the-counter, with a very limited record of efficacy. But I insist on safety as well as not spending a fortune on unproven treatments. In the case of infection with COVID-19 and consistent with FDA guidance, I would advise patients with infection who really want treatment to try to enter a clinical treatment trial, if possible, an option that is realistic for my patients living in a major metropolitan center with multiple academic health centers.
And while I would not recommend specific treatment to prevent COVID-19 infection, I would respect patient choice to take a vitamin or supplement if they were also adhering to the measures that we know work to prevent the infection. In this situation, the patient should be encouraged to quarantine away from her partner, though that may be too little too late. The Centers for Disease Control and Prevention (CDC) provides information for families in this situation.
We have to acknowledge what we do not know while also committing to staying up-to-date on the most recent evidence and guidelines regarding COVID-19.
The NIH website provides the latest information describing guidelines for treatment. CDC has a similar site for healthcare professionals:
But what do you think? Please share your comments and I will respond soon. Thank you!
Charles P. Vega, MD, is a clinical professor of family medicine at UC Irvine and also serves as the UCI School of Medicine assistant dean for culture and community education. He focuses on medical education with an intent to resolve health disparities.
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