Pulse Check: "Does OTC nasal spray Azelastine hold a key to COVID and respiratory virus prevention and treatment?"

Respiratory virus season is upon us. Azelastine is a commonly used antihistamine nasal spray with a low side-effect profile. Could it be repurposed to help fight COVID? What about Influenza and RSV?

Welcome back to Pulse Check: Your healthcare questions answered. This week: “I keep catching every respiratory virus. I’m already vaccinated against COVID and influenza. I can’t avoid everyone forever— is there anything I can take that will cut down my risk?”

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The most popular holiday gift this season was…respiratory viruses! Influenza was the trendiest present, but COVID, RSV, and whatever that awful viral crud is that leaves people with six weeks of a constant, percussive, post-viral cough, weren’t far behind.

Many viral illnesses were re-gifted¹ to ER docs, who saw an increase in visits in December (COVID visits to the ER went up 12.8% in the last week of 2023, with a 20.4% increase in severity and a 12.5% increase in deaths; if you go to an ER, be smart and wear an n95):  

“Can’t you do something for me, doc?”

Unfortunately, holiday cheer was squashed when most patients seeking medical attention were discharged with instructions to take some Tylenol and Ibuprofen, make a Hot Toddy², and get rest. The high-risk patients who qualified got a prescription for Paxlovid, which stops the Sars-Cov-2 virus from multiplying and reduces viral load, therefore reducing risk of hospitalization, death, and long-COVID.³ Starting Nov. 1, Paxlovid is no longer purchased and distributed by the government. A Paxlovid course now costs $1390, with insurance coverage varying. Paxlovid, while useful, also tastes like pennies, soap and sadness, and comes with a 20.8% rebound rate. I prescribe it when indicated, but I wish I had something better.

One tragedy is that the FDA won’t allow Japan’s Xocova into the United States. Although we don’t fully understand the rebound effect, rebound seems rare with Xocova. Xocova has significantly fewer side effects and doesn’t make your mouth taste like the morning after that one time in college when you woke up on the floor of a frat house surrounded by bottles of Jäegermeister with your lips glued shut from dehydration.

But because the FDA has failed to recognize the virtue of reciprocity—allowing drugs already tested, approved, and in-use in other countries, to be automatically approved in the USA—I can’t write you that Xocova prescription.

So, if the FDA won’t approve anything new that’s been adequately tested in another country, even a high-risk country like, er, Japan, and better than what we have, maybe we can reappropriate what the FDA has so kindly allowed us. Hydroxychloroquine was an early—and failed—attempt to repurpose an existing drug, but I think it worthwhile to root around in our medical pockets and see what’s potentially useful, as long as we seek real, evidence-based data to confirm or deny the hypothesis.

Might any existing drugs prevent and treat COVID?

Azelastine, an over the counter nasal antihistamine, might play a role in both treating COVID and preventing long-COVID.

What’s Azelastine? Is it from World of Warcraft? Or a Tolkien character?

Azelastine is a nasal spray that acts as a histamine 1 receptor-blocker, which means it treats the symptoms of allergic rhinitis, such a congestion. Azelastine hydrochloride, the active substance in Azelastine, shows anti-inflammatory effects via mast cell stabilization and inhibition of leukotriene and pro-inflammatory cytokine production. In other words, it calms down the release of histamine and inflammation.

It was identified as a potential treatment for SARS-CoV-2 via both screening assays for virus entry inhibitors, as well as computational approaches which searched amongst commercially available drugs. Via computational analysis:

Antiviral efficacy was observed at an EC₅₀ of ~ 6 µM, which is an approximately 400-fold lower concentration compared to commercially available azelastine nasal sprays. In a highly relevant and translational in vitro model using reconstituted human nasal tissue, a fivefold diluted commercially available azelastine nasal spray solution inhibited viral replication almost completely within 72 h after SARS-CoV-2 infection

In other words, when researchers exposed a SARS-CoV-2 infected nasal tissue culture to diluted over-the-counter Azelastine nasal spray, the COVID virus stopped replicating within 3 days.

A study by Klussmann and Grosheva registered in the German Clinical Trial Register performed a randomized, parallel, double-blind, placebo-controlled trial in which ninety SARS-CoV-2 positive patients were randomized into three groups: placebo, 0.02% Azelastine spray, or 0.1% Azelastine spray for 11 days, but, disappointingly, results showed that no statistical differences were observed between groups when it came to symptom expression. Only one symptom—“shortness of breath”—was significantly improved on day 3 in the 0.1% Azelastine group when compared to others. However, it’s hard to anticipate if this will replicate in other studies, given the similarity in other symptoms across groups

Like most respiratory viruses, symptoms reliably improve over time. Unfortunately, they didn’t improve much faster for the people on Azelastine.

Symptoms didn’t really improve faster with Azelastine. So what did it do?

Symptoms, other than shortness of breath, may not have shown much variability, but there was a marked variability in actual viral load:

The viral load decrease based on the detection of the ORF 1a/b gene over the 11-day treatment period showed a significantly greater reduction of virus load in the 0.1% azelastine group compared to placebo.

…Significantly greater decrease in viral load was shown on day 4 of treatment in patients with high viral burden (Ct < 25) treated with 0.1% azelastine compared to placebo, indicating that azelastine treatment may be advantageous for this patient population, particularly at an early timepoint of infection. Recent publications indicating that in vitro infectivity correlates with high virus concentrations

Why does this matter if the spray isn’t making people feel much better than placebo?

Viral load can be used as a surrogate measure of how infectious a person is, suggesting that Azelastine might decrease infectivity.

High viral load may also induce long COVID. A 2023 study in Microorganisms: “Analyzing the Interplay between COVID-19 Viral Load, Inflammatory Markers, and Lymphocyte Subpopulations on the Development of Long COVID,” demonstrates a correlation between maximum peak viral load and long COVID. Yale immunologist Akiko Iwasaki, in an interview with the New York Times, states:

The quicker one can eliminate the virus, the less likelihood of developing persistent virus or autoimmunity, which may drive long Covid."

In addition to decreasing viral load of Sars-COV-2, Azelastine appears to have a broad antiviral effect, reducing viral load soon after infection with RSV and influenza. Is there enough data to recommend Azelastine to everyone with COVID, flu or RSV? No, but for patients unable or unwilling to take Paxlovid, the potential for decreasing viral load warrants larger scale studies. With a low and tolerable side effect profile, ER docs would be a great group on which to test Azelastine’s prevention potential, since we’re constantly exposed to seasonal viruses, have a negligible sense of personal safety, and like science.

Many of us took part in local studies in early 2020, evaluating hydroxychloroquine’s potential to prevent COVID (studies showed it doesn’t work), and would be more than happy to be guinea pigs again. A statistically significant reduction in infection and/or length of infection could lead to a low-risk, some-reward treatment. I already use Azelastine intermittently for allergies and am tempted to become a more regular user during respiratory virus season. Maybe I’ll write up and submit an IRB request to create the study I want to see in the world—anyone interested in making it multi-institution?

If you found this article useful, consider the Go Fund Me that’s funding my husband Jake’s ongoing cancer treatment. I can demystify healthcare, but I sadly can’t make it any cheaper.

Next post: But wait, there’s more! Can Metformin, a well-known diabetes medication, reduce the risk of Long Covid? An evaluation of the COVID-OUT trial.

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1.

A re-gifter!:

2. Evidence-based enough for me, especially after two Hot Toddies. They can be made without alcohol, but if you can’t breathe through your nose, you’re (doing the right thing, right?) and staying home despite fun parties, and the world seems grim, why would you want to?

3. Xie Y, Choi T, Al-Aly Z. Association of treatment with nirmatrelvir and the risk of post-COVID-19 condition. JAMA Internal Medicine. March 23, 2023. DOI: https://doi.org/10.1001/jamainternalmed.2023.0743 “The analysis showed that Paxlovid reduced the risk of long COVID-19 by 26% over a six-month period. Similarly, during the same time span, Paxlovid decreased the risk of death by 47% and the risk of hospitalization by 24%.the same time span, Paxlovid decreased the risk of death by 47% and the risk of hospitalization by 24%