Can nasal antihistamines prevent Long COVID?

If it sounds too good to be true, and it's published in a journal you've never heard of as a doctor... Quick Boost #17

One of my good friends found an exciting, newly published study about preventing long Covid. A major reduction in risk was found. She knows that would be of great interest to me as a primary care doctor who is still paying attention to Covid, both for myself and others I might advise. She asked if I could take a look at the study. It’s been going around on Bluesky and X. So I did. I was hoping to have a new tool to add to my self-treatment plan. But unfortunately, the use of an antihistamine nasal spray containing chlorpheniramine can’t be added as examined tonight. But I think the process of examination was well worth the effort, so I’ll briefly report it here.

Reviewing published research is hard. It’s hard for doctors, scientists, and readers of all levels. There are thousands of journals out there now, and it’s hard to know which are legit, semi-legit, or downright bad. It’s one of the reasons I try to stick with the world's most reputable medical journals like NEJM, JAMA, The Lancet, BMJ, Nature Medicine, Cell, CID, Science Translational Medicine, Annals of Internal Medicine, etc. And so the very first thing I look at with a study is where it has been published.

This one was published in a journal called BMC Infectious Diseases. Not one I subscribe to or know about. Researching the journal revealed no major complaints online, but its business model accepts studies from authors who agree to pay about $3K for “peer review” by one or two reviewers, followed by publication if up to snuff.

It does not seem to be a predatory journal per se. Predatory journals are deceptive publications that prioritize profit over scientific integrity by charging authors publication fees while failing to provide legitimate peer review, editorial oversight, or quality control measures that are standard in reputable academic publishing. Dr. Paul Sax wrote a good article for NEJM about predatory journals if you want to learn more. And this article from The New York Times discusses how many academics, particularly those at less prestigious institutions with heavy teaching loads, are knowingly publishing in predatory journals that will accept almost anything for a fee, despite these publications being considered academically fraudulent. This practice has led to the proliferation of over 10,000 such journals, with academics often receiving promotions and rewards for publishing in them, even though it potentially undermines scientific credibility and wastes taxpayer money.

That recent study about a nasal antihistamine spray for preventing long Covid? Too good to be true?

Patients from two small clinical trials who received either intranasal chlorpheniramine (antihistamine) or a placebo during acute Covid infection were followed with questionnaires. The researchers reported dramatically lower rates of long Covid symptoms in people who received the antihistamine spray.

However, there are multiple red flags that should make us cautious about these findings.

First, this wasn't a study originally designed to look at Long Covid. The researchers went back and surveyed participants from previous small trials about their Long Covid symptoms. This type of after-the-fact analysis is much less reliable than a study specifically designed to answer an original question.

More concerning is the timing issue. Some participants were surveyed 12-13 months after their infection, while others were only surveyed 2-3 months later. This makes it very difficult to draw meaningful conclusions about long-term effects.

And most concerning were the results themselves: they border on preposterous. The researchers report dramatically lower rates of long Covid symptoms in people who received the antihistamine spray. In fact, they found almost no Long Covid symptoms in the treatment group. Specifically, only 1 out of 139 patients (0.7%) in the treatment group reported any Long Covid symptoms, compared to 86 out of 120 patients (71.7%) in the placebo group. This represents an absolute risk reduction of 71% and a relative risk reduction of 99% - remarkably large effects that are unusual in medical research. Not to mention that neither of these long Covid rates line up with consensus prevalence.

And then there were the little things you pick up reading the study. Misspellings, like PASC and PACS in the same paragraph when referring to Post-Acute Sequelae of SARS-CoV-2. Kind of flowery, less than technical language at times. Many coauthors with previous research in totally different subjects published in obscure journals. A sloppy discussion section, with a kind of lame “study limitations” acknowledgment. Research study sponsorship by a company that makes… wait for it… an over-the-counter chlorpheniramine spray.

Nonetheless we should not dismiss this class of medicines completely. What do we actually know about antihistamines and Covid? The scientific evidence is still being hashed out. While laboratory studies show that antihistamines might affect how the virus enters cells and replicates, this hasn't yet translated into clear clinical evidence. Some small studies have looked at antihistamines (mostly oral ones) for treating acute Covid or established Long Covid symptoms, but we lack large, well-designed trials. Maybe they help reduce symptoms for a subset of long Covid patients with mast cell activation.

The biology is intriguing - we know that mast cells (which release histamine) play a role in Covid’s effects on the body. This suggests that antihistamines might be helpful. However, the leap from "biologically plausible" to "clinically proven" is a big one that requires rigorous research to confirm. This study is not that, trending or not.

So what's the bottom line? Until we have much higher-quality evidence, it's premature to recommend nasal antihistamines specifically for preventing long Covid. The quality of the reference matters, and though I am not a world class expert, I did pay attention in medical school and residency journal club. I keep practicing and reading. I think there is good evidence for using nasal saline in the treatment of viral upper respiratory infections, and I plan to keep doing that when sick, Covid or not. I’ve also written a deep dive on the putative benefits of using various nasal sprays like saline, iota-carrageenan, nitric oxide, and azelastine for preventing and treating Covid. Overall some promise perhaps, and I’m not dismissing the idea of nasal sprays, but we need much better evidence.

“A happy person spraying a nasal spray up their nose” as generated by AI. Seemed appropriate for examining a lackluster study!