Why Is It So Hard to Study Covid-Related Smell Loss?

Why Is It So Hard to Study Covid-Related Smell Loss?
In March, scientists in the United Kingdom started to notice an unexpected phenomenon. Alongside a fever, dry cough, and general malaise, Covid-19 patients were also reporting a sudden and alarming symptom: They couldn’t smell anything. Anecdotal evidence shared on medical message boards from physicians in Iran, France, Italy, and the United States all described a sharp rise in anosmia, or the inability to smell. In Germany at that time, more than two out of three positive cases were anosmic.

Given all of these reports, ENT UK, the professional group that represents ear, nose, and throat specialists in the United Kingdom, recommended that people who suddenly lose their sense of smell isolate for seven days. In a joint letter, Claire Hopkins, president of the British Rhinological Society, and Nirmal Kumar, president of ENT UK, wrote that anosmia “could potentially be used as a screening tool to help identify otherwise asymptomatic patients, who could then be better instructed on self-isolation.”

By late April, the Centers for Disease Control had added anosmia to the list of Covid-19 symptoms, and in late July scientists identified which cells in the olfactory system are affected by the virus SARS-CoV-2. But smell screening tools aren’t widespread yet, and researchers are still trying to puzzle out how prevalent anosmia is among Covid-19 patients, and why it lasts only a few weeks in some people and months in others. It’s not clear whether some patients will ever get their sense of smell back or if there are any therapies that can help them.

While research on vaccines, monoclonal antibodies, and treatments for Covid-19 has raced along, the pandemic has made other kinds of research much more complicated. For olfaction, this is especially true. How do you study someone’s sense of smell or look deep inside their nose when they have a highly contagious respiratory disease? Even as this field has become more important than ever, figuring out how to do the work safely and with scientific rigor is adding an extra dimension of difficulty for researchers. “Never in a million years would I have guessed that I would have skills that would be relevant during a global pandemic,” says John Hayes, director of the Sensory Evaluation Center at Pennsylvania State University. “There’s a whole level of urgency that doesn’t exist in my normal work.”

Anosmia isn’t unique to Covid-19. It’s associated with other conditions like aging and head trauma. People sometimes experience persistent anosmia after viral infections like influenza, and of course it’s common for people to lose their sense of smell when they get a cold. Usually, no one is alarmed because their nose is stuffed up: It makes sense that you can’t smell anything when mucus is blocking molecules from traveling up the nasal passages to the olfactory neurons that live at the very top of the nose, right on the other side of the skull from the brain. Usually, once your congestion is gone, your olfactory powers are restored.

But Covid-19 anosmia is notable because it’s immediate and often arrives without any congestion. “The smell loss in Covid is not nuanced for most people,” says Danielle Reed, associate director at the Monell Chemical Senses Center, where researchers work on issues related to smell and taste. “People who are not hyper-attentive to their sensory world, they notice. At least, eventually.”

Traditionally, researchers would bring their subjects into the lab and measure their powers of smell using scientifically-validated tools like an olfactometer, a device that delivers precise amounts of scents to the subject’s nose, or a scratch and sniff booklet called the University of Pennsylvania Smell Identification Test (UPSIT) that requires subjects to smell a scent and correctly identify it from among four choices.

But thanks to the pandemic, many labs are closed and patients cannot come in for screenings. Even if they could bring people in, the tests Hayes would normally use can’t easily be adapted for Covid-19 research. The UPSIT, he says, is not great for getting thousands of responses in just a few weeks. Another test called Sniffin’ Sticks asks subjects to take deep whiffs of different scents contained in long tubes. “How am I going to decontaminate those between people?” Hayes asks. Even as other public facilities have started to reopen, Hayes decided to keep his lab closed out of safety concerns. Subjects are often asked to breathe heavily to inhale scents, or to chew and spit out different foods, activities that he feels are too dangerous to resume just yet.

In the absence of in-person data collection, researchers have had to get creative to measure and track Covid-19 anosmia. In March, scientists around the world banded together to create the Global Consortium for Chemosensory Research. Hayes worked with consortium colleagues to create an online questionnaire that walks respondents through more than 40 questions about their symptoms, including whether they’re congested, how well they were able to smell before their illness, and how well they are able to smell now.

The questionnaire also asks respondents to think about a food or beverage they consume regularly and to describe how that experience has changed during their illness. Smell and taste are intricately linked. While receptors on the tongue can sense basic tastes like sweet or sour, the perception of complex flavors—the mixed nutty, salty, and cheesy flavor of Parmesan cheese, for example—is created in combination with the olfactory system as molecules from the food float up the back of the throat to the nose. Asking different questions about the quality of smell and taste helps researchers establish a baseline to evaluate how profound Covid-19 anosmia is.

“A survey isn’t ideal in some ways,” Hayes says. “We really want to bring people into the lab and test them under controlled conditions. But we couldn’t do that either ethically or quickly. This is the only way to get this data.”

The survey has helped the consortium bypass some research roadblocks and collect interesting data. It gathered 4,000 usable responses in just 11 days and the results, published in June in Chemical Senses, and now available in 23 languages, helped validate anecdotal reports and early data linking smell loss and Covid-19 infection. It also revealed that taste and chemesthesis—the burning, tingling sensation you feel after eating hot peppers or gargling a mentholated mouthwash—are also affected by the virus. Other results from the survey, authored by GCCR members and published in July in a preprint, suggest that anosmia is the single best predictor of Covid-19. While a low fever or cough is easy for people to ignore or attribute to other problems like allergies, sudden anosmia, especially without congestion, is both notable and harder to explain away, says Hayes.

Other researchers have also created diagnostic tools to help people track smell loss as a screening tool for Covid-19. Researchers at the Weitzman Olfaction Research Group, which studies the neurobiology of smell and its impact on health, created an app that asks users to find five mundane objects in their homes that they will smell every day: items like peanut butter, wasabi, coffee, or vanilla extract and rates them in the app. The app’s algorithm learns a person’s unique “olfactory fingerprint” and tracks their scent perception over time. If the quality of that perception starts to change, the algorithm will notice and alert the user that they may have a symptom of Covid-19.

But creating a smell screening tool that could be used at offices, food processing plants, or skilled nursing facilities is a bit more complicated. The test has to be consistent and reliable, to include variation so people can’t guess the answers, and be fast, cheap, and easy to use so workers can get back to the job quickly. Researchers at Monell are working on a test, and so are those Penn State, where they hope to use it as a screening tool for students. But any new tool requires a lot of testing to figure out what works, and this one comes with some unusual constraints, since the test needs to be taken by each patient several times a week, and has to be quick to administer to people standing in a long line to get in. “It’s been just a really hard pivot from the way that we normally do things and the reason we normally do things,” says Reed. “Smell research is usually kind of academic and it’s gotten really practical really quickly.”

And other questions will just take a long time to answer, even when labs are back up and running at full capacity. “Ideally you want to do quantitative testing, and hopefully repeated testing, so we can get a bigger picture of what potentially is going on long term,” says Paule Joseph, a researcher at the National Institutes of Health. Some Covid-19 anosmics recover their sense of smell after a few weeks. Others say their anosmia has lasted for months and doesn’t seem to be improving. How does the virus behave over time? Joseph says we just don’t know yet.

Even with good surveys, home tests, and repeated follow-ups, ultimately, not all research can happen online or at a distance. A study in July in Science Advances co-authored by researchers in the US, UK, Italy, and Belgium determined that SARS-CoV-2 binds to the sustentacular cells, a set of accessory cells that are located in the nose and aren’t directly involved in sensing the volatile molecules that make up a scent. So how does SARS-CoV-2 affect the whole olfactory system by binding to these ancillary cells? To figure that out, scientists need to get a better look at a patient’s entire smelling mechanism, including taking samples of their olfactory epithelium, a small piece of tissue located at the top of the nose, right where it meets the skull and where all of these sensing and accessory cells live.

“I think that would be tough,” says Reed. Taking biopsies of the olfactory epithelium is difficult even under normal circumstances because you have to go very far up the nose and, she says, these biopsies happen too close to the brain to be just routine procedures. During a pandemic, “it’s kind of a nonstarter,” Reed says, because the procedure could aerosolize the virus, exposing the doctor to a spray of virus-laden particles. “I don’t know that any IRB is going to go for that,” she says, referring to the academic ethics boards that review and approve scientific studies.

Sandeep Robert Datta, a neurologist at Harvard Medical School, was the primary author on the paper identifying sustentacular cells as the place where SARS-CoV-2 binds in the olfactory system. It was a huge step towards working out the Covid-19 anosmia puzzle. But then he couldn’t get the olfactory tissue samples he needed to continue the research. “We aren’t really working on COVID any more,” he wrote via email.

It’s hard enough to reopen his lab, which can only operate at 50 percent capacity to comply with social distancing protocols, and to keep teaching and supervising his students. “Most of the best moments in science happen fortuitously when people are in a room together just chatting; I have had zero interesting ideas to date over Zoom,” says Datta, who also has to find a new way to train students in lab techniques from six feet away. “Getting back to real speed with our experiments is not going to be possible for a while.”


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