During the height of the COVID-19 pandemic, the World Health Organization officially recognized olfactory dysfunction (loss or alteration of the sense of smell) as a common symptom of SARS-CoV-2 infection. Olfactory dysfunction was reported by half to two-thirds of patients in eighteen studies conducted in 2020, and this number was even higher when psychophysical testing methods were used instead of subjective reports. In fact, several studies demonstrated that sudden loss of smell was one of the most accurate indicators of having COVID-19, among patients with respiratory symptoms.
This news may be unsurprising at first glance, as other viral upper respiratory infections like influenza and the common cold can present with a frustrating, but usually temporary, loss of smell and taste. This is usually attributed to inflammation and swelling of the nasal passages, which physically obstructs odor molecules from reaching the receptors in the olfactory epithelium. Once the infection resolves and the inflammation dissipates, a normal sense of smell typically returns.
But COVID-19 didn’t follow the usual pattern. In up to 28 percent of patients, olfactory dysfunction was reported as the first or only presenting symptom of COVID, even in the absence of a runny nose or nasal congestion. Nearly half of patients reported persistent olfactory dysfunction for at least six months after recovering from the infection (although this number varies widely according to age, sex, virus variants, and other factors). While many people had a reduction in smell intensity (anosmia), some also reported persistent parosmia -- a distorted perception of odor (say for example, a typically pleasant smell like coffee suddenly smelling rotten). Concerningly, these findings pointed to a potential neurological change in how odor stimuli were perceived.
The ability to smell is often taken for granted, but smell is a vital component of how we perceive the world. We rely on our sense of smell every day, from enjoying the aromas and flavors of food, to maintaining personal hygiene, to detecting hazards like smoke or toxic chemicals. Losing the ability to smell has been linked to depression and a reduced quality of life. For this reason, it became a priority to uncover the mechanisms behind post-COVID olfactory dysfunction, and to establish treatments aimed at restoring the sense of smell.
In the years since the pandemic started, as we have learned more about how the SARS-CoV-2 virus infects the body, a clearer picture has emerged for how the virus affects the olfactory system in such a unique way.
An important clue came from a study investigating human olfactory tissue collected shortly after death from individuals who had active COVID-19. This study found signs of infection and viral replication in the sustentacular cells of the olfactory epithelium. The sustentacular cells provide metabolic, secretory, absorptive, structural, and other support to the olfactory sensory neurons (OSNs), which perform the complex role of detecting odor molecules and transmitting this information to the brain. Notably, there was a lack of viral RNA within the olfactory neurons themselves.
With this discovery, it became clear that post-COVID olfactory dysfunction does involve long-term neurological changes, but not because of direct viral infection of neurons or retrograde viral spread into the central nervous system, which was the initial concern. Instead, acute COVID-related olfactory dysfunction may be caused by direct injury to the support cells, which leads to inflammation that damages the olfactory epithelium. The loss of the support architecture leads to irreparable damage to the OSNs, which need to be entirely regenerated before olfactory function can return. This process can take months, which correlates with the prolonged loss or reduction in the ability to smell seen in individuals recovering from COVID.
Furthermore, the phenomenon of delayed parosmia could be a result of aberrant regeneration of OSNs in response to the widespread damage. This could happen in two ways: either by a “miswiring” effect in which the new neurons project to incorrect targets in the brain, or by incomplete regeneration in which only a subset of neurons regenerates while some remain missing, leaving gaps in the range of detectable molecules. In either case, this can lead to the brain misperceiving or misinterpreting smell stimuli.
So the question then becomes, how can persistent anosmia and parosmia after COVID be managed?
Prior to the pandemic, research into treatments to restore smell function was limited. But the high prevalence of post-viral olfactory dysfunction around the world during the pandemic accelerated research into pathophysiology and potential treatments, while simultaneously allowing for larger-scale studies that were previously not feasible.
One of the most promising treatments is olfactory training, a therapy that involves sniffing a set of scents, such as lemon, rose, eucalyptus, and cloves, for 15 seconds each twice a day over several months. Patients are encouraged to try to imagine how they remember these scents smelling as they sniff them. The goal of olfactory training is to stimulate the olfactory system, encourage neural regeneration, and strengthen odor processing networks in the brain. This treatment has been used previously for loss of smell due to other causes, but new research demonstrated it might improve the sense of smell in patients with long COVID olfactory dysfunction as well. Olfactory training is currently recommended as the first-line treatment for post-viral loss of smell, due to the ease of access and absence of side effects.
Although olfactory training seems promising, the actual success rate is unclear, and many who lost their sense of smell after having COVID might not fully recover it. For this reason, it is vital to provide psychological treatment and patient support in addition to physiological treatment. Counseling should be provided for patients with persistent olfactory dysfunction to help manage potential depression. Additionally, patients should be informed of patient advocacy groups, such as SmellTaste or AbScent, which provide information about the loss of smell and offer helpful advice on how to live with the condition.
The insights gained from the recent burst of research on olfactory dysfunction extend beyond COVID-19, offering new hope for people with persistent olfactory disorders from other causes, including non-COVID viral infections, chronic rhinosinusitis, and even neurodegenerative diseases like Parkinson disease. Continued research can improve diagnosis, deepen our understanding of olfactory function, and expand treatment options for a wide range of patients.
