Visual-OLfactory Training in Participants With COVID-19 Resultant Loss of Smell

Over 200,000 people visit physicians yearly for taste and smell disorders and given the
well-documented prevalence of olfactory dysfunction in COVID-19 infection, there is likely to
be an increased need to address these concerns. The loss of the sense of smell has been shown
to be linked to decreased quality of life, depression, decreased enjoyment of the flavor of
foods, and may even be a contributing factor in the physiologic anorexia of aging.

Some of the most common causes of olfactory dysfunction include post-infectious,
post-traumatic, and neurodegenerative. Of these, post-viral olfactory dysfunction is the
leading cause, accounting for an estimated 18.6 to 42.5% of individuals with olfactory
dysfunction. Respiratory viruses found to be responsible for olfactory loss include common
respiratory viruses including rhinovirus, coronavirus, parainfluenza virus, adenovirus, and
influenza virus. It is then no surprise, that olfactory dysfunction is a defining symptom of
COVID-19 infection. Estimates for the prevalence of smell dysfunction in COVID-19 infection
vary. In a cross-sectional survey of 59 patients with COVID-19, 34% (20/59) self-reported a
smell and/or taste disorder. In a multi-center European study, 85.6% (357/417) of cases with
confirmed COVID-19 experienced olfactory dysfunction. Only an estimated 44% of these patients
experienced recovery of olfaction after 2 weeks of convalescence from COVID-19 infection.
Although it is impossible to know the long-term recovery rates of this newly emerging
pathogen, as the total number of confirmed COVID-19 cases approaches 19 million in the United
States, unpublished data generated by Amish Mustafa Khan in Dr. Jay F. Piccirillo's lab at
Washington University estimates nearly 250,000 to 500,000 new cases of chronic olfactory
dysfunction.

There is no gold standard set of guidelines for the diagnosis and treatment of post-viral
hyposmia or anosmia. Most evidence for pharmacological interventions is weak, with very few
controlled studies that account for spontaneous improvement overtime. Moreover, treatments
that are effective for sino-nasal disease such as topical corticosteroids are not effective
for sensorineural post-viral olfactory loss. A systemic review of post-viral olfactory
dysfunction studied eight commonly utilized pharmacological treatments: Oral corticosteroids,
local corticosteroids, zinc sulfate, alpha-lipoic acid, caroverine, Vitamin A, Gingko Bilboa,
Minocycle. Improvement was noted for study participants receiving oral corticosteroids, local
corticosteroids, alpha lipoid acid, and caroverine. However, these studies were of poor
quality, and the authors conclude that there is no strong evidence supporting the use of any
pharmacological intervention for the treatment of post-viral olfactory dysfunction.

One proposed treatment shown to be beneficial for a wide variety of etiologies of olfactory
dysfunction, including post-viral upper respiratory infection, is olfactory training. The
theoretical basis for olfactory training emerges from multiple experimental and clinical
studies suggesting that the olfactory pathway has neuroplasticity to recover, both
peripherally, due to the regenerative capacity of olfactory receptor cells, and centrally. In
a study using fMRI after olfactory training, there were increased functional connections in
olfactory areas such as the anterior entorhinal cortex, inferior prefrontal gyrus, and the
primary somatosensory cortex, suggesting that the olfactory pathways are capable of
reorganization with training. In another study, increased exposure by anosmic participants to
androstenone resulted in an increase in amplitude of the olfactory evoked potential and the
olfactory event-related potential, suggesting that that the peripheral olfactory receptor
cells are also neuroplastic, likely due to an increase in expression of olfactory neuron
receptors in response to training.

The investigators believe that patients experiencing olfactory dysfunction secondary to
COVID-19 are especially good candidates for olfactory training for two reasons. Firstly, the
pathophysiology of COVID-19 olfactory dysfunction is mediated through damage to the
peripheral olfactory receptor cells located in the nasal epithelium lining the nasal cavity
and central pathways via neuro-invasion through the olfactory pathway. This suggests that
interventions most likely to be efficacious in this patient population target both central
and peripheral pathways, as olfactory training does. Secondly, relative to other causes of
olfactory dysfunction, post-viral olfactory dysfunction more commonly presents with hyposmia,
rather than anosmia. Residual olfactory function is an important prognosticator that improves
the likelihood of improvement. Furthermore, patients with post-viral olfactory dysfunction
more commonly present with concurrent dysosmia than other common causes of olfactory
dysfunction. It is likely that dysomia may be a result of disordered axonal regeneration.
This further suggests that patients with post-viral olfactory loss are most likely to benefit
from olfactory training.

Olfactory training typically consists of a patient smelling a scented oil dropped in a
labeled jar on a cotton ball for a specified length of time a certain number of times per
day. The details of the most efficacious method for olfactory training is not yet described,
with various studies adjusting the length of time of training, frequency of training, or even
adding nasal corticosteroids alongside olfactory training. While olfactory training is
promising, these inconsistencies highlight the inadequacies in the training. Two unstudied
areas include the effects of a bimodal visual-olfactory approach to olfactory training as
well as the effects of patient preference in determining the scents in which to undergo the
training.

Bimodal training has been shown to be effective in other sensory training, such as through
audio-visual training to enhance the auditory adaptation process, and even in animal studies
with ferrets with bilateral cochlear implants, improving auditory spatial processing. Loss of
hearing has been shown to result in improved vision, adding to the hypothesis that an
intimate connection exists between senses and that its relationship is worthy of continued
modulation and study. Furthermore, perhaps many patients have undergone olfactory training
with scents that patients have no interest in being able to smell, and perhaps patient
compliance has been an underreported cause of the variability in olfactory training results
due to the resulting decreased motivation to smell scents patients have no desire to be able
to smell. The original clinical trial on olfactory training, and most since, have chosen to
evaluate the efficacy of olfactory training using four pre-determined scents: rose (flowery),
lemon (fruity), eucalyptus (resinous), and cloves (aromatic). These scents were chosen due to
the work of German psychologist Hans Henning who categorized smells into six different
categories: floral, putrid, fruity, burned, spicy, and resinous. The unpleasant smells of
putrid and burned were omitted from the olfactory training protocol, resulting in the four
smells that are often studied today. Although humans respond to odors as members of odor
categories, there is little scientific basis behind making these four specific scents the
standard for olfactory training. There are various studies that have used select scents or an
array of other scents, however, there are no known studies that have used patient preference
in choosing scents in which to undergo olfactory training.

The investigators hypothesize that using patient preference in choosing the scents that the
participant is to undergo olfactory training and adding in a visual component to the training
will not only be a patient-centered research approach, but also a more effective means of
improving olfactory function.