Visual-OLfactory Training in Participants With COVID-19 Resultant Loss of Smell
Condition: Anosmia; Covid19; Ageusia; Hyposmia; Hypogeusia; SARS-CoV-2 Infection; COVID-19 Pandemic
MeSH terms: COVID-19; Anosmia; Ageusia
Study type: Interventional

Summary: 
      Olfactory dysfunction is a defining symptom of COVID-19 infection. As the number of total,
      confirmed COVID-19 cases approached 19 million in the United States, it is estimated that
      there will be 250,000 to 500,000 new cases of chronically diminished smell (hyposmia) and
      loss of smell (anosmia) this year. Olfactory dysfunction is proposed to worsen numerous
      common co-morbidities in patients and has been shown to lead to a decreased quality of life.
      There are very few effective treatments for hyposmia or anosmia, and there is no gold
      standard of treatment.

      One proposed treatment option is smell training, which has shown promising yet variable
      results in a multitude of studies. It garners its theoretical basis from the high degree of
      neuroplasticity within the olfactory system, both peripherally and centrally. However, due to
      a relative inadequacy of proper studies on olfactory training, it is unknown what the most
      efficacious method in which to undergo the training is. This study proposes two novel
      procedural modifications to smell training in an attempt to enhance its efficacy. The
      investigators propose using a bimodal visual-olfactory approach, rather than relying on
      olfaction alone, during smell training, as well as using patient-preferred scents in the
      training that are identified as important by the study participant, rather than
      pre-determined scents with inadequate scientific backing. The investigators hypothesize that
      by utilizing bimodal visual-olfactory training and patient-selected scents, the olfactory
      training will be more efficacious and more motivating for participants.
    

Detailed description: 
      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.
    

Intervention name(s): Smell Training
Intervention type(s): Behavioral
Intervention description(s): Participants will be provided with 4 labeled jars, each containing an odor pre-impregnated cotton pad. Participants will sniff each scent for 10 seconds, twice daily, once in the morning and once in evening. The participant will take 30 seconds of rest between each scent. All participants will undergo this smell training regimen for 12 weeks.
Other intervention name(s): Olfactory Training
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: Two-by-two factorial interventional study design will lend to achieving the study aims. Participants meeting eligibility criterion will be randomized to one of four arms:
Unimodal Olfactory Training with Conventional Odors
Unimodal Olfactory Training with Patient-Preferred Odors
Bimodal Visual, Olfactory Training with Conventional Odors
Bimodal Visual, Olfactory Training with Patient-Preferred Odors
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Anosmia; Loss of Smell; Loss of Taste; Hyposmia; Ageusia; Covid-19; SARS-CoV-2