INTRODUCING SMELLREGEN

SMELLREGEN is an olfactory rehabilitation kit specially designed to help patients regain their sense of smell and taste through a safe, effective, and cost efficient treatment method in the comforts of your own home.

Management of COVID-19-Induced Anosmia

The Olfactory System

The sense of smell and taste (gustatory system) are often referred together as the chemosensory system; they provide information to the brain about the chemical composition of substances through a process called transduction.  Humans possess a main olfactory system, which detects airborne substances, and an accessory system which sense fluid-phase stimuli.

Much of our knowledge about olfaction has been gleaned from the research from Linda Buck and Richard Axel, who won the Nobel Prize in Medicine in 2004. They estimated that there are over 1000 different genes for olfactory receptors, and remarkably, that each olfactory receptor neuron expresses one kind of olfactory receptor protein and that the input from the same receptors is all collected by a single glomerulus of the olfactory bulb.  Another significant fact of the olfactory system is that olfactory neurons are direct projections from the brain and therefore dysfunction within olfaction can be an early harbinger of pathophysiologic processes occurring within the brain.

Olfaction occurs when odor molecules (odorants) reach the nasal cavity during inhalation or through retro-nasal olfaction which occurs during chewing when the tongue pushes air into the nasopharynx. The middle turbinate and superior turbinate are erectile organs within the nasal cavity that provide variable resistance to dissect nasal airflow and allow a small portion of our nasal airflow to lose velocity and allow for diffusion of odorants. Inside the nasal cavity, odorants dissolve through the mucociliary blanket and in some cases are metabolized by enzymes secreted by the olfactory neuroepithelium.

Dissolved odorants then bind to unique olfactory receptors located in the cilia of the olfactory neuroepithelium. In a process called sensory transduction, the cilia of the olfactory neuroepithelium transmit a signal through the cribiform plate of the ethmoid bone to the olfactory bulb and then to the limbic system and many gyri within the brain. The olfactory bulb transmits pulses via variable timing (timing code) which allows the brain to note differences between similar odorants.

Olfaction also occurs through the vomeronasal organ with processes specialized odorants known as pheromones, allomones, and kairomones. The impact of this organ is thought to limited but still important in humans compared to other mammals.

The neuroepithelium in the nasal cavity is sensitive to both pathophysiologic and regenerative processes. Bowman’s glands produce the mucus, metabolic enzymes, and ionic milieu required for odorant binding to the cilia of the olfactory receptor neurons. In addition, the neuroepithelium is supported by basal cells and sustentacular cells. While this anatomic arrangement allows for olfactory neurons to directly sample chemicals inhaled into the nasal cavity, this leaves olfactory neurons anatomically exposed to damaging volatile chemicals, viruses, and inflammatory signals diffusing from respiratory mucosa.  In rats, nasal stem cells provide a repository of olfactory receptor neurons that are completely replaced every 6 to 8 weeks. The neuroepithelium is also supported by sustentacular cells, microvillar cells, basal cells, and contain brush cells that allow for sensation via a trigeminal nerve mediated process.

Olfactory Regeneration / Olfactory Training

In 2004, the basal cell layer was determined to possess the regenerative ability to restore olfactory function. However, this was also found to dependent on the mechanism of injury, as gliosis and scar tissue formation could lead to permanent anosmia. Specifically, globose basal cells (GBC’s) and horizonal basal cells (HBC’s) were found to reproduce and improve olfaction if globose basal cell progenitors were kept intact. Olfactory ensheathing cells via NF-kappa B mediated pathways also responded differently to steroids versus repetitive exposure of odorants (olfactory training). This gave hope that for some mechanisms of olfactory loss that did not induce gliosis or scarring, that olfactory could be regenerated via different mechanisms such as anti-inflammatory therapy and olfactory training.

In 2009, Thomas Hummel et. al. demonstrated in a prospective study of 56 patients who did not have sinonasal disease that patients who were exposed twice daily to four intense odors over a period of 12 weeks compared to controls had an objective improvement in their olfactory function. Since then, olfactory training has been validated as a viable therapy in multiple studies to improve anosmia from a variety (but not all) pathologic processes.

In 2014, Michael Damm et. al. led a multicenter, randomized, controlled, single-blinded study that demonstrated a dose dependent beneficial effect of olfactory training in patients with post-infectious olfactory loss. 63% of patients with olfactory loss of less than one year developed improvement with high-concentration olfactory training, compared to only 19% in a low concentration olfactory training.

COVID-19 and Olfaction

In addition to the 12% of the U.S. population that reports some level of impairment in sense of taste or smell, patients with COVID-19 are 27 times more likely to develop smell impairment compared to non COVID-19 infected individuals. Up to 85% percent of patients with COVID-19 develop some smell or taste dysfunction, and 25% of patients may report smell dysfunction as their first symptom. Nicolas Meunier infected golden Syrian hamsters with SARS-COV-2 and found that olfactory receptor neurons, which do not contain ACE2 (the binding site for the S2 subunit of SARS-COV-2 required for cell entry) remain uninfected after viral exposure, and rather it was the sustentacular cells that primarily were infected.  However, olfactory receptor neurons underwent rapid deciliation, likely the pathologic event that caused the smell loss.  Thomas Hummel examined olfactory training in 153 patients with post-infectious olfactory loss and found that olfactory training was helpful, particularly in patients who maintained some sense of smell and did not experience complete olfactory loss.

Management Algorithm

 Katherine Whitcroft and Thomas Hummel, in a clinical update published in May of 2020, published the following guideline for managing smell loss in COVID-19. Specifically, they recommended that all patients who continue to have olfactory dysfunction after resolution of their other COVID-19 symptoms and have completed an adequate quarantine period should be referred to an otolaryngologist for nasal endoscopy and/or imaging.  Sinonasal, posttraumatic, malignant, and neurodegenerative mechanisms of olfactory dysfunction should be evaluated with appropriate treatment if necessary. If patients undergo a negative workup for other causes of olfactory dysfunction, then safety counseling, olfactory training, and adjuvant medical therapies can be considered.

Medications for the Treatment of Anosmia

 Several classes of medicines have been studied for their ability to treat anosmia. Systemic glucocorticoids reduce mucosal edema and polypoid edema, effectively treating hyposmia induced by sinonasal disease.  They are particularly helpful for restoring smell in patients suffering from nasal polyps and eosinophilic sinonasal disease. However,long-term glucocorticoid use comes with a plethora of adverse side effects, some of which such as avascular necrosis of the hip are catastrophic.  As a result, systemic glucocorticoid therapy should be limited to short courses and patients should be monitored closely for the development of adverse reactions and for possible hypothalamic-pituitary-adrenal axis suppression.  Intranasal glucocorticoids have been examined for their ability to treat both primary anosmia and anosmia associated with sinonasal disease.  Therapeutic value has been mixed.  Inadequate drug dispersal and delivery to the olfactory cleft has limited the value of intranasal glucocorticoids.  Newer agents such as budesonide and mometasone delivered via sinonasal irrigations and aerosolized forms of fluticasone have shown more promise in the treatment of anosmia associated with sinonasal disease, however benefits to patients with post-infectious smell loss have not been definitively shown.  In particular, smell regeneration requires a pro-inflammatory initiating cascade, which maybe deleteriously impacted by topical glucocorticoids in post-infectious anosmia. In an open label, prospective study of 312 patients with hyposmia from a variety of causes, theophylline, a phosphodiesterase inhibitor that raises intracellular cyclic AMP and reduces inflammation and innate immunity, was found to improve subjective smell loss in 50 percent of patients, with higher doses associated with improved smell function. Topical intranasal Vitamin A has also been shown to improve anosmia by 14% greater than controls in patients with post-infectious and post-traumatic smell loss. 

Smell Training Protocol

In a recent trial by Hummel et al, higher concentrations of odorants led to improved smell compared to patients receiving lower concentrations of odorants.  Current recommendations include deliberate smelling of essential oils placed on a cotton tipped applicator and smelled vigorously for 20 seconds at a time at least twice a day for 3 months. Essential oils are available for purchase online in smell regeneration kits; rose, lemon, clove, and eucalyptus are commonly used.

Summary

Olfactory loss is a common affliction, affecting approximately 12% of the population and up to 85% of patients suffering from COVID-19. Fortunately, the neuroepithelium is supported by a robust layer of stem cells and is capable of regenerating from many insults, including post-infectious damage, particularly if rehabilitative therapy is initiated within the first year.  Patients who recover from COVID-19 should be queried for any residual symptoms.  For those who report olfactory or taste dysfunction, these patients should be referred to otolaryngology for further evaluation via nasal endoscopy and/or imaging to rule out sinonasal, posttraumatic, malignant, or neurodegenerative causes of olfaction.  For those in which other causes have been ruled out and presumed to have postinfectious olfactory loss, therapy with safety counseling, olfactory training, and adjuvant medical therapies should be implemented.