Ellie Goldenberg Legacy Award

Ellie Goldenberg (z"l) was one of the most genuine, loyal, talented, kind-hearted, and passionate people you could ever hope to know.

Ellie cared about those she loved like no other; she did all she could for you when you were sad, cheered you on when you succeeded, and, most importantly, pushed you to be your very best self. Her love was unconditional and so very deep. She would go to the ends of the earth for her friends and family.

And then, there was that voice. Ellie was always singing; in the shower, in the kitchen, and in the bathroom. She would sing when she was happy, when she was sad, and when she was angry. When Ellie sang, we would stop whatever we were doing to listen. Her voice melted our hearts. We still hear her voice in our dreams.

Ellie was the hardest-working person you could ever know. We used to joke with her that in a family of doctors and future doctors, she got off easy majoring in "jazz hands and accents," but nothing was farther from the truth. When studying a playwright or preparing for a show by a specific author, Ellie bought all their plays and read them cover to cover until she could predict every right acting choice and understand the intention of each of the author's words. Then, she would stand in the shower singing the same note or line of a song repeatedly until she was sure it was perfect. That was Ellie.

But of all of these things, most importantly, Ellie was genuine and passionate. She did everything with purpose, determination, and with all of her heart. In establishing this resident award at the Pennsylvania Academy of Otolaryngology, we, her family, wanted her legacy of hard work, dedication, and kindness to be commemorated and perpetuated. The Ellie Goldenberg Award will recognize an Otolaryngology resident within the Commonwealth of Pennsylvania who demonstrates a strong work ethic, diligence, initiative, and kindness. The award will be presented at the annual PAO meeting.

Jennifer E. Douglas, MD University of Pennsylvania

With the development of the COVID-19 pandemic, smell loss has emerged as a particularly common symptom among patients recently infected by SARS-CoV-2. Current literature indicates that around 40% of patients experience some form of smell or taste dysfunction following SARS-CoV-2 infection. Anosmia poses a variety of safety concerns, such as the loss of odor recognition of fires, gas leaks, and spoiled food. Given the safety concerns and long-term quality of life issues associated with this condition, knowledge of current treatments addressing COVID-related anosmia is critical. In the past several years, a number of investigations have occurred regarding effective treatment methods, and we have sought to highlight these findings.

COVID 19 Pathophysiology

While further research is necessary to better understand the mechanisms through which SARS-CoV-2 is able to cause infection, relatively high rates of angiotensin converting enzyme 2 (ACE2) expression among cells infected with SARS-CoV-2 point towards ACE2 involvement in viral infection. Current studies highlight the role of ACE2 as a receptor that permits SARS-CoV-2 entry into cells and subsequent initiation of viral replication. Transmembrane serine protease 2 (TMPRSS2), which is involved in priming of the spike protein in SARS-CoV-2 through cleavage at the S1/S2 and S2 site, is also associated with COVID-19 infection. Given the much broader spread of TMPRSS2 across various organs and tissues, a focus on ACE2 provides a more tailored approach to addressing the mechanisms through which SARS-CoV-2 is able to affect various systems. Some studies indicate that SARS-CoV-2 can utilize ACE2 and TMPRSS2 to facilitate viral infection without inducing a local inflammatory response, providing an explanation for the relatively large body of patients who experience anosmia as the only symptom of COVID-19 infection and illustrating the importance of educating patients about anosmia as an indicator of viral infection. In addition to determining the role of ACE2 and TRMPSS2 in SARS-CoV-2 infection, a recent multiancestry genome-wide association study involving self-reported data from 69,841 23andMe participants identified a genetic locus at chr4q13.3 linked to COVID-associated anosmia. Two of the genes identified within 150 kb of this locus, UGT2A1 and UGT2A2, are uridine diphosphate glycosyltransferases present in the olfactory epithelium and have been shown to be involved in olfactory signal termination in animal studies.

A number of other theories have been presented regarding the mechanisms through which SARS-CoV-2 is able to induce anosmia among patients who have been recently affected. The sustentacular cells of the olfactory epithelium have been a particular point of focus given their role in the maintenance of the olfactory epithelium and the relatively high rates of ACE2 and TMPRSS2 expressed among these cells. Damage to the sustentacular cells and the release of tumor necrosis factor-(TNF-) can directly cause dysfunction of the olfactory epithelium via local inflammation and indirectly limit the activity of olfactory sensory neurons through destruction of the cilia layer involved in olfactory transduction. Despite the relatively low levels of ACE2 expressed in OSNs, studies continue to examine mechanisms through which SARSCoV-2 is able gain entrance to the central nervous system in light of the presence of neuronal infection via the olfactory nerve in SARS-CoV-1. As research progresses, more recent studies have begun to incorporate multi-modal MRI analysis to assess alterations to the function of cortical structures involved in olfactory function among patients suffering from long-term COVID-induced anosmia. Treatments aim at addressing the particular mechanisms through which SARS-CoV-2 infects cells via olfactory pathways and results in an increased prevalence of anosmia among infected patients.

Treatment Options

Olfactory Training

Olfactory training, which involves repeated, brief exposure to a series of odorants over a period of months, remains one of the most common methods for addressing COVID-induced anosmia. Following an extensive review of 107 articles addressing management of postinfectious olfactory dysfunction, the Clinical Olfactory Working Group highly endorsed olfactory training to address postinfectious olfactory dysfunction. One study reported a significant increase in olfactory function following repeated twice-daily exposure to rose, eucalyptus, lemon, and cloves over the course of 12 weeks compared to a control group that showed no improvement without olfactory training.

Additional research has been completed regarding the effectiveness of olfactory testing in combination with other odorants or treatment methods. Among three groups of patients completing either a modified olfactory training, standard olfactory training, or no olfactory training over the course of 36 weeks, the group completing modified olfactory training showed significant improvement in olfactory function compared to the groups completing standard olfactory training or no olfactory training. The modified olfactory training utilized three sets of four different odorants administered for 12 weeks at a time in comparison to the standard olfactory training, which utilized the same four odorants (rose, eucalyptol, lemon, cloves) over the 36-week period. Additional odorants utilized in modified olfactory training included menthol, thyme, tangerine, jasmine, green tea, bergamot, rosemary, gardenia. Considering the promising results of recent studies, as well as the accessibility of smell training to many patients experiencing postinfectious olfactory dysfunction, more research is warranted on this method of treatment.

Corticosteroids

While widely employed based on their anti-inflammatory abilities in treating CRS and respiratory distress, the use of corticosteroids in conjunction with olfactory training has also proven promising in treating COVID-related anosmia. In a randomized controlled trial with 138 patients experiencing olfactory loss and without signs of sinonasal inflammation, patients were asked to either complete olfactory training in conjunction with saline irrigation or olfactory training in conjunction with budesonide irrigations for 6 months. Subject outcomes were determined based on the results of the University of Pennsylvania Smell Identification Test (UPSIT). Of the 47 patients showing improvement in olfactory function, 43.9% of patients completing the budesonide irrigations and olfactory training and 26.9% of patients completing saline irrigations and olfactory training demonstrated improvement.

Another study examining the use of oral and intranasal corticosteroid use in conjunction with olfactory training among 152 patients experiencing COVID-related olfactory dysfunction found a significant improvement in patients using oral corticosteroids in early usage but found that any significant improvement in comparison to intranasal corticosteroid use or olfactory training alone diminished after two months. The study divided patients into three groups, who were instructed to use oral corticosteroids while completing olfactory training, intranasal corticosteroids while completing olfactory training, or olfactory training alone. Subject olfactory function was examined using Sniffin’ Sticks. No patients experienced a worsening of COVID symptoms. A similar outcome was observed in a study examining 100 subjects experiencing COVIDinduced anosmia who were instructed to administer mometasone furoate nasal spray in each nostril once daily for three weeks while performing olfactory training or were instructed to complete olfactory training alone. While smell scores improved for both subject groups, there was no significant difference in outcome between the two groups.

Of note, some earlier studies have raised concern regarding delayed viral clearance and immunosuppression as a result of frequent or prolonged corticosteroid use. While current research is generally promising regarding the use of corticosteroids in managing postinfectious olfactory dysfunction, further discussion of the use of this treatment in patients recently infected with SARS-CoV-2 or the need for adjuvant therapies during treatment requires further examination.

Additional Treatments

A number of other treatments have shown promising results in improving symptoms of anosmia following COVID-19 infection, including theophylline, sodium citrate, fatty acids, and platelet-rich plasma (PRP). These treatments operate through a variety of methods. Parotid saliva levels of cAMP and cGMP have been shown to be decreased in patients experiencing smell loss, and theophylline is thought to improve olfactory sensitivity by inhibiting phosphodiesterase, thereby increasing neuronal levels of second messengers cAMP and cGMP. Sodium citrate operates via sequestering of calcium to reduce feedback inhibition in olfactory signaling transduction. Fatty acids utilize their anti-inflammatory, antioxidative, and protective functions in order to improve olfactory function.

The injection of PRP, an autologous blood product, into the olfactory cleft constitutes a new approach to addressing olfactory dysfunction following COVID-induced anosmia. The anti-inflammatory and regenerative capacity of PRP occurs via degranulation of platelets containing high concentrations of growth factors and other proteins involved in inflammation and tissue regeneration. Based on comparative analysis of TDI scores in a study involving 56 patients experiencing COVID-induced olfactory dysfunction, PRP injections led to a significant improvement in olfactory function after 1 month compared to the control group. A single-blinded, randomized controlled study involving 29 patients extended the period in which subjects were followed from 1 to 3 months and employed a placebo injection. Results of this second study demonstrated a significant improvement in olfaction scores and smell discrimination among patients receiving a PRP injection at both the 1-month and 3-month mark compared to the placebo group, but no significant difference in smell identification, smell threshold, or subjective scores. No long-standing adverse effects were noted in either study.

Conclusion

Ongoing discussion is warranted regarding the best treatment methods for improving olfactory loss following SARS-CoV-2 infection. While olfactory training remains a highly regarded treatment method, recent studies indicate that combined therapies including corticosteroids may be a more appropriate form of treatment among patients experiencing persistent anosmia. As treatment methods continue to develop, organizations such as the Smell and Taste Association of North America (STANA), the Monell Chemical Senses Center Smell for Life Project, AbScent, and Anosmia Awareness Organization provide resources, opportunities, and other forms of support for patients experiencing anosmia.

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