Chronic olfactory dysfunction from the COVID-19 pandemic is a growing public health crisis with up to 1.2 million people in the Unites States affected. Olfactory dysfunction impacts one's quality of life significantly by decreasing the enjoyment of foods, creating environmental safety concerns, and affecting one's ability to perform certain jobs. Olfactory dysfunction is also an independent predictor of anxiety, depression, and even mortality. While the pandemic has increased the interest by the scientific community in combating the burgeoning health crisis, few effective treatments currently exist for olfactory dysfunction. Furthermore, patients impacted by "long COVID," or chronic symptoms after an acute COVID-19 infection, experience impairments other than olfactory and gustatory dysfunction, such as chronic dyspnea, impaired memory and concentration, and severe fatigue. These symptoms have been hypothesized to be a result of sympathetic positive feedback loops and dysautonomia. Stellate ganglion blocks have been proposed to treat this hyper-sympathetic activation by blocking the sympathetic neuronal firing and resetting the balance of the autonomic nervous system. Studies prior to the COVID-19 pandemic have supported a beneficial effect of stellate ganglion blocks on olfactory dysfunction, and recent news reports and a published case series have described a dramatic benefit in both olfactory function and other long COVID symptoms in patients receiving stellate ganglion blocks. Therefore, we propose a single cohort prospective study to generate pilot data on the efficacy and safety of sequential stellate ganglion blocks for the treatment of COVID-19-induced olfactory dysfunction and other long COVID symptoms.

One of the hallmark symptoms of infection with SARS-CoV-2 is olfactory dysfunction, and it is estimated that up to 1.2 million people in the United States will experience chronic olfactory dysfunction from the COVID-19 pandemic. While the majority of patients recover from COVID dysosmia, up to 15%-25% have long-term hyposmia. Olfactory impairment can take the form of hyposmia (diminished sense of smell), anosmia (absent sense of smell), or parosmia (distorted sense of smell). Etiologies of olfactory dysfunction include post-viral, traumatic, inflammatory (e.g., chronic rhinosinusitis), neurodegenerative (e.g., Parkinson's disease), and congenital, among others. Prior to the pandemic, post-viral anosmia was the most common cause of olfactory dysfunction, which has further increased as the dominant etiology as a result of COVID-19. The proposed pathophysiologic mechanisms of chronic COVID-19-induced olfactory dysfunction include inflammatory cytokine release, damage to the supporting environment of the olfactory epithelium, and retrograde propagation to higher order neurons. A unique feature of COVID-19-associated olfactory dysfunction is the high rate of persistent parosmia. In one study of 222 patients with COVID-19-associated olfactory dysfunction, 148 (67%) of these patients experienced parosmia at some point. Of the 148 patients with parosmia at any point, 84 (57%) had persistent parosmia after a mean of 6.5 months, distinguishing COVID-19-induced olfactory dysfunction from any other etiologies of olfactory dysfunction. Patients with olfactory dysfunction have decreased quality-of-life and describe their life as if "living in a box." These patients have concern for environmental safety, decreased enjoyment of their food, depression, anxiety, and even higher risk of mortality. The COVID-19 pandemic has highlighted the importance of the sense of olfaction, however, there is a scarcity of effective treatments for olfactory dysfunction. Furthermore, chronic olfactory dysfunction is just one of the constellation of symptoms included in "long COVID," or persistent symptoms after recovery from acute illness due to COVID-19. Other symptoms of long COVID include fatigue, dyspnea, cough, and impaired memory and concentration, among many others.These chronic symptoms are hypothesized to be, at least in part, a result of sympathetic hyperactivity resulting in positive feedback loops. Therefore, the stellate ganglion block, which inhibits the sympathetic nervous system, is hypothesized to reset the balance of the autonomic nervous system and provide relief for long COVID symptoms, including olfactory dysfunction.

Treatment No standard of care treatment for post-viral olfactory dysfunction exists. The most commonly used treatment for post-viral olfactory dysfunction is olfactory training; however, a large proportion of patients do not receive benefit and continue to have persistent symptoms. A multitude of other therapies have been tried with minimal success, including theophylline, vitamin A, sodium citrate, and intranasal insulin. As a result, there is a critical need for the development of a novel intervention to address the large volume of patients with olfactory dysfunction as a result of the COVID-19 pandemic.

The stellate ganglion block (SGB) involves an ultrasound-guided injection of a local anesthetic to inhibit the stellate ganglion. The SGB is proposed to inhibit the sympathetic neural connections within the head, neck, and upper extremity, improve regional blood flow, reduce adrenal hormone concentration, and even reestablish circadian rhythms through modulation of melatonin. The SGB has been used successfully in a multitude of disorders, including post-traumatic stress disorder, cluster headache, complex regional pain syndrome, and peripheral vascular disease.

The SGB was first proposed to treat olfactory dysfunction by Lee et al in 2003, where 38 post-viral olfactory dysfunction participants were treated with SGB and 13 participants remained untreated as controls. Subjective olfactory function improved in 27 (71%) of the treated participants compared to zero (0%) of the controls. Olfactory perception was improved significantly in the SGB group assessed both by the butanol threshold test and odor identification test. There were no complications of SGB in the 38 treated participants. Another study in 2007 by Moon et al found that in 13 participants with various etiologies of olfactory dysfunction, seven (54%) demonstrated improvement with repeated SGBs. The same group conducted a study published in 2013 looking at the long-term results of SGB in treating olfactory dysfunction from various etiologies. Of 37 participants with olfactory dysfunction unresponsive to oral or intranasal steroids who underwent SGB, 15 (41%) were determined to be responsive and 22 (59%) unresponsive to the treatment. Importantly, the responsive group had a mean duration of olfactory dysfunction of 1.6 years vs. a mean duration of olfactory dysfunction of 4 years in the unresponsive group. The study found that in those who respond to SGB, the beneficial effects on olfaction last at least 5 years. Of the 37 treated participants there was only 1 who experienced a complication, which was a temporary brachial plexus block.

Most recently, anecdotal news reports and a published case series point to a possible beneficial effect of SGB on both chronic COVID-19-induced olfactory dysfunction and various other long COVID symptoms. A published case series by Liu et al describes two patients who underwent SGB for long COVID symptoms, including olfactory dysfunction. SGB was performed on the right side then either one or two days later to the left side. Both patients reported significant and durable improvement in symptoms, including fatigue, "brain fog," and olfactory and gustatory dysfunction that persisted at 60-day follow-up. Nearly all other long COVID symptoms, including cough, chest pain, heart palpitations, and orthostatic dizziness, also improved at the one week and two-month follow-up time points. The authors concluded that although the sample size is limited, SGB may have a significant impact on the dysautonomia caused by COVID-19 and improve long COVID symptoms, giving rationale to conduct a larger study. Therefore, we propose a single cohort prospective study to generate pilot data on the effectiveness and safety of sequential stellate ganglion blocks for the treatment of COVID-19-induced olfactory dysfunction and other long COVID symptoms.

Inclusion Criteria:

1. Adults age 18 to 70
2. Diagnosis of COVID at least 12 months prior to study enrollment with self-reported olfactory dysfunction
3. Objective olfactory dysfunction due to COVID-19 that has persisted despite viral recovery, as defined by the UPSIT (≤ 34 in women, ≤ 33 in men)
4. Ability to read, write, and understand English

Exclusion Criteria:

1. History of smell loss prior to COVID-19 infection

2. History of conditions known to impact olfactory function:

   1. Chronic rhinosinusitis
   2. History of prior sinonasal or skull base surgery
   3. Neurodegenerative disorders (Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Lewy body dementia, frontotemporal dementia)

3. Currently using concomitant therapies specifically for the treatment of olfactory dysfunction

4. Inability to tolerate a needle injection into the neck

5. History of coexisting conditions that make SGB contraindicated:

   1. Unilateral vocal cord paralysis
   2. Severe COPD (FEV1 between 30-50% of predicted)
   3. Recent myocardial infarction within the last year
   4. Glaucoma
   5. Cardiac conduction block of any degree

6. Currently taking blood thinners or antiplatelet agents

7. Allergy to local anesthetic

8. Inability to extend the neck for any reason (e.g., severe arthritis)

5 weeks

Adverse events were reported per injection. Since all participants received two injections, there were a total of 40 possible reported events for each particular adverse event.