How our specialty can contribute and benefit from COVID-19 research.

To the Editor

Since the first reports of severe acute respiratory syndrome‒coronavirus‐2 (SARS‐CoV2) infections were reported in December 2019, there have been >34 million cases, resulting in over 1 million deaths globally from coronavirus‐2019 (COVID‐19). Given the nature of this rapidly evolving pandemic, there has been an incredible focus worldwide in COVID‐19 research. I review how rhinologists can play a leading role in combating this disease.

CV2 virus identification and angiotensin‐coverting enzyme 2 receptor

CV2 is the virus etiologic for COVID‐19. SARS‐coronaviruses (CV1 and CV2) infect cells via the spike protein, which contains a receptor binding domain that binds to the angiotensin‐converting enzyme 2 (ACE2) receptor. Before ACE2 binding, the spike protein is primed by TMPRRS2, a furin protease that exposes the fusion domain of the receptor binding protein.

Nasal tissues as target of interest in COVID‐19 binding, replication, and immune‐signaling

There has been an intensified focus to identify factors that impact ACE2 expression, in the hope of understanding the initial steps of CV2 viral binding and COVID‐19 disease pathogenesis. Scientists rapidly discovered that ACE2 was highly expressed in ciliated and goblet cells of nasal and sinus epithelia, in part due to the contribution of publicly available RNA‐sequencing data sets from sinonasal researchers. One gap in the current knowledge is identification of risk factors for CV2 binding and replication. Rhinologists can assist the scientific community by investigating CV2 viral dynamics in nasal and sinus tissue ex vivo (resected surgical samples) and in differentiated air‐liquid interface (ALI) cultures. Similar studies in SARS‐CoV2 pathology have suggested that increased ACE2 expression can result in enhanced viral binding. These findings are clinically relevant as the viral load of CV2 infection, as measured by nasal swabs, has been shown to correlate with COVID‐19 disease severity.

Once CV2 binding occurs, the immune system initiates an antiviral response. This immune response allows the majority of respiratory viral infections to self‐resolve after 5 to 7 days. Locally, nasal epithelia secrete interferons and cytokines as part of the innate immune response to limit the progression of disease. In the majority of people, this response results in resolution of symptoms after 5 to 7 days. However, the severe hyperinflammatory phase (cytokine storm) seen in critically ill patients suggests that an exuberant host immune response may be associated with COVID‐19 mortality. Numerous SARS‐CV‐2‒induced cytokines have been identified, secreted by nasal epithelial cells, and associated with COVID‐19 disease progression. The adaptive immune response, characterized by memory T cells primed to recognize previous exposure to pathogens or antigens, is critical to the implementation of a successful COVID‐19 vaccination strategy. Interestingly, half of those individuals unexposed to SARS‐CoV2 or via vaccination had a positive adaptive T‐cell response. A follow‐up study suggested that this response may be due to previous exposure to other nonsevere coronaviruses and suggests that the presence of this T‐cell memory may reduce COVID‐19 disease severity. A second gap in knowledge is to determine why the majority of those with COVID‐19 are have mild or asymptomatic disease, whereas others may require hospitalization with an aberrant antiviral response. Rhinologists are well‐equipped to quantify the expression of nasal cytokines from samples taken from the nose of those with COVID‐19 or in nasal airway cultures infected with CV2 to characterize the local innate immune response. Clinically, the knowledge of innate and adaptive immune responses to CV2 could predict persons at risk for severe COVID‐19.

COVID‐19 and anosmia

One of the most dramatic symptoms characterized by otolaryngologists of COVID‐19 has been the sudden onset of anosmia. This can present in 34% to 98% of those infected, last for weeks, and may be the only presenting symptom of COVID‐19. However, there is a gap in understanding the mechanisms of how CV2 viral infection results in anosmia, as the majority of the studies are observational and retrospective in nature. Recent work by Chen et al identified that the ACE2 receptor was highly expressed in human biopsies of olfactory epithelia, suggesting that CV2 viral binding to olfactory tissues may account for local tissue damage and loss of smell. Clinical longitudinal studies may differentiate specific populations at greater risk for anosmia and subsequent rates of recovery. Moreover, molecular research into the mechanisms of anosmia could result in novel therapies for viral‐associated anosmia.

Preparing for this winter

The rapid and sudden onset of COVID‐19 caught many of us by surprise this spring and summer. Fortunately, in many parts of the country, we are seeing decreasing infection rates and associated hospitalization and intensive care unit utilization with the implementation of enhanced hygiene, social distancing, and masking. However, there is significant concern that, in the cold/flu season this winter, COVID‐19 rates may increase and further burden the health‐care system. There is a critical need to identify potential risk factors of coinfections with COVID‐19 with common respiratory viral infections, including rhinovirus (RV) and influenza. Kim et al looked at 1206 patients over a 1‐month period in March from symptomatic patients being evaluated in northern California and found that 20% were positive for viral coinfections including rhinovirus, respiratory synctial virus, and other coronaviruses. Work from our laboratory identified that RV and influenza infections in nasal airway epithelia increased the expression of ACE2 by 3‐ to 6‐fold and induced the secretion of COVID‐19‒associated cytokines. These findings suggest that, as common respiratory viral infections circulate this winter, a synergistic effect may result in increased COVID‐19 infection rates, higher CV2 viral loads, and more severe infections. Now is the time for us to take a deep breath and adequately prepare so that we can contribute to the understanding and prevention of this devastating disease.

Our rhinologic community can continue to contribute by identifying COVID‐19 risk factors and pathophysiologic mechanisms of disease. Benefits to advancing scientific knowledge of COVID‐19 include strengthening collaborations within and outside of our specialty, which may spur advances in the viral pathophysioglogy of sinusitis. For example, druggable targets or vaccines identified in COVID‐19 could be repurposed to help slow the progression of chronic sinusitis and be efficacious against exacerbations of viral‐induced acute sinusitis and chronic rhinosinusitus.