In this prospective study of a high-risk HCW population, we assessed smell loss alongside routine viral testing, finding that HCW who acquired SARS-CoV-2 infection over the course of the study had significantly increased odds of reporting smell loss compared to COVID-negative HCW. This finding was consistent across bivariate (OR = 3.7), regression-adjusted (OR = 4.5), and matched (OR = 6.0) analyses. Likewise, COVID-positive HCW reported significantly more severe smell loss compared to COVID-negative HCW. Overall, our findings add to the accumulating evidence demonstrating the efficacy and feasibility of using prospective, self-administered, athome assessments of smell sensitivity to track changes over time in a group of individuals at high risk for SARS-CoV-2 infection.

Our findings are consistent with recent research demonstrating robust associations between smell perturbations and SARS-CoV-2 infection. Specifically, smell and taste impairments are reported prior to (20%) or during (13%) hospitalization [10], typically lasting 4-17 days [28], and provide better predictive ability than fever or cough [29], two of the more commonly used symptoms to screen for COVID-19. Indeed, a large cross-sectional study found that sudden self-reported smell loss was the best predictive indicator of COVID-19 infection [30]. Our study extends these findings by uniquely assessing for prospective smell loss alongside viral screening in a high-risk group, all of whom were COVID-19 negative at study entry. Moreover, distortion in smell was a better predictor of COVID-19 than many other physical symptoms. Cough, headache, and dyspnea were also significantly associated with increased odds of COVID-19 diagnosis in this study. However, these symptoms are commonly experienced in other respiratory infections and not specific symptoms for COVID-19, and therefore less useful than loss of smell for monitoring for COVID-19 among asymptomatic individuals.

Interestingly, we found an association between reduction in smell ability and neurological symptoms in COVID-19. While the exact pathophysiology underlying COVID-19 related smell loss remains incompletely understood, the association between smell loss and other neurological symptoms suggests a potential common mechanism underlying these symptoms. A growing body of evidence has demonstrated the potential for SARS-CoV-2 to infect neurons [31, 32], and our results lend support to the hypothesis that smell loss may be related to central nervous system infection by SARSCoV-2, consistent with studies reporting MRI abnormalities in the olfactory bulb in a subset of patients with COVID-19 related anosmia [33, 34].

Our study has several limitations. Smell sensitivity and loss using the Yale Jiffy were evaluated using both categorical responses and a VAS [35]. Indeed, those indicating severe loss reported an average of an 8.3cm decrease on the 10cm scale, compared to a 2.2cm reduction in those indicating slight loss, suggesting categorical responses are sufficient for identifying asymptomatic carriers. However, because many participants already had smell loss the first time they completed the VAS, we were not able to detect any changes. Consistent daily ratings of a household item could prove useful for further evaluating the magnitude of loss but would require further instructions and possibly practice using the scale. Adopting the generalized labeled magnitude scale (gLMS), a specialized line scale with semantic labels at empirically derived intervals, may also improve outcomes, as this scale is less subject to floor and ceiling effects [36]. However, it requires some training and practice. Additionally, the low number of positive cases limited statistical power.

In our study, self-reported changes in smell perception were predictive of SARSCoV-2 infection in a healthcare worker population. At-home smell assessments should be considered for non-invasive screening of groups that are at high risk for COVID-19.