Understanding COVID-19–Related Olfactory Dysfunction—Reply

In Reply We thank Chee and Wang for their appreciation of our original investigation titled “Evolution of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19.”¹

We agree that it would be useful to include more frequent evaluation of olfactory function; this was not possible in this current study owing to the overwhelming demands on clinicians at the peak of the pandemic, but hopefully future studies will be able to recruit patients and evaluate with both self-reported and psychophysical testing of olfactory function at more frequent intervals.

We encourage the self-reported evaluation of anosmia because it has as a baseline parameter of comparison to the subjective perception of smell preceding the onset of COVID-19; although it has been shown to lack sensitivity in mild hyposmia. In contrast, evaluation by psychophysical tests, although essential to better characterize the olfactory dysfunction, may overestimate the prevalence of COVID-19–related smell disorders because it can detect preexisting impairment unrelated to SARS-CoV-2 infection. In older adults, for example, the prevalence of objective olfactory impairment in the setting of no reported deficit is 15%.²

Furthermore, a long-term evaluation of chemical senses both in patients with mild-to-moderate COVID-19 and those with severe disease, the latter apparently having less frequently an altered sense of smell during the acute phase of the disease, is mandatory to estimate the burden of persistent smell disturbance following SARS-CoV-2 infection.

Nonetheless, based on evidence showing the absence of expression of ACE2 and TMPRSS2 in neurons, current data suggest that SARS-CoV-2 is not directly neuroinvasive, with the alteration of chemical perception being a consequence of targeting nonneuronal support cells by SARS-CoV-2.³ Much remains to be learned, and there is still much work to be done to evaluate the pathophysiological mechanisms of olfactory function, looking at patients with anosmia/hyposmia, including imaging studies, postmortem examination, and in vivo histopathological assessment. Finally, a more accurate evaluation of the sense of taste to discriminate between real loss, if any,⁴ and loss of retronasal olfaction as well as an assessment of chemesthesis is fundamental. This will better direct therapeutic strategies for the large and increasing numbers of patients experiencing ongoing symptoms.

Corresponding Author: Daniele Borsetto, MD, Guy’s Hospital, London SE1 9RT, United Kingdom (daniele.borsetto@gmail.com).

Published Online: November 19, 2020. doi:10.1001/jamaoto.2020.4272

Conflict of Interest Disclosures: None reported.