Understanding COVID-19–Related Olfactory Dysfunction | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Comment & Response
November 19, 2020

Understanding COVID-19–Related Olfactory Dysfunction

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, National University Hospital, Singapore
  • 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
JAMA Otolaryngol Head Neck Surg. 2021;147(1):109. doi:10.1001/jamaoto.2020.4269

To the Editor: We read with interest the article by Boscolo-Rizzo et al1 titled “Evolution of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19.” We would like to commend the authors for this important work in the documentation of the natural history of olfactory dysfunction in patients with COVID-19. We concur that the pattern of symptoms reported suggests a sensorineural cause of the olfactory dysfunction.

Postviral anosmia, most frequently investigated among patients with the influenza virus, is often attributed to infection and consequent apoptosis of olfactory neurons. In contrast, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been hypothesized to affect olfactory function via infection of the sustentacular, perivascular, and stem cells in view of its affinity with the angiotensin-converting enzyme 2 (ACE2). These cells, and not the olfactory sensory neurons, have been shown to have high expressions of ACE2 and TMPRSS2.2 Bryche et al3 reported that SARS-CoV-2 infection of the sustentacular cells resulted in massive infiltration of immune cells and damage to the olfactory ciliary layer within a short period of 2 days in a golden Syrian hamster model. They further reported partial restitution of the ciliary structure at 14 days after infection, which is postulated to reflect differentiation of progenitor cells to sustentacular cells and mature olfactory receptor neurons.4 In contrast, other studies have shown functional recovery at 45 days and odorant receptor expression at 90 days after olfactory neuronal damage.5

The authors have described a high proportion of recovery of olfactory function at 4 weeks from the initial diagnosis of COVID-19.1 However, the timing of onset and recovery of olfactory dysfunction was unclear in the article. Being able to establish a proper timeline of olfactory symptoms would help to further shed light on the pathogenesis of olfactory dysfunction. We would therefore like to suggest considering critical testing time points of 2 to 3 days,3 14 days,3 and 1 to 3 months5 after infection.

To further complicate matters, recent data have emerged showing that SARS-CoV-2 may be able to infect apparently ACE2-negative cell types5—either via other participative molecules such as BSG, neuropilin-1, and PIKfyve, or perhaps that very low-level ACE2 expression is sufficient to mediate infection.

Having a clear account of the symptomatology and evolution of olfactory dysfunction at regular intervals would allow researchers to compare and correlate post–COVID-19 olfactory dysfunction with other olfactory disorders on a cellular level. This may play an important role in furthering our understanding of the pathogenesis of SARS-CoV-2.

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Article Information

Corresponding Author: Jeremy Chee, MBBS, Department of Otolaryngology–Head and Neck Surgery, National University Health System, 1E Kent Ridge Rd, Singapore 119228 (jeremy_chee@nuhs.edu.sg).

Published Online: November 19, 2020. doi:10.1001/jamaoto.2020.4269

Conflict of Interest Disclosures: None reported.

Boscolo-Rizzo  P, Borsetto  D, Fabbris  C,  et al.  Evolution of altered sense of smell or taste in patients with mildly symptomatic COVID-19.   JAMA Otolaryngol Head Neck Surg. Published online July 2, 2020. doi:10.1001/jamaoto.2020.1379PubMedGoogle Scholar
Brann  D, Tsukahara  T, Weinreb  C. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. BioRxiv. Accessed October 13, 2020. https://www.biorxiv.org/content/10.1101/2020.03.25.009084v4
Bryche  B, St Albin  A, Murri  S,  et al.  Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters.   Brain Behav Immun. 2020;S0889-1591(20)31358-1.PubMedGoogle Scholar
Bilinska  K, Butowt  R.  Anosmia in COVID-19: a bumpy road to establishing a cellular mechanism.   ACS Chem Neurosci. 2020;11(15):2152-2155. doi:10.1021/acschemneuro.0c00406PubMedGoogle ScholarCrossref
Cooper  KW, Brann  DH, Farruggia  MC,  et al.  COVID-19 and the chemical senses: supporting players take center stage.   Neuron. 2020;107(2):219-233. doi:10.1016/j.neuron.2020.06.032PubMedGoogle ScholarCrossref
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