Olfactory Dysfunction in Coronavirus Disease 2019 Patients: Observational Cohort Study and Systematic Review

Abstract

Background: Olfactory dysfunction (OD) has been reported in coronavirus disease 2019 (COVID-19). However, there are knowledge gaps about the severity, prevalence, etiology, and duration of OD in COVID-19 patients.

Methods: Olfactory function was assessed in all participants using questionnaires and the butanol threshold test (BTT). Patients with COVID-19 and abnormal olfaction were further evaluated using the smell identification test (SIT), sinus imaging, and nasoendoscopy. Selected patients received nasal biopsies. Systematic review was performed according to PRISMA guidelines. PubMed items from January 1, 2020 to April 23, 2020 were searched. Studies that reported clinical data on olfactory disturbances in COVID-19 patients were analyzed.

Results: We included 18 COVID-19 patients and 18 controls. Among COVID-19 patients, 12 of 18 (67%) reported olfactory symptoms and OD was confirmed in 6 patients by BTT and SIT. Olfactory dysfunction was the only symptom in 2 patients. Mean BTT score of patients was worse than controls (P = .004, difference in means = 1.8; 95% confidence interval, 0.6-2.9). Sinusitis and olfactory cleft obstruction were absent in most patients. Immunohistochemical analysis of nasal biopsy revealed the presence of infiltrative CD68⁺ macrophages harboring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen in the stroma. Olfactory dysfunction persisted in 2 patients despite clinical recovery. Systematic review showed that the prevalence of olfactory disturbances in COVID-19 ranged from 5% to 98%. Most studies did not assess olfaction quantitatively.

Conclusions: Olfactory dysfunction is common in COVID-19 and may be the only symptom. Coronavirus disease 2019-related OD can be severe and prolonged. Mucosal infiltration by CD68⁺ macrophages expressing SARS-CoV-2 viral antigen may contribute to COVID-19-related OD.

Keywords: COVID-19; SARS-CoV-2; anosmia; olfactory dysfunction; smell impairment.

Figure 1.

Comparison of butanol threshold test (BTT) scores between coronavirus disease 2019 (COVID-19) patients and healthy controls. Bars represent mean and standard error of mean (A). Comparison of mean BTT scores of COVID-19 patients and healthy controls stratified by age group (B). ** indicates statistically significant difference between means of groups.

Figure 2.

Computed tomography scans of the nasal cavities and sinuses of coronavirus disease 2019 patients with olfactory dysfunction showing olfactory cleft opacification: complete opacification (A), partial opacification (B), and no opacification (C). Sinusitis was absent.

Figure 3.

Representative histopathological and immunofluorescence staining results of nasal biopsy tissue sections. (A) Hematoxylin and eosin-stained section showed few intraepithelial neutrophils (white arrows). (B) Small numbers of lymphocytes, plasma cells, and occasional neutrophils amongst mucous glands in the stroma (black arrows). Immunofluorescence staining of CD68 showing presence of scattered macrophages in the (C) epithelium and (D) stroma (green), the area in the boxes was magnified to demonstrate cytoplasmic staining of CD68 (white arrows). (E) Immunofluorescence staining of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (NP) in the nasal mucosa (green) and in magnified image (white arrows). Localization of SARS-CoV-2 NP in CD68⁺ macrophages by double immunofluorescence staining of CD68 (F, green) and SARS-CoV-2 NP (G, red, using mouse anti-SARS-CoV-2 NP and Texas-Red-conjugated Donkey antimouse secondary antibody), cell nuclei counterstained by 4’,6-diamidino-2-phenylindole (DAPI) in blue (H) and merged image (I).

Figure 3.

Representative histopathological and immunofluorescence staining results of nasal biopsy tissue sections. (A) Hematoxylin and eosin-stained section showed few intraepithelial neutrophils (white arrows). (B) Small numbers of lymphocytes, plasma cells, and occasional neutrophils amongst mucous glands in the stroma (black arrows). Immunofluorescence staining of CD68 showing presence of scattered macrophages in the (C) epithelium and (D) stroma (green), the area in the boxes was magnified to demonstrate cytoplasmic staining of CD68 (white arrows). (E) Immunofluorescence staining of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (NP) in the nasal mucosa (green) and in magnified image (white arrows). Localization of SARS-CoV-2 NP in CD68⁺ macrophages by double immunofluorescence staining of CD68 (F, green) and SARS-CoV-2 NP (G, red, using mouse anti-SARS-CoV-2 NP and Texas-Red-conjugated Donkey antimouse secondary antibody), cell nuclei counterstained by 4’,6-diamidino-2-phenylindole (DAPI) in blue (H) and merged image (I).

Figure 4.

Serial progression of butanol threshold test scores in patients with olfactory dysfunction.

Figure 5.

Study selection.