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J Clin Med
. 2026 Feb 22;15(4):1659.
doi: 10.3390/jcm15041659.
Associations Between Nasal Receptors and Olfactory Dysfunction and Dysgeusia in Coronavirus Disease 2019 (COVID-19)
Ana María Piqueras-Sánchez 1 2 , José Francisco López-Gil 3 4 , Diego Hellín-Meseguer 1 2 5 , Juan Cabezas-Herrera 5 6 , Ginés Francisco Blesa-Llaona 1 2 , José Meseguer-Cabezas 1 , Enrique Bernal-Morell 5 7 , Alfredo Minguela-Puras 5 8 , José Antonio Díaz-Manzano 1 2 5
Affiliations
Background/Objectives: Olfactory dysfunction and dysgeusia are common neurosensory manifestations of Coronavirus Disease 2019 (COVID-19), affecting approximately 60% of patients. These symptoms have been mechanistically linked to receptors involved in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) cell entry, including angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), furin, and neuropilin-1 (NRP1), which are highly expressed in the olfactory epithelium. Nevertheless, clinical evidence supporting a direct association between receptor expression and sensory impairment remains inconsistent. Methods: We conducted a multicenter, observational, cross-sectional study including 104 adults with polymerase chain reaction-confirmed SARS-CoV-2 infection during the first and second pandemic waves. Approximately 75 days after diagnosis, nasal and/or pharyngeal samples were obtained to quantify gene expression levels of ACE2, TMPRSS2, furin, and NRP1 using quantitative polymerase chain reaction. Olfactory dysfunction and dysgeusia were recorded as dichotomous variables. Logistic regression analyses were performed with adjustment for age, sex, and race, considering receptor expression as continuous variables and as tertiles. Missing data were addressed using multiple imputation methods. Results: Olfactory dysfunction was reported by 37.5% of participants, and dysgeusia by 36.5%. No statistically significant associations were observed between baseline expression levels of ACE2, TMPRSS2, furin, or NRP1 and the presence of olfactory dysfunction or dysgeusia in either adjusted continuous or categorical models. Although these associations did not reach statistical significance, higher ACE2 and furin expression showed a nonsignificant trend toward an increased probability of sensory alterations, whereas intermediate NRP1 levels were associated with lower disease severity. Conclusions: COVID-19-related olfactory dysfunction and dysgeusia do not appear to be directly determined by isolated baseline expression of SARS-CoV-2 entry receptors. These findings support a multifactorial and dynamic pathophysiological model involving temporal receptor regulation, inflammatory processes, and host-related factors, highlighting the need for longitudinal and interventional studies.
Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; dysgeusia; furin; nasal epithelium; neuropilin-1; olfactory dysfunction.
. 2026 Feb 22;15(4):1659.
doi: 10.3390/jcm15041659.
Associations Between Nasal Receptors and Olfactory Dysfunction and Dysgeusia in Coronavirus Disease 2019 (COVID-19)
Ana María Piqueras-Sánchez 1 2 , José Francisco López-Gil 3 4 , Diego Hellín-Meseguer 1 2 5 , Juan Cabezas-Herrera 5 6 , Ginés Francisco Blesa-Llaona 1 2 , José Meseguer-Cabezas 1 , Enrique Bernal-Morell 5 7 , Alfredo Minguela-Puras 5 8 , José Antonio Díaz-Manzano 1 2 5
Affiliations
- PMID: 41753345
- PMCID: PMC12941534
- DOI: 10.3390/jcm15041659
Background/Objectives: Olfactory dysfunction and dysgeusia are common neurosensory manifestations of Coronavirus Disease 2019 (COVID-19), affecting approximately 60% of patients. These symptoms have been mechanistically linked to receptors involved in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) cell entry, including angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), furin, and neuropilin-1 (NRP1), which are highly expressed in the olfactory epithelium. Nevertheless, clinical evidence supporting a direct association between receptor expression and sensory impairment remains inconsistent. Methods: We conducted a multicenter, observational, cross-sectional study including 104 adults with polymerase chain reaction-confirmed SARS-CoV-2 infection during the first and second pandemic waves. Approximately 75 days after diagnosis, nasal and/or pharyngeal samples were obtained to quantify gene expression levels of ACE2, TMPRSS2, furin, and NRP1 using quantitative polymerase chain reaction. Olfactory dysfunction and dysgeusia were recorded as dichotomous variables. Logistic regression analyses were performed with adjustment for age, sex, and race, considering receptor expression as continuous variables and as tertiles. Missing data were addressed using multiple imputation methods. Results: Olfactory dysfunction was reported by 37.5% of participants, and dysgeusia by 36.5%. No statistically significant associations were observed between baseline expression levels of ACE2, TMPRSS2, furin, or NRP1 and the presence of olfactory dysfunction or dysgeusia in either adjusted continuous or categorical models. Although these associations did not reach statistical significance, higher ACE2 and furin expression showed a nonsignificant trend toward an increased probability of sensory alterations, whereas intermediate NRP1 levels were associated with lower disease severity. Conclusions: COVID-19-related olfactory dysfunction and dysgeusia do not appear to be directly determined by isolated baseline expression of SARS-CoV-2 entry receptors. These findings support a multifactorial and dynamic pathophysiological model involving temporal receptor regulation, inflammatory processes, and host-related factors, highlighting the need for longitudinal and interventional studies.
Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; dysgeusia; furin; nasal epithelium; neuropilin-1; olfactory dysfunction.