Post-Acute Nasal Expression of ACE2, TMPRSS2, FURIN, and NRP1 in Relation to COVID-19 Severity: A Multicenter...

Background/Objectives: Host factors angiotensin-converting enzyme 2 (ACE2), transmembrane protease-serine 2 (TMPRSS2), furin paired basic amino acid cleaving enzyme (FURIN), and neuropilin-1 (NRP1) facilitate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry, but it is unclear whether their upper-airway expression after recovery is associated with the severity of the preceding acute illness. We examined the association between post-acute expression of these genes and previous coronavirus disease 2019 (COVID-19) severity. Methods: This multicenter cross-sectional study included 104 adults with polymerase chain reaction (PCR)-confirmed COVID-19 during the first two pandemic waves in Murcia, Spain. Nasal and/or oropharyngeal swabs were collected in the post-acute phase, at a median of 75 days after symptom onset, and transcript levels were quantified by quantitative real-time PCR. Severity was categorized using the World Health Organization (WHO) Clinical Progression Scale, and associations were evaluated using logistic regression adjusted for age, sex, and race/ethnicity. Results: In the primary analyses using continuous expression measures, none of the four genes was significantly associated with severity. In exploratory tertile-based analyses, the intermediate ACE2 tertile (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.05-0.61; p = 0.007) and intermediate NRP1 tertile (OR = 0.29, 95% CI 0.10-0.88; p = 0.030) were associated with lower odds of severe disease; no significant associations were observed for the high tertiles or for FURIN or TMPRSS2. Conclusions: Primary adjusted analyses did not reveal statistically significant associations between post-acute nasal expression of ACE2, TMPRSS2, FURIN, or NRP1 and COVID-19 severity. Because expression was measured after clinical recovery, these associations cannot be interpreted as predictors of acute severity and may instead reflect persistent molecular remodeling after more severe disease; reverse causation cannot be excluded. Longitudinal studies with acute-phase and serial post-acute sampling and healthy controls are needed.