2.1. Study Population and Demographic Data

This longitudinal study was conducted in a tertiary referral hospital in Rome from April 2021 to October 2021. To recruit patients, we used word-of-mouth communication among clinicians and calls through newspapers, television, and the internet (mass media). All centers used the same procedures and protocols. Patients were assigned a number at the time of recruitment, and they were informed that the purpose of the study was to investigate approaches for treating persistent loss of smell after COVID-19. Patients were also advised that, after the baseline assessment, they would have a follow-up olfactory assessment at 90 days, with up to two possible intermediary olfactory assessments, as dictated by protocol. Patients were instructed that their participation was voluntary and that they could withdraw from the study at any time. A single physician at each center performed an endoscopy to rule out baseline pathologies (e.g., polyps or tumors), and a second physician performed olfactory testing using validated measures of threshold, discrimination, and identification scores. Self-reported data on mental clouding/brain fog were also collected. The physician who performed the nasal endoscopy had knowledge of the experimental groups and did not participate in the olfactory assessment. All the collected data were anonymized and recorded on a protected Excel sheet shared by all the centers (Google (Mountain View, CA, USA)). Study participants were included or excluded based on the following criteria:

Eligible patients for the study included outpatients, ages 18 to 80 years, with a confirmed history of COVID-19 (positive nasopharyngeal swab for SARS-CoV-2), and anosmia/hyposmia confirmed with the 16-pen version of the Burghart Sniffin’ Sticks psychophysical test (I score 0–16), with olfactory impairment persisting ≥ 180 days (6 months) after a subsequent negative COVID-19 nasopharyngeal swab. Chronic olfactory dysfunction after SARS-CoV-2 thus served as a marker for long COVID, and signed informed consent was obtained from all the individuals opting to participate in the study.

Exclusion criteria included a previous history of olfactory–gustatory disorders, previous known/perceived/referred disorders of memory, active chemotherapy or treatment with estrogen inhibitors (aromatase), impaired cognitive function, history of neurodegenerative disease (Alzheimer’s and Parkinson’s disease), medical therapy with known detrimental effects on olfactory function, the presence of active rhinologic disorders (sinusitis, rhinosinusitis, sinonasal polyposis, atrophic rhinitis, allergy) at the time of enrollment, history or chemoradiotherapy of the head and neck region, history of stroke or neurotrauma, severe nasal blockage from stenosis or deformity, severe psychiatric illness (e.g., schizophrenia, bipolar disorder, olfactory hallucination), previous sinonasal or nasopharyngeal tumors, or corticosteroid therapy used to treat olfactory dysfunction within the previous 30 days. Additionally, any of the patients who were using medications with anti-inflammatory or immune-modulating effects that could either independently reduce inflammation or interfere with PEA-LUT were excluded from the study.