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Nearly one in four COVID-19 patients with olfactory dysfunction said they did not recover their sense of smell 60 days after losing it, a large prospective study in Europe showed.

Among nearly 2,600 people with confirmed SARS-CoV-2 infection, patient-reported prevalence of olfactory dysfunction was 85.9% in mild COVID-19 cases, 4.5% in moderate cases, and 6.9% in severe-to-critical cases, reported Jerome Lechien, MD, PhD, of Paris Saclay University in France, and co-authors in the .

About 24% of patients did not subjectively recover olfaction 60 days after dysfunction started. When a smaller sample of patients was evaluated with objective olfactory tests, 15.3% still showed deficiency at 60 days and 4.7% had not recovered olfaction at 6 months.

"Olfactory dysfunction is more prevalent in mild COVID-19 forms than in moderate-to-critical forms, and 95% of patients recover their sense of smell at 6 months post-infection," Lechien said in a statement.

The study evaluated 2,581 ambulatory and hospitalized COVID-19 patients identified at 18 European hospitals from March 22 to June 3, 2020. In total, 2,194 patients (85.0%) had mild disease, 110 (4.3%) had moderate disease, and 277 (10.7%) had severe-to-critical COVID-19. Mild, moderate, severe, and critical patients were defined using .

Most participants were women (62.9%), but the proportion of women was higher in the mild patient group than in others (P=0.001). Patients with mild COVID-19 had a mean age of 42; mean ages were 69 for moderate COVID-19 and 72 for severe and critical disease. About 84% of the sample was Caucasian.

Participants answered olfactory and gustatory questions based on the of the CDC's National Health and Nutrition Examination Survey. The average duration of patient-reported olfactory dysfunction was 21.6 days.

Of the total patients in the study, 233 completed objective olfactory evaluations, including 181 with mild and 52 with moderate-to-critical COVID-19. Objective evaluations identified hyposmia or anosmia in 54.7% of patients with mild disease and 36.6% of patients with moderate-to-critical disease (P=0.001).

Mean values on the test -- an olfactory evaluation using 16 smell pens -- were significantly lower in the mild patient group than in patients with moderate-to-critical COVID-19 (P=0.001). Baseline mean values of Sniffin Sticks tests significantly improved after 30 and 60 days of follow-up (P=0.001). Higher baseline severity of objective olfactory evaluations strongly predicted 2-month persistent loss (P<0.001).

The main hypothesis underlying the higher prevalence of anosmia in mild COVID-19, according to Lechien and colleagues, is that milder cases develop a more robust local immune response to infection. The inflammation associated with that response, however, may lead to stronger impairment of olfactory cells, the researchers suggested.

That olfactory dysfunction in COVID-19 is so common that it supports a need for primary care physicians, ENT specialists, and neurologists to counsel patients about recovery likelihood and identify people at risk of persistent olfactory dysfunction, Lechien and colleagues said. "Considering both subjective and objective data, we may suggest that the 60-day recovery rate ranges from 75% to 85%," they wrote.

The study has several limitations, including a lack of clinical olfactory examination or imaging at disease onset. Many severe-to-critical patients had a nasogastric feeding tube, which delayed assessment and may have biased some results.

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