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Olfactory recovery following omicron variant infection: a psychophysical prospective case–control study with six-month follow up

Published online by Cambridge University Press:  17 May 2023

Luigi Angelo Vaira Open the ORCID record for Luigi Angelo Vaira [Opens in a new window] ,
Paolo Boscolo-Rizzo ,
Jerome R Lechien Open the ORCID record for Jerome R Lechien [Opens in a new window] ,
Miguel Mayo-Yáñez Open the ORCID record for Miguel Mayo-Yáñez [Opens in a new window] ,
Marzia Petrocelli ,
Laura Pistidda ,
Giovanni Salzano ,
Fabio Maglitto ,
Claire Hopkins  and
Giacomo De Riu
Luigi Angelo Vaira*
Affiliation:
Maxillofacial Surgery Operative Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy Biomedical Science Department, School of Biomedical Science, University of Sassari, Sassari, Italy
Paolo Boscolo-Rizzo
Affiliation:
Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, Trieste, Italy
Jerome R Lechien
Affiliation:
Department of Anatomy and Experimental Oncology, Mons School of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons, Mons, Belgium Department of Otolaryngology – Head Neck Surgery, Elsan Polyclinic of Poitiers, Poitiers, France
Miguel Mayo-Yáñez
Affiliation:
Otorhinolaryngology, Head and Neck Surgery Department, University Hospital Complex of A Coruña (‘CHUAC’), A Coruña, Spain
Marzia Petrocelli
Affiliation:
Maxillofacial Surgery Operative Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy Maxillofacial Surgery Unit, Bellaria-Maggiore Hospital, Azienda Unità Sanitaria Locale della (‘AUSL’) Bologna, Bologna, Italy
Laura Pistidda
Affiliation:
Intensive Care Unit Operative Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy
Giovanni Salzano
Affiliation:
Maxillofacial Surgery Operative Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy Department of Maxillofacial Surgery, University of Naples ‘Federico II’, Naples, Italy
Fabio Maglitto
Affiliation:
Maxillofacial Surgery Operative Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy Department of Maxillofacial Surgery, University of Naples ‘Federico II’, Naples, Italy
Claire Hopkins
Affiliation:
Rhinology, King's College, London, UK British Rhinological Society, London, UK
Giacomo De Riu
Affiliation:
Maxillofacial Surgery Operative Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy
*
Corresponding author: Luigi Angelo Vaira; Email: [email protected]
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Abstract

Objective

This study aimed to evaluate the recovery of olfactory function at six months in individuals infected with the coronavirus disease 2019 omicron variant, using psychophysical tests.

Methods

A prospective case–control study that included severe acute respiratory syndrome coronavirus-2 patients infected in February and March 2022 was conducted. Patients underwent the Sniffin’ Sticks test within 10 days of infection and again after at least 6 months. The olfactory scores were compared with those of a control group.

Results

In all, 102 patients and 120 controls were enrolled in the study. At baseline, 26 patients (25.5 per cent) self-reported smell loss. The median threshold, discrimination and identification score was 33.6 (interquartile range, 12.5) for the cases and 36.5 (interquartile range, 4.38) for the controls (p < 0.001). Based on the threshold, discrimination and identification scores, 12 controls and 34 patients reported olfactory dysfunction (p < 0.001). Eighty cases underwent re-evaluation at six months; the median threshold, discrimination and identification score was 37.1 (interquartile range, 4.75) with no significant differences compared with the controls.

Conclusion

Six months after infection, the prevalence of olfactory dysfunction in patients did not differ significantly from the control population.

Keywords

AnosmiaageusiaCovid-19smellSARS-CoV-2coronavirustasteotolaryngology
Type
Main Article
Information
The Journal of Laryngology & Otology , Volume 137 , Issue 12 , December 2023 , pp. 1395 - 1400
Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press on behalf of J.L.O. (1984) LIMITED

Introduction

Persistent olfactory dysfunction represents a frequent symptom of long coronavirus disease 2019 (Covid-19), affecting 5–30 per cent of the individuals one year after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.Reference Vaira, Salzano, Le Bon, Maglio, Petrocelli and Steffens1–Reference Boscolo-Rizzo, Hummel, Invitto, Spinato, Tomasoni and Emanuelli5 Given this high prevalence and the devastating effects on patients’ quality of life,Reference Vaira, Gessa, Deiana, Salzano, Maglitto and Lechien6,Reference Saniasiaya and Prepageran7 persistent olfactory dysfunction has become a healthcare challenge.Reference Boscolo-Rizzo, Polesel and Vaira8

Fortunately, it appears that the prevalence of olfactory dysfunction as a result of infection has decreased over time, from over 50 per cent in the early pandemic wavesReference Saniasiaya, Islam and Abdullah9,Reference Vaira, Lechien, Khalife, Petrocelli, Hans and Distinguin10 to 1–30 per cent in those with Covid-19 caused by the omicron variant.Reference Boscolo-Rizzo, Tirelli, Meloni, Hopkins, Madeddu and De Vito11–Reference Cardoso, Rossi, Galliez, Faffe, Tanuri and Castiñeiras13 However, to date no studies have assessed whether this lower prevalence corresponds to a lower frequency of persistent olfactory dysfunction.

This study aimed to evaluate by psychophysical tests the recovery of olfactory function at six months in individuals infected with the omicron variant.

Materials and methods

This prospective case–control study was conducted at the University Hospital of Sassari from February to October 2022. The study protocol was approved by the ethics committee of the University Hospital of Cagliari (ethical approval code: PG 2021/7118) and written informed consent was obtained from each participant.

The study included patients with a confirmed diagnosis of SARS-CoV-2 infection in February and March 2022. During this period, the omicron variant had a prevalence of over 98 per cent in the Sardinia region for more than two weeks.14 In order to reduce the risk of inclusion bias, patients were enrolled consecutively using the lists of individuals with positive infection results as provided by the Department of Prevention of the University Hospital of Sassari. Furthermore, a group of healthy individuals who had never been diagnosed with SARS-CoV-2 infection were included as controls. All these individuals were part of the hospital staff and therefore subjected to frequent checks with swabs and serological tests, with consistently negative results.

The exclusion criteria for both groups were: (1) previous Covid-19; (2) history of olfactory dysfunction; (3) previous surgery, radiotherapy or trauma to the nasal cavity; (4) chronic rhinosinusitis with and without nasal polyps; (5) neurological or psychiatric co-morbidities; and (6) age less than 18 years. Some of the patients and control participants were included in a previous study on the prevalence of olfactory dysfunction during omicron variant infection.Reference Vaira, Lechien, Deiana, Salzano, Maglitto and Piombino12

Data collection

Some general data were collected for all enrolled individuals, including age, gender and vaccination status. Self-reported olfactory loss was investigated using the specific entry of the Covid-19 symptom index, which classifies olfactory function as normal, reduced or completely abolished.Reference Lechien, Chiesa-Estomba, Hans, Calvo-Henriquez, Mayo-Yanez and Tucciarone15 Evaluation of olfactory function was performed through the extended version of the Sniffin’ Sticks test according to the administration protocol previously described.Reference Hummel, Kobal, Gudziol and Mackay-Sim16,Reference Hummel, Sekinger, Wolf, Pauli and Kobal17 The Sniffin’ Sticks test evaluates three domains of olfactory function: threshold, discrimination and identification. Each of these functions is assigned a variable score of 1–16 for threshold and 0–16 for discrimination and identification. The sum of these scores leads to an overall threshold, discrimination and identification score that categorises olfactory function as normosmia (threshold, discrimination and identification score of ≥ 31), hyposmia (threshold, discrimination and identification score of 17–30.75) or anosmia (threshold, discrimination and identification score of < 17). The evaluation took place within 10 days of the diagnosis of infection in the case group.

All the cases were re-evaluated in the same way at least six months after the first evaluation. Patients were excluded from re-evaluation if they contracted the infection during the follow-up period.

Statistical analysis

Statistical analyses were performed using jamovi version 2.3.18.0, a freeware and open statistical software for desktop computers and ‘the cloud’ servers.18 Categorical variables are reported in numerals and percentages of the total. Descriptive statistics for quantitative variables are given as the median (interquartile range). For the purposes of the statistical analysis, patients were classified into three categories of olfactory function according to the psychophysical scores obtained: normal, hyposmic and anosmic. A chi-square test was performed to evaluate the differences between cases and controls in terms of proportions of normal, hyposmic and anosmic individuals. Analysis of the differences between the Sniffin’ Sticks test results at baseline and at six months was performed by the Wilcoxon signed rank test. Differences in the Sniffin’ Sticks test results between groups was assessed with the Mann–Whitney U test. The level of statistical significance was set at p < 0.05, with a 95 per cent confidence interval. Sample size was calculated using the ‘jpower’ module of the jamovi software. Considering a minimally interesting effect size of 0.5, a power of 80 per cent and a 5 per cent margin of error, the calculated minimum sample size for each group was 64 individuals.

Results

In all, 102 patients and 120 controls who met the inclusion and exclusion criteria were enrolled in the study. The case group consisted of 49 women and 53 men with a median age of 45 years (interquartile age range, 11 years) and a vaccination rate of 99 per cent. The control group consisted of 61 women and 51 men with a median age of 44 years (interquartile age range, 8 years) and a vaccination rate of 100 per cent. The two groups were homogeneous for gender (p = 0.678), age (p = 0.229) and vaccination rate (p = 1).

At baseline in the case group, 10 (9.8 per cent) and 16 (15.7 per cent) patients reported a complete or partial loss of smell, respectively. For the psychophysical tests, the median threshold, discrimination and identification score was 33.6 (interquartile range, 12.5) for the cases and 36.5 (interquartile range, 4.38) for the controls, with a statistically significant difference between the two groups (p < 0.001) (Figure 1). Based on the threshold, discrimination and identification scores, 12 of the 120 (10 per cent) controls had hyposmia; in contrast, 34 of the 102 (33.3 per cent) patients in the case group reported an olfactory dysfunction, including 16 cases (15.7 per cent) of anosmia and 18 cases (17.6 per cent) of hyposmia (Figure 2). The differences between the two groups were statistically significant (p < 0.001).

Figure 1. Comparison of baseline threshold, discrimination and identification (TDI) scores between the case group and control group. Circles indicate individual data points. The boxes span 25th–75th percentiles, with the horizontal lines representing the median, the whiskers indicating the 95 per cent confidence interval, and the curved lines reflecting the distribution of the data points.

Figure 2. Comparison of clinical diagnosis of olfactory function between the case group and control group at baseline.

Re-evaluation was carried out at least six months later (range, 180–212 days) on 80 patients from the case group (78 per cent); 9 patients were excluded, including 8 who developed a second infection and 1 who suffered a nasal fracture during the follow-up period, and 13 patients did not attend for re-evaluation. The two groups were still homogeneous for gender (p = 0.908), age (p = 0.803) and vaccination rate (p = 1). In the case group, four patients (5 per cent) self-reported persistent hyposmia, associated in two cases with mild parosmia. With psychophysical testing, the median threshold, discrimination and identification score was 37.1 (interquartile range, 4.75) for cases, with no statistically significant differences between the two groups (37.1 vs 36.5; p = 0.580) (Figure 3). Changes in the threshold, discrimination and identification score of the case group over time were statistically significant (p < 0.001). Based on the threshold, discrimination and identification scores, nine patients (11.3 per cent) had olfactory dysfunction, including eight cases (10 per cent) of hyposmia and one case (1.3 per cent) of anosmia (Figure 4). The difference between the two groups was not statistically significant (p = 0.470).

Figure 3. Comparison of six-month threshold, discrimination and identification (TDI) scores between the case group and control group. Circles indicate individual data points. The boxes span 25th–75th percentiles, with the horizontal lines representing the median, the whiskers indicating the 95 per cent confidence interval, and the curved lines reflecting the distribution of the data points.

Figure 4. Comparison of clinical diagnosis of olfactory function between the case group and control group at the six-month follow up.

Discussion

Since the beginning of the pandemic, SARS-CoV-2 has undergone numerous mutations that have led to a succession of variants of concern. The omicron variant made its appearance in South Africa in October 2021.19 As a result of its high contagiousness, the omicron variant spread rapidly around the world becoming the predominant variant of concern at the end of January 2022.Reference Boscolo-Rizzo, Hummel, Hopkins, D'Alessandro, Menini and Dibattista20 Similarly, the characteristics of the general population have changed over time due to immunisation obtained with vaccination or with previous infection. It is therefore unsurprising that the clinical picture of Covid-19 has changed over time.Reference Maisa, Spaccaferri, Fournier, Schaeffer, Deniau and Rolland21

During the pandemic, there was a gradual reduction in the prevalence of olfactory dysfunction,Reference Klimek, Hagemann, Hummel, Altundag, Hintschich and Stielow22,Reference Hintschich, Vielsmeier, Bohr, Hagemann and Klimek23 with a significant difference comparing the omicron variant with the first pandemic waves.Reference Boscolo-Rizzo, Tirelli, Meloni, Hopkins, Madeddu and De Vito11–Reference Cardoso, Rossi, Galliez, Faffe, Tanuri and Castiñeiras13 In this study, 25.5 per cent of patients self-reported a loss of smell during infection, and 33.3 per cent had threshold, discrimination and identification scores indicative of olfactory dysfunction. This prevalence is significantly lower than that recorded in the Sardinia region itself during the first pandemic waves, which exceeded 70 per cent.Reference Vaira, De Vito, Deiana, Pes, Giovanditto and Fiore24–Reference Vaira, Deiana, Fois, Pirina, Madeddu and De Vito26 However, impairment of olfactory function still affects more than one-third of patients and therefore remains an important symptom to be considered in order to suspect SARS-CoV-2 infection.

The reasons behind the reduced ability of the omicron variant to induce olfactory dysfunction are not yet fully understood. In fact, the omicron variant presents the D614 G mutation of the spike protein, which has been associated in the past with a higher incidence of olfactory dysfunction.Reference von Bartheld, Mathew and Butowt27 It is therefore possible that the lower olfactory dysfunction rate is due to the fact that the omicron variant diffuses less easily in the nasal mucusReference Butowt, Bilinska and von Bartheld28 and that it uses transmembrane serine protease 2 less effectively as an access route into the olfactory epithelium cells.Reference Butowt, Bilinska and von Bartheld28,Reference Meng, Abdullahi, Ferreira, Goonawardane, Saito and Kimura29 On the other hand, it is possible that the more effective response in immunised subjects leads to a more rapid viral wash out before this can induce sufficient damage to cause clinically evident olfactory dysfunction.Reference Vaira, Lechien, Salzano, Maglitto, Saussez and De Riu30,Reference Sheikh-Mohamed, Isho, Chao, Zuo, Cohen and Lustig31 However, it is likely that both of these factors are implicated, because olfactory dysfunction has been found to be frequent with previous variants of concern, even in already immunised subjects.Reference Lechien, Chiesa-Estomba, Radulesco, Michel, Caira and Le Bon32,Reference Vaira, De Vito, Lechien, Chiesa-Estomba, Mayo-Yàñez and Calvo-Henrìquez33

The very high number of patients with Covid-19 who self-reported persistent olfactory dysfunction represents a major challenge. A recent meta-analysisReference Tan, Han, Zhao, Tan, Quah and Tan3 estimated that 5.6 per cent of patients self-reported a persistent olfactory disorder six months after Covid-19, with the prevalence rising to over 30 per cent when evaluated with psychophysical tests.Reference Boscolo-Rizzo, Hummel, Hopkins, Dibattista, Menini and Spinago34 Persistent olfactory dysfunction has a devastating effect on the quality of life of patients, who may isolate themselves socially, reduce their work productivity and withdraw from normal daily activities.Reference Vaira, Gessa, Deiana, Salzano, Maglitto and Lechien6,Reference Saniasiaya and Prepageran7,Reference Boesveldt and Parma35 For these reasons, persistent olfactory dysfunction represents an unprecedented health challenge.Reference Boscolo-Rizzo, Polesel and Vaira8,Reference Vaira, De Riu, Salzano, Maglitto, Boscolo-Rizzo and Lechien36–Reference Lechner, Liu, Counsell, Gillespie, Chandrasekharan and Ta38

To the best of our knowledge, the recovery rate of olfactory function after omicron variant infection has not yet been investigated. The assessment of olfactory recovery should include psychophysical tests because patients often tend to overestimate recovery, especially if they present with complete anosmia at baseline,Reference Vaira, Salzano, Le Bon, Maglio, Petrocelli and Steffens1,Reference Boscolo-Rizzo, Hummel, Hopkins, Dibattista, Menini and Spinago34 and the follow up should be long enough to detect delayed recoveries that are significantly frequent in the first three months after infection.Reference Petrocelli, Cutrupi, Salzano, Maglitto, Salzano and Lechien39 In this study, the prevalence of persistent olfactory dysfunction was 11.3 per cent, with only one case of anosmia. The differences between the cases and the controls were not significant either for the threshold, discrimination and identification score or for the clinical classifications of olfactory function. In the pandemic waves caused by previous variants of concern, several authors found a six-month rate of complete anosmia of around 10 per cent, exceeding 25 per cent if we consider the hyposmic subjects.Reference Petrocelli, Cutrupi, Salzano, Maglitto, Salzano and Lechien39–Reference Boscolo-Rizzo, Menegaldo, Fabbris, Spinato, Borsetto and Vaira43

  • • Olfactory dysfunction prevalence from infection decreased from over 50 per cent in early pandemic waves to 1–30 per cent during coronavirus disease 2019 caused by the omicron variant

  • • No studies have assessed whether this lower prevalence corresponds to a lower frequency of persistent olfactory dysfunction

  • • In this study, omicron variant infection was associated with a significantly lower persistent olfactory dysfunction rate than previous variants

  • • At six months, the prevalence of olfactory dysfunction in infected patients did not differ significantly from the general population

The pathogenetic mechanism and risk factors underlying the persistence of olfactory dysfunction in some individuals have not been established with certainty.Reference Paderno, Schreiber, Grammatica, Raffetti, Tomasoni and Gualtieri44–Reference Amadu, Vaira, Lechien, Scaglione, Saba and Lampus46 It has been hypothesised that the damage to the olfactory epithelium during infection is so severe and extensive in some individuals that it causes the loss of basal cells, which are necessary for the epithelium to regenerate.Reference Dias de Melo, Lazarini, Levallois, Hautefort, Michel and Larrous47–Reference Vaira, Hopkins, Sandison, Manca, Machouchas and Turilli49 In this sense, the omicron variant has been shown not to cause such severe damage to the olfactory epithelium as previous variants of concernReference Armando, Beythien, Kaiser, Allnoch, Heydemann and Rosiak50 and it does not appear to have neuroinvasive capabilities.Reference Armando, Beythien, Kaiser, Allnoch, Heydemann and Rosiak50,Reference Bauer, Rissmann, Benavides, Leijten, van Run and Begeman51 Moreover, a high concentration of nasal immunoglobulins was detected as a protective factor for the development of persistent olfactory dysfunction.Reference Saussez, Sharma, Thiriard, Olislagers, Vu Duc and Le Bon52,Reference Vaira, De Riu, Mayo-Yàñez, Gengler and Lechien53 Vaccinated subjects have been shown to have higher levels of nasal and salivary secretory immunoglobulins compared to post-infection immunised individuals, especially after the second dose.Reference Sheikh-Mohamed, Isho, Chao, Zuo, Cohen and Lustig31,Reference Guerrieri, Francavilla, Fiorelli, Nuccetelli, Passali and Coppeta54

Finally, another reason for this improved long-term outcome may be related to the fact that all patients included in this study were initiated early on a therapeutic protocol of olfactory training associated with palmitoylethanolamide and luteolin supplementation.Reference Di Stadio, D'Ascanio, Vaira, Cantone, De Luca and Cingolani55 Several authors have demonstrated the effectiveness of olfactory training in promoting and speeding up the recovery of olfactory function after SARS-CoV-2 infection.Reference Altundag, Ylmaz and Kesimli56–Reference Asvapoositkul, Samuthopongtorn, Aeumjaturapat, Snidvongs, Chusakul and Seresirikachorn59 However, in our opinion, it is important to closely monitor patients with olfactory dysfunction during infection, starting them with olfactory training early for at least two reasons. Firstly, in this study, 5 per cent of patients still self-reported incomplete recovery at six months. Secondly, the 60-day re-evaluation of controls who developed infection in the follow-up period found that although threshold, discrimination and identification scores returned to levels that classified individuals as normosmic, median T values were significantly lower than before infection.Reference Vaira, Lechien, Salzano, Maglitto, Boscolo-Rizzo and Hopkins60 This olfactory alteration, although unconscious and therefore not affecting quality of life, can expose patients to environmental dangers.

This study has some limitations that need to be acknowledged. Firstly, although patient enrolment occurred when omicron variant circulation was greater than 98 per cent for more than two weeks, variant of concern determination was not performed and contamination may have occurred. Secondly, to reduce the risk of selection bias, patients were enrolled consecutively from lists provided by the Department of Prevention of the University Hospital of Sassari, and it was not initially disclosed that the test would involve smell. It is possible that patients with more severe symptoms were more likely to agree to evaluation, as well as individuals with self-perceived olfactory dysfunction at baseline agreeing to undergo re-evaluation at six months. Thirdly, the controls were not tested for SARS-CoV-2 infection at the time of olfactory evaluation. However, the individuals included in the control group were part of the hospital staff and then subjected to regular antigenic swabs and immunoglobulin assays, which were consistently negative. Fourthly, the six-month follow up is not long enough to rule out late recoveries that can occur spontaneously, even two years after infection.Reference Lee, Lee, Wee and Kim61

Conclusion

Based on the results of the present study, patients infected with the Covid-19 omicron variant appear to exhibit a significantly lower persistent olfactory dysfunction rate than with previous Covid-19 variants. At six months, the prevalence of olfactory dysfunction in patients who had been infected did not differ significantly from the general population.

Competing interests

None declared.

Footnotes

Luigi Angelo Vaira takes responsibility for the integrity of the content of this paper

References

Vaira, LA, Salzano, G, Le Bon, S, Maglio, A, Petrocelli, M, Steffens, Y et al. Prevalence of persistent olfactory disorders in patients with COVID-19: a psychophysical case-control study with 1-year follow-up. Otolaryngol Head Neck Surg 2022;167:183–6CrossRefGoogle ScholarPubMed
Boscolo-Rizzo, P, Guida, F, Polesel, J, Marcuzzo, AV, Antonucci, P, Capriotti, V et al. Self-reported smell and taste recovery in coronavirus disease 2019 patients: a one-year prospective study. Eur Arch Otorhinolaryngol 2022;279:515–20CrossRefGoogle ScholarPubMed
Tan, BKJ, Han, R, Zhao, JJ, Tan, NKW, Quah, ESH, Tan, CJ et al. Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves. BMJ 2022;378:e069503CrossRefGoogle ScholarPubMed
Lechien, JR, Vaira, LA, Saussez, S. Prevalence and 24-month recovery of olfactory dysfunction in COVID-19 patients: a multicentre prospective study. J Intern Med 2023;293:82–90CrossRefGoogle ScholarPubMed
Boscolo-Rizzo, P, Hummel, T, Invitto, S, Spinato, G, Tomasoni, M, Emanuelli, E et al. Psychophysical assessment of olfactory and gustatory function in post-mild COVID-19 patients: a matched case-control study with two-year follow-up. Int Forum Allergy Rhinol 2023. Epub 2023 Feb 28CrossRefGoogle Scholar
Vaira, LA, Gessa, C, Deiana, G, Salzano, G, Maglitto, F, Lechien, JR et al. The effects of persistent olfactory and gustatory dysfunctions on quality of life in long-COVID-19 patients. Life (Basel) 2022;12:141Google ScholarPubMed
Saniasiaya, J, Prepageran, N. Impact of olfactory dysfunction on quality of life in coronavirus disease 2019 patients: a systematic review. J Laryngol Otol 2021;135:947–52CrossRefGoogle ScholarPubMed
Boscolo-Rizzo, P, Polesel, J, Vaira, LA. Smell and taste dysfunction after covid-19. BMJ 2022;378:o1653CrossRefGoogle ScholarPubMed
Saniasiaya, J, Islam, MA, Abdullah, B. Prevalence of olfactory dysfunction in coronavirus disease 2019 (COVID-19): a meta-analysis of 27,492 patients. Laryngoscope 2021;131:865–78CrossRefGoogle Scholar
Vaira, LA, Lechien, JR, Khalife, M, Petrocelli, M, Hans, S, Distinguin, L et al. Psychophysical evaluation of the olfactory function: European multicenter study on 774 COVID-19 patients. Pathogens 2021;10:62CrossRefGoogle ScholarPubMed
Boscolo-Rizzo, P, Tirelli, G, Meloni, P, Hopkins, C, Madeddu, G, De Vito, A et al. Coronavirus disease 2019 (COVID-19)-related smell and taste impairment with widespread diffusion of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) omicron variant. Int Forum Allergy Rhinol 2022;12:1273–81CrossRefGoogle ScholarPubMed
Vaira, LA, Lechien, JR, Deiana, G, Salzano, G, Maglitto, F, Piombino, P et al. Prevalence of olfactory dysfunction in D614G, alpha, delta and omicron waves: a psychophysical case-control study. Rhinology 2023;61:32–8Google ScholarPubMed
Cardoso, CC, Rossi, AD, Galliez, RM, Faffe, DS, Tanuri, A, Castiñeiras, TMPP. Olfactory dysfunction in patients with mild COVID-19 during gamma, delta and omicron waves in Rio de Janeiro, Brazil. JAMA 2022;328:582–3CrossRefGoogle ScholarPubMed
Overview of Variants in Countries. In: https://covariants.org/per-country [25 August 2022]Google Scholar
Lechien, JR, Chiesa-Estomba, CM, Hans, S, Calvo-Henriquez, C, Mayo-Yanez, M, Tucciarone, M et al. Validity and reliability of the COVID-19 symptom index, an instrument evaluating severity of general and otolaryngological symptoms. Acta Otolaryngol 2021;141:615–20CrossRefGoogle ScholarPubMed
Hummel, T, Kobal, G, Gudziol, H, Mackay-Sim, A. Normative data for the “Sniffin’ Sticks” including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol 2007;264:237–43CrossRefGoogle Scholar
Hummel, T, Sekinger, B, Wolf, SR, Pauli, E, Kobal, G. ‘Sniffin’ sticks’: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 1997;22:39–52CrossRefGoogle ScholarPubMed
The jamovi project, Version 2.3 [computer software]. Jamovi: Sydney, 2022. In: http://jamovi.orgGoogle Scholar
World Health Organization. Classification of omicron (B.1.1.529): SARS-CoV-2 variant of concern. In: https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern [2 November 2022]Google Scholar
Boscolo-Rizzo, P, Hummel, T, Hopkins, C, D'Alessandro, A, Menini, A, Dibattista, M et al. Comprehensive chemosensory psychophysical evaluation of self-reported gustatory dysfunction in patients with long-term COVID-19: a cross-sectional study. JAMA Otolaryngol Head Neck Surg 2022;148:281–2CrossRefGoogle ScholarPubMed
Maisa, A, Spaccaferri, G, Fournier, L, Schaeffer, J, Deniau, J, Rolland, P et al. First cases of omicron in France are exhibiting mild symptoms, November 2021–January 2022. Infect Dis Now 2022;52:160–4CrossRefGoogle ScholarPubMed
Klimek, L, Hagemann, J, Hummel, T, Altundag, A, Hintschich, C, Stielow, S et al. Olfactory dysfunction is more severe in wild-type SARS-CoV-2 infection than in the Delta variant (B.1.617.2). World Allergy Organ J 2022;15:100653CrossRefGoogle ScholarPubMed
Hintschich, CA, Vielsmeier, V, Bohr, C, Hagemann, J, Klimek, L. Prevalence of acute olfactory dysfunction differs between variants of SARS-CoV-2—results from chemosensitive testing in wild type, VOC alpha (B.1.1.7) and VOC delta (B.1617.2). Eur Arch Otorhinolaringol 2022;279:5445–7CrossRefGoogle ScholarPubMed
Vaira, LA, De Vito, A, Deiana, G, Pes, C, Giovanditto, F, Fiore, V et al. Correlations between IL-6 serum level and olfactory dysfunction severity in COVID-19 patients: a preliminary study. Eur Arch Otorhinolaryngol 2021;279:811–16CrossRefGoogle ScholarPubMed
Vaira, LA, Deiana, G, Lechien, JR, De Vito, A, Cossu, A, Dettori, M et al. Correlations between olfactory psychophysical scores and SARS-CoV-2 viral load in COVID-19 patients. Laryngoscope 2021;131:2312–18CrossRefGoogle ScholarPubMed
Vaira, LA, Deiana, G, Fois, AG, Pirina, P, Madeddu, G, De Vito, A et al. Objective evaluation of anosmia and ageusia in COVID-19 patients: single-center experience on 72 cases. Head Neck 2020;42:1252–8CrossRefGoogle ScholarPubMed
von Bartheld, CS, Mathew, D, Butowt, R. New study on prevalence of anosmia in COVID-19 implicates the D614 G virus mutation as a major contributing factor to chemosensory dysfunction. Eur Arch Otorhinolaryngol 2021;278:3593–4CrossRefGoogle Scholar
Butowt, R, Bilinska, K, von Bartheld, C. Why does the omicron variant largely spare olfactory function? Implications for the pathogenesis of anosmia in coronavirus disease 2019. J Infect Dis 2022;226:1304–8CrossRefGoogle ScholarPubMed
Meng, B, Abdullahi, A, Ferreira, IATM, Goonawardane, N, Saito, A, Kimura, I et al. Altered TMPRSS2 usage by SARS-CoV-2 omicron impacts infectivity and fusogenicity. Nature 2022;603:706–14CrossRefGoogle ScholarPubMed
Vaira, LA, Lechien, JR, Salzano, G, Maglitto, F, Saussez, S, De Riu, G. The role of nasal immunoglobulins in the recovery of olfactory function in COVID-19 patients. Am J Otolaryngol 2022;43:103301CrossRefGoogle ScholarPubMed
Sheikh-Mohamed, S, Isho, B, Chao, GYC, Zuo, M, Cohen, C, Lustig, Y et al. Systemic and mucosal IgA responses are variably induced in response to SARS-CoV-2 mRNA vaccination and are associated with protection against subsequent infection. Mucosal Immunol 2022;15:799–808CrossRefGoogle ScholarPubMed
Lechien, JR, Chiesa-Estomba, CM, Radulesco, T, Michel, J, Caira, LA, Le Bon, SD et al. Clinical features of patients who had two COVID-19 episodes: a European multicentre case series. J Intern Med 2021;290:421–9CrossRefGoogle ScholarPubMed
Vaira, LA, De Vito, A, Lechien, JR, Chiesa-Estomba, CM, Mayo-Yàñez, M, Calvo-Henrìquez, C et al. New onset of smell and taste loss are common findings also in patients with symptomatic COVID-19 after complete vaccination. Laryngoscope 2022;132:419–21CrossRefGoogle ScholarPubMed
Boscolo-Rizzo, P, Hummel, T, Hopkins, C, Dibattista, M, Menini, A, Spinago, G et al. High prevalence of long-term olfactory, gustatory, and chemesthesis dysfunction in post-COVID-19 patients: a matched case-control study with one-year follow-up using a comprehensive psychophysical evaluation. Rhinology 2021;59:517–27Google ScholarPubMed
Boesveldt, S, Parma, V. The importance of the olfactory system in human well-being, through nutrition and social behaviour. Cell Tissue Res 2021;383:559–67CrossRefGoogle Scholar
Vaira, LA, De Riu, G, Salzano, G, Maglitto, F, Boscolo-Rizzo, P, Lechien, JR. COVID-19 related persistent olfactory disorders represent an unprecedented challenge. Am J Otolaryngol 2022;44:103667CrossRefGoogle ScholarPubMed
Tan, NKW, Tan, CJ, Tan, BKJ, Han, R, Zhao, JJ, Quah, ESH et al. The burden of prolonged smell and taste loss in covid-19. BMJ 2022;378:o1895CrossRefGoogle Scholar
Lechner, M, Liu, J, Counsell, N, Gillespie, D, Chandrasekharan, D, Ta, NH et al. The burden of olfactory dysfunction during the COVID-19 pandemic in the United Kingdom. Rhinology 2023;61:93–6Google ScholarPubMed
Petrocelli, M, Cutrupi, S, Salzano, G, Maglitto, F, Salzano, FA, Lechien, JR et al. Six-month smell and taste recovery rates in coronavirus disease 2019 patients: a prospective psychophysical study. J Laryngol Otol 2021;135:436–41CrossRefGoogle ScholarPubMed
Hopkins, C, Surda, P, Vaira, LA, Lechien, JR, Safarian, M, Saussez, S et al. Six month follow-up of self-reported loss of smell during the COVID-19 pandemic. Rhinology 2021;59:26–31Google ScholarPubMed
Riestra-Ayora, J, Yanes-Diaz, J, Esteban-Sanchez, J, Vaduva, C, Molina-Quiros, C, Larrano-Jimenez, A et al. Long-term follow-up of olfactory and gustatory dysfunction in COVID-19: 6 months case-control study of health workers. Eur Arch Otorhinolaryngol 2021;278:4831–7CrossRefGoogle ScholarPubMed
Teaima, AA, Salem, OM, Teama, MAEM, Mansour, OI, Taha, MS, Bard, FM et al. Patterns and clinical outcomes of olfactory and gustatory disorders in six months: prospective study of 1031 COVID-19 patients. Am J Otolaryngol 2022;43:103259CrossRefGoogle ScholarPubMed
Boscolo-Rizzo, P, Menegaldo, A, Fabbris, C, Spinato, G, Borsetto, D, Vaira, LA et al. Six-month psychophysical evaluation of olfactory dysfunction in patients with COVID-19. Chem Senses 2021;46:bjab006CrossRefGoogle ScholarPubMed
Paderno, A, Schreiber, A, Grammatica, A, Raffetti, E, Tomasoni, M, Gualtieri, T et al. Smell and taste alterations in COVID-19: a cross-sectional analysis of different cohorts. Int Forum Allergy Rhinol 2020;10:955–62CrossRefGoogle ScholarPubMed
Chary, E, Carsuzaa, F, Trijolet, JP, Capitaine, AL, Roncato-Saberan, M, Fouet, K et al. Prevalence and recovery from olfactory and gustatory dysfunctions in Covid-19 infection: a prospective multicenter study. Am J Rhinol Allergy 2020;34:686–93CrossRefGoogle ScholarPubMed
Amadu, AM, Vaira, LA, Lechien, JR, Scaglione, M, Saba, L, Lampus, ML et al. Analysis of the correlations between the severity of lung involvement and olfactory psychophysical scores in coronavirus disease 2019 (COVID-19) patients. Int Forum Allergy Rhinol 2022;12:103–7CrossRefGoogle ScholarPubMed
Dias de Melo, G, Lazarini, F, Levallois, S, Hautefort, C, Michel, V, Larrous, F et al. COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Sci Transl Med 2021;13:eabf8396CrossRefGoogle Scholar
Khan, M, Yoo, SJ, Clijsters, M, Backaert, W, Vanstapel, A, Speleman, K et al. Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb. Cell 2021;184:5932–49CrossRefGoogle ScholarPubMed
Vaira, LA, Hopkins, C, Sandison, A, Manca, A, Machouchas, N, Turilli, D et al. Olfactory epithelium histopathological findings in long-term coronavirus disease 2019 related anosmia. J Laryngol Otol 2020;134:1123–7CrossRefGoogle ScholarPubMed
Armando, F, Beythien, G, Kaiser, FK, Allnoch, L, Heydemann, L, Rosiak, M et al. SARS-CoV-2 omicron variant causes mild pathology in the upper and lower respiratory tract of hamsters. Nat Commun 2022;13:3519CrossRefGoogle ScholarPubMed
Bauer, L, Rissmann, M, Benavides, FFW, Leijten, L, van Run, P, Begeman, L et al. In vitro and in vivo differences in neurovirulence between D614G, delta and omicron BA.1 SARS-Cov-2 variants. Acta Neuropathol Commun 2022;10:124CrossRefGoogle ScholarPubMed
Saussez, S, Sharma, S, Thiriard, A, Olislagers, V, Vu Duc, I, Le Bon, SD et al. Predictive factors of smell recovery in a clinical series of 288 coronavirus disease 2019 patients with olfactory dysfunction. Eur J Neurol 2021;28:3702–11CrossRefGoogle Scholar
Vaira, LA, De Riu, G, Mayo-Yàñez, M, Gengler, IM, Lechien, JR. Prevalence of chemosensitive disorders with omicron infections and the possible impacts of vaccination. Int J Infect Dis 2023;129:205–6CrossRefGoogle ScholarPubMed
Guerrieri, M, Francavilla, B, Fiorelli, D, Nuccetelli, M, Passali, FM, Coppeta, L et al. Nasal and salivary mucosal humoral immune response elicited by mRNA BNT162b2 COVID-19 vaccine compared to SARS-CoV-2 natural infection. Vaccines (Basel) 2021;9:1499CrossRefGoogle ScholarPubMed
Di Stadio, A, D'Ascanio, L, Vaira, LA, Cantone, E, De Luca, P, Cingolani, C et al. Ultramicronized palmitoylethanolamide and luteolin supplement combined with olfactory training to treat post-COVID-19 olfactory impairment: a multicenter double-blinded randomized placebo-controlled clinical trial. Curr Neuropharmacol 2022;20:2001–12CrossRefGoogle ScholarPubMed
Altundag, A, Ylmaz, E, Kesimli, MC. Modified olfactory training is an effective treatment method for COVID-19 induced parosmia. Laryngoscope 2022;132:1433–8CrossRefGoogle ScholarPubMed
Kattar, N, Do, TM, Unis, GD, Migneron, MR, Thomas, AJ, McCoul, ED. Olfactory training for postviral olfactory dysfunction: systematic review and meta-analysis. Otolaryngol Head Neck Surg 2021;164:244–54CrossRefGoogle ScholarPubMed
Lechien, JR, Vaira, LA, Saussez, S. Effectiveness of olfactory training in COVID-19 patients with olfactory dysfunction: a prospective study. Eur Arch Otolaryngol 2023;280:1255–63CrossRefGoogle ScholarPubMed
Asvapoositkul, V, Samuthopongtorn, J, Aeumjaturapat, S, Snidvongs, K, Chusakul, S, Seresirikachorn, K et al. Therapeutic options of post-COVID-19 related olfactory dysfunction: a systematic review and meta-analysis. Rhinology 2023;61:2–11Google ScholarPubMed
Vaira, LA, Lechien, JR, Salzano, G, Maglitto, F, Boscolo-Rizzo, P, Hopkins, C et al. SARS-CoV-2 effects on psychophysical olfactory scores: prospective study with evaluation before and 60-days after infection. Otolaryngol Head Neck Surg 2023;168:1249–52CrossRefGoogle ScholarPubMed
Lee, DY, Lee, WH, Wee, JH, Kim, JW. Prognosis of postviral olfactory loss: follow-up study for longer than one year. Am J Rhinol Allergy 2014;28:419–22CrossRefGoogle ScholarPubMed
Figure 0

Figure 1. Comparison of baseline threshold, discrimination and identification (TDI) scores between the case group and control group. Circles indicate individual data points. The boxes span 25th–75th percentiles, with the horizontal lines representing the median, the whiskers indicating the 95 per cent confidence interval, and the curved lines reflecting the distribution of the data points.

Figure 1

Figure 2. Comparison of clinical diagnosis of olfactory function between the case group and control group at baseline.

Figure 2

Figure 3. Comparison of six-month threshold, discrimination and identification (TDI) scores between the case group and control group. Circles indicate individual data points. The boxes span 25th–75th percentiles, with the horizontal lines representing the median, the whiskers indicating the 95 per cent confidence interval, and the curved lines reflecting the distribution of the data points.

Figure 3

Figure 4. Comparison of clinical diagnosis of olfactory function between the case group and control group at the six-month follow up.