Olfactory dysfunction after COVID‐19: metanalysis reveals persistence in one-third of patients 6 months after initial infection

Abstract

Recently, Deng et al. reported a significant proportion of patients having persistent olfactory dysfunction (OD) even 2 years after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.1Deng Y.K. Shi K.T. Liu Z. Zeng M. Persistent olfactory dysfunction 2 years after onset of COVID-19.J Infect. 2022; Google Scholar Moreover, the prevalence of OD evaluated by psychophysical tests was higher than that estimated based on self-reported information. We had a valuable opportunity to carefully read this interesting manuscript and additional published studies to further explore the persistent OD after the coronavirus disease 2019 (COVID-19) infection. COVID-19 was caused by SARS-CoV-2 infection, and it was listed as a global pandemic by the World Health Organization on March 11, 2020. The virus is mainly transmitted through respiratory droplets and physical contact. Besides respiratory symptoms, the most common symptom is dysfunction of smell and taste. Post-acute COVID-19 syndrome, also known as long COVID, is a prolonged illness after the acute phase of COVID-19. It is defined as “the collection of symptoms that develop during or following a confirmed or suspected case of COVID-19 and continue for more than 28 days”.2Alfadda A.A. Rafiullah M. Alkhowaiter M. Alotaibi N. Alzahrani M. Binkhamis K. Siddiqui K. Youssef A. Altalhi H. Almaghlouth I. et al.Clinical and biochemical characteristics of people experiencing post-coronavirus disease 2019-related symptoms: A prospective follow-up investigation.Frontiers in medicine. 2022; 9: 1067082Crossref Scopus (0) Google Scholar The OD associated with COVID-19 is usually transient, and it tends to subside spontaneously within a few weeks after the infection, especially in mild-to-moderate patients. However, some patients still complain of persistent OD 6 months after infection. Lechien et al. found the prevalence of OD significantly decreased from 50.8% (baseline) to 18.7% (1 year) and 3.5% (2 years) according to the psychophysical olfactory evaluations.3Lechien J.R. Vaira L.A. Saussez S. Prevalence and 24-month recovery of olfactory dysfunction in COVID-19 patients: A multicentre prospective study.Journal of internal medicine. 2023; 293: 82-90Crossref PubMed Scopus (4) Google Scholar Some authors reported significantly higher rates of persistent OD, but only a few of them investigated the prevalence of OD after 6 months or even more than 1 year of infection using objective methods. Loss of smell can have a serious impact on quality of life as it can negatively affect food enjoyment, nutritional balance, social communication, cognitive skills, and psychological functioning. In addition, it can expose patients and their families to dangerous situations.4Yaylacı A. Azak E. Önal A. Aktürk D.R. Karadenizli A. Effects of classical olfactory training in patients with COVID-19-related persistent loss of smell.European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2022; : 1-7Google Scholar Given the above-mentioned harms, there is an urgent need to develop effective treatments. We sought to explore the prevalence of persistent OD after COVID-19 infection, which is essential to understand the chronic symptoms of long COVID and to guide treatments. For this reason, PubMed, Web of Science, Embase, and Cochrane Library databases were extensively searched for all compliant studies published from January 1, 2020, to December 27, 2022. The inclusion criteria were as follows: (1) adult patients with COVID-19 confirmed by reverse transcriptase–polymerase chain reaction; (2) peer-reviewed original studies in English; (3) OD after COVID-19 persisting for more than 6 months after infection; and (4) normal cognitive function before COVID-19 and no severe nasal injuries. Twelve studies report persistent OD after COVID-19 infection. General information about the included studies is summarized in supplementary material (Table 1). We focused on recording the number of patients with COVID-19 having OD for more than 6 months; especially those in which the dysfunction persisted for more than 1 year were of more concern to us. The results of twelve studies listed in Figure 1 showed among patients with COVID-19, OD lasted for more than 6 months in about 30% of patients (95% CI, 0.20–0.40; P < 0.01). The heterogeneity (I2) was 97.4% and the Begg's test P-value was 0.631, indicating no publication bias. To further explore the persistence of olfactory impairment, we categorized the duration into 6 months to 1 year and more than 1 year. Similar rates were found for those in which the dysfunction lasted more than 1 year. The estimated prevalence rate was 31% (95% CI, 0.10–0.52; P < 0.01). OD can be subdivided into anosmia and hyposmia. In five studies, patients had anosmia 6 months after being infected with COVID-19, and the proportion was 4% (95% CI, 0.03–0.06; P < 0.01). Also, in six studies, the rate of patients having hyposmia was 22% (95% CI, 0.10–0.34; P < 0.01).Table 1The basic information of the included literature. OD: olfactory dysfunction. N: no data.AuthorCountryAgeDurationTotal No. of persistent ODTotal No. of ODMaríaSpain46.8 ± 13.912 months4378JeromeMulticenter45.0 ± 12.024 months6(4 anosmia,2 hyposmia)123CanFrance50.4± 18.99.5 months93(11 anosmia,82 hyposmia)229ConstantinGermany49.0±14.48 months85(55 hyposmia)212LuigiItaly38.4±12.5253.4±70.5 days127(18 anosmia,109 hyposmia)306FrancescaItalyN12 months46176LuigiMulticenter39.9±0.5419.8 days45(8 anosmia,37 hyposmia)119AmeenIsrael37.5 (19-74)229 days3165MartinGermany45±2.06201 days126JRMulticenter44.5±16.46 months11(6 anosmia,5 hyposmia)233NhuFrance456 months136584MadsMulticenter43.36 months1234 Open table in a new tab Within 50 days after COVID-19 diagnosis, acute symptoms such as diarrhea, stomach pain, and cold-like symptoms develop. However, what make people suffer more physically and mentally are the persistent cardiopulmonary symptoms, musculoskeletal symptoms, sensory symptoms (taste loss or olfactory disturbance), and general symptoms within 90-150 days after diagnosis.5Ballering A.V. van Zon S.K.R. Olde Hartman T.C. Rosmalen J.G.M. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study.Lancet (London, England). 2022; 400: 452-461Abstract Full Text Full Text PDF PubMed Google Scholar It is estimated that as many as 1.6 million people in the United States have chronic OD due to COVID-19.6Bhutani D.L. Ross A.G. Lehman A.Y. Shindler K.S. Resolution of COVID-19 induced anosmia following treatment with ST266.Otolaryngology case reports. 2022; 25100475Crossref PubMed Scopus (0) Google Scholar Chronic olfactory disorders may lead to eating behavior disorders, depression, and a general decrease in quality of life. However, little is known about the long-term course of OD associated with COVID-19. Previously, it was thought that SARS-CoV-2 caused anosmia by affecting the olfactory epithelium, the peripheral organ for olfaction that lines the olfactory cleft of the nasal cavity. The olfactory epithelium houses the primary olfactory sensory neurons responsible for detecting odors. Transient gene expression changes in olfactory sensory neurons, alterations in the characteristics of the mucus layer surrounding their cilia, and inflammation are thought to cause acute anosmia in animal models of SARS-CoV-2 infection.7Zazhytska M. Kodra A. Hoagland D.A. Frere J. Fullard J.F. Shayya H. McArthur N.G. Moeller R. Uhl S. Omer A.D. et al.Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia.Cell. 2022; 185 (e1012): 1052-1064Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Recent findings indicate that acute SARS-CoV-2 infection drives a proinflammatory reprogramming that is thought to induce long-term alterations in the function of other immune cells. T cell-mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post-COVID-19 smell loss.8Finlay J.B. Brann D.H. Abi Hachem R. Jang D.W. Oliva A.D. Ko T. Gupta R. Wellford S.A. Moseman E.A. Jang S.S. et al.Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium.Science translational medicine. 2022; 14: eadd0484Crossref PubMed Scopus (1) Google Scholar These mechanisms suggest therapeutic strategies. The persistent COVID-19-related chemical sensory dysfunction, a harmful sequela, needs to be treated physically and psychologically. For example, oral and intranasal corticosteroids, olfactory training, and oral vitamin–mineral supplementation are all feasible treatments. The olfactory scores indicate that the effect of rehabilitation combined with drugs may not be significantly different from that of single olfactory training therapy. However, there is an improvement in olfactory function after olfactory training.9Asvapoositkul V. Samuthpongtorn J. Aeumjaturapat S. Snidvongs K. Chusakul S. Seresirikachorn K. Kanjanaumporn J. Therapeutic options of post-COVID-19 related olfactory dysfunction: a systematic review and meta-analysis.Rhinology. 2022; Crossref Scopus (0) Google Scholar Therefore, olfactory training cannot be ignored as an easy-to-administer, low-cost treatment with negligible side effects. In conclusion, one third of the patients still have OD 6 months after the first COVID-19 infection. Even after recovery from COVID-19, persistent symptoms still deserve our attention. In the future, large-scale long-term follow-ups of patients with OD may provide continuous insights into the etiology and treatment of OD.