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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 27
| Issue : 4 | Page : 326-336 |
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Evolution of COVID-19-related olfactory disorders: A systematic review and meta-analysis
Foster T Orji1, James O Akpeh1, Nekwu E Okolugbo2, Ethel N Chime1
1 Department of Otolaryngology, University of Nigeria, Nsukka, and University of Nigeria Teaching Hospital, Enugu, Nigeria
2 Department of Surgery, Delta State University, Abraka, Nigeria
| Date of Submission | 18-Feb-2022 |
| Date of Decision | 25-May-2022 |
| Date of Acceptance | 29-Jul-2022 |
| Date of Web Publication | 22-Sep-2022 |
Correspondence Address:
Foster T Orji
Department of Otolaryngology, University of Nigeria, Nsukka, and University of Nigeria Teaching Hospital, Enugu
Nigeria
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ijmh.ijmh_42_22
Recently acquired olfactory dysfunction (OD) has emerged as one of the hallmark manifestations of the novel coronavirus disease (COVID-19), but the evolution of its spontaneous recovery has remained inconclusive, with reports of persistence of OD beyond 6 months of onset. We undertook this systematic review and meta-analysis with a view of generating a pooled recovery rate of COVID-19-associated ODs and attempt to examine the predictors of olfactory recovery. A systematic search of Scopus, Google Scholar, and PubMed databases, comprising all longitudinal studies reporting the trajectory of COVID-19-related OD, was carried out. The pooled recovery rate was estimated with random-effects model, and the potential heterogeneity of the subgroup sources was analyzed using a meta-regression test. After the Preferred Reporting Items for Systematic Reviews and Meta-Analysis selection process, 28 studies from 16 countries were included, with a total of 5,175 OD patients, among 11,948 COVID-19 cases. The estimated global pooled recovery rate of OD was 82.7% (95% confidence interval, 77.46–88.04%), with a pooled median duration of OD of 11.6 days. Only 2 out of 28 studies had recovery data beyond a period of 2 months. But no significant difference was found in the recovery rate regarding the length of follow-up (P = 0.840). Studies that conducted objective olfactory assessments showed a significantly higher recovery rate than those with subjective assessments (P = 0.001). Although 10 studies (36%) reported >90% recovery, 9 studies (32%) documented persistence of OD in >25% of their patients. Five out of six studies showed that hyposnia tended to show complete recovery than anosmia. Age, co-morbidities, and intranasal treatments had no effects. Test of homogeneity between subgroups using Cochran’s Q test was not significant (Q = 0.69, P = 0.40). Our meta-analysis revealed high rates of early- and medium-term recovery of COVID-19-related OD. However, it also showed disturbing rates of persistence of OD. Anosmia tended to be predictive of residual OD than hyposmia. Age, comorbidities, intranasal corticosteroid, and decongestants had no effects on OD recovery. Keywords: Anosmia, coronavirus, COVID-19, hyposmia, olfactory dysfunction, recovery
How to cite this article:
Orji FT, Akpeh JO, Okolugbo NE, Chime EN. Evolution of COVID-19-related olfactory disorders: A systematic review and meta-analysis. Int J Med Health Dev 2022;27:326-36 |
How to cite this URL:
Orji FT, Akpeh JO, Okolugbo NE, Chime EN. Evolution of COVID-19-related olfactory disorders: A systematic review and meta-analysis. Int J Med Health Dev [serial online] 2022 [cited 2023 Mar 29];27:326-36. Available from: https://www.ijmhdev.com/text.asp?2022/27/4/326/356633 |
| Introduction | |  |
Since the emergence of coronavirus disease-2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, in December 2019, the disease has spread exponentially across the globe affecting more than 94 million people with more than 2 million deaths in over 200 countries, as on January 19, 2021.[1] Among the major established symptoms associated with the disease such as fever, dry cough, sore throat, and shortness of breath, emerging evidence supports recently acquired anosmia (complete loss of smell) and hyposmia (partial loss of smell), with or without loss of taste as consistent symptoms of COVID-19, with prevalence ranging from 31% to 54%.[2],[3],[4],[5] In response to the amassing evidence of the association of anosmia and ageusia as consistent symptoms of COVID-19, the Centers for Disease Control and Prevention and the World Health Organization officially included losses of smell and taste as major diagnostic symptoms of COVID-19.[6],[7]
Olfactory dysfunction (OD) following upper respiratory tract infections has been a well-recognized presentation by many otorhinolaryngologists. However, smell disorder associated with COVID-19 seems to be a unique presentation, with several reports showing OD as the solitary presentation of COVID-19.[5],[8],[9] Perhaps, the most unique feature of OD in COVID-19 is related to the pattern of recovery of the smell disorder. The persistence of anosmia remains one of the nagging concerns of post-COVID-19 patients after their recovery from the more severe acute symptoms of the disease, thus requiring several visits to a number of otolaryngologists. There is a growing concern that long-term or perhaps even permanent olfactory impairment will persist well after the recovery from acute COVID-19 illness.
While complete and early recoveries have predominantly been reported,[2],[8],[10],[11] increasing number of researchers has documented persistence of COVID-19-related anosmia/hyposmia among a significant number of patients even after 6 months of recovery from the primary COVID-19 infections.[2],[8] The differences in the reported recovery rates may be attributed to different inclusion parameters, the range of symptom severity across patients, and the length of follow-up across various series. In some of the reports, researchers relied on subjective self-reported symptoms of smell disorders. In others, although there were objective measures of the smell disorders, the outcome measures were not standardized. There has not been any existing consensus among researchers regarding the method of assessment of OD, nor uniform follow-up period of the COVID-19-related OD. At the moment, there are few systematic reviews of the available recovery figures in the literature. We therefore undertook this systematic review and meta-analysis of the available evidence with a view of generating a pooled recovery rate of COVID-19-associated ODs and attempt to examine the predictors of olfactory recovery.
| Materials and Methods | | |
We conducted a systematic review of the available evidence relating to the rate and determinants of recovery of COVID-19-related OD. Although we did not get the review protocols in this study registered in the PROSPERO data, the search was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines[12] [Figure 1]. Literature items were searched in the databases of PubMed (from January 2020 to August 2021), Google Scholar, and Scopus using the following keywords in combination: [Coronavirus] OR [COVID-19] OR [SARS-CoV-2]; [Olfactory-dysfunction] OR [Anosmia] OR [Hyposmia] OR [Parosmia] OR [Phantosmia]; [Recovery] OR [Outcome]. The retrieved data were screened by the title and abstract to determine the eligibility of studies for inclusion. Two authors (FTO and JOA) separately screened the titles and abstracts to provide full-text reviews of studies. Disagreements were resolved by consensus. Duplicate publications were removed. The appropriate full-text articles that met our inclusion criteria were retrieved, read, and discussed by the researchers before the final selection of each of the included studies. | Figure 1: PRISMA flow diagram for the selection of articles included in the study
Click here to view |
We adopted the following inclusion criteria: English language-written or translated studies; type of study (original papers, abstracts, reports, reviews, letters to the editor, and clinical trials); study design [randomized controlled trials (RCTs), case–control studies, prospective or retrospective cohort studies]; publication date from January 2020 to January 2021; follow-up duration of at least 1 month; and study population consisting of adult COVID-19 patients confirmed by reverse transcription–polymerase chain reaction (RT–PCR) technique.
We excluded: studies with similar topics and data that were not relevant to the main objective of the study, ongoing studies, studies that made reference to prevalence of COVID-19-associated ODs without reference to the recovery of OD, or those with follow-up length of less than 4 weeks. We also excluded correspondences, editorials, and review articles that did not contain new clinical data.
The following information was retrieved: authors, country, sample size (of COVID-19 and OD cases), the method of assessment of olfaction, the prevalence report of OD, follow-up duration, number and percentage recovery of OD at 4 and/or 8/12 weeks, mean/median duration of OD, interventions/treatments for the OD, and proposed predictive factors for recovery of OD.
In recognition of the use of different parameters by researchers for definitions of recovery outcome of OD, we defined our outcome of interest as “complete recovery,” “partial recovery,” and “no recovery.”
Quality of the study and risk of bias
Majority of the included studies were simple observational studies, with only two analytical study designs. None of the studies utilized RCT design. The risk of bias and publication bias of the included studies were, however, not analyzed.
Data analysis
The extracted data were entered into Microsoft Excel and analyzed using Statistical Package for Scientific Solutions (IBM SPSS), version 26. The “random meta-analysis effect model” of weighted error of mean and effect size was utilized to obtain an overall summary of the percentage of recovery of OD across studies. Heterogeneity between studies was assessed using the I2 statistic (I2> 75% indicating substantial heterogeneity) in addition to using Cochran’s Q test to identify the significance of heterogeneity. Forest plot was utilized to outline the comparative effect size across the studies.
| Results | | |
The PRISMA flow diagram as shown in [Figure 1] outlined the data extraction steps. We screened a total of 426 articles from Scopus, PubMed, and Google scholar and included 28 studies[2],[8],[9],[10],[11],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] from 16 countries (India 4, France 3, Italy 3, Belgium 2, Brazil 2, Egypt 2, Spain 2, Turkey 2, Hong Kong 1, Korea 1, Greece 1, Malaysia 1, Iran 1, UK 1, USA 1, Mexico 1).
The sample sizes of the included studies ranged from 12 to 1,916, and a total of 5,175 patients had OD, among a total of 11,948 PCR-diagnosed COVID-19 patients. This gave a pooled prevalence of COVID-19-related OD of 43.31% [95% confidence interval (CI) = 40.27–45.94].
The quantitative and qualitative characteristics of the included studies were outlined in [Table 1]. The predominant olfactory assessment was by subjective approach in 79% (22/28) of the studies, utilizing self-reported or visual analog scale (VAS) questionnaires at in-person clinical consultations or telephone/online interviews. Objective quantitative/qualitative olfactory evaluation was adopted in only 21% (6/28) of the studies. Majority of the studies (68%) had a follow-up period of just 1 month. Only two studies conducted a follow-up olfactory reassessment beyond 2 months.
[Figure 2] outlined the forest plot of the effect size of the overall mean recovery rate and in relation to the methods of olfactory assessment. The data on the overall rate of clinical recovery of OD ranged from 57% to 100%, with a pooled mean of 82.7 ± 14.31%. The mean OD recovery was significantly higher among studies that conducted objective olfactory assessment than the subjective group (85.2% vs. 82.1%, respectively) (P = 0.001). Although the two studies that reassessed the olfaction after the 3rd and 6th month, respectively, reported relatively higher recovery, the difference was not significant from the other groups with 1 and 2 months follow-up (F = 0.175; P = 0.840) [Figure 3].  | Figure 3: Forest plot of recovery of olfactory dysfunction vs. follow-up
Click here to view |
[Table 2] outlined the recovery rates among the selected studies. In most of the reported recovery of olfactory functions, there were no data to indicate whether the recoveries were complete or partial, except in only 11 (39%) of the studies. Majority of the studies (68%) reported some degree of recovery in more than 80% of their respective COVID-19-related olfactory disorders, with 10 studies reporting >90% overall recovery. Persistence of OD in up to 25% of the patients was reported in 9 (32%) of the studies. | Table 2: Pattern of recovery of olfactory dysfunction among the selected studies (n = 28)
Click here to view |
The median or mean durations of OD range from 5 to 22 days, with a pooled average of 11.6 days. Reports of early short-term median duration of recovery within 10 days were documented in 55% of the studies that had data on the duration of OD. The shortest reported durations were 5 and 6 days from India and Brazil, respectively.
Homogeneity analysis
The heterogeneity analysis of the 28 studies that reported data on recovery of OD using I2 statistics, as shown in [Figure 3], indicated significant heterogeneity of the studies within the groups, with a variation at 99%. Test of homogeneity between subgroups using Cochran’s Q test was not significant (Q = 0.69, P = 0.40). The random effect sizes in the studies are similar despite their significant heterogeneity, with significant overlap of 95% CIs.
Regarding factors influencing recovery of OD, there were only few studies that presented data on potential predictive factors for recovery [Table 3]. Four of the studies that evaluated the effect of age on recovery reported no effect, with only one study (from Egypt) showing better recovery among the age group 31–40 years. Regarding the severity of OD, five out of six studies gave consistent reports of higher baseline OD predictive of persistence of OD, with hyposmia tending to show complete recovery than anosmia. The report on the effect of the presence of nasal symptoms was the most inconsistent with 50% of the studies either showing improved recovery or incomplete recovery/no relationship. Three of the studies that assessed the effect of the presence of comorbidities either reported no effect or poor recovery of OD. Only in three studies were treatments offered for the OD, which included intranasal steroid spray, nasal decongestants, and saline irrigation (in one study). All the studies reported no effect on olfactory function recovery. Curiously, no study evaluated the effects of COVID-19 severity on the recovery of OD. | Table 3: Potential determinant factors in relation to the recovery rates of olfactory dysfunction
Click here to view |
| Discussion | | |
There has been a large pool of evidence of early and complete recovery of olfactory disorders accompanying the novel COVID-19 infection. However, increasing anecdotal evidence also tends to point to the persistence of smell disorders long after other symptoms of COVID-19 have resolved. As a result, smell disorders are increasingly being recognized as one of the frequent long-term morbidities after SARS-CoV-2 infection.[2],[11],[12],[13],[14],[15],[19],[33],[36] In this systematic review and meta-analysis, we review the emerging available evidence regarding the recovery rate of COVID-19-associated OD. Our study represents one of the few attempts at conducting a meta-analysis of the evolving global reports on COVID-19-associated olfactory disorder recovery. To our knowledge, up to the time of this write-up, there has been only one published systematic review/meta-analysis of individual data on recovery of olfactory disorders among COVID-19 patients.[36] In the present study, we made an attempt to group and analyze the selected studies in relation to the length of follow-up.
Our systematic analysis revealed that most of the studies meeting our inclusion criteria followed up their patients for a period of only 1 month, with only two studies conducting a follow-up schedule beyond 3 months. However, our study showed a high rate of spontaneous recovery of OD among COVID-19 patients. The meta-analysis using the random-effects model computed an estimated global pooled recovery rate of 82.7% (95% CI: 77.46–88.04%). This estimate is slightly less than the recovery reported by Boscutti et al.[36] (90%), which included combined pooled recovery data of both olfactory and gustatory dysfunction.
A good number of our selected studies reported high rates of early short-term olfactory recovery,[13],[17],[18],[21],[25],[26],[28],[29],[30],[34],[35] ranging from 90% to 100%, with a median duration of recovery of 10 days. In contrast, a significant number of studies equally confirmed the notion of high rates of persistence of OD in more than 25% of their respective series.[9],[11],[15],[16],[22],[23],[24],[27],[33] However, follow-up durations in none of these studies were reasonably long enough to evaluate the pattern of persistence of OD on long-term basis. Interestingly, the two studies that documented the longest follow-up time (Ugurlu et al.[10]and Lechein et al.[2]) equally documented the presence of residual OD 14.2% and 15.3% of the patients, respectively, after a mean of 135 days of OD onset. The persistence of OD after SARS-CoV-2 infection remains a major concern to the sufferers, as chronic OD is associated with disturbances in eating behavior, depression, and a general reduction of the quality of life.[22],[30],[33],[36] Future studies with longer following-up schedule would be desirable to evaluate patients with residual OD.
The mechanisms of COVID-19-related OD are still inconclusive, but several pathological patterns are increasingly being recognized, such as a nasal mucosal edema, olfactory epithelial damage (predominantly the supporting cells as well as the neural epithelial cells), and also central olfactory pathways.[30],[37] It has been shown that angiotensin-converting enzyme (ACE)2 expression was found in the basal layer of the non-keratinizing squamous epithelium in nasal and oral mucosa and the nasopharynx, with the nasal epithelial cells, specifically goblet cells and ciliated cells, displaying the highest ACE2 expression among human respiratory epithelial cells.[30],[37],[38],[39] This has led to the suggestion that nasal goblet and ciliated cells could have a special crucial role in the early viral targets and potential reservoirs of SARS-CoV-2 infection.[30],[39]
In line with the high rate of early short-term olfactory recovery, our meta-analysis data may be in support of the hypothesis that the non-neural olfactory epithelial cells are the potential target of SARS-CoV-2.[30],[37] This was further supported by the report of Brann et al.,[37] who demonstrated that ACE2 and TMPRSS2 were not detected in mature olfactory sensory neurons but were detected in many sustentacular and olfactory stem cells in the human olfactory epithelium. They suggested that SARS-CoV-2 may not directly gain entry into the olfactory sensory neural cells, but instead could target tufted and sustentacular olfactory supporting cells with resultant gross damages in the olfactory epithelium.
It has however been suggested that these cells could transfer the virus to the mature olfactory sensory neurons through axonal transport.[40] Using mouse model, Dubé et al.[41] were able to demonstrate neuron-to-neuron propagation of human coronavirus, HCoV-OC43, via axonal transport. Similarly, Netland et al.[42] demonstrated that coronaviruses, such as SARS-CoV, were able to infect the olfactory bulb and downstream areas such as the piriform cortex and the brain stem through the nasal epithelial pathway. So, SARS-CoV-2 may not be excluded from this pathway.
The significance of these observations is that it is possible that stem cells such as horizontal basal cells and olfactory neural bipolar cells can be infected. In this case, it would require more time to recover the olfactory function. If a large percentage of basal cells or olfactory neural cells are damaged, the olfactory epithelium may not effectively renew over time resulting in long-lasting anosmia.[43] This may explain the persistence of OD in high numbers in a good number of our included studies, similar to the observation reported by another meta-analysis by Boscutti et al.[36]
Potential factors influencing recovery of OD
Only a handful of the studies included data on the associated influential factors on recovery, thereby making it difficult for any reasonable conclusions to be drawn. Nevertheless, among a few studies that evaluated these potential factors, few patterns could be observed. Severe form of OD, namely anosmia, was consistently associated with the persistence of OD. The implication is that presence of anosmia rather than hyposmia could be predictive of residual OD even after resolution of other COVID symptoms. In contrast, age was consistently shown to have no influence on the recovery rate or pattern of OD. However, the severity of COVID-19 could be a cofounder as almost all the studies assessed by default recruited only mild and moderate COVID-19 cases, which are predominantly seen in younger age groups. Incidentally, there was no consensus observation among the studies, regarding the influence of the presence of associated nasal symptoms or comorbidities in predicting recovery. However, there was a marginal predominance of data in favor of improved recovery in the presence of associated nasal obstruction. This could indicate nasal mucosal edema that may quite easily respond to topical decongestants with improved outcomes.
More interestingly, the three studies that evaluated the effect of nasal corticosteroid and decongestant treatments showed consistently no benefit. This has a huge implication in the evolving management recommendations for these patients. A natural inclination would be to initiate ancillary measures in a bit to improving their chances of recovery. But there has to be supportive evidence. Some centers adopt using short course of oral steroids in patients with persistent and residual COVID-19-related OD, as they believe that this protocol seems to give improved outcomes.[44] The European Rhinologic Society (ERS) and the ENT UK Association advise against giving systemic corticosteroids to patients with sudden OD as corticosteroids cause immune suppression by impairing the innate immunity; their use has been largely discouraged because of the fear of worsening of viral propagation.[27],[45] On the contrary, the “Allergic Rhinitis and its Impact on Asthma and European Academy of Allergy and Clinical Immunology” society advised to continue intranasal corticosteroids in patients with allergic rhinitis who became infected with SARS-CoV-2. It was in the belief that no evidence exists that this could lead to deterioration or a worse outcome.[27],[46] The evidence for this recommendation has to be investigated in more robust well-designed studies in future.
Unfortunately, none of the reviewed studies in our meta-analysis examined the effect of the severity of COVID-19 infection or viral load on recovery rate, which would have been an interesting observation. This was probably as a result of the design of almost all the studies assessed. They all recruited mild and moderate cases to the exclusion of severe COVID-19 patients, which is quite understandable as severe cases would be too sick and ethically not appropriate for inclusion.
Limitations
Although the screening process was performed in a rigorous way, most authors performing clinical studies on recovery of COVID-19-related OD included data primarily on the prevalence of OD, with data on recovery as secondary consideration. Therefore, there were missing data on the target parameters.
The design of the studies was highly heterogeneous: some were prospective hospital-based and others were retrospective telephone/internet-based interviews and questionnaire with risk recall bias. The method of detection of OD was also variable, with some adopting objective testing, whereas most adopted heterogeneous subjective methods. Although the follow-up durations were stated, the attrition rates were not uniformly specified. While some of the studies specified the number of lost at follow-up, others did not. The risk of bias and publication bias of the included studies were however not analyzed, but will be assessed in future systematic reviews.
Although the protocol of this present systematic review followed the prescribed standards, the emerging nature of the COVID-19 pandemic as at the time of the commencement of this review accounted for the non-actualization of the intention to register the study protocol in PROSPERO.
| Conclusion | | |
Although our meta-analysis showed high rate of early- and medium-term recovery of COVID-19-related OD, it equally revealed disturbing rates of persistence of OD in the medium and long-term, of which the full reversal is not certain. Our review also revealed that presence of anosmia, as opposed to hyposmia, could be predictive of residual OD. Recovery was not influenced by intranasal corticosteroid/decongestant treatments, age of patients, and presence of co-morbidities; but was marginally improved by the presence of nasal obstruction.
Since COVID-19 is a new disease, and the understanding of its exact nature and scope is still evolving, it may take years to fully characterize the scope of its symptomatology and pathogenesis. This may well reflect on the quality of the gathered evidence, which was generally low, with most of the studies tending to show bias. Therefore, further well-designed studies are needed, especially RCT, to examine the effect of treatment on recovery of OD.
Financial support and sponsorship
No funding was received for conducting this study or to assist with the preparation of this manuscript.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical approval
This article does not contain any studies with human participants performed by any of the authors.
Authors’ contribution
This manuscript has been read and approved by all the authors. The requirements for authorship were met as outlined below.
FTO: Concept, design, definition of intellectual content, literature search, article screening, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript review. Also takes responsibility for the integrity of the content of this manuscript. JOA: Literature search, article screening, data acquisition, manuscript preparation, manuscript review. NEO: Data acquisition, manuscript preparation, manuscript editing, manuscript review. ENC: Manuscript review.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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