key: cord-0783362-4moxmxc7 authors: Kim, Jeong-Whun; Han, Seung Cheol; Jo, Hyung Dong; Cho, Sung-Woo; Kim, Jin Youp title: Regional and Chronological Variation of Chemosensory Dysfunction in COVID-19: a Meta-Analysis date: 2021-01-19 journal: J Korean Med Sci DOI: 10.3346/jkms.2021.36.e40 sha: badc9ca0b590b529d6ce6756a74a6829e4413ffd doc_id: 783362 cord_uid: 4moxmxc7 BACKGROUND: Olfactory and gustatory dysfunction are frequently reported in patients with coronavirus disease 2019 (COVID-19). However, the reported prevalence of olfactory and/or gustatory dysfunction varies widely, and the reason for the inter-study differences is unclear. Hence, in this meta-analysis, we performed subgroup analyses to investigate the factors that contribute to the inter-study variability in the prevalence of olfactory and gustatory dysfunction. METHODS: Out of 943 citations, we included 55 eligible studies with 13,527 patients with COVID-19 for a meta-analysis. Calculating the data extracted from each study, the weighted summary prevalence of olfactory and gustatory dysfunction was estimated using a Freeman-Tukey transformation with models based on random-effects assumptions. A meta-analysis of variance compared the prevalence of olfactory and gustatory dysfunction according to regional, chronological, demographic, and methodologic factors, respectively. RESULTS: The overall pooled prevalence rates of olfactory and gustatory dysfunction were 51.4% and 47.5%, respectively, in the random-effect model. In subgroup analyses, the prevalence rates of olfactory and gustatory dysfunction were significantly different among four geographical regions (both P < 0.001, respectively). Although the prevalence rates of olfactory and gustatory dysfunction did not significantly differ according to the time of enrollment, the subgroup analyses including only studies from the same geographical region (Europe) revealed a significant difference in olfactory dysfunction according to the time of enrollment. CONCLUSION: The regional and chronological differences in the prevalence rates of olfactory and gustatory dysfunctions partly explain the wide inter-study variability. Coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide since it was first identified in Wuhan, China in 2019. Although most COVID-19 patients have mild clinical manifestations, about 5% progress to critical status with respiratory failure and/or multi-organ failure. 1 A previous study suggested that the sinonasal tract may play a significant role in the infection, transmission, and pathogenesis of the SARS-CoV-2. 2 In addition, nasal swabs the characteristics of the population of individual studies, there were 29 studies of the general population, including both hospitalized and non-hospitalized patients, 15 studies of only hospitalized patients, eight studies of only non-hospitalized patients, and three studies of healthcare workers. Ten studies used history taking of olfactory and/or gustatory evaluation, 31 used self-reported surveys, six used validated surveys, and eight used validated instruments. Patients were diagnosed as COVID-19 by real-time polymerase chain reaction in most studies, except four 6,23,49,51 that did not report the testing tool. Quality assessment of the individual studies is demonstrated in Supplementary Table 1 . The mean overall score was 3.5, indicating overall low to moderate risk of procedure bias, and there were 29 and 26 studies with low and moderate risk of procedure bias, respectively. No study had a high risk of methodological bias because the prevalence of olfactory and/ or gustatory dysfunction was similarly evaluated in patients. However, the studies with hospitalized, non-hospitalized, or healthcare worker populations that did not represent the general population were commonly evaluated as studies with a moderate risk of bias. Most individual studies were cross-sectional, which contains an implicit risk of bias if the number of patients omitted was not recorded accurately. A total of 13,527 patients were identified for assessment of olfactory dysfunction in 55 studies. The prevalence of olfactory dysfunction in individual studies ranged from 5.1% to 99.0%, and the prevalence was 51.4% in the random-effects model with severe inter-study heterogeneity (95% confidence interval [CI], 43.7-59.1; I 2 = 98.6%; Supplementary Fig. 1A Records identified through database searching (PubMed, Embase, Scopus) (n ) Full-text articles assessed for eligibility (n ) Records excluded (n ) Duplicates (n ) Review article (n ) Records excluded (n ) Irrelevant study design or outcomes (n ) Case report (n ) Not English literature (n ) Studies about animal (n ) Full-text not available (n ) Olfactory and gustatory dysfunction not reported separately (n ) Multicenter study beyond continent (n ) Same cohort (n ) Inconsistent diagnostic criteria for COVID (n ) Studies included in meta-analysis (n ) Records screened (n ) Fig. 1 . Study selection diagram. Fig. 2A prevalence of olfactory dysfunction in East Asia was significantly lower than that in Europe or the Middle East (P = 0.001 and P = 0.021, respectively), and prevalence of gustatory dysfunction in East Asia was significantly lower than that in Europe or North America (P = 0.001 and P = 0.048, respectively). Considering the possibility that olfactory or gustatory dysfunction was not accurately recorded when the history taking was used as the evaluation method, an ANOVA was performed without the studies conducted with history taking as the evaluation method, and the results also showed a significant difference among the regions (P = 0.005 and P < 0.001, respectively; Supplementary Fig. 2A and B ). The regional prevalence rates of olfactory and gustatory dysfunction are shown in Fig. 3 . The time of enrollment was clarified in 29 out of 55 studies. The time of enrollment in the included studies ranged from January 16, 2020 to May 2, 2020. The beginning date of the time of enrollment in the included studies ranged from January 16, 2020 to April 6, 2020, and the end date ranged from February 9, 2020 to May 2, 2020. After calculating the median date (mid-date) between the beginning and end date of the time of enrollment, the individual studies were categorized into three groups: 1st period (mid-date February 2, 2020 to March 17, 2020), 2nd period (mid-date March 20, 2020 to March 29, 2020), and 3rd period (mid-date March 30, 2020 to April 9, 2020). The numbers of included studies of olfactory and gustatory dysfunction in each period were n = 10 and n = 8 for the 1st period, n = 11 and n = 9 for the 2nd period, and n = 8 and n = 6 for the 3rd period, respectively. The prevalence rates of olfactory and gustatory dysfunction for the three periods were 39.5% and 40.9% for the 1st period, 57.7% and 51.2% for the 2nd period, and 49.0 and 40.5% for the 3rd period, respectively; however, no significant difference was found with regard to the time of enrollment (P = 0.391 and P = 0.778; Fig. 4A and B) . As the region can be a potential confounding factor, we performed ANOVA for the studies conducted in Europe (n = 16). The ANOVA of the studies from Europe demonstrated that there were significant differences in the prevalence rates of olfactory dysfunction among the three periods (P = 0.013; Fig. 4C significant difference in the prevalence of gustatory dysfunction (Fig. 4D) . Post-hoc analysis revealed that the prevalence of olfactory dysfunction in the 2nd period was significantly higher than that in the 1st period (P = 0.046). Furthermore, the chronological difference among the studies from Europe was significant even when studies in which history taking was used as an evaluation method were omitted (P = 0.038, Supplementary Fig. 3) . The chronological prevalence rates of olfactory and gustatory dysfunction are shown in Fig. 5 . The prevalence rates of olfactory and gustatory dysfunction according to the four different evaluation methods were 23 Luers et al. Tsivgoulis et al. Dell'Era et al. Paderno et al. Beltrán-Corbellini et al. Speth et al. Subgroup prevalence Heterogeneity: I %, τ . , P . Lee et al. Yan et al. Liang et al. Petrocelli et al. Vaira et al. Izquierdo-Domínguez et al. Altin et al. rd period 5 50 Pinna et al. Mao et al. Kim et al. Subgroup prevalence Heterogeneity: I %, τ . , P . Iravani et al. 26 68 Lagi et al. Mercante et al. Patel et al. 42 59 Yan et al. 15 42 Levinson et al. Liang et al. 12 18 Chung et al. Petrocelli et al. Vaira et al. Izquierdo-Domínguez et al. Altin et al. rd period 3 50 Pinna et al. 23 46 Yan et al. Mao et al. Kim et al. Subgroup prevalence Heterogeneity: I %, τ . , P . Iravani et al. 37 70 Zayet et al. 17 68 Lagi et al. Mercante et al. Tostmann et al. Patel et al. 40 59 Yan et al. 14 42 Levinson et al. Luers et al. Tsivgoulis et al. Dell'Era et al. Paderno et al. Beltrán-Corbellini et al. Speth et al. Heterogeneity: I %, τ . , P . Petrocelli et al. Vaira et al. Izquierdo-Domínguez et al. Altin et al. Iravani et al. 37 70 Zayet et al. 17 68 Lagi et al. Mercante et al. Tostmann et al. Patel et al. Luers et al. 16 22 Tsivgoulis et al. Dell'Era et al. Paderno et al. Beltrán-Corbellini et al. Luers et al. 16 22 Tsivgoulis et al. Dell'Era et al. Paderno et al. Beltrán-Corbellini et al. Speth et al. Subgroup prevalence Heterogeneity: I %, τ . , P . Yan et al. Moein et al. Fig. 5 . The pooled prevalence of olfactory and gustatory dysfunction was presented chronologically. The overall and European pooled prevalence rates of olfactory and gustatory dysfunction are shown, discriminated by color. The prevalence rates of both olfactory and gustatory tended to increase from the 1st to 2nd period but decreased from the 2nd to 3rd period. Vaira et al. Izquierdo-Domínguez et al. Altin et al. 3 50 Pinna et al. 23 46 Yan et al. Luers et al. Tsivgoulis et al. Dell'Era et al. Paderno et al. Beltrán-Corbellini et al. Speth et al. Heterogeneity: I %, τ . , P . Petrocelli et al. Vaira et al. Izquierdo-Domínguez et al. Altin et al. Iravani et al. 37 70 Zayet et al. 17 68 Lagi et al. Mercante et al. Tostmann et al. Patel et al. Luers et al. 16 22 Tsivgoulis et al. Dell'Era et al. Paderno et al. Beltrán-Corbellini et al. instruments, respectively, and there was a significant difference among the regions (both P < 0.001, respectively; Fig. 6A and B) . In a post-hoc analysis, the prevalence of olfactory dysfunction evaluated by history taking was lower than that evaluated by other methods (all P < 0.001, respectively), and the prevalence evaluated by the self-reported survey was lower than that evaluated by validated survey (P = 0.033). In addition, the prevalence of gustatory dysfunction by history taking was lower than that evaluated by the self-reported survey, validated survey, and validated instruments (P < 0.001, P < 0.001, and P = 0.004, respectively). The prevalence rates of olfactory and gustatory dysfunction according to the four population groups were 58.7% and 56.2% in the general population, 36.7% and 28.3% in hospitalized patients, 52.3% and 51.1% in non-hospitalized patients, and 48.9% and 51.5% in health care workers, respectively ( Fig. 7A and B) . Interestingly, a significant difference was found in the prevalence of gustatory dysfunction depending on the characteristics of the population (P = 0.013) but not in that of olfactory dysfunction (P = 0.173). Post-hoc analysis showed that the prevalence of gustatory dysfunction of the hospitalized patients was significantly lower than that of the general population (P = 0.030). The funnel plot demonstrated potential publication bias in the analysis ( Supplementary Fig. 4A and B) . In Egger's test, there was a potential publication bias for the prevalence rates of olfactory and gustatory dysfunction (P = 0.031, P = 0.028). However, asymmetry in the funnel plots may be attributed to the various factors that elicited different prevalence rates, such as region, time of enrollment, and evaluation method, rather than publication bias. Olfactory and gustatory dysfunction were not recognized as typical symptoms of COVID-19 in the early phase of virus' spread. However, as olfactory and gustatory dysfunction were frequently found in patients with COVID-19, these symptoms became significant. Furthermore, as a previous study reported, 17% of COVID-19 patients with anosmia were otherwise asymptomatic, meaning that isolated olfactory or gustatory dysfunction could be used as potential early indicators of SARS-CoV-2 infection during the COVID-19 pandemic. 62 Possible mechanisms of olfactory dysfunctions in COVID-19 patients are conductive anosmia, disruption of olfactory epithelium following local infection, and retrograde propagation to higher-order neurons in the olfactory pathway. 63 However, there is limited evidence to conclusively determine the mechanism of olfactory dysfunction in COVID-19. 63 Considering gustatory dysfunction in COVID-19, it is unclear whether gustatory dysfunction is a distinct clinical feature of SARS-CoV-2 or occurs secondary to olfactory dysfunction. Although olfactory and gustatory dysfunction were noted frequently in COVID-19, the prevalence rates of olfactory and gustatory dysfunction were variable among previous studies. In this metaanalysis, subgroup analysis was performed to explain the variability of the prevalence rate of olfactory and gustatory dysfunction among patients with COVID-19. In this meta-analysis, the prevalence rates of olfactory and gustatory dysfunction in COVID-19 patients were 51.4% and 47.5%, with severe inter-study heterogeneity (both I 2 = 98.6%, respectively), respectively. We performed subgroup analysis based on region, time of enrollment, demographics, and the evaluation method to explain the inter-study heterogeneity. As we hypothesized, the prevalence rates of olfactory and gustatory dysfunction were different among the four geographical regions. The prevalence of olfactory dysfunction in East Asia was significantly lower than that in Europe or the Middle East and prevalence of gustatory dysfunction in East Asia was significantly lower than that in Europe and North America. In the subgroup analysis on the time of enrollment, there was no significant difference among the three periods. However, considering the spread of the virus occurred regionally and chronologically, the regional factor might be a potential confounding factor. In an ANOVA of the studies from Europe alone, there were significant differences in the prevalence rates of olfactory dysfunction among the three time period groups, indicating that a genetic mutation of virus in the same region may have affected the prevalence of olfactory dysfunction. The prevalence rates of olfactory dysfunction of the all regions were 39.5% for the 1st period, 57.7% for the 2nd period, and 49.0% for the 3rd period, which was a similar tendency compared to that of Europe: 45.2% for the 1st period, 65.4% for the 2nd period, and 59.0% for the 3rd period. Interestingly, olfactory dysfunction increased from the 1st to 2nd period but slightly decreased from the 2nd to 3rd period. Because the included studies were performed with various evaluation methods and populations, we carried out further subgroup analyses on the evaluation methods and population group to explain the heterogeneity. In subgroup analysis on the evaluation methods, the prevalence rates of olfactory and gustatory dysfunction evaluated by history taking were lower than those by other evaluation methods. In contrast to survey or objective test, simple history taking may have a risk of omitting questions about olfactory and gustatory dysfunction. The chemosensory function of these patients was often regarded as normal, leading to a low prevalence of olfactory and gustatory dysfunction. Therefore, we confirmed the results of the subgroup analysis on the geographical region and the time of enrollment by omitting studies in which history taking was used as the evaluation method, and we found that it still showed a statistical significance. In subgroup analysis on the population group, interestingly, a significant difference was found in the prevalence of gustatory dysfunction depending on population characteristics but not in that of olfactory dysfunction. In a post-hoc analysis, the prevalence of gustatory dysfunction of the hospitalized patients was lower than that of the general population, which may be attributed to the higher rate of the history taking as the evaluation method in hospitalized patients than that in the general population (46.7% vs. 6.9%, respectively). There are some possible explanations for the regional and chronological differences in olfactory and gustatory dysfunction in COVID-19-first, the ethnic differences in the frequency variants of angiotensin-converting enzyme 2 (ACE2). As previous studies indicate, ACE2 is a possible host receptor of SARS-CoV-2. 64, 65 Variants of ACE2 may affect the course of infection, including susceptibility and symptoms depending on the expression level and pattern of ACE2 in different tissues. 66 In a previous study, presence of a difference in variants of ACE2 according to geographical and ethnic factors was demonstrated, 66 and it is assumed that the difference in variants of ACE2 expressed in olfactory epithelial cells according to populations from different geographical regions can influence the prevalence of olfactory and gustatory dysfunction. Second, phylogenetic mutation may contribute to regional and chronological differences. As the prevalence of olfactory dysfunction was significantly different according to time of enrollment in subgroup analysis with the studies from European countries, the ethnic differences may not be sufficient to explain the chronological differences in the prevalence rates of olfactory dysfunction. Recent studies reported that SARS-CoV-2 has rapidly attained mutations as a typical coronavirus, allowing for tracking its spread. 67, 68 The prevalence of S type and L type of SARS-CoV-2 were 3.7% and 96.3% in viral isolates in Wuhan, respectively, yet viral isolates outside of Wuhan were 38.4% S type and 61.3% L type. 68 Furthermore, the mutation may cause regional differences in virus type. For instance, a previous study revealed that the B1 clade is dominant in the West Coast of the United States, while the A2a clade, which seems to have spread through Europe and Italy, is dominant in the East Coast of the United States. 69 In addition to the regional differences, the expanding phylogenetic diversity can induce a chronologic difference in the type of SARS-CoV-2. A previous study revealed the global transition of the SARS-CoV-2 spike protein from the original D614 to the G614 variant. 70 To be specific, through March 1, 2020, the G614 variant was rare outside Europe; however, it increased in frequency worldwide by the end of March. 70 As the virus types and genetic mutations were different regionally and chronologically, 68-70 the influence of SARS-CoV-2 on the olfactory epithelium may have differed according to virus type and genetic mutation. Lastly, heterogeneity in the study designs may have caused different prevalence rates of olfactory and gustatory dysfunction. The study populations and evaluation methods were variable in the individual studies. As shown in the results, evaluation method may lead to different prevalence. To reduce the confounding effect of the evaluation method, we performed a subgroup analysis without the studies in which history taking was used as an evaluation method. However, the other three methods may also have had differences, although statistical significance was not found. In addition, different characteristics of populations might affect the prevalence rate in individual studies. In conclusion, olfactory and gustatory dysfunction are commonly reported in patients with COVID-19 and noted as significant symptoms; however, the prevalence rates are variable. This meta-analysis revealed that regional and chronological differences in the prevalence rates of olfactory and gustatory dysfunction explain the inter-study heterogeneity. Supplementary Table 1 Quality assessment for the included studies Middle East) showed 32.6%, 56.7%, 58.9%, and 47.9% pooled subgroup prevalence in the random-effect model, respectively (P < 0.001 for subgroup difference). The diamonds represent pooled prevalence with 95% CI, and the estimates of individual studies are represented as squares The time of enrollment was clarified in 29 out of 55 studies. 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