Olfactory Dysfunction in Patients With Mild COVID-19 During Gamma, Delta, and Omicron Waves in Rio de Janeiro, Brazil | Global Health | JAMA | JAMA Network
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Table 1.  Characteristics of Participants With Mild COVID-19 Who Reported Olfactory Dysfunction
Characteristics of Participants With Mild COVID-19 Who Reported Olfactory Dysfunction
Table 2.  Association Between SARS-CoV-2 Lineage and Self-reported Olfactory Dysfunction
Association Between SARS-CoV-2 Lineage and Self-reported Olfactory Dysfunction
1.
Lechien  JR, Chiesa-Estomba  CM, Beckers  E,  et al.  Prevalence and 6-month recovery of olfactory dysfunction.   J Intern Med. 2021;290(2):451-461.PubMedGoogle ScholarCrossref
2.
Shelton  JF, Shastri  AJ, Fletez-Brant  K,  et al.  The UGT2A1/UGT2A2 locus is associated with COVID-19–related loss of smell or taste.   Nat Genet. 2022;54(2):121-124.PubMedGoogle ScholarCrossref
3.
de Melo  GD, Lazarini  F, Levallois  S,  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(596):285-287.PubMedGoogle ScholarCrossref
4.
Sungnak  W, Huang  N, Bécavin  C,  et al.  SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.   Nat Med. 2020;26:681-687. doi:10.1038/s41591-020-0868-6Google ScholarCrossref
5.
Zazhytska  M, Kodra  A, Hoagland  DA,  et al.  Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19–induced anosmia.   Cell. 2022;185(6):1052-1064.e12.PubMedGoogle ScholarCrossref
6.
Secretaria de Saúde do Rio de Janeiro. Coronaômica-RJ: vigilância genômica do Estado do Rio de Janeiro. Accessed May 13, 2022. http://www.corona-omica.rj.lncc.br/#/nota-tecnica
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    Research Letter
    June 24, 2022

    Olfactory Dysfunction in Patients With Mild COVID-19 During Gamma, Delta, and Omicron Waves in Rio de Janeiro, Brazil

    Author Affiliations
    • 1Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    • 2Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    • 3Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    JAMA. 2022;328(6):582-583. doi:10.1001/jama.2022.11006

    Olfactory dysfunction is a common symptom of COVID-19, with reported rates as high as 70%. This symptom can be associated with mild COVID-19, mostly occurs within 5 days after symptom onset, and can persist for a few days to several months after infection resolution.1 The mechanism of SARS-CoV-2–related olfactory dysfunction is not completely understood.

    Host genetics,2 acute inflammation in the olfactory epithelium,3 local ACE2 expression,4 and downregulation of olfactory receptors5 seem to play a role; however, the viral contribution remains to be explored. We conducted a retrospective analysis of individuals with mild COVID-19 during different SARS-CoV-2 variant waves to assess the prevalence of self-reported olfactory dysfunction.

    Methods

    Individuals with SARS-CoV-2 infection confirmed by quantitative reverse transcriptase–polymerase chain reaction were enrolled at the Center for COVID-19 Diagnosis at the Federal University of Rio de Janeiro between March 16, 2020, and March 28, 2022. Participants were aged 18 years or older and presented with mild symptoms at the time of sample collection for diagnosis. The study was approved by the Brazilian national commission of ethics in research and written informed consent was obtained from all participants.

    Clinical and demographic data were obtained through an updated version of the Brazilian National Health System Questionnaire for COVID-19 that was administered by qualified specialists. Participants could answer “yes” or “no” to the question: “Have you experienced olfactory/smell loss since the date of symptoms onset?”

    Viral lineages were attributed to each participant using genomic surveillance data from the state of Rio de Janeiro.6 A lineage was considered predominant when it was detected in more than 90% of the individuals diagnosed during a given period. Individuals were recruited when the original lineages (B.1.1.28 and B.1.1.33) were circulating in Rio de Janeiro between March 16 and December 22, 2020, when Gamma was circulating between March 1 and June 30, 2021, when Delta was circulating between August 2 and November 10, 2021, and when Omicron was circulating between January 4 and March 28, 2022. The study did not include individuals diagnosed during periods when 2 or more lineages co-circulated at a high frequency.

    Association analyses were conducted using logistic regression models with the original lineage period as the reference group. Age, sex, viral load, time since symptom onset, hypertension, diabetes, and smoking status were evaluated as potential confounders. A sensitivity analysis including only individuals diagnosed when COVID-19 vaccines were available (after February 2021) also was performed, adding vaccination status as an additional variable in the logistic regression models. Because no vaccines were available during the period of the original lineages, the Gamma period was used as the reference group.

    The analyses were conducted using R version 4.1.2 (R Foundation for Statistical Computing). A 2-sided P value <.05 was considered statistically significant.

    Results

    Of the 6053 participants with mild COVID-19 in the cohort, 2650 reported olfactory dysfunction (Table 1) and 3403 did not report this symptom. Olfactory dysfunction was reported by 2223 of the 4227 participants (52.6% [95% CI, 51.1%-54.1%]) diagnosed during the period of the original lineages (Table 2). The prevalence decreased to 27.5% (95% CI, 24.3%-30.8%) during Gamma, 42.1% (95% CI, 37.4%-47.0%) during Delta, and 5.8% (95% CI, 4.4%-8.5%) during Omicron.

    The odds of olfactory dysfunction were lower for those infected during Gamma (adjusted odds ratio [OR], 0.48 [95% CI, 0.39-0.59]; P < .001) and Omicron (adjusted OR, 0.07 [95% CI, 0.05-0.10]; P < .001) compared with the original lineages period (Table 2). No association was observed during Delta (adjusted OR, 0.90 [95% CI, 0.71-1.15]; P = .41). The sensitivity analysis found an adjusted OR of 0.09 (95% CI, 0.06-0.15; P < .001) for olfactory dysfunction during Omicron vs Gamma after additional adjustment for vaccination status.

    Discussion

    This study found that individuals with mild COVID-19 infected during the Gamma and Omicron waves had lower odds of reporting olfactory dysfunction than individuals infected during the period of the original lineages. These results suggest that the type of SARS-CoV-2 variant might be a risk factor for olfactory dysfunction, along with host genetic susceptibility.2 The association with Omicron also was observed after controlling for vaccination status, supporting its independence of host immunologic factors.

    Limitations of this study include self-reported outcome, variant attribution according to epidemiological surveillance data, and possible unmeasured confounding. The present findings highlight the importance of considering SARS-CoV-2 variants when modeling olfactory outcomes and suggest that olfactory dysfunction might not be a hallmark of COVID-19 with certain variants.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
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    Article Information

    Accepted for Publication: June 9, 2022.

    Published Online: June 24, 2022. doi:10.1001/jama.2022.11006

    Corresponding Author: Cynthia Chester Cardoso, PhD, Universidade Federal do Rio de Janeiro, Av Carlos Chagas Filho 373, CCS, Bloco A, Sala 121 Ilha do Fundão, Rio de Janeiro, Brazil 21941 (cynthiac@biologia.ufrj.br).

    Author Contributions: Drs Cardoso and Castiñeiras had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Cardoso, Tanuri, Castiñeiras.

    Acquisition, analysis, or interpretation of data: Cardoso, Rossi, Galliez, Faffe, Castiñeiras.

    Drafting of the manuscript: Cardoso, Rossi, Tanuri.

    Critical revision of the manuscript for important intellectual content: Rossi, Galliez, Faffe, Castiñeiras.

    Statistical analysis: Cardoso.

    Obtained funding: Faffe, Tanuri, Castiñeiras.

    Administrative, technical, or material support: Rossi, Galliez, Faffe.

    Supervision: Galliez, Faffe, Tanuri, Castiñeiras.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This work was supported by grants E-26/210.178/2020 and E-26/211.111/2021 (awarded to Dr Tanuri) and grants E-26/210.658/2021 and E-26/210.785/2021 (awarded to Dr Castiñeiras) from Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro.

    Role of the Funder/Sponsor: Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We are grateful to Anna Carla Pinto Castiñeiras, MD, Bianca Ortiz da Silva, PhD, Debora Gomes Marins, Guilherme Sant'Anna de Lira, MD, Isabela de Carvalho Leitão, MD, Victoria Cortes Bastos, MD, and Victor Akira Ota, MD (all with the Centro de Triagem e Diagnóstico para COVID-19, Universidade Federal do Rio de Janeiro), and Helena Toledo Scheid, Isabela Labarba Carvalho de Almeida, and Laura Zalcberg Renault (all with the Faculdade de Medicina, Universidade Federal do Rio de Janeiro) for their assistance with participant enrollment and clinical data collection. We thank Cássia Cristina Alves Gonçalves, MSc, Cíntia Policarpo, MSc, Diana Mariani, PhD, Érica Ramos dos Santos Nascimento, MSc, Gleidson Silva Oliveira, MSc, Leandro Ponheiro Batista, Lia Lima, PhD, Lídia Theodoro Boullosa, MSc, Luiza Mendonça Higa, PhD, Pedro Henrique Costa da Paz, Ricardo José Barbosa Salviano, MSc, Rodrigo de Moraes Brindeiro, PhD, and Thais Félix Cordeiro, PhD (all with the Instituto de Biologia, Universidade Federal do Rio de Janeiro), for laboratory diagnosis. We are also grateful to Carolina Moreira Voloch, PhD, and Orlando da Costa Ferreira Júnior, PhD (both with the Instituto de Biologia, Universidade Federal do Rio de Janeiro), for their advice. No compensation was received by any of the contributors to this work.

    References
    1.
    Lechien  JR, Chiesa-Estomba  CM, Beckers  E,  et al.  Prevalence and 6-month recovery of olfactory dysfunction.   J Intern Med. 2021;290(2):451-461.PubMedGoogle ScholarCrossref
    2.
    Shelton  JF, Shastri  AJ, Fletez-Brant  K,  et al.  The UGT2A1/UGT2A2 locus is associated with COVID-19–related loss of smell or taste.   Nat Genet. 2022;54(2):121-124.PubMedGoogle ScholarCrossref
    3.
    de Melo  GD, Lazarini  F, Levallois  S,  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(596):285-287.PubMedGoogle ScholarCrossref
    4.
    Sungnak  W, Huang  N, Bécavin  C,  et al.  SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.   Nat Med. 2020;26:681-687. doi:10.1038/s41591-020-0868-6Google ScholarCrossref
    5.
    Zazhytska  M, Kodra  A, Hoagland  DA,  et al.  Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19–induced anosmia.   Cell. 2022;185(6):1052-1064.e12.PubMedGoogle ScholarCrossref
    6.
    Secretaria de Saúde do Rio de Janeiro. Coronaômica-RJ: vigilância genômica do Estado do Rio de Janeiro. Accessed May 13, 2022. http://www.corona-omica.rj.lncc.br/#/nota-tecnica
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