Evaluation of the Incidence of Other Cranial Neuropathies in Patients With Postviral Olfactory Loss | Neurology | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Table 1.  Description of Patients With Postviral Olfactory Loss
Description of Patients With Postviral Olfactory Loss
Table 2.  Characteristics of Cases With Postviral Olfactory Loss and Matched Controlsa
Characteristics of Cases With Postviral Olfactory Loss and Matched Controlsa
1.
Cavazzana  A, Larsson  M, Münch  M, Hähner  A, Hummel  T.  Postinfectious olfactory loss: a retrospective study on 791 patients.   Laryngoscope. 2018;128(1):10-15. doi:10.1002/lary.26606PubMedGoogle ScholarCrossref
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Rombaux  P, Huart  C, Deggouj  N, Duprez  T, Hummel  T.  Prognostic value of olfactory bulb volume measurement for recovery in postinfectious and posttraumatic olfactory loss.   Otolaryngol Head Neck Surg. 2012;147(6):1136-1141. doi:10.1177/0194599812459704PubMedGoogle ScholarCrossref
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Park  JH, Byeon  HK, Park  KN,  et al.  Epidemiological association of olfactory dysfunction with hearing loss and dysphonia in the Korean population: a cross-sectional study.   Medicine (Baltimore). 2017;96(47):e8890. doi:10.1097/MD.0000000000008890PubMedGoogle Scholar
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Amin  MR, Koufman  JA.  Vagal neuropathy after upper respiratory infection: a viral etiology?   Am J Otolaryngol. 2001;22(4):251-256. doi:10.1053/ajot.2001.24823PubMedGoogle ScholarCrossref
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Chitose  SI, Umeno  H, Hamakawa  S, Nakashima  T, Shoji  H.  Unilateral associated laryngeal paralysis due to varicella-zoster virus: virus antibody testing and videofluoroscopic findings.   J Laryngol Otol. 2008;122(2):170-176. doi:10.1017/S0022215107000898PubMedGoogle ScholarCrossref
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Rees  CJ, Henderson  AH, Belafsky  PC.  Postviral vagal neuropathy.   Ann Otol Rhinol Laryngol. 2009;118(4):247-252. doi:10.1177/000348940911800402PubMedGoogle ScholarCrossref
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Bhatt  NK, Pipkorn  P, Paniello  RC.  Association between upper respiratory infection and idiopathic unilateral vocal fold paralysis.   Ann Otol Rhinol Laryngol. 2018;127(10):667-671. doi:10.1177/0003489418787542PubMedGoogle ScholarCrossref
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Stachler  RJ, Chandrasekhar  SS, Archer  SM,  et al; American Academy of Otolaryngology–Head and Neck Surgery.  Clinical practice guideline: sudden hearing loss.   Otolaryngol Head Neck Surg. 2012;146(3)(suppl):S1-S35. doi:10.1177/0194599812436449PubMedGoogle ScholarCrossref
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Tsai  YT, Fang  KH, Yang  YH,  et al.  Risk of developing sudden sensorineural hearing loss in patients with hepatitis B virus infection: a population-based study.   Ear Nose Throat J. 2018;97(10-11):E19-E27.PubMedGoogle Scholar
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Ribeiro  BNF, Guimarães  AC, Yazawa  F, Takara  TFM, de Carvalho  GM, Zappelini  CEM.  Sensorineural hearing loss in hemorrhagic dengue?   Int J Surg Case Rep. 2015;8C:38-41. doi:10.1016/j.ijscr.2014.10.057PubMedGoogle ScholarCrossref
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Yao  L, Yi  X, Pinto  JM,  et al.  Olfactory cortex and olfactory bulb volume alterations in patients with post-infectious olfactory loss.   Brain Imaging Behav. 2018;12(5):1355-1362. doi:10.1007/s11682-017-9807-7PubMedGoogle ScholarCrossref
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Tian  J, Pinto  JM, Cui  X,  et al.  Sendai virus induces persistent olfactory dysfunction in a murine model of PVOD via effects on apoptosis, cell proliferation, and response to odorants.   PLoS One. 2016;11(7):e0159033. doi:10.1371/journal.pone.0159033PubMedGoogle Scholar
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van Riel  D, Verdijk  R, Kuiken  T.  The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system.   J Pathol. 2015;235(2):277-287. doi:10.1002/path.4461PubMedGoogle ScholarCrossref
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Cain  MD, Salimi  H, Gong  Y,  et al.  Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection.   J Neuroimmunol. 2017;308:118-130. doi:10.1016/j.jneuroim.2017.04.008PubMedGoogle ScholarCrossref
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Gellrich  J, Han  P, Manesse  C,  et al.  Brain volume changes in hyposmic patients before and after olfactory training.   Laryngoscope. 2018;128(7):1531-1536. doi:10.1002/lary.27045PubMedGoogle ScholarCrossref
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Wang  JH, Kwon  HJ, Jang  YJ.  Detection of parainfluenza virus 3 in turbinate epithelial cells of postviral olfactory dysfunction patients.   Laryngoscope. 2007;117(8):1445-1449. doi:10.1097/MLG.0b013e318063e878PubMedGoogle ScholarCrossref
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Frasnelli  J, Schuster  B, Hummel  T.  Olfactory dysfunction affects thresholds to trigeminal chemosensory sensations.   Neurosci Lett. 2010;468(3):259-263. doi:10.1016/j.neulet.2009.11.008PubMedGoogle ScholarCrossref
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Ren  Y, Yang  L, Guo  Y, Xutao  M, Li  K, Wei  Y.  Intranasal trigeminal chemosensitivity in patients with postviral and post-traumatic olfactory dysfunction.   Acta Otolaryngol. 2012;132(9):974-980. doi:10.3109/00016489.2012.663933PubMedGoogle ScholarCrossref
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Patel  ZM, DelGaudio  JM, Wise  SK.  Higher body mass index is associated with subjective olfactory dysfunction.   Behav Neurol. 2015;2015:675635. doi:10.1155/2015/675635PubMedGoogle Scholar
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    Original Investigation
    April 2, 2020

    Evaluation of the Incidence of Other Cranial Neuropathies in Patients With Postviral Olfactory Loss

    Author Affiliations
    • 1Department of Otolaryngology, Navamindradhiraj University, Bangkok, Thailand
    • 2Department of Otolaryngology, Thammasat University, Pathumthani, Thailand
    • 3Department of Otolaryngology–Head and Neck Surgery, Stanford University School of Medicine, Palo Alto, California
    JAMA Otolaryngol Head Neck Surg. 2020;146(5):465-470. doi:10.1001/jamaoto.2020.0225
    Key Points

    Question  Is there increased risk of other cranial neuropathies in patients with postviral olfactory loss compared with a control population?

    Findings  In this case-control study of 91 patients with olfactory loss and 100 control patients without olfactory loss, the incidence of other cranial neuropathies in the postviral olfactory loss group was 11%, which was significantly higher than the 2% incidence found in the control group.

    Meaning  This finding suggests that there may be an inherent vulnerability to cranial nerve damage or decreased ability for cranial nerve recovery in patients who experience this disease process.

    Abstract

    Importance  Postviral olfactory loss is a common cause of olfactory impairment, affecting both quality of life as well as overall patient mortality. It is currently unclear why some patients are able to recover fully after a loss while others experience permanent deficit. There is a lack of research on the possible association between postviral olfactory loss and other cranial neuropathies.

    Objective  To evaluate the incidence of other cranial nerve deficits in patients with postviral olfactory loss and determine if there is an association with neurologic injury in this group. This study also sought to determine if other known risk factors were associated with postviral olfactory loss.

    Design, Setting, and Participants  A case-control study was conducted at a tertiary care rhinology clinic from January 2015 to January 2018 to review the incidence of cranial neuropathies in 2 groups of patients, those with postviral olfactory loss and those with chronic rhinosinusitis without olfactory loss used as a control group.

    Exposures  The Stanford Translational Research Integrated Database Environment (STRIDE) system was used for patient identification and data extraction. Patients with a history of olfactory loss or chronic rhinosinusitis as well as incidence of cranial neuropathies were identified by using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.

    Main Outcomes and Measures  This study reviewed incidence of postviral or idiopathic cranial neuropathies in both patient groups, while also evaluating for any difference in demographic characteristics, comorbidities, or other patient-related factors.

    Results  There were 91 patients in the postviral olfactory loss group and 100 patients in the control group, which were age and sex matched as closely as possible. Of the 91 patients with postviral olfactory loss, mean (SD) age was 56.8 (15.3), and 58 (64%) were women; for the control group, the mean (SD) age was 57.5 (15.6) years, and 63 (63%) were women. Racial breakdown was similar across cases and controls, with white individuals making up 59% to 65%; Asian individuals, 20% to 24%; black individuals, approximately 3%; Hispanic individuals, approximately 1%; and the remaining patients being of other race/ethnicity. The incidence of other cranial neuropathies in the postviral olfactory loss group was 11% compared with 2% within the control group (odds ratio, 6.1; 95% CI, 1.3-28.4). The study also found 2 cases of multiple cranial neuropathies within a single patient within the olfactory group. Family history of neurologic disease was associated with more than 2-fold greater odds of cranial nerve deficit (odds ratio, 3.05; 95% CI, 0.59-15.68).

    Conclusions and Relevance  Postviral olfactory loss appears to be associated with a higher incidence of other cranial neuropathies. It is possible that there is an inherent vulnerability to nerve damage or decreased ability for nerve recovery in patients who experience this disease process.

    Introduction

    Postviral olfactory loss is characterized by sensorineural loss of olfactory function after a viral infection of the upper respiratory airway, which can occur without inflammatory symptoms but is often associated with the sensation of a common cold or influenza.1,2 It is one of the leading causes of olfactory dysfunction.3,4 Postviral olfactory loss is associated with 18% to 45% of the clinical population of people with anosmia or hyposmia and is more common in women 50 years and older but can occur in any age group and either sex.5 Patients can present with anosmia (36%-53%), hyposmia (47%-64%), and parosmia (approximately 15%).6-8

    Any upper respiratory tract infection can cause temporary conductive obstruction of the olfactory cleft and can result in olfactory loss. In most patients, this olfactory loss resolves when the nasal airway becomes patent after the inflammation subsides. However, in some patients this olfactory loss persists without improvement or only partial recovery, despite a lack of residual nasal congestion or obvious persistent sinonasal pathology.8-10 This then compromises quality of life in various ways, such as impeding the detection of hazardous smells and reducing satisfaction from food, and can lead to psychological stress, such as depression and social isolation.11

    It is currently unclear why some patients are able to recover completely from the loss, while others experience permanent deficit.9,12 We hypothesized that there may be some potential inherent vulnerability of the olfactory nerves, or perhaps all cranial nerves, in particular patients. To our knowledge, there is no current literature focusing on the incidence of other cranial neuropathies in this group of patients, but the senior author (Z.M.P.) had begun to notice an increased prevalence in her olfactory loss patient population. The aim of this study was to evaluate the incidence of other cranial nerve deficits in patients with postviral olfactory loss and determine if there may be an increased incidence compared with a control patient population. We also sought to determine if other known risk factors were associated with olfactory loss.

    Methods

    We performed a case-control study that reviewed medical records of patients with postviral olfactory loss (cases) at a tertiary olfactory loss clinic and patients with chronic rhinosinusitis (controls) who presented to the Stanford Sinus Center at Stanford University Medical Center from January 2015 to January 2018. The Stanford Translational Research Integrated Database Environment (STRIDE) system was used for patient identification and data extraction. This project was approved by the institutional review board of Stanford University. Patient informed consent was waived for this review as per our institutional review board protocol and institutional policy.

    Cases and Controls

    We collected data from 2 patient groups—cases and controls. Cases were defined as those patients with postviral olfactory loss, while patients with chronic rhinosinusitis were the controls. For the cases, inclusion criteria were age 18 years or older and patients who were diagnosed with postviral olfactory loss by criteria including (1) history of olfactory disorder lasting at least 6 months after clear history of infection of the upper respiratory tract that resolved without using antibiotics and (2) objective evidence of olfactory dysfunction assessed by the University of Pennsylvania Smell Identification Test (UPSIT),13 which was classified as hyposmia at a score of less than 35 and anosmia at less than 19. Patients with other causes of olfactory disorders (eg, trauma, sinonasal disease, neurodegenerative disease, idiopathic cause) were excluded from this review.

    Ninety-one patients were identified who met the inclusion criteria of the postviral olfactory loss group. Demographic data such as age and sex were reviewed. One-hundred age- and sex-matched patients were then selected from patients with chronic rhinosinusitis presenting to the Stanford Sinus Center over the same time period to act as a comparative control group.

    We then reviewed the medical records of these 191 patients from the 2 groups to evaluate incidence of other cranial neuropathies and possible predisposing factors of cranial nerve susceptibility, such as body mass index (BMI), smoking, diabetes mellitus (DM), hypertension, dyslipidemia, and family history of neurologic diseases.

    Cranial neuropathy was defined as paresis or paralysis of any of the cranial nerves II through XII from viral and/or idiopathic causes. We included all cranial neuropathies that patients experienced at any time over their lifetime before the time of record review. Other identified causes of cranial neuropathies, such as tumor, trauma, stroke, or neurodegenerative origins, were excluded.

    Statistical Analysis

    The statistical analysis was performed using SAS statistical software, version 9.4 (SAS Institute). Categorical variables between 2 groups were summarized by counts and frequencies and compared using odds ratio (OR) with 95% CIs. The normally distributed variables were presented with means and SDs; otherwise, they were presented with medians and interquartile ranges. A univariable logistic regression model was performed to evaluate the potential risk of having other cranial neuropathies. Multivariable logistic regression model was not reported owing to the small number of events and preliminary nature of the study.

    Results
    Demographic Data

    The basic demographic characteristics of patients with postviral olfactory loss are summarized in Table 1. There were 91 patients in the postviral olfactory loss group and 100 patients in the control group, which were age and sex matched as closely as possible. Of the 91 patients with postviral olfactory loss, mean (SD) age was 56.8 (15.3), and 58 (64%) were women. Racial breakdown was very similar across cases and controls, with white individuals making up 59% to 65%; Asian individuals, 20% to 24%; black individuals, approximately 3%; Hispanic individuals, approximately 1%; and the remaining patients being of other race/ethnicity. There were no significant differences in baseline demographic characteristics, including age, sex, race/ethnicity, average BMI, or comorbidities other than DM. The postviral olfactory loss group had a lower rate of DM than the controls (difference, 13.4%; 95% CI, 4.1%-22.8%). The incidence of family history of neurologic diseases, such as dementia, not otherwise specified (2 patients [2%]), Alzheimer disease (3 patients [3%]), Parkinson disease (1 patient [1%]), stroke (3 patients [3%]), and other (1 patient [1%]), was 11% (10 of 91 patients) in the postviral olfactory loss group and 2% (2 of 100 patients) in the control group (OR, 3.05; 95% CI, 0.59-15.68). This was a large percentage difference between the 2 groups, but the large width of the CI, owing to the small sample size, undermines an attempt to draw meaningful conclusions. The median UPSIT score of the postviral olfactory loss group was 23 (interquartile range, 14-27), with the majority falling into the severe microsmia group, followed by moderate microsmia; a minority were scored in the minimal microsmia or complete anosmia groups; and no patients were in the normosmia group (Table 1). We found that 10 of 91 patients (11%) in the postviral olfactory loss group had other cranial neuropathies, compared with 2 of 100 patients (2%) in the control group for absolute percentage difference of 9.0% (95% CI, 2%-17.2%) and OR of 6.50 (95% CI, 1.24-24.4). The symptoms of other cranial nerve deficits included 5 instances of vocal fold paralysis (CN X), 4 instances of sudden sensorineural hearing loss (CN VIII), 1 instance of facial numbness (CN V), 1 instance of facial nerve palsy (CN VII), and 1 instance of optic neuropathy (CN II), all either unexplained or also associated with a viral illness. We also found 2 cases (2%) of multiple cranial neuropathies in the postviral olfactory loss group. However, the overall incidence of this was very low and there was no incidence in the control group; thus, the precision of the effect size estimate is quite low and no meaningful conclusion can be made.

    Association Between Postviral Olfactory Loss and Baseline Factors

    Presence of other cranial nerve deficit and family history of neurologic disease were strongly associated with postviral olfactory dysfunction. The postviral olfactory loss group had 6.05-times higher odds of both having other cranial neuropathies than the control group as well as having the presence of family history of neurologic disease compared with the control group, both OR 6.05 (95% CI, 1.29-28.4) (Table 2). The wide CIs denote the imprecision of these confidence intervals. The imprecision of the estimate is likely due to the low numbers of patients with family history of neurodegenerative disease and other cranial nerve deficits. Only 1 of the 10 patients with a family history of neurodegenerative disease crossed over into the group of 10 patients with multiple cranial nerve deficits.

    There was a smaller percentage of patients in the postviral olfactory loss group with DM than in the control group. Although at first this may suggest a protective association, one should keep in mind that in this particular study we are only looking at the postviral subcategory of patients with olfactory loss (not including all the other various causes of olfactory loss) and that there is significant literature demonstrating that DM leads to decreased olfactory function in that patient group, as it leads to dysfunction in most other parts of the nervous system.14

    Incidence of cranial neuropathy was not associated with severity of olfactory deficit by UPSIT score. Every 10-year increment increase in age increased the odds of cranial neuropathies, but this did not meet statistical significance. BMI was similarly borderline to significance, but in the end not significantly associated. Other factors, such as sex, race/ethnicity, smoking, hypertension, hyperlipidemia, and heart disease, were not associated with increased odds of other cranial neuropathies.

    Discussion

    Postviral olfactory loss has been reported as a major issue of olfactory impairment around the world. Exact pathophysiology of the persistent loss in all cases has not been completely elucidated, but it is presumed that the inflammation caused by the viral insult causes sensorineural damage at the level of olfactory receptor cells and/or central olfactory pathways.6,8,15 Thirty-six percent of patients may spontaneously improve to some extent, usually within a few months after the loss, while in others these losses are permanent.16 The exact factors associated with recovery of olfactory function are currently ill defined, outside of age and duration of loss. We evaluated the incidence of other cranial neuropathies in this study because we postulated a possible innate vulnerability or sensitivity to loss in the patient population experiencing permanent deficit.9,16

    Park et al17 reported higher prevalence of hearing loss and dysphonia in patients with olfactory dysfunction (hearing loss: 18.1% vs 11.3%; dysphonia: 11.1% vs 5.9%) by using the fifth Korea National Health and Nutrition Examination Surveys in 2010-2012. However, etiology of those other cranial neuropathies was not presented in that study.17

    Over the past 2 decades, other studies have suggested that viral causes may be responsible for vagal neuropathies leading to vocal fold paralysis.18-20 Bhatt et al21 investigated 107 patients presenting with idiopathic unilateral vocal fold paralysis in 2002 to 2012, revealing that 38 of 107 patients (35.5%) reported symptoms of upper respiratory tract infection at the onset. Likewise, many studies have pointed to the association between sudden sensorineural hearing loss and viral causes such as influenza B, enterovirus, hepatitis B virus, measles, mumps, rubella, varicella-zoster, herpes simplex virus, and dengue infection. The pathophysiologic mechanisms that have been proposed to explain this include viral invasion, reactivation of the latent virus, and systemic reactions triggering an antibody response that cross-reacts with an inner ear antigen.22-24 Similarly, the pathophysiology of postviral olfactory loss has been shown to involve neuroinflammation, apoptosis, and destruction of olfactory neurons, causing morphological alteration of the olfactory cortex and olfactory bulb.25-30

    Frasnelli et al31 reported that trigeminal chemosensory detection thresholds for CO2 detection are higher in patients with olfactory dysfunction than in controls and improvement of olfactory dysfunction was accompanied by decreased trigeminal threshold.31,32 However, the study represented only the chemosensory aspect of trigeminal nerve function. In our study, we found only 1 case of facial numbness due to trigeminal neuropathy, but this exhibits possible association with the nonchemosensory aspect as well.

    High BMI has been reported as an associated factor of olfactory dysfunction.33 It has been shown that the response to the starvation signal peptide adiponectin in animal models is an increasing olfactory acuity in starvation and fasting stages. As olfactory dysfunction increases with increasing BMI, the normal olfactory mechanisms that allow humans to control portion size and express satiety become more dysfunctional, which contributes to a cycle of increasing food intake.33-35 The pathophysiologic mechanism behind why other cranial nerves would also be more susceptible in a patient group with increased BMI is less clear but may be similarly connected to our evolutionary heightening of all the senses when in starvation mode and the need is high to find food to survive. However, in our study, perhaps again because of small sample size, BMI did not have a significant association with other cranial neuropathy in this sample.

    Severity and persistence of neuronal inflammation in the brain following a viral insult tend to be associated with several genes. Limited evidence points to neuronal damage occurring not only peripherally but also centrally after viral respiratory infection.15,29 In our study, the finding of family history of neurologic diseases, such as dementia, Alzheimer disease, Parkinson disease, and stroke, being a potential risk factor of having both postviral olfactory loss as well as other cranial neuropathies again supports the idea of an association with the neurologic system in these patients. When considering this more global neurologic association, an individual’s genetic propensity to mount a systemic inflammatory response to a viral attack may prove relevant when considering the associated vulnerability of other cranial nerves.

    Limitations

    This study is limited by relatively small sample size, which resulted in imprecise point estimates of effect size as demonstrated by the wide 95% CI, meaning we are unable to make any definitive conclusions from these data. Retrospective reviews are also always subject to certain inherent biases—for example, inadequacies in the medical record, ascertainment bias based on more intense surveillance of this group, and possible referral bias at a tertiary academic care center. Case-control studies are limited usually by issues with identification of controls and the possible biases this may introduce, as well as recall bias. In our study, these 2 main sources of bias are unlikely to have affected results. In spite of the limitations, the data presented here can lay the groundwork for future prospective studies investigating these associations further and add to a growing body of evidence regarding global neurologic susceptibility to an inflammatory insult. Furthermore, this finding could improve patient counseling and may possibly lead to broader treatment options in the future, such as testing and applying therapies proven effective for one cranial nerve disorder to others.

    Conclusions

    Patients with postviral olfactory loss appear to have a higher incidence of other cranial neuropathies. It is possible that there is an inherent vulnerability to neural damage or decreased ability of nerve recovery in patients experiencing these pathologies. Patients with high BMI and possibly those who have family history of neurologic disease may also be more susceptible.

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    Article Information

    Accepted for Publication: February 1, 2020.

    Corresponding Author: Zara M. Patel, MD, Department of Otolaryngology–Head and Neck Surgery, Stanford University School of Medicine, 801 Welch Rd, Palo Alto, CA 94305 (zmpatel@stanford.edu).

    Published Online: April 2, 2020. doi:10.1001/jamaoto.2020.0225

    Author Contributions: Dr Patel had full access to all the data in the study and takes responsibility for the integrity of data and accuracy of analysis.

    Study concept and design: Jitaroon, Patel.

    Acquisition, analysis, or interpretation of data: Jitaroon, Wangworawut, Ma.

    Drafting of the manuscript: Jitaroon, Ma.

    Critical revision of the manuscript for important intellectual content: Jitaroon, Wangworawut, Patel.

    Statistical analysis: Wangworawut, Ma.

    Administrative, technical, or material support: Jitaroon, Wangworawut, Patel.

    Study supervision: Wangworawut, Patel.

    Conflict of Interest Disclosures: Dr Patel reported serving as a consultant for Medtronic, Stryker, and Intersect and serving on an advisory board for Optinose. No other disclosures were reported.

    Meeting Presentation: This study was presented at Rhinoworld, June 9, 2019, Chicago, Illinois.

    References
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    Cavazzana  A, Larsson  M, Münch  M, Hähner  A, Hummel  T.  Postinfectious olfactory loss: a retrospective study on 791 patients.   Laryngoscope. 2018;128(1):10-15. doi:10.1002/lary.26606PubMedGoogle ScholarCrossref
    2.
    Seiden  AM.  Postviral olfactory loss.   Otolaryngol Clin North Am. 2004;37(6):1159-1166. doi:10.1016/j.otc.2004.06.007PubMedGoogle ScholarCrossref
    3.
    Nordin  S, Brämerson  A.  Complaints of olfactory disorders: epidemiology, assessment and clinical implications.   Curr Opin Allergy Clin Immunol. 2008;8(1):10-15. doi:10.1097/ACI.0b013e3282f3f473PubMedGoogle ScholarCrossref
    4.
    Whitcroft  KL, Cuevas  M, Haehner  A, Hummel  T.  Patterns of olfactory impairment reflect underlying disease etiology.   Laryngoscope. 2017;127(2):291-295. doi:10.1002/lary.26229PubMedGoogle ScholarCrossref
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