Smell and Taste Disorders: Diagnosis

Number: 0390

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses diagnosis of smell and taste disorders.

1. Medical Necessity

   1. Aetna considers certain procedures/services medically necessary for the evaluations of members with unexplained olfactory dysfunction (e.g., anosmia, hyposmia, dysosmia) and gustatory dysfunction (e.g., ageusia, hypogeusia, dysgeusia):
      
      
      1. Biopsy of the olfactory mucosa
      2. Drug assays and chemical analyses when certain medications or nutritional deficiencies are the suspected causes of the disorders
      3. Electroencephalography (EEG) for members with a history of seizures
      4. Hematological tests (e.g., hematocrit count, hemoglobin level, white blood cell count, urea nitrogen level, creatinine level, glucose level, erythrocyte sedimentation rate, eosinophil count, and immunoglobulin E level)
      5. Medical evaluation (complete medical history and physical examination)
      6. Nasal endoscopy
      7. Neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI) to rule out an intra-cranial or peripheral nerve abnormality
      8. Neurological consultation
      9. Otolaryngological consultation
      10. Psychiatrical consultation
      11. Standard taste tests such as Taste-Threshold Test (also known as Whole-Mouth Taste-Threshold Test), Taste-Suprathreshold Test, Taste-Quadrant Test, and Flavor Discrimination Test (for evaluation of both taste and smell sensation)
      12. Standardized olfactory tests such as the University Of Pennsylvania Smell Identification Test (UPSIT) or “Sniffin' Sticks”, the University of Connecticut Test Battery, the Pocket Smell Test, or the Brief Smell Identification Test.  Other tests include Smell-Threshold Test, Smell-Suprathreshold Test, and Smell Unilateral Test.  For use of olfactory testing in Parkinson disease, see CPB 0307 - Parkinson's Disease 
      13. Thyroid function studies.

      Note: An initial and follow-up visit is considered medically necessary for smell and/or taste dysfunction testing.  Additional visits for testing are considered not medically necessary.

      Note: Members with taste loss may need smell testing in addition to taste testing.

2. Experimental, Investigational, or Unproven

   1. Aetna considers the following services as a means of diagnosing an unexplained olfactory dysfunction and gustatory dysfunction experimental, investigational, or unproven because the peer-reviewed medical literature does not support the use of these studies for this indication:

      1. Cerebrospinal fluid SARS-CoV-2 antibody testing
      2. Electrogustometry
      3. Genotyping of the TAS2R38 gene
      4. Magnetic resonance imaging for evaluation of COVID-19 olfactory dysfunction
      5. Measurement of nasal nitric oxide levels
      6. Olfactometry 
      7. Olfactory and gustatory event potentials 
      8. Positron emission tomography (PET) 
      9. Rhinomanometry 
      10. Rhinometry (also known as acoustic rhinometry) 
      11. Single photon emission computed tomography (SPECT)
      12. Tests for Helicobacter pylori infection.

3. Related Policies

   • CPB 0071 - Positron Emission Tomography (PET)
   • CPB 0181 - Evoked Potential Studies
   • CPB 0307 - Parkinson's Disease
   • CPB 0376 - Single Photon Emission Computed Tomography (SPECT)
   • CPB 0700 - Rhinometry and Rhinomanometry

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
30100	Biopsy, intranasal
31231	Nasal endoscopy, diagnostic, unilateral or bilateral (separate procedure)
70450	Computed tomography head or brain; without contrast material
70460	with contrast material(s)
70470	without contrast material, followed by contrast material(s) and further sections
70496	Computed tomographic angiography, head, with contrast material(s), including noncontrast images, if performed, and image postprocessing
70551	Magnetic resonance (e.g., proton) imaging, brain (including brain stem); without contrast material
70552	with contrast material(s)
70553	without contrast material, followed by contrast material(s) and further sequences
82565	Creatinine; blood
82947	Glucose; quantitative, blood (except reagent strip)
84443	Thyroid stimulating hormone (TSH)
84520	Urea nitrogen; quantitative
85014	Blood count; hematocrit (Hct)
85018	hemoglobin (Hgb)
85032	manual cell count (erythrocyte, leukocyte, or platelet) each
85048	leukocyte (WBC), automated
85651 - 85652	Sedimentation rate, erythrocyte
86003	Allergen specific IgE; quantitative or semiquantitative, each allergen
CPT codes not covered for indications listed in the CPB:
Genotyping of the TAS2R38 gene, cerebrospinal fluid SARS-CoV-2 antibody testing - no specific code:
70540	Magnetic resonance (eg, proton) imaging, orbit, face, and/or neck; without contrast material(s)
70542	with contrast material(s)
70543	without contrast material(s), followed by contrast material(s) and further sequences
78267	Urea breath test, C-14 (isotopic); acquisition for analysis [Helicobacter pylori]
78268	analysis [Helicobacter pylori]
78608	Brain imaging, positron emission tomography (PET); metabolic evaluation
83013	Helicobacter pylori; breath test analysis for urease activity, non-radioactive isotope (eg, C-13)
83014	drug administration
87338	Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme-linked immunosorbent assay [ELISA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative, multiple-step method; Helicobacter pylori, stool
92512	Nasal function studies (e.g., rhinomanometry)
95012	Nitric oxide expired gas determination
Other CPT codes related to the CPB:
31233	Nasal/sinus endoscopy, diagnostic with maxillary sinusoscopy (via inferior meatus or canine fossa puncture)
31235	Nasal/sinus endoscopy, diagnostic with sphenoid sinusoscopy (via puncture of sphenoid face or cannulation of ostium)
31237	Nasal/sinus endoscopy, surgical; with biopsy, polypectomy, or debridement (separate procedure)
80150 - 80202	Therapeutic drug assays
84630	Zinc
92511	Nasopharyngoscopy with endoscope (separate procedure)
95816 - 95819	Electroencephalogram (EEG) including recording awake and drowsy or including awake and asleep
ICD-10 codes covered if selection criteria are met:
R43.0 - R43.9	Disturbances of smell and taste
ICD-10 codes not covered if selection criteria are met:
G52.0	Disorders of olfactory nerve [COVID-19 olfactory dysfunction]
U09.9	Post COVID-19 condition, unspecified [COVID-19 olfactory dysfunction]

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Background

Normal olfactory and gustatory functioning plays a key role in nutrition and food selection, and thus is important for the maintenance of a good quality of life.  Smell and taste are closely inter-related.  An impairment of the function of one sense often affects the function of the other sense.  In fact, complaints of gustatory loss usually reflect smell rather than taste dysfunction.  Deficits in these senses not only can reduce the pleasure and comfort from food, but can also lead to food poisoning or over-exposure to environmentally hazardous agents that are otherwise detectable by smell and taste.

More than 2 millions Americans suffer from smell and taste disorders.  Olfactory dysfunction is more common than gustatory dysfunction because of the vulnerability and anatomical distinctiveness of the olfactory system, and because a decline in olfactory function is part of the normal aging process.  Common olfactory and gustatory disturbances could be the consequence of a variety of medications, upper respiratory infections, nasal and paranasal sinus diseases, depression, hypothyroidism, and damage to peripheral nerves supplying smell and taste.  In particular, inflammation (nasal and sinus disease), viral infection, and head trauma are the most frequent causes of smell disorders; while oral and perioral infections (e.g., gingivitis and candidiasis), oral appliances (e.g., dentures and filling materials), dental procedures and Bell's palsy are the most common causes of taste disorders.

Anosmia refers to an absence of the smell sensation; hyposmia is defined as reduced sensitivity to odorants (odor stimuli), and dysosmia refers to an altered perception of smell.  Dysosmia can be further classified into phantosmia (a perception of an odor without the stimulus present) and parosmia or troposmia (an altered perception of an odor with a stimulus present).

Ageusia refers to an absence of the taste sensation; hypogeusia is defined as reduced sensitivity to tastants (taste stimuli), and dysgeusia refers to an altered perception to taste with or without the presence of a tastant.

A careful medical history of systemic illnesses and medication use as well as a thorough physical examination are essential for the diagnosis of smell and taste disorders.  Work-up should not commence until a standardized test such as the University of Pennsylvania Smell Identification Test (UPSIT) or the University of Connecticut Test Battery has been given to establish impairment of the sense of smell.  The University of Pennsylvania Smell Identification Test (UPSIT) is an objective, quantitative test of olfactory function.  The test consists of 40 odors, each of which is microencapsulated on a pad that, one at a time, the patient scratches with a pencil and sniffs.  The patient is provided with a list of 4 choices for each pad, and from which the correct answer must be chosen or a guess made.  It has been demonstrated that there is good correlation between UPSIT and other olfactory function tests such as the T&T olfactometer threshold test, Cain's odor identification test, and Le Nez du Vin-derived smell identification test.  Furthermore, it has been reported that the UPSIT and its 10-, 20-, and 30-item fragments have very high internal consistency reliability.

The recent practice parameter on diagnosis and prognosis of new onset Parkinson disease by the American Academy of Neurology (Suchowersky et al, 2006) stated that olfactory testing using either the UPSIT or “Sniffin' Sticks” should be considered to differentiate progressive supranuclear palsy and corticobasal degeneration from Parkinson's disease.

Nasal mucous membranes should be examined for abnormal conditions.  Biopsy is necessary if intra-nasal or intra-oral neoplasm is suspected to be the cause of the dysfunction.  Furthermore, intra-nasal biopsy is also helpful in diagnosing post-upper respiratory infection-induced olfactory loss.  Drug assays, chemical analyses and thyroid function studies may be necessary since distortion of chemosensory sensations are associated with the use of certain medications (e.g., anti-depressants and anti-convulsants, anti-psychotics, anti-hypertensives and cardiac medications, lipid-lowering agents, and anti-Parkinsonian agents), nutritional deficiency (e.g., zinc deficiency), and thyroid disease.

Neuroimaging such as CT or MRI may be necessary to rule out intra-cranial or peripheral nerve abnormalities.  Computed tomography is useful in imaging the nasal and sinus cavities, skull base, olfactory cleft, nasopharynx, parotid, oropharynx, neck, and mandible.  Bone abnormalities and widening of cranial nerve foramina are best observed with CT.  Magnetic resonance imaging is useful in evaluating the olfactory bulbs, ventricles, other soft tissues in the brain, soft tissues of the tongue, tongue base, blood vessels and nerves in the skull base and neck.  Studies such as SPECT and PET do not play a significant role in the diagnosis of olfactory and gustatory dysfunctions.  Patients with a history of seizure disorder should be referred for EEG.  Otolaryngological, neurological, and psychiatrical consultation may be necessary if the underlying cause of the olfactory/gustatory dysfunction is diagnosed as a condition, which may require further evaluation and treatment, by a specialist in such discipline.

Ellegard and colleagues (2007) examined if electrogustometry is useful for screening abnormalities of taste.  These investigators asked 114 subjects, some healthy but most with medical conditions possibly affecting taste, to rate their overall taste ability, on a scale of 0 to 10.  Those who had current symptoms related to taste, and who rated their taste as 5 or worse were defined as "aberrant tasters".  These researchers recorded automated electrogustometry thresholds, and visual analog scale intensity ratings, for solutions of the four basic tastes (sweet, sour, salty and bitter).  A visual analog scale score of 50 was used as a cut-off point to identify "poor tasters".  The sensitivity and specificity of electrogustometry in identifying abnormal taste function were low.  The authors concluded that automated electrogustometry is not a useful clinical screening method for taste disturbance in this group of subjects.

There is insufficient scientific evidence to support the usefulness of olfactory evoked potentials, olfactometry, rhinometry, rhinomanometry, or electrogustometry in the diagnosis of smell and taste disorders.

Cecchini and colleagues (2013) stated that Helicobacter pylori (H. pylori) has been found in dental plaque, saliva and lingual sites.  To-date, taste or olfaction disorders related to H. pylori infections have never been reported.  In a review of the literature these researchers found 2 papers just referring to a sour taste sensation during H. pylori infection.  Studies in animal models suggested that changes in taste perception may relate to infections that damage taste buds.  These investigators observed an interesting clinical case of a 24-year old Ghanaian woman with documented H. pylori gastric infection, complaining of cacosmia and cacogeusia.  Taste evaluation indicated hypogeusia and high-lighted a specific difficulty in discriminating between bitter and acid tastes.  Saliva fluid was found positive for the ureA gene (H. pylori urease A).  On the basis of this report, the authors hypothesized that taste perception might be correlated with a documented H. pylori infection.  So, in a dyspeptic clinical picture in both pre- and post-diagnostic phase when H. pylori infection is suspected, taste evaluation might be important.  Moreover, they stated that further studies are certainly needed in a large patient population to clarify the possible connection between H. pylori infection and smell-taste distortion.

In a prospective study, Elsherif et al (2007) examined the relationship between nasal nitric oxide (nNO) concentration and its influence on olfactory function.  A total of 64 patients suffering from chronic rhinosinusitis and 20 healthy subjects participated in this study.  The nNO concentration was measured by chemiluminescence and olfactory thresholds were measured with the phenyl ethanol threshold of the Sniffin' Sticks.  In chronic rhinosinusitis patients this measure was done pre-operatively and 3 months after endoscopic sinus surgery.  Healthy subjects had significantly higher nNO concentrations and better olfactory thresholds compared to the chronic rhinosinusitis patients, both before and after those had undergone sinus surgery.  Olfactory thresholds and nNO concentrations remained unchanged after surgery in the chronic rhinosinusitis group.  In the chronic rhinosinusitis group, nNO concentrations correlated positively with the olfactory threshold pre-operatively (p < 0.0001) and 3 months after surgery (p < 0.05).  In the control group, nNO production did not correlate with the olfactory thresholds (p > 0.05).  The authors concluded that olfactory function and nNO concentration correlated in chronic rhinosinusitis patients but not in healthy subjects.  This suggested that both parameters do rather not directly influence each other but it might be the inflammatory processes found in chronic rhinosinusitis that affects olfaction and nNO.  They stated that nNO produced by the paranasal sinuses appeared not to directly influence olfactory function.

Gupta and associates (2013) stated that nNO and olfactory function are decreased in patients with chronic inflammatory sinonasal disease, suggesting a link between these 2 parameters.  These researchers examined nNO levels in patients with olfactory dysfunction due to different causes.  Post-traumatic (n = 11), idiopathic (n = 13), and sinonasal-related olfactory-impaired patients (n = 55) were compared with healthy subjects (n = 11).  Nasal NO levels, olfactory testing (Sniffin' Sticks), and rhino-sinusitis questionnaires (Short-Form 36, Sinonasal Outcome Test 22, Rhinosinusitis Disability Index) were obtained.  No significant difference in nNO levels were found between the different olfactory dysfunction causes.  Nasal NO correlated negatively with age and positively with overall olfactory function, olfactory discrimination, and identification but not with olfactory thresholds.  The more nasal symptoms prevailed in the Rhinosinusitis Disability Index, the lower the nNO.  The authors concluded that nNO levels did not allow for discrimination between olfactory loss due to various etiologies based on the present data.  Nasal NO production appeared to decrease with age and also seemed to be associated to overall olfactory function and in particular to central nervous system tasks such as olfactory discrimination and identification but not to olfactory thresholds.  The authors stated that these findings raised questions about the link and interaction between olfactory function and nNO.

Genotyping of the TAS2R38 Gene for Taste Disorders

Melis and colleagues (2019) noted that taste sensitivity varies greatly among individuals influencing eating behavior and health, consequently the disorders of this sense can affect the quality of life (QOL).  The ability to perceive the bitter of thiourea compounds, such as phenylthiocarbamide (PTC), has been largely reported as a marker of the general taste sensitivity, food preferences, and health.  PTC sensitivity is mediated by the TAS2R38 receptor and its genetic common variants.  In a prospective, cohort study, these researchers examined the role of the TAS2R38 receptor in taste disorders with the aim of understanding if these could be genetically determined.  Differences in the PTC responsiveness between the patients cohort and healthy controls were examined.  All subjects received standardized tests for smell and taste function and were genotyped for the TAS2R38 gene.  PAV/PAV homozygous patients gave high PTC ratings, whereas PAV/AVI genotypes reported lower values, which were similar to those determined in AVI/AVI or rare genotypes.  In addition, the patients cohort did not meet the Hardy-Weinberg equilibrium at the TAS2R38 locus, showing a very low frequency of subjects carrying the PAV/AVI diplotype.  Independently, in healthy controls who were in equilibrium at the locus, PAV/PAV homozygous and heterozygous rated PTC bitterness higher compared to AVI/AVI or rare genotypes.  The authors concluded that these findings, by showing that an only taster haplotype (PAV) was insufficient to evoke high responses of TAS2R38 receptor in patients with taste disorders, suggest that the genetic constitution may represent a risk factor for the development of taste disorders.

Furthermore, an UpToDate review on “Evaluation and treatment of taste and smell disorders” (Mann and Lafreniere, 2019) does not mention genetic testing as a management tool.

Retro-Nasal Olfaction Test Methods

In a systematic review, Ozay and colleagues (2019) produced a bibliographic study of psychophysical tests proposed clinical assessments of retro-nasal olfaction.  These investigators reviewed how these tests can be used and discussed their methodological properties.  They carried out a literature review examining the retro-nasal olfaction test methods. PubMed, the free online Medline database on biomedical sciences, was searched for the period from 1984 to 2015 using the following relevant key phrases: “retronasal olfaction”, “orthonasal olfaction”, “olfaction disorders”, and “olfaction test”.  For each of the selected titles cited in this study, the full manuscript was read and analyzed by each of the 3 authors of this paper independently before collaborative discussion for summation and analytical reporting. Two reviewers independently read the abstracts and full texts and categorized them into 1 of 3 subgroups as follow – suitable, not-suitable, and unsure.  Then they cross-checked the results, and a third reviewer assigned the group “unsure” to either the suitable group or the not-suitable group.  A total of 58 studies revealed as suitable for review by 2 authors whereas 13 were found not suitable for review.  The total amount of 60 uncertain (unsure) or differently categorized articles were further examined by the third author that resulted in 41 approvals and 19 rejections. Thus, a total of 99 approved articles passed the next step. Exclusion criteria were reviews, case-reports, animal studies, and the articles of which methodology was a lack of olfaction tests; 69 papers were excluded by this way, and finally, 30 original human research articles were taken as the data.  The study found that the 3 most widely used and accepted retro-nasal olfaction test methods were the retro-nasal olfaction test, the candy smell test and odorant presentation containers. All of the 3 psychophysical retro-nasal olfaction tests were combined with ortho-nasal tests in clinical use to examine and understand the smell function of the patient completely. There were 2 limitations concerning testing: “the lack concentrations and doses of test materials” and “performing measurements within the supra-threshold zone”. The authors concluded that the appropriate test agents and optimal concentrations for the retro-nasal olfaction tests remain unclear and emerge as limitations of the retro-nasal olfaction test technique.  The first step to overcoming these limitations will probably require identification of retro-nasal olfaction thresholds.  Once these are determined, the concept of retro-nasal olfaction and its testing methods may be thoroughly reviewed.

The authors stated that their study of the literature consistently revealed 2 limitations of olfaction testing: a lack of use of known concentrations and doses of the test substances and conducting tests within the supra-threshold zone.  Additionally, no particular procedure was described to detect threshold sensation.  The absence of such standardizations probably underlies the delay in progress of these tests and prevents them from being employed in routine clinical use.

Smell Tests to Distinguish Parkinson's Disease from Other Neurological Disorders

Alonso and colleagues (2021) noted that olfactory impairment has been considered for differential diagnosis in Parkinson's disease (PD) patients.  These researchers identified the tests used to evaluate the olfactory function in PD patients and examined these tests' ability to distinguish them from other neurological disorders.  Cross-sectional studies published until May 2020 comparing the olfactory function of PD patients to other neurological disorders were searched on PubMed, PsycInfo, Cinahl, and Web of Science databases using search terms related to PD, olfactory function, and assessment.  A total of 5,304 studies were screened, and 35 were included in the systematic review; 6 smell tests that examined a total of 1,544 PD patients were identified.  Data of 1,144 patients included in the meta-analyses revealed worse smell performance than individuals with other neurological disorders, such as progressive supranuclear palsy and essential tremor, but not with idiopathic rapid eye movement sleep behavior disorder.  The authors concluded that the University of Pennsylvania Smell Identification Test was the most used test to examine the olfactory function of PD.  Smell loss was worse in PD than in some neurological disorders.  Moreover, these researchers stated that the smell tests' ability in differentiating PD from other neurological disorders still deserves more attention in future studies.

Cerebrospinal Fluid SARS-CoV-2 Antibody Testing from COVID-19 Patients with Olfactory/Gustatory Dysfunction

In a systematic review, Lewis and colleagues (2021) examined the literature on cerebrospinal fluid (CSF) testing in patients with altered olfactory/gustatory function due to COVID-19 for evidence of viral neuro-invasion.  These researchers carried out searches of Medline and Embase to identify publications that described at least 1 patient with COVID-19 who had altered olfactory/gustatory function and had CSF testing performed.  The search ranged from December 1, 2019 to November 18, 2020.  They identified 51 publications that described 70 patients who met inclusion criteria.  Of 51 patients who had CSF SARS-CoV-2 PCR testing, 3 (6 %) patients had positive results and 1 (2 %) patient had indeterminate results.  Cycle threshold (Ct; the number of amplification cycles required for the target gene to exceed the threshold, which is inversely related to viral load) was not provided for the patients with a positive PCR.  The patient with indeterminate results had a Ct of 37 initially, then no evidence of SARS-CoV-2 RNA on repeat testing.  Of 6 patients who had CSF SARS-CoV-2 antibody testing, 3 (50 %) were positive.  Testing to distinguish intra-thecal antibody synthesis from transudation of antibodies to the CSF via breakdown of the blood-brain barrier (BBB) was carried out in 1/3 (33 %) patients; this demonstrated antibody transmission to the CSF via transudation.  The authors concluded that altered olfactory and/or gustatory function in patients with COVID-19 is common; however, the mechanism for these symptoms is uncertain.  These researchers stated that the findings of this systematic review suggested that detection of viral neuro-invasion in this patient population via CSF SARS-CoV-2 PCR or evaluation for intra-thecal antibody synthesis is rare.  They stated that additional research is needed to clarify the pathogenesis of these symptoms in patients with COVID-19.

The authors stated that this review had several drawbacks.  These findings exhibited both publication bias as well as limitations of the search methodology.  There were likely additional patients with COVID-19 who had altered olfactory and/or gustatory function and had CSF obtained that were not included because they did not (or could not) report these symptoms; or there was no published report of the clinical details of their case during the search period, so they were not captured in the literature search.  Furthermore, CSF results can change over time, and the CSF from the patients included in this review was not obtained at a specific time-point relative to the onset of altered olfactory and/or gustatory function.  Finally, although these investigators excluded patients who had subarachnoid hemorrhage or meningitis/ventriculitis/encephalitis due to an infectious organism other than COVID-19, it is worth noting that these researchers included patients with inflammatory diagnoses that could have altered the CSF profile, such as acute disseminated encephalomyelitis.

Magnetic Resonance Imaging for Evaluation of COVID-19 Olfactory Dysfunction

Tan et al (2022) stated that olfactory dysfunction (OD) is a common presenting symptom of COVID-19 infection.  Radiological imaging of the olfactory structures in patients with COVID-19 and OD can potentially shed light on its pathogenesis, and guide clinicians in prognostication and intervention.  PubMed, Embase, Cochrane, SCOPUS were searched from inception to August 1, 2021.  A total of 3 reviewers selected observational studies, case series, and case reports reporting radiological changes in the olfactory structures, detected on MRI, CT, or other imaging modalities, in patients aged 18 years of age or older with COVID-19 infection and OD, following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.  These investigators described the proportion of radiological outcomes; and used random-effects meta-analyses to pool the prevalence of olfactory cleft opacification, olfactory bulb (OB) signal abnormalities, and olfactory mucosa abnormalities in patients with and without COVID-19-associated OD.  They included 7 case-control studies (n = 353), 11 case series (n = 154), and 12 case reports (n = 12).  The pooled prevalence of olfactory cleft opacification in patients with COVID-19 infection and OD (63 %, 95 % CI: 0.38 to 0.82) was significantly higher than that in controls (4 %, 95 % CI: 0.01 to 0.13).  Conversely, similar proportions of cases and controls demonstrated OB signal abnormalities (88 % and 94 %) and olfactory mucosa abnormalities (2 % and 0 %).  Descriptive analysis found that 55.6 % and 43.5 % of patients with COVID-19 infection and OD had morphological abnormalities of the OB and olfactory nerve, respectively, while 60.0 % had abnormal OB volumes.  The authors concluded that olfactory cleft opacification is a key radiological marker of COVID‐19‐associated OD, while other findings like OB signal abnormalities, and olfactory mucosa abnormalities, appear less related.  This had mechanistic implications and suggested that conductive mechanisms of olfactory loss may have an important role in the pathogenesis of COVID‐19‐associated OD.  Such imaging findings may also guide prognostication and treatment of OD.  These researchers stated that inclusion of studies with larger sample sizes, robust study designs, data on normosmic COVID‐19 controls, and consistent imaging techniques specific to the olfactory system will allow more reliable conclusions to be drawn.

The authors stated that future studies should examine radiological changes to the olfactory structures in a longitudinal fashion.  By following patients up over a protracted duration, improvement or progression of imaging findings can be tracked, with correlation to patients' clinical symptoms.  Changes in radiological findings in response to targeted treatment for OD may also be useful to monitor; and may inform the underlying mechanisms of COVID‐19‐associated OD.  Furthermore, other long‐term clinical outcomes following COVID‐19 infection, including post‐infectious cognitive outcomes, can also be examined.  Lastly, correlation of these findings with histopathological studies may potentially reveal greater mechanistic data.  However, large cohort studies examining histopathological findings are largely unfeasible, requiring either invasive endoscopic biopsy, or post‐mortem autopsy in deceased patients who had COVID‐19‐associated OD.

Hura et al (2022) noted that patients with acquired, idiopathic OD commonly undergo MRI evaluation to rule out intra-cranial pathologies.  This practice is highly debated given the expense of MRI relative to the probability of detecting a treatable lesion.  This, combined with the increasing use of MRI in research to examine the mechanisms underlying OD, provided the impetus for this comprehensive review.  In a systematic review, these investigators examined the use of MRI in diagnosis of idiopathic OD and described MRI findings among mixed OD etiologies to better understand its role as a research tool in this patient population.  They carried out a literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for studies with original MRI data for patients with OD.  Studies exclusively examining patients with neurocognitive deficits or those studying traumatic or congenital etiologies of OD were excluded.  From a total of 1,758 studies, 33 were included; 4 studies reviewed patients with idiopathic OD for structural pathologies on MRI, of which 17 of 372 (4.6 %) patients had a potential central cause identified, and 3 (0.8 %) had an olfactory meningioma or olfactory neuroblastoma; 14 studies (42.4 %) reported significant correlation between OB volume and olfactory outcomes, and 6 studies (18.8 %) reported gray matter volume reduction, specifically in the orbito-frontal cortex, anterior cingulate cortex, insular cortex, para-hippocampal, and piriform cortex areas, in patients with mixed OD etiologies.  Functional MRI studies reported reduced brain activation and functional connectivity in olfactory network areas.  The authors concluded that MRI uncommonly detects intra-cranial pathology in patients with idiopathic OD.  Among patients with mixed OD etiologies, reduced OB and gray matter volume were the most common abnormal findings on MRI.  Moreover, these researchers stated that further investigation is needed to better understand the role of MRI and its cost-effectiveness in patients with acquired, idiopathic OD.

Mohammadi et al (2023) stated that the neurotropism of SARS-CoV-2 and the consequential damage to the olfactory system have been proposed as one of the possible underlying causes of OD in COVID-19.  In a systematic review and meta-analysis, these researchers examined the results of the studies that reported imaging of the olfactory system of patients with COVID-19 versus controls.  PubMed and Embase were searched to identify relevant studies reporting the structural imaging characteristics of the OB, olfactory cleft, olfactory sulcus (OS), or olfactory tract in COVID-19 patients.  Hedge's g and weighted mean difference (MD) were used as a measure of effect size.  Quality assessment, subgroup analyses, meta-regression, and sensitivity analysis were also carried out.  A total of 10 studies were included in the qualitative synthesis, out of which 7 studies with 183 cases with COVID-19 and 308 controls without COVID-19 were enrolled in the quantitative synthesis.  No significant differences were detected in analyses of right OB volume and left OB volume.  Similarly, right OS depth and left OS depth were also not significantly different in COVID-19 cases compared to non-COVID-19 controls.  Furthermore, these researchers performed subgroup analysis, meta-regression, and sensitivity analysis to examine the potential effect of confounding moderators.  The authors concluded that the findings of this review did not confirm alterations in structural imaging of the olfactory system, including OB volume and OS depth by Covid-19 which is consistent with the results of recent histopathological evaluations.  This may reduce the possibility of using these variables as diagnostic or prognostic indices.  However, future studies of olfactory anatomy with longitudinal designs conducted with standardized protocols controlling possible confounders and biases may reveal new insights.  In addition, the combined application of imaging modalities with endoscopic techniques and histopathological findings of biopsy specimens of the components of the olfactory system in the COVID-19 patients might provide a better understanding of the pathophysiology of the COVID-19-mediated OD.

The authors stated that this study had 2 main drawbacks that mainly arise from the novelty of the subject.  First, small study populations along with demographic (e.g., age and nationality) and methodologic (e.g., the trait of controls and chronicity of OD) inter-study differences caused significant heterogeneity in the results of the analysis.  Second, the lack of comparability between cases and controls, which may result in significant biases in the included studies as only 2 studies had age-matched subjects.

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References