Introduction

Many patients are not aware of their olfactory deficits.[1] Therefore, olfactory testing is important. Additionally, common causes of olfactory decline create distinct patterns of olfactory deficits that are revealed through multicomponent olfactory tests.[2][3] Moreover, olfactory deficits may be a warning-sign for neurodegenerative disorders or infections such as coronavirus disease 2019 (COVID-19).[4] Thus, olfactory testing may uncover important clues of potentially dangerous conditions.

Procedures

History and Ear Nose and Throat (ENT) Exam

Before performing the actual olfactory testing, it is important to take a thorough history and perform a physical exam.[3] The history often suggests the diagnosis or helps to narrow down the differential diagnoses.[3] When taking the history, it is important to ask if there is an impairment with the sense of smell, an impairment with flavor/taste, or impairment of basic gustatory perception (such as salty, sweet, sour, or bitter)? Besides onset (such as sudden versus gradual) and course of the olfactory deficit (such as fluctuating or static), it is of central importance to also ask about quantitative olfactory dysfunction (such as the severity of olfactory alteration and the kind of odors affected) and qualitative olfactory dysfunction (distorted perception when the olfactory stimulus is present versus the perception of an odor when no odor stimulus is present). Furthermore, it is also important to inquire how olfactory decline impacts daily life (such as nutrition, interpersonal communication, home safety). Finally, it is critical to obtain information about past medical history, head injuries, nasal symptoms (such as obstruction, rhinorrhea, sneezing), past and current medication intake, allergies, smoking habits, toxin exposure, and relevant family history. Besides a general physical exam, a full ENT exam should be performed as well as an anterior rhinoscopy and nasal endoscopy.

General Concept of Olfactory Testing

Olfactory impairment may be quantitative (= impairment of the strength) and/or qualitative (= impairment of the quality or degree of distortion). Olfactory testing primarily provides information about quantitative impairment, while history gives crucial information on qualitative impairment (such as distortion).

The general concept of olfactory testing in the clinic is that an olfactory probe is presented at the patient’s nostrils, and the response of the patient is documented. This is also referred to as psychophysical testing.[3][5] Olfactory testing requires a patient who can cooperate with the procedure, understands the instructions, and can communicate the choices.[3] Olfactory tests are generally subdivided into odor threshold tests and suprathreshold tests of olfaction, such as tests for odor identification and odor discrimination. While tests for odor threshold more likely to assess peripheral olfactory ability (such as a conductive and sensorineural function of the nose), suprathreshold tests are more likely to assess central processing of olfactory information (such as the functioning of central nervous system structures involved in olfaction).[2][3] Thus, olfactory testing may include both tests for odor threshold and suprathreshold tests of olfaction.

Odor Threshold Tests

For odor threshold tests, probes with either phenyl ethyl alcohol or n-butanol in increasing concentration are presented sequentially and typically intermixed with probes with no odor (“blanks”).[3][5] Patients are asked to answer, even if they are uncertain if they have perceived an odor (= forced-choice procedure).[3] When the transition between no detection and detection of the odor probe has been reached, the odor concentration slightly decreases and increases in several runs.[5] This is done to form the average of the reversals and therefore increases reliability.[5] Tests commonly used in clinical practice are the Snap & Sniff threshold test[6] and the threshold test using pen-like odor dispensing devices.[7] 

Suprathreshold Tests of Olfaction

Suprathreshold tests use odor concentrations that are detectable by the patient. The most common suprathreshold tests used are odor identification tests such as the University of Pennsylvania Smell Identification Test (UPSIT) and the odor identification test with pen-like odor dispensing devices.[8][9] After written or visual answer options are presented to the patient, the patient sniffs an odor probe and is asked to choose an answer they think is right (= forced-choice procedure). The number of correct answers is recorded as the result of the test. Some of the odors presented are culturally specific and, therefore, must be validated and reliable to the respective population assessed.[5] Normative data are available for most of these tests, which allow percentile ranking regarding sex and age.[3][5] A different suprathreshold test is the odor discrimination test, such as the odor discrimination test with pen-like odor dispensing devices.[9] In these tests, different odorous probes are presented to the patient, and the patient is asked to memorize and distinguish different odors, but they do not have to name the odors presented specifically. Again, the number of correct answers is recorded as the result of the test. Suprathreshold odor tests are cognitively more challenging than odor threshold tests as they require executive functioning and semantic memory ability.[10]

Another variant of suprathreshold tests for olfaction is a test for the hedonic value of an odor.[3][5] These tests assess how pleasant or unpleasant an odor is perceived and thus involves emotional components. Tests for hedonic value are rarely applied in clinical practice.

Tests to Screen for Gustatory Abilities

Patients often report impairment of taste when they have an impairment of smell.[3][5] This is because volatiles from food can reach the olfactory receptors through the nasal pharynx and stimulate the olfactory receptors on the olfactory epithelium through this retronasal route. The odors of food are perceived as “taste,” although the gustatory ability is normal. Therefore, olfactory testing should include screening for gustatory functioning, such as liquids applied to the tongue or the taste strip test.[11][12] Typically, the probe is dropped or placed on the patient's tongue, and the patient is asked to answer if it tastes salty, sour, better, or sweet. The number of correct answers is recorded as the result of the test.

Subjective Olfactory Self-assessment

We do not always become aware of olfactory signals (or their absence) and their impact on our behavior.[3][5] Additionally, there is a poor correlation between subjective patient self-assessment and more objective measures of olfactory abilities.[1][13] However, if subjective reporting of olfactory ability is needed, for example, for epidemiological studies, a scale from zero (none) to ten (superb) may be used.[14]

Indications

Indications for olfactory testing include:

• Olfactory assessment is indicated when the patient reports on olfactory alterations.
• When the patient reports on impairment of taste and flavor but an impairment of olfaction is suspected, olfactory testing in addition to their gustatory abilities is indicated.
• Multicomponent olfactory testing may give additional information about the etiology of the olfactory decline.  
• Olfactory assessment is indicated when an olfactory decline is suspected, but the patient does not perceive deficits with olfaction.  

Potential Diagnosis

Olfactory Dysfunction Secondary to Sinonasal Disease

This is one of the most common causes of olfactory dysfunction and often caused by rhinosinusitis (acute: < 12 weeks versus chronic ≥ 12 weeks) with hyposmia or anosmia as an important symptom besides rhinal symptoms (such as nasal discharge, pressure-like pain in the face and nasal obstruction).[15][16] The olfactory decline occurs gradually and is not associated with parosmia.[17] ENT exam may reveal nasal polyps and inflammation of the mucosa of the nose. Olfactory testing typically shows diminished odor threshold and odor discrimination but normal odor identification.[2] In addition to the olfactory testing, computer tomography of the skull base and paranasal sinuses may help document polys and other alterations of the sinuses, which are not visible with the clinical examination.

Post-infectious Olfactory Dysfunction 

This is typically caused by (severe) upper respiratory tract infection by a virus, and it is one of the most common causes of olfactory decline. The onset of perceived loss of smell and possibly loss of flavor perception may occur somewhat suddenly. Patients often report on parosmia (perception of an odor when an odor’s stimulus is present, but the perception is distorted). As with olfactory dysfunction secondary to sinonasal disease, olfactory testing with post-infectious olfactory dysfunction shows diminished odor threshold but normal odor identification.[2] How upper respiratory tract infections cause olfactory decline is incompletely understood. It is most likely related to an impairment of the olfactory epithelium and replacement with respiratory epithelium.[18][3] Most subjects with COVID-19 infection-related decline of the chemical senses fall into this category.[4]

Posttraumatic Olfactory Dysfunction 

This may occur suddenly or with a delay after injury. Frequently patients describe phantosmia (perception of an odor when no odorous stimulus is present). Typically, olfactory tests show diminished odor threshold and odor discrimination ability, while odor identification is normal.[2] To rule out any brain, skull base, or nasal injuries that may require surgery, imaging is essential in managing the patient.[19]

Olfactory Dysfunction Associated With Neurological Disease

Several neurological disorders are associated with olfactory decline, and thus diminished sense of smell is not specific to a distinct neurological illness.[20] In neurological disorders, olfactory dysfunction is primarily characterized by diminished performance in suprathreshold tests, such as tests for odor identification and odor discrimination, while the odor threshold is normal. Also, the olfactory decline has a gradual onset, and there is no parosmia.[2] The two most common neurological diseases associated with olfactory decline are likely Alzheimer's disease and idiopathic Parkinson’s disease.[21][22] Besides olfactory testing, information from patient history and the physical exam are important to support these diagnoses. For instance, patients with idiopathic Parkinson’s disease typically have a history of constipation, REM-Sleep behavior disorder, and depression in addition to olfactory decline many years before the onset of motor deficits such as rigidity, bradykinesia, tremor, stooped posture, and diminished arm swing when walking.[23] Brain imaging with the radioactive tracer Loflupane 123 is typically abnormal in subjects with idiopathic Parkinson’s disease, with some degree of asymmetry.[24] Patients with Alzheimer dementia undergo a change in their personality (loss of interest), they can have difficulty keeping up with their daily routine and have cognitive decline such as losing one’s train of thought and word-finding impairment.[25] Furthermore, depression, as one of the most common psychiatric disorders, can also cause diminished olfactory functioning and need to be considered a differential diagnosis when clinically warranted.  

Olfactory Dysfunction Associated with Exposure to Drugs and Toxins

Several drugs and toxins can cause olfactory decline.[26][27][3] Such medications mainly fall in the category of anesthetics, antimicrobials, and antithyroid medication. Toxins that can cause a diminished sense of smell commonly include heavy metals, herbicides, solvents, and pesticides. Suspicion for this type of olfactory decline comes from patient history information, in particular work history and medications used. 

Congenital Olfactory Dysfunction 

This type of olfactory decline is present from birth and is severe. There is no parosmia. Besides olfactory testing, which typically reveals anosmia, information from neuroimaging is increasingly recognized as an important component in making the diagnosis.[3] For instance, magnetic resonance imaging in these patients commonly shows hypoplasia or aplasia of the olfactory bulb as well as shortening of the olfactory sulcus.[28][29] After making the diagnosis, patients should have a genetic and endocrine evaluation to assess the presence of diseases such as Kallmann syndrome and Turner syndrome, which commonly cause congenital olfactory dysfunction.[30][3][31]

Olfactory Dysfunction Associated with Aging 

As with other sensory modalities, the sense of smell decreases with age. For instance, while about one-fifth of the general population has diminished olfaction,[32] about two-thirds of individuals of age eighty and older have olfactory decline.[33] Age-associated onset is gradual, and there is no parosmia. In olfactory testing with psychophysical tests, it is important to compare findings in a given patient with normative values to see if the findings are below the age- and sex-matched normal range. There are multiple causes for this type of olfactory decline, such as reduced mucociliary activity, diminished blood flow in the mucosa, and reduced mucus production in the nose.[34] 

Other Disorders Associated With Olfactory Decline

Several different conditions can cause diminished olfaction. These may include:

• Tumors (of nose and brain)
• Surgery of nose, sinuses, and skull (such as septoplasty or surgery of the anterior skull base)
• Disorders of the endocrine system and metabolic disorders (such as thyroid disorders and diabetes mellitus)
• Metabolic disorders such as diabetes mellitus
• Vitamin deficiency (such as deficiency of vitamin B12) 
• Substance misuse (such as alcohol and cocaine)
• Nicotine use/tobacco use to some degree; however, this association is controversial.

Idiopathic olfactory dysfunction:

This diagnosis is made by carefully excluding all other causes of olfactory decline. Even though this diagnosis is the product of a comprehensive assessment, follow-up assessment with an interdisciplinary approach may be considered as the olfactory decline found could be an early sign of a neurodegenerative disorder such as Parkinson disease.[35]

Normal and Critical Findings

Quantitative Olfactory Function and Dysfunction

Normosmia: olfactory function is normal, compared to age- and sex-matched normative olfactory test values

Hyposmia: the score on olfactory tests is lower than the normal range, but the olfactory ability present is of some use for the patient in daily life (such as the ability to defect the fumes of fire and the odor of natural gas) 

Hyperosmia: olfactory ability falls abnormally above the normal range.      

Anosmia: no olfactory functioning is present 

Functional Anosmia: the score on olfactory tests falls markedly below the normal range, but the olfactory function of the patient is not useful for daily life.

Qualitative Olfactory Function and Dysfunction

Parosmia: the perception of an odor when an odor’s stimulus is present, but the perception is distorted (for instance, the odor of a rose is perceived as the sulfurous odor of a rotten egg). 

Phantosmia: the perception of an odor when no odorous stimulus is present (for instance, the perception of a flower fragrance but no odor stimulus such as a flower is present).

Cacosmia: when the perception of an unpleasant odor without the presence of an odor stimulus.

Interfering Factors

Suprathreshold olfactory tests such as tests for odor identification and odor discrimination require semantic and episodic memory.[10][36] Therefore, cognitive deficits in these domains interfere with suprathreshold olfactory testing. In contrast, odor threshold tests appear to be unrelated to cognitive factors.[10] Besides cognitive deficits, psychiatric illnesses such as depression and anxiety may impact the sense of smell.[37][38] Thus, in case of clinical suspicion for cognitive deficits and psychiatric illnesses, respective referrals should be considered.

Complications

There are no known complications of olfactory testing. However, the olfactory testing procedure may be experienced as tiring by patients as complete olfactory testing can take up to 30 minutes.

Following international guidelines, anterior rhinoscopy and nasal endoscopy should be done as part of the ENT evaluation to rule out intranasal pathology, potentially impeding the sense of smell.[3] The complications of these procedures have been reviewed before.[39]

Patient Safety and Education

The patient is instructed that the olfactory tests will measure the lowest concentration of an odor the patient can detect and how well the patient can identify and differentiate odors. Furthermore, the patient has informed the tests will most likely help identify the cause of the patient’s olfactory disturbance, which in turn can lead to a specific treatment. Moreover, the patient will be educated that with some olfactory tests, an odor will not be consciously perceptible, but they will always be asked to answer, even if it is a guess.

Clinical Significance

For several reasons, olfactory testing is of clinical significance.[3][5] First, olfactory testing gives a more objective measure of olfactory abilities. This is important as many patients are neither aware of the degree of their olfactory deficits. Second, many patients experience an olfactory decline as a diminished perception of flavor. Therefore, olfactory testing can explore if a patient is experiencing olfactory rather than gustatory decline. Third, olfactory testing with multicomponent tests including olfactory threshold testing and suprathreshold tests such as odor identification and odor discrimination can reveal a pattern of olfactory decline, which may help to delineate the etiology of the olfactory decline.[2] For instance, a disease that primarily affects the nose, such as sinonasal disease, negatively impacts odor threshold while suprathreshold test results are normal.

In contrast, diseases of the brain which affect olfaction, such as Parkinson’s disease, negatively impact performance on suprathreshold tests while the odor threshold is normal. Thus, besides history and a physical exam, olfactory testing can be fundamental in making a diagnosis and therefore leads to proper treatment. Finally, olfactory testing is easy to do.[40] Health care providers can learn the correct administration of olfactory testing in little time. The instructions to the patients are straightforward, and olfactory testing in the clinic is inexpensive and time-efficient.