key: cord-1032327-bagn59qc
authors: Saltagi, Abdul K.; Saltagi, Mohamad Z.; Nag, Amit K.; Wu, Arthur W.; Higgins, Thomas S.; Knisely, Anna; Ting, Jonathan Y.; Illing, Elisa A.
title: Diagnosis of Anosmia and Hyposmia: A Systematic Review
date: 2021-07-05
journal: Allergy Rhinol (Providence)
DOI: 10.1177/21526567211026568
sha: defc73c41bc3e59ece33cbb638fe6fb25f7d9bb2
doc_id: 1032327
cord_uid: bagn59qc

BACKGROUND: Anosmia and hyposmia have many etiologies, including trauma, chronic sinusitis, neoplasms, and respiratory viral infections such as rhinovirus and SARS-CoV-2. We aimed to systematically review the literature on the diagnostic evaluation of anosmia/hyposmia. METHODS: PubMed, EMBASE, and Cochrane databases were searched for articles published since January 1990 using terms combined with Medical Subject Headings (MeSH). We included articles evaluating diagnostic modalities for anosmia, written in the English language, used original data, and had two or more patients. RESULTS: A total of 2065 unique titles were returned upon the initial search. Of these, 226 abstracts were examined, yielding 27 full-text articles meeting inclusion criteria (Level of evidence ranging from 1 to 4; most level 2). The studies included a total of 13,577 patients. The most utilized diagnostic tools were orthonasal smell tests (such as the Sniffin’ Sticks and the UPSIT, along with validated abridged smell tests). Though various imaging modalities (including MRI and CT) were frequently mentioned in the workup of olfactory dysfunction, routine imaging was not used to primarily diagnose smell loss. CONCLUSION: The literature includes several studies on validity and reliability for various smell tests in diagnosing anosmia. Along with a thorough history and physical, validated orthonasal smell tests should be part of the workup of the patient with suspected olfactory dysfunction. The most widely studied modality was MRI, but criteria for the timing and sequence of imaging modalities was heterogenous.

The sense of smell has an enormous impact on a patient's quality of life, and olfactory dysfunction has been associated with alterations in appetite and mood. 1, 2 With increasing attention to smell disturbance as a symptom of SARS-CoV-2 infection, the medical community should be prepared to accurately diagnose olfactory dysfunction. To this end, focused history and physical exam are imperative, and ancillary tests such as smell tests [including orthonasal (smell through sniffing) 3 and retronasal (smell through eating/drinking) 3 ] and imaging (including CT and MRI) have been utilized in the past. However, numerous diagnostic tests exist, and there remains variability in the clinical diagnosis of anosmia and hyposmia.

To confirm suspected common etiologies of anosmia and hyposmia due to head trauma, chronic rhinosinusitis (CRS) with or without polyposis, congenital syndromes, or neoplasms, physicians have utilized computed tomography (CT) or magnetic resonance imaging (MRI) in the past. Alternatively, viral upper respiratory infection (URI) and idiopathic anosmia/hyposmia are diagnoses of exclusion after appropriate testing has been completed. 2, 4 Regardless of etiology, clinicians must be prepared to properly diagnose and manage patients with smell disturbance in everyday practice.

To this aim, we performed a systematic review of the literature focusing on diagnosis of anosmia and hyposmia in the clinical setting. Our goal was to identify which diagnostic modalities of olfactory dysfunction have the strongest evidence, and to provide guidance to clinicians for approaching anosmia, particularly in the current climate of increased prevalence secondary to COVID-19.

A systematic review of English-language published literature was conducted to investigate diagnosis of anosmia and hyposmia. Our study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and statement recommendations. 5 The following PICOS (Participants, Interventions, Comparisons, Outcomes, and Study Design) criteria were utilized: [Patients: those with hyposmia or anosmia; Intervention: established or novel diagnostic smell tests and imaging modalities; Comparison: assessing the validity/utilization of various smell tests and imaging modalities between anosmics and normosmics; Outcomes: classifying the severity of anosmia accurately for smell tests as well as determining common findings on imaging for anosmics; Setting: one retrospective study and numerous prospective cohort studies] On March 10th, 2020, we searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE databases for relevant publications, beginning after January 1990 through March 2020. We again performed the search on April 30th, 2020 to identify COVID-19-related articles on anosmia, which had been published since the March search. An electronic search strategy was utilized for each database. The search included combined key terms and exploded medical subject headings (MeSH), including: anosmia, hyposmia, smelling disorder, olfaction disorder, diagnosis, microbiology, prevention, disease management, drug therapy, drug administration, pharmacology, imaging, history, rehabilitation, statistics and numerical data, surgery, virology.

The articles utilized in this review were limited to those written in the English language that included original data. These articles included cohort studies, casecontrol studies, and pilot studies. Two members of the investigation team (A.N. and A.S.) independently reviewed the articles to include in this study. A third member of the team (M.S.) then reviewed the articles as well. The following inclusion criteria were applied: original data; English language; at least 2 patients included in the study; well-defined and measurable outcomes obtained; and published after January 1990. Studies with no measurable outcomes; review articles; articles with little relevance to our study aims; studies focused on chronic rhinosinusitis with or without polyposis; and all basic science, cadaver, and animal-model studies were excluded.

Data were extracted and reviewed independently. Any disagreement in inclusion or exclusion of articles was rereviewed for a consensus between investigators. Articles were then evaluated for time of study, etiology of smell loss, number of patients, age of patients, and diagnostic modality used. The level of evidence was then assigned based on the published guidelines by the Oxford Centre for Evidence-based Medicine, Levels of Evidence. 6 

Risk of bias was assigned by evaluating each individual paper for its methodology and outcomes. Nonrandomized studies were assigned a risk of bias: "low", "moderate", "serious", or "critical", based on the ROBINS-I Cochrane risk of bias tool. 7

Due to the heterogenous nature of outcome measurements in studies meeting inclusion criteria and underpowered diagnostic modality groups, quantitative analysis was not possible per our statistician.

The article selection process is illustrated in Figure 1 . A total of 2065 unique titles were returned upon initial search, after which 226 abstracts were selected and examined, yielding 33 full-text articles for review and ultimately 27 articles that met inclusion criteria ( Figure 1) . 24 studies were level II evidence, and the other 3 studies were level I, III, and IV, respectively. The studies included a total of 13,577 patients (Table 1) . Endpoints were based on diagnostic test findings among anosmic/hyposmic patients. Diagnostic methods discussed in the studies included Orthonasal smell tests, [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] Retronasal smell tests, 19, 20 Olfactory Event Related Potentials (OERP), 21, 22 Functional MRI (fMRI), [23] [24] [25] 19, [26] [27] [28] [29] Single-Photon Emission CT (SPECT), [29] [30] [31] [32] CT, 32 and Positron Emission Tomography (PET) Scans 33, 34 (Table 1) . Per the exclusion criteria, any diagnostic studies focusing strictly on CRS were excluded.

Orthonasal smell tests with cutoffs. A total of 11 studies using orthonasal smell tests [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] were included, totaling 12,257 patients (Table 1) . 7/11 studies specified cutoffs differentiating normosmia from hyposmia. [8] [9] [10] [11] [12] [13] [14] Among these, Lotsch et al. 8 reported that cinnamon, banana, and fish odors provided enough specificity and sensitivity (84.3% and 80.4%, respectively) to establish normal olfactory function compared to Sniffin' Sticks (SS) ( Table 1) . Jackman et al. 9 similarly reported findings comparing the Q-SIT, a 3-item smell test, to the University of Pennsylvania Smell Identification Test (UPSIT) (Table 1) . Similarly, Takebayashi et al. 10 found a positive correlation between the scores of the Self-Administered Odor Questionnaire (SAOQ) and the well-established Visual Analogue Scale (VAS) ( Table 1) . Tsukatani et al. 11 compared the Connecticut Chemosensory Clinical Research Center (CCCRC) test and the Jet Stream Olfactometer (JSO) and found a significant correlation between them for detection threshold and identification and recognition scores (P < .01). Welge-Lussen et al. 12 found a significant difference in threshold detection identification (TDI) score in 23.4% of anosmics between the right and left nostrils when using SS (Table 1) . Oleszkiewicz et al. 13 investigated the relationship between SS scores and age, concluding that overal TDI score decreases most between 61-70 years (Table 1) . Poletti et al. 14 correlated SS TDI scores with the Olfactory Cleft-Specific Lund-Kennedy (OC-LK) score among various etiologies of anosmia and found that post-traumatic anosmics had the lowest TDI scores, and as a group overall, anosmic patients had higher OC-LK scores when compared to normosmics (Table 1) .

Orthonasal smell tests without cutoffs. Four orthonasal smell test studies did not specify cutoffs. [15] [16] [17] [18] Kobal et al. 15 performed a "random" test consisting of varying concentrations of rose and citrus and found a correlation with TDI (SS) (r ¼ .82) ( Table 1) . Villwock et al. 16 compared a novel smell test, AROMA, with UPSIT and SNOT-22 and found significant correlations between them. Robson et al. 17 used a butanol threshold smell test and found that anosmic patients had significantly lower scores than normosmics. Davidson and Murphy 18 developed a smell test with 70% isopropyl alcohol in which the distance where a subject first identifies the odor is measured, and found significantly lower scores for anosmic patients (Table 1) .

Retronasal smell tests. Two studies using retronasal smell tests 19, 20 were included, totaling 211 patients. Rombaux et al. 19 found that post-infectious (PI), post-traumatic (PT), and nasal polyposis (NP) anosmic patients had significantly lower retronasal smell test scores than normosmics (P < .001), with PI and PT patients scoring worse than NP patients (P < .001). Haxel et al. 20 compared the novel Candy Smell Test (CST) to SS and found a significant correlation between the two, defining anosmia as <13/23 and hyposmia as (13-16)/23 on CST (Table 1) .

Olfactory event related potentials (OERP). Two studies investigated OERP detection 21, 22 in patients with various etiologies of anosmia/hyposmia. Lotsch and Hummel 21 found that OERP can be used to detect existing olfactory function, but is not very effective in diagnosing anosmia/hyposmia (Table 1 ). Rombaux et al. 22 found that OERPs were recorded in 22/33 hyposmic patients and 0/32 anosmic patients, indicating it can be used to screen for anosmia but is not effective for determining a definitive diagnosis.

Functional MRI. Three studies (83 patients) investigated fMRI [23] [24] [25] findings in patients with known olfactory dysfunction. Levy el al 23,24 measured brain activation in response to amyl acetate, menthone, and pyridine, reporting reduced activation in orbitofrontal, middle frontal, inferior frontal, and temporal cortices in hyposmics relative to normosmics (Table 1) . Moon et al. 25 reported reduced activation in bilateral primary and secondary olfactory cortices in post-traumatic anosmics ( Table 1) .

Magnetic resonance imaging. Five studies (365 patients) utilized conventional MRI 19, [26] [27] [28] [29] to evaluate findings among known anosmics/hyposmics. Hoekman et al. 26 investigated the feasibility of MRI as a diagnostic tool for anosmia and reported that only 4.6% of MRIs were abnormal in patients with idiopathic olfactory loss, concluding that MRI is not cost-effective in diagnosing anosmia (Table 1 ). Goektas et al. 27 found a significant correlation between objective (Chemosensory evoked potentials), but not subjective (Sniffin' Sticks), olfactometry and olfactory bulb volume on MRI. Further, this suggests that trauma affects olfactory filaments and thus decreases olfactory bulb volume, while virus-induced olfactory dysfunction is associated with damage to olfactory epithelium, in particular olfactory mucosa, and does not result in loss of olfactory bulb volume (Table 1) . Lotsch et al. 28 analyzed brain lesion patterns in post-traumatic anosmics and found that, when compared to normosmics, these patients tended to have lesions in the right olfactory bulb region. Rombaux et al. 19 found that olfactory bulb volumes were higher in normosmics when compared to nasal polyposis, post-trauma, and post-infectious anosmics (P < .001). Atighechi et al. 29 found that 86% of post-traumatic anosmic patients had abnormal MRIs, of which 71.4% entailed frontal lobe abnormalities (Table 1) .

SPECT/CT. Four studies used SPECT, [29] [30] [31] [32] one of which also used CT, 32 totaling 123 patients. Atighechi et al. 29 found that SPECT identified abnormalities (typically frontal hypoperfusion) in over 80% of posttraumatic anosmics (Table 1) . Eftekhari et al. 30 corroborated these findings. Varney et al. 31 found significantly lower count ratios in post-traumatic anosmics in the orbital frontal cortex when compared to normosmics. Shiga et al. 32 used SPECT and CT to evaluate migration of nasal thallium to the olfactory bulb, and found that olfactory-impaired patients had significantly lower migration when compared to normosmics (Table 1) .

PET scans. Two studies used PET 33, 34 to observe differences among olfactory impaired patients, totaling 40 patients. Kim et al. 33 found significant hypometabolism in the right piriform gyrus and parahippocampus among post-viral anosmic patients. Varney et al. 34 found decreased metabolic activity in the bilateral orbitofrontal cortices, rectal gyrus, and frontal pole in posttraumatic anosmics when compared to normosmics ( Table 1) .

Among the studies in this systematic review, 14 had a low risk of bias, 10 had a moderate risk of bias, and 3 had a serious risk of bias.

Olfactory dysfunction has profound effects on quality of life, impacting both the ability to experience reward related to smell and the ability to detect potentially harmful odors and substances. 35, 36 This dysfunction can range from a slightly diminished sense of smell (hyposmia) to a complete loss of smell (anosmia). 37 Smell dysfunction has numerous etiologies, including viral infections, trauma, obstruction, CRS, and idiopathic causes. 37 Notably, the SARS-CoV-2 pandemic has been shown to cause olfactory dysfunction in patients who might otherwise be asymptomatic, 38, 39 highlighting the crucial need for clinicians to be able to properly diagnose and manage individuals with smell disturbance.

Based on this systematic review, orthonasal smell tests (such as Sniffin' Sticks and UPSIT) should be utilized as an initial diagnostic tool for smell dysfunction. 8, [12] [13] [14] [15] 20 UPSIT, the most widely-used diagnostic smell test, entails presenting 40 odors in a forced multiple-choice manner (scored up to 40); a score <18 is consistent with anosmia, whereas >33 in men or >34 in women is considered normosmia, with varying levels of microsmia in between. 40 SS involves utilizing 12 smells to produce a TDI score, encompassing odor threshold, discrimination, and identification 13 ; a score of 31 or greater indicates normal olfactory function, while <16 indicates anosmia, with anything in between being hyposmia. 13 Although SS and UPSIT are widelyused and validated tests, they are often considered tedious. In light of this, providers may consider utilizing more efficient tests, such as those presenting odors in randomized order, 15 or tests presenting a limited subset of odors, 8, 9 which have been utilized with comparable results to SS and/or UPSIT (Table 1) .

Of note, Landis et al. 3 determined that patients with smell loss, without a loss of taste, have diminished orthonasal olfaction but intact retronasal olfaction, indicating that orthonasal and retronasal olfaction might be processed differently. Thus, retronasal smell tests are an important method to consider when diagnosing anosmia or hyposmia if orthonasal smell tests do not fully explain the patient's clinical picture.

In addition to diagnostic smell tests, imaging has been used to investigate findings among patients with smell disturbance, but imaging is not commonly used as a primary diagnostic tool. The most widely used imaging modality is MRI, including both traditional and fMRI. 19, [23] [24] [25] [26] [27] [28] [29] Other imaging modalities include SPECT and PET, [29] [30] [31] [32] [33] [34] however mostly in academic settings and not in routine use, and findings among studied patients are detailed in Table 1 . Overall, the most common finding in anosmics and hyposmics, across multiple imaging modalities was abnormality within the orbitofrontal region. When excluding control patients, this was present in 29/45 subjects in the fMRI studies, 23-25 92/351 conventional MRI subjects, 19,26-29 34/55 SPECT subjects, 29-32 and 11/20 PET subjects 33, 34 (Table 1 ). The orbitofrontal cortex is known to be involved in the conscious perception and processing of smell, and lesions here have been linked to anosmia. 41 Trauma is a very common cause of lesions to the orbitofrontal region and may explain the loss of smell in these individuals. 41 An important study included in this systematic review discusses the cost-effectiveness and feasibility of using MRI to diagnose idiopathic anosmia/hyposmia. 26 Among 130 patients who underwent MRI, only six MRIs were considered abnormal, only one of which could potentially explain anosmia. Assuming an average MRI cost of $2500, the authors determined that the expense associated with identifying a single abnormality potentially explaining anosmia on MRI is $3,25,000 (Table 1) . It is important to note, however, that all patients in the study had an idiopathic etiology of olfactory loss, which could explain why the MRI results of this study vary widely from the other imaging studies included in this systematic review.

Based on the most feasible and reliable diagnostic tools reviewed in this paper, we propose an algorithm that can assist the clinician in working up the patient with suspected anosmia/hyposmia (Figure 2 ). In the current climate, screening for symptoms of COVID-19 should be considered given this has been identified as an early marker for disease. 37 For patients with concern for COVID-19 infection, referral for testing is prudent prior to in-office evaluation, if possible. For all patients, appropriate personal protective equipment precautions should be followed. [42] [43] [44] Then, in order to determine the etiology of olfactory loss, a detailed history and physical examination should be performed. Patients with a sudden onset of olfactory loss are typically those with post-viral or post-traumatic etiologies, although posttraumatic anosmia can present a few weeks after the incident. 37 We suggest patients should be evaluated using a well-established diagnostic orthonasal smell tests such as SS or UPSIT, if available, prior to any topical nasal medications or manipulation. Alternatively, a clinician may choose among the less time-consuming validated methods discussed, such as the three odors determined by Lotsch et al. 8 or the Q-SIT. 9 If possible, these smell tests should be performed individually for each nostril to rule out lateralized dysfunction. 12 Next, as part of the physical exam, nasal endoscopy should be performed to rule out an obstructive anatomic/pathologic cause of anosmia. 37 Following these diagnostic measures, fMRI or SPECT may be considered if there is post-traumatic etiology to localize the abnormality, though it is unclear if findings on either imaging modality would change clinical management. This systematic review did not find that benign or malignant tumors were a significant finding in patients with reduced sense of smell, which brings into question whether imaging is necessary for routine workup of isolated reduced smell without other neurologic or rhinologic symptoms. Based on the evidence available, this review does not support the routine use of imaging in working up smell disturbance.

There are a few limitations of this systematic review. First, we excluded papers solely focusing on CRS-related anosmia. Given the large body of literature available on CRS, we felt it prudent to concentrate on post-infectious and post-traumatic etiologies and evaluate these independently. Additionally, due to the varying studies using different methods to diagnose anosmia, a metaanalysis on the data was unable to be performed. In addition, many of the studies included had small sample sizes and very specific populations, which may limit generalizability of the study. Furthermore, many of the imaging studies in this systematic review focused on post-traumatic anosmia, which presents with different imaging findings than the other etiologies of olfactory dysfunction. This limits our ability to draw definitive and broad conclusions on the role of imaging in working up smell dysfunction. Finally, many of the imaging studies included were not necessarily diagnostic, as the patients had already been diagnosed with olfactory dysfunction, and the imaging was subsequently performed for characterizing imaging findings or ruling out intracranial neoplasms.

The literature on the diagnosis of anosmia and hyposmia includes diagnostic smell tests and imaging modalities. A thorough history and physical, followed by orthonasal smell tests such as SS or UPSIT should be used as a firstline method to diagnose anosmia, although validated abridged smell tests may be used as well. Although imaging modalities can be used to investigate olfactory dysfunction, their feasibility is questionable and is not cost-effective in the patient without suspicion for underlying mass or neurological disorder. One potential benefit for using imaging modalities includes localizing an abnormality, which can then potentially lead to better prognostic accuracy or guidance on potential future treatments such as olfactory epithelium transplantation or electronic olfactory implant. 45 Further study is needed on these topics.

This article does not contain any studies with human or animal subjects.

There are no human subjects in this article and informed consent is not applicable.

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Thanks to George Eckert, MAS (Indiana University-Purdue University Indianapolis -Department of Biostatistics) for assistance with data analysis and biostatistics.

This study was deemed exempt by our institutional review boards. 

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.