key: cord-0967492-b17kgos0
authors: Green, Barry G
title: Surveying Chemosensory Dysfunction in COVID-19
date: 2020-09-26
journal: Chem Senses
DOI: 10.1093/chemse/bjaa048
sha: 8ea1426be8d6819c1aacb8e9672a8f12662f9e69
doc_id: 967492
cord_uid: b17kgos0

Soon after the outbreak of COVID-19, reports that smell and taste are disrupted by the illness drew the attention of chemosensory scientists and clinicians throughout the world. While other upper respiratory viruses are known to produce such disruptions, their occurrence with the deadly and highly infectious SARS-CoV-2 virus raised new questions about the nature of the deficits, their cause, and whether they might serve as indicators of the onset of the disease. Published in the July and August 2020 issues of Chemical Senses are 2 innovative, large-scale survey studies that were quickly devised and launched by separate multinational groups to address these questions in olfaction, taste, and chemesthesis. The surveys, which took different approaches and had somewhat different goals, add significant new data on the incidence and severity of smell loss in COVID-19, and the potential for olfactory dysfunction to serve as an indicator of the spread and severity of the disease. Less definitive evidence of the frequency, characteristics, and magnitude of disruptions in taste and chemesthesis point to the need for future survey studies that combine and refine the strengths of the present ones, as well as clinical studies designed to selectively measure deficits in all 3 chemosensory systems.

Since reports began to appear in March of this year that COVID-19 is accompanied by smell and taste loss, numerous papers that address this phenomenon have been published or prepublished (see Pellegrino et al. 2020 in the July issue of Chemical Senses for a comprehensive review). The lack of wide-spread testing for the highly infectious and deadly SARS-CoV-2 virus in much of the world led scientists and clinicians to focus urgently on smell and taste deficits as possible early indicators of COVID-19 and to gain insight into how the virus enters the body in the upper airway (Mainland et al. 2020; Xu et al. 2020; Zou et al. 2020) . In their review, Pellegrino et al. (2020) point to the need for studies to provide 1) better quantification of the occurrence of the dysfunctions, 2) improved understanding of the relationship among dysfunctions of olfaction, taste, and chemesthesis, the 3 chemosensitive systems that serve the nose and mouth, and 3) to determine the persistence of the chemosensory losses following recovery from COVID-19.

The first 2 of these questions were recently addressed in 2 innovative and ambitious survey studies published in this journal: In the July issue of Chemical Senses, Iravani et al. (2020) reported the results of an online survey conducted in Sweden that targeted the effects of the disease on olfactory and nasal trigeminal function using in-home ratings of the odors of common household items. In this issue of the journal, Parma et al. (2020) report preliminary results from an online, first-of-its-kind worldwide survey of the self-assessed effects of COVID-19 on smell, taste, and oral chemesthesis.

The Parma et al. (2020) survey was devised by the Global Consortium for Chemosensory Research (GCCR), an international group of hundreds of chemosensory scientists and clinicians from at least 56 countries that joined together in March 2020 to investigate the early reports of smell and taste dysfunctions in COVID-19. Members of GCCR quickly designed an online survey that was launched in 10 languages, creating an unprecedented opportunity to rapidly collect data on the effects of COVID-19 on chemosensory perception experienced throughout much of the world. Without the ability to conduct direct psychophysical measurements on chemosensory perception, the authors devised a clever strategy in which respondents were asked to make 2 separate ratings of their "ability to smell" everyday odors (e.g., flowers, soap, or garbage) before versus during COVID-19. The 2 retrospective ratings enabled calculation of a difference score reflecting the mean change in perceived olfactory ability during the illness. In just the first 11 days of the survey, data from 4039 respondents diagnosed with COVID-19 by lab test or clinical assessment reported a mean difference in the ability to smell of −79.1 points on a scale of 0-100 (SD ±28.7). While the ultimate sensitivity and reliability of such judgments are uncertain, the large magnitude of the difference score definitively supports prior evidence of significant olfactory dysfunction obtained in smaller studies (e.g., Eliezer et al. 2020; Vaira et al. 2020) . Also in agreement with other studies, the perceived difference in the ability to smell could not be explained by ratings of nasal congestion. Impairment in the ability to taste (defined in the survey as sweetness, sourness, saltiness, and bitterness "experienced in the mouth") was calculated in the same subjective manner and also yielded a large difference score (−69.0 ± 32.6), which is also consistent with other reports of significant taste loss in COVID-19 (see Pellegrino et al. 2020) . However, reports of deficits in taste based only on retrospective report can be difficult to interpret when olfactory dysfunction is also present. In such cases lower ratings of the ability to taste may reflect, in part or in whole, reductions in the perceptual referral of odors to the mouth that occurs in flavor perception (e.g., Rozin 1982; Stevenson et al. 1999; Lim and Johnson 2012; Fondberg et al. 2018 ). Nevertheless it is notable that the most frequently reported taste deficit was saltiness, which unlike sweetness and sourness is not a perceptual quality commonly that is commonly attributed to odors. This suggests the instructions to respondents to consider specific taste qualities (e.g., sweet, salty, sour, and bitter) when rating the ability to taste may have reduced odor-taste confusions. However, the authors point out that more research is necessary to confidently interpret the apparent deficits in taste.

Similarly, while the ability to perceive chemesthetic sensations in the mouth (defined in the survey as "other sensations in your mouth, like burning, cooling, or tingling") was rated lower during COVID-19, the results are difficult to interpret. First, the rated reduction in oral chemesthesis (−37.3 ± 36.2) was much less than reductions in olfaction and taste, and the variance in ratings was proportionally much higher. A cluster analysis that grouped respondents according to reported changes in smell, taste, and oral chemesthesis further showed that only 13.5% (N = 548) fell into a cluster reporting "substantial" loss of oral chemesthesis. Second, it is unclear why nasal chemesthesis was not studied instead of (or together with) oral chemesthesis. While the presence of angiotensin-converting enzyme II, a likely cell receptor of the SARS-CoV-2 virus, in the oral epithelium (Xu et al. 2020) indicates the possible presence of the virus, the virus itself has been found in abundance in olfactory and upper airway epithelial cells (Sungnak et al. 2020; Zou et al. 2020) .

Taking a different but equally innovative approach, the survey by Iravani et al. (2020) was designed to determine if chemosensory data collected online could be used to make inferences about the prevalence and severity of COVID-19 in the general population. The authors invited Swedish respondents who either did or did not have symptoms of COVID-19 to assess their odor perception by sniffing 5 items chosen from lists of food, spice, and personal care items commonly found in the home. Data collected over a 5-day period in April 2020 (N = 2440) showed that mean odor intensity ratings of the 5 items decreased over time. The authors then compared their data with a model of the predicted prevalence of COVID-19 in the Stockholm area created by the Public Health Agency of Sweden and found that the decline in odor intensity ratings closely tracked the predicted level of COVID-19 in the population, supporting the idea that changes in olfactory perception can be used to predict the spread of the disease. By also collecting data on symptoms of COVID-19, the authors further showed that rated olfactory intensity varied inversely with the number of symptoms reported, suggesting that olfactory deficits detected by their survey method can also be used to infer the severity of the disease. In addition, because survey respondents could use a unique password to log onto the website over several days, the authors were also able to assess changes in odor ratings over time. Data from 107 individuals who made ratings over multiple days, and who also transitioned from reporting no symptoms to reporting 1 or more symptoms, showed that odor intensity was rated significantly higher in the first session with symptoms than in the last session without symptoms. Because the average time between the 2 sessions was 1.82 days, the data suggest that olfactory function began to decline at or soon after the onset of COVID-19 symptoms. This finding is generally consistent with data collected in a telephone survey of COVID-19 patients (N = 202) in Italy who were asked retrospectively about the onset of smell and taste disorders (Spinato et al. 2020) . Of the 124 individuals in that survey who experienced more than 1 COVID-19 symptom, 70 (56.5%) reported smell or taste loss was either the first symptom or appeared concomitant with other symptoms. On the other hand, the Iravani et al. results are not consistent with the results of a survey of COVID-19 patients in European hospitals (N = 417), which found that 65.7% reported olfactory dysfunction occurred after the appearance of "general ENT symptoms" (Lechien et al. 2020) . Thus, still more data are needed to establish whether olfactory changes are any more reliable than other symptoms as an indicator of the onset of the disease.

Finally, Iravani et al. (2020) investigated possible changes in chemesthetic perception by including on their list of household items "bimodal odors" (e.g., vinegar, chopped onion, and mint tea) which are expected to also stimulate the trigeminal nerve. Separate analyses of the intensity ratings of bimodal and unimodal olfactory items showed that they both varied inversely with predicted COVID-19 levels, implying that COVID-19 may disrupt both nasal chemesthesis and olfaction. This possibility is consistent with prior studies that have found nasal trigeminal sensitivity is generally reduced in individuals with smell loss from upper respiratory infections and other causes (Hummel et al. 1996; Frasnelli et al. 2007; de Haro-Licer et al. 2013) . Although testing with bimodal stimuli that evoke both smell and chemesthetic sensations is not ideal for determining the specific effects of COVID-19 on nasal chemesthesis, the study adds to the evidence that the disease can affect nasal chemesthesis. But because chemesthesis arises from a variety of somatosensory receptors and neural pathways that encode temperature, touch, and pain (Bandell et al. 2007; Roper 2014) , it is questionable whether COVID-19 (or any single virus) would affect all of the receptors and central pathways equally. However, it has been proposed that impairment of nasal trigeminal perception with anosmia may occur indirectly via central neural interactions between the 2 systems (Frasnelli et al. 2007 ). To resolve this question will require testing with unimodal chemesthetic stimuli such as menthol, capsaicin, and CO 2 that are known to stimulate specific receptors, which would be challenging to achieve in a large survey study.

In summary, these 2 trail-blazing studies demonstrate the power of online surveys to rapidly assess chemosensory dysfunction associated with COVID-19 on regional and global scales, and to estimate the prevalence and severity of the disease in a population. By incorporating a strategy for chemosensory testing similar to that used by Iravani et al. (2020) with the global reach achieved by Parma et al. (2020) , future surveys would have the potential to obtain definitive data on the scope and timing of the effects of the virus on human olfaction. The 2 studies also point to the need for additional smaller scale studies which use test stimuli that are differentially selective for olfaction, taste, and chemesthesis. By further clarifying the chemosensory dysfunctions the virus can cause, such studies will provide data relevant to understanding the mechanism or mechanisms that underlie the dysfunctions.

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