key: cord-0815440-j9b33iwk
authors: Bussiere, N.; Mei, J.; Levesque-Boissonneault, C.; Blais, M.; Carazo, S.; Gros-Louis, F.; De Serres, G.; Dupre, N.; Frasnelli, J.
title: COVID-19 Has Long Term Effects on Chemosensory Functions
date: 2021-07-01
journal: nan
DOI: 10.1101/2021.06.28.21259639
sha: e347ad8721fe4f7817145303df24d60d794173ae
doc_id: 815440
cord_uid: j9b33iwk

Importance: A number of studies have revealed either self-reported chemosensory alterations in large groups or objective quantified chemosensory impairments in smaller populations of patients diagnosed with COVID-19. However, due to the great variability in published results regarding COVID-19-induced chemosensory impairments and their follow-up, prognosis for chemosensory functions in patients with such complaints remains unclear. Objective: To describe the various chemosensory alterations associated with COVID-19 and their prevalence and evolution at 3 to 7 months after infection. Design, Setting, and Participants: A follow-up study of 704 health care workers with a RT-PCR confirmed SARS-CoV-2 infection between 28/2/2020 and 14/6/2020 was conducted 3 to 7 months after onset of symptoms. Data were collected with an online questionnaire. Participant had to be [≥]18 years old without respiratory illness in the 2 weeks prior to questionnaire completion. Main outcomes and measures: Outcomes included differences in reported chemosensory self-assessment of olfactory, gustatory, and trigeminal functions across time points and Chemosensory Perception Test scores from an easy-to-use at-home self-administered chemosensory test. Results: Among the 704 health care worker participants, 593 (84.2%) were women, the mean (SD) age was 42 (12) years and the questionnaire was answered on average 4.8 (0.8) months after COVID-19. During COVID-19, a decrease in olfactory, gustatory, and trigeminal sensitivities were reported by 81.3%, 81.5% and 48.0% respectively. Three to seven months later, reduced sensitivity was still reported by 52.0%, 41.9% and 23.3% respectively. Chemosensory Perception Test scores indicate that 19.5% of participants had objective olfactory impairment. Conclusions and relevance: A significant proportion of COVID-19 cases have persistent chemosensory impairments at 3 to 7 months after their infection but the majority of those who had completely lost their olfactory, gustatory and trigeminal sensitivity have improved. Given the possible neurological underpinnings of this observation and the important number of individuals infected with SARS-CoV-2, further longitudinal studies are needed to better characterize this phenotype and to report eventual post-COVID-19 neurological sequelae.

Coronavirus disease-2019 (COVID- 19) is an ongoing major public health challenge. Olfactory dysfunction (OD) is a specific symptom that may affect approximately 60% of patients suffering from COVID-19 1-3 , and is now considered as a stronger indicator of COVID-19 than fever, cough and shortness of breath 4 .

Investigation of the long-term effects of COVID-19 on chemosensory function is hindered by the recent onset of the pandemic and other challenges: First, many studies include a relatively small number of participants 5, 6 or participants with severe forms of COVID-19 7, 8 .

Secondly, many studies include participants with an unclear diagnosis of COVID-19, and/or selfdiagnosis 9, 10 . Lastly, while individuals with anosmia can usually evaluate their olfactory function with accuracy 11 , this self-assessment is often challenging for individuals with intermediate forms of OD (e.g., hyposmia) 12 .

OD can be quantitative or qualitative. Quantitative OD defines a reduction of olfactory sensitivity which can be either a complete (anosmia) or a partial (hyposmia) loss of olfactory function 13 . Qualitative OD describes an altered perception of olfactory stimuli, such as parosmia, the perception of qualitatively altered smells, or phantosmia, the perception of a smell in the absence of an objective odorant 13, 14 . Overall, the prevalence of OD in the general population is around 20% 15, 16 , and all different forms of OD are associated with reduced quality of life and increased risk of depression and anxiety 17 . In addition to OD, COVID-19 also appears to affect other chemosensory functions, i.e. gustatory and trigeminal perception 9, 18 .

To comprehensively understand long-term olfactory, gustatory, and trigeminal alterations after COVID-19, we analyzed questionnaire responses from a cohort of health care workers infected with SARS-CoV-2 during the first wave of the pandemic (February -June 2020). We . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 1, 2021. ; https://doi.org/10.1101/2021.06.28.21259639 doi: medRxiv preprint also developed a Chemosensory Perception Test (CPT), a formal test employing common household odorants and tastants, to enable accessible yet accurate self-evaluation of chemosensory functions.

This study was reviewed and approved by the research ethics board of the CHU de Québec -Université Laval (MP-20-2021-5228) and all protocols were reviewed by an independent Scientific Review Committee. All participants provided an online informed consent prior to participation. The study received funding from the Fonds de recherche du Québec-Santé. No compensation or incentive was offered for participation. Data were collected from August 11 to October 29, 2020. Up to four attempts were made to reach by email potential participants. At the time of data collection, participants were 3-7 months after the onset of COVID-19 symptoms.

Participants were recruited from a Quebec health care worker cohort who have had SARS-CoV-2 infection between 28/2/2020 and 14/6/2020. They were part of a study from the Institut National de Santé Publique du Québec and had agreed to be contacted for other research projects 19 . Inclusion criteria were (1) RT-PCR confirmed COVID-19 (2) above 18 years of age,

(3) French or English speakers, (4) completed the online questionnaire, and (5) did not report of other respiratory diseases (bacterial or viral infection, or/and allergies with rhinorrhea) within 2 weeks prior to questionnaire completion or chronic sinusitis.

All participants were asked to complete an online questionnaire which was adapted from the core questionnaire of the Global Consortium on Chemosensory Research 9 .

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The copyright holder for this preprint this version posted July 1, 2021. ; https://doi.org/10.1101/2021.06.28.21259639 doi: medRxiv preprint Demographic information: In the first part of the questionnaire, demographic information was collected from all participants. Participants were then instructed to provide medical history and indicate the presence of specific COVID-19 symptoms ( Figure S1 ).

Chemosensory self-assessment: Participants were asked to self-evaluate and report their olfactory, gustatory, and trigeminal sensitivity using a 10-point visual analog scale (VAS; Figure   S1 ) for three timepoints: (1) before SARS-CoV-2 infection, (2) during SARS-CoV-2 infection and (3) at questionnaire completion. Further, information on the presence of parosmia or phantosmia following the infection 20 and alterations in the 5 tastes (sweet, salty, sour, bitter, umami) was collected.

Chemosensory Perception Test (CPT): Items commonly found in North American households were used to assess participants' olfactory and gustatory functions, as odor intensity is the best single predictor to classify individuals with normosmia 21 . Participants had to smell three substances (peanut butter, jam/jelly, and coffee) and rate odor intensity on a 10-point VAS (0: no smell at all; 10: very strong smell). We obtained olfactory scores by averaging these ratings. Pilot data on a total of 93 participants show these scores to be correlated with the established UPSIT (r=0.377; P=0.004) and to accurately detect OD when compared to the Sniffin' Sticks (cut-off score: 6; sensitivity: 0.765; specificity: 0.895; Supplement 3). Participants were asked to prepare saline and sweet water by dissolving respectively a teaspoon of salt or 3 teaspoons of sugar in a cup (250 mL) of lukewarm water. Then, they were asked to taste saline and sweet water and to rate taste intensities on a 10-point VAS. We obtained gustatory scores by averaging these ratings.

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The copyright holder for this preprint this version posted July 1, 2021. Friedman's test was followed by Dunn's post-hoc test to correct for multiple comparisons. To assess the correlation between self-reported olfactory, gustatory, and trigeminal abilities and results of the CPT, Pearson correlation coefficient or Spearman's rank correlation coefficient was used. For all statistical tests, alpha was set at 0.05. All results are expressed as mean (SD) unless otherwise specified.

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The copyright holder for this preprint this version posted July 1, 2021. ; https://doi.org/10.1101/2021.06.28.21259639 doi: medRxiv preprint Results:

A total of 704 health care workers (593(84.2%) women, mean age of 42.0 (SD:11.7, range 18 -70) years were included. The questionnaire was completed on average 4.8 (SD: 0.8, range 3-7) months after symptoms onset. COVID-19 symptoms reported by the 704 participants are listed in supplementary materials (Supplement 2).

Before COVID-19, average self-reported score was 9.0 (1.6), 9.2 (1.3) and 8.9 (1.9) of 10 for olfaction, gustation and trigeminal function, respectively. Among participants, 0.9%, 0.7% and 1.8% respectively reported an absence of olfaction, gustation and trigeminal function (score 0; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 1, 2021. Figure 2B ) and gender (F(1, 701)=9.80, P=.002, ! " =0.014; women<men), but no effect of age. We also observed significant interactions of time*age (F(2, 1402))=5.97, P=.005, ! " =0.008) and time*gender (F(2, 1402))=20.02 , P<.001, ! " =0.028).

With regards to trigeminal function, we observed significant main effects of time (F(2,1402)=3.91, P=.020, ! " =0.006; during<after<before; all P<.001; Figure 2C ), and age ((1,701)=5.08, P=.025, ! " =0.007) but no effect of gender. We also identified significant . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Among included participants, 78 (11.1%) reported parosmia, 73 (10.4%) experienced phantosmia and/or 82 (11.6%) had waxing and waning of olfaction following infection. In addition, 42 (6.0%) claimed that they experienced other forms of OD (hyposmia to specific substances, hyperosmia, parosmia only at high concentrations or slow identification times).

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This study reports chemosensory dysfunction 3 to 7 months following SARS-CoV-2 infection in a large cohort of RT-PCR-confirmed health care workers. In addition to confirming the now well-established detrimental effect of acute COVID-19 on all three chemosensory systems (olfactory, gustatory, trigeminal), our major findings are: (1) the detrimental effect of COVID-19 lasts beyond the acute phase after the infection, half of those affected indicated that olfactory function had not returned to the baseline levels 3 to 7 months later, while 20% of infected participants reported scores in a formal test that are consistent with the presentation of hyposmia/anosmia; (2) approximately 10% of the patients exhibit parosmia and/or phantosmia;

(3) women are more heavily affected than men.

We observed chemosensory dysfunction in the acute phase of COVID-19, which was most pronounced for olfactory function, but less so for gustatory function and even less for trigeminal function. The proportion of participants describing OD and GD in the acute phase of COVID-19 in this study was comparable to earlier studies 23 . Nevertheless, on average 4.8 months after infection and thus well after the acute phase, approximately 50% and 40% of patients reported persistent alterations in olfactory and gustatory sensitivity, respectively; these numbers are higher than what has been reported 24, 25 .

We found a moderate-to-strong correlation between self-reported olfactory and gustatory changes, which were stronger than with self-reported trigeminal changes. This could be due to similar pathophysiological alterations in the olfactory and gustatory systems and their differences from that of the trigeminal system. Knowing that the general population often mixes up retroolfaction (perceiving odors from the substances in the mouth traveling posteriorly and rostrally to the olfactory epithelium) with taste, an alternative explanation would be a misunderstanding of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 1, 2021. ; https://doi.org/10.1101/2021.06.28.21259639 doi: medRxiv preprint this nuance by participants despite the fact that specific definitions for each modality were given 26 27 . The latter hypothesis is more probable since the correlation between gustatory selfreport and CPT gustatory scores using strict gustatory stimuli (salt, sugar) is lower than the correlation between olfactory self-report and CPT olfactory scores.

Moreover, approximately 10% reported parosmia and/or phantosmia following SARS-CoV-2 infection. These qualitative smell disorders usually involve unpleasant olfactory sensations (rotten eggs, sewage, smoke). While the exact pathomechanism of parosmia and phantosmia are still to be elucidated, parosmia is probably linked to altered peripheral input/central processing of olfactory stimuli 28 . Importantly, patients with postviral OD and parosmia exhibit better recovery rates following olfactory training than those without parosmia 29 .

Follow-ups will determine to what extent parosmia predicts a better outcome.

Women's chemical senses were more affected than men by the infection. Women typically have better scores in olfactory testing than men 30 . In turn, women exhibit a higher prevalence and a longer persistence of postviral OD 31, 32 , in line with our results. Gender differences could be explained by a multitude of neuroendocrine, social, and cognitive factors 31 . This suggests that the burden of COVID-19-related OD is more important for women than for men. Different theories have been proposed to explain the persistence of OD in certain individuals, ranging from olfactory epithelium dysfunction to central nervous system infection [33] [34] [35] . Since cells of the olfactory epithelium possess the ability to regenerate, the re-establishment of olfactory function is possible in the context of postinfectious OD 36 , as well as in COVID-19related OD, where 75-85% of the affected individuals recovered olfactory function within 60 days 24, 37 . In addition to OD and GD, TD has also been reported in patients with COVID-19 9, 18 .

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The copyright holder for this preprint this version posted July 1, 2021. Olfactory and other chemosensory dysfunctions may have detrimental effects. First, affected individuals can expose themselves to harmful substances such as smoke, gas or spoiled food 52, 53 . It may trigger dysfunctional nutritional patterns like increased salt and sugar consumption and anorexia 54, 55 . Individuals with OD also have higher rates of anxiety and depression 17, 56 . Moreover, a functioning olfactory system may be a necessity in some workplaces such as in healthcare, where staff are required to have the ability to detect and qualify the smell of urine, excrement, infected wounds or abnormal smells of breath 57 . Currently, there is no approved therapy for COVID-19-induced OD, although olfactory training has a significant effect on olfactory function according to studies on other viral infections [58] [59] [60] . Most importantly, long-term follow-up of these patients will be necessary to assess other signs of neurological damage.

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Given the cross-sectional design of the study, a recall bias is possible for all self-reported peri-SARS-CoV-2 infection values before or during the SARS-CoV-2 infection due to the 3-to-7-month gap. This study did not control for potential confounding factors like race and level of education. Finally, the CPT requires further validation for its gustatory and trigeminal components, and it relies on substances found in participants' homes, which may lead to variation in test results due to the differences in the brand, quality, or expiration date of substances and consequently, their ability to trigger equal sensorineural responses.

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Nearly two thirds of SARS-CoV-2 infected patients had chemosensory impairments during their infection and despite improvements, impairments persist in more than half of them 3 to 7 months after COVID-19. Quantitative and qualitative olfactory dysfunction as well as persisting gustatory and trigeminal deficits were common in the cohort presented in this study.

Given the frequency of these problems and the possible neurological underpinnings of these observations, it will be critical to understand the underlying mechanisms of these chemosensory dysfunctions, their evolution, and possible therapeutic options.

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We thank Josiane Rivard for preparing the online questionnaire, Cécilia Tremblay, Émilie Aubry-Lafontaine and Frédérique Roy-Côté for data collection and the validation of the Chemosensory Perception Test, and all study participants and frontline health care workers facing the COVID-19 pandemic. This work was supported financially by Fonds de recherche du Québec -Santé (chercheur boursier junior 2 #283144 to JF). NB and JF had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. FGL is the recipient of a tier-2 Canada research Chair. All authors declare no conflict of interest.

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The copyright holder for this preprint this version posted July 1, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 1, 2021. Self repor ed rigeminal f nc ion score Self reported g station score

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