Olfactory loss is an early and reliable marker for COVID-19 (preprint)

Detection of early and reliable symptoms is important in relation to limiting the spread of an infectious disease. For COVID-19, the most prevalent symptom is either losing or experiencing reduced olfactory functions. Anecdotal evidence suggests that olfactory dysfunction is also one of the earlier symptoms of COVID-19 but objective measures supporting this notion are currently missing. To determine whether olfactory dysfunction is an early sign of COVID-19, we assessed available longitudinal data from a web-based interface enabling individuals to test their sense of smell by rating the intensity of selected household odors. Individuals continuously used the interface to assess their olfactory functions and at each login, in addition to odor ratings, recorded their symptoms and result from potential COVID-19 test. A total of 205 COVID-19 positive individuals and 156 pseudo-randomly matched control individuals lacking positive test provided longitudinal data which enabled us to assess olfactory functions in relation to their test results date. We found that odor intensity ratings started to decline in the COVID-19 group as early as 6 days prior to test result date. Symptoms such as sore throat, aches, and runny nose appear around the same point in time; however, with a lower predictability of a COVID-19 diagnose. Our results suggest that olfactory dysfunction is an early symptom but does not appear before other related COVID-19 symptoms. Olfactory dysfunction is, however, more predictive of an COVID-19 diagnose than other early symptoms.

Effects of COVID-19 on the human central olfactory system: a natural pre-post experiment (preprint)

Reduced olfactory function is the symptom with the highest prevalence in COVID-19 with nearly 70% of individuals with COVID-19 experiencing partial or total loss of their sense of smell at some point during the disease. The exact cause is not known but beyond peripheral damage, studies have demonstrated insults to both the olfactory bulb and central olfactory brain areas. However, these studies often lack both baseline pre-COVID-19 assessments and a control group and could therefore simply reflect preexisting risk factors. Right before the COVID-19 outbreak, we completed an olfactory focused study including structural MR brain images and a full clinical olfactory test. Opportunistically, we invited participants back one year later, including 9 participants who had experienced mild to medium COVID-19 (C19+) and 12 that had not (C19-), thereby creating a pre-post controlled natural experiment with a control group. Despite C19+ participants reporting subjective olfactory dysfunction, few showed signs of objectively altered function one year later. Critically, all but one individual in the C19+ group had reduced olfactory bulb volume with an average volume reduction of 14.3%, but this did not amount to a significant between group difference compared to the control group (2.3% reduction) using inference statistics. No morphological differences in cerebral olfactory areas were found but we found stronger functional connectivity between olfactory brain areas in the C19+ croup at the post measure. Taken together, these data suggest that COVID-19 might cause a long-term reduction in olfactory bulb volume but with no discernible differences in cerebral olfactory regions.

Smelling Household-Odorants Effectively Screens for COVID-19 (preprint)

Key to curtailing the COVID-19 pandemic are wide-scale testing strategies 1,2 . An ideal test is one that would not rely on transporting, distributing, and collecting physical specimens. Given the olfactory impairment associated with COVID-19 3-7 , we developed a novel measure of olfactory perception that relies on smelling household odorants and rating them online. We tested the performance of this real-time tool in 12,020 participants from 134 countries who provided 171,500 perceptual ratings of 60 different household odorants. We observed that olfactory ratings were indicative of COVID-19 status in a country, significantly correlating with national infection rates over time. More importantly, we observed remarkable indicative power at the individual level (90% sensitivity and 80% specificity). Critically, olfactory testing remained highly effective in participants with COVID-19 but without symptoms, and in participants with symptoms but without COVID-19. In this, the current odorant-based olfactory test stands apart from symptom-checkers (including olfactory symptom-checkers) 3 , and even from antigen tests 8 , to potentially provide a first line of screening that can help halt disease progression at the population level.

Recent smell loss is the best predictor of COVID-19: a preregistered, cross-sectional study (preprint)

Background: COVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19. Methods: This preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery. Results: Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean{+/-}SD, C19+: -82.5{+/-}27.2 points; C19-: -59.8{+/-}37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing no significant model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ~50% of participants and was best predicted by time since illness onset. Conclusions: As smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings [≤]2 indicate high odds of symptomatic COVID-19 (10

Relationship between odor intensity estimates and COVID-19 population prediction in a Swedish sample (preprint)

In response to the COVID-19 pandemic, countries have implemented various strategies to reduce and slow the spread of the disease in the general population. For countries that have implemented restrictions on its population in a step-wise manner, monitoring of COVID-19 prevalence is of importance to guide decision on when to impose new, or when to abolish old, restrictions. We are here determining whether measures of odor intensity in a large sample can serve as one such measure. Online measures of how intense common household odors are perceived and symptoms of COVID-19 were collected from 2440 Swedes. Average odor intensity ratings were then compared to predicted COVID-19 population prevalence over time in the Swedish population and were found to closely track each other (r=-0.83). Moreover, we found that there was a large difference in rated intensity between individuals with and without COVID-19 symptoms and number of symptoms was related to odor intensity ratings. Finally, we found that individuals progressing from reporting no symptoms to subsequently reporting COVID-19 symptoms demonstrated a large drop in olfactory performance. These data suggest that measures of odor intensity, if obtained in a large and representative sample, can be used as an indicator of COVID-19 disease in the general population. Importantly, this simple measure could easily be implemented in countries without wide-spread access to COVID-19 testing or implemented as a fast early response before widespread testing can be facilitated.

More than just smell - COVID-19 is associated with severe impairment of smell, taste, and chemesthesis (preprint)

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, generally lacked quantitative measurements, were mostly restricted to data from single countries. Here, we report the development, implementation and initial results of a multi-lingual, international questionnaire to assess self-reported quantity and quality of perception in three distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, 8 other, ages 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change+/-100) revealed a mean reduction of smell (-79.7+/- 28.7, mean+/- SD), taste (-69.0+/- 32.6), and chemesthetic (-37.3+/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell, but also affects taste and chemesthesis. The multimodal impact of COVID-19 and lack of perceived nasal obstruction suggest that SARS-CoV-2 infection may disrupt sensory-neural mechanisms.