key: cord-0691904-077hrna8
authors: Klimek, Ludger; Hagemann, Jan; Hummel, Thomas; Altundag, Aytug; Hintschich, Constantin; Stielow, Sabine; Bousquet, Jean
title: Olfactory dysfunction is more severe in wild-type SARS-CoV-2 infection than in the Delta variant (B.1.617.2)
date: 2022-05-12
journal: World Allergy Organ J
DOI: 10.1016/j.waojou.2022.100653
sha: 1c4950071c5355ae0863b1f9a04f47df96f3ab46
doc_id: 691904
cord_uid: 077hrna8

Olfactory dysfunction is common in COVID-19, and sudden-onset dysosmia is an early marker for wild-type SARS-CoV-2 infection. Over 10,000 mutations of SARS-CoV-2 have been registered, with variants of concern (VOC) under particular scrutiny. We report a telemedicine-based, multicentre, prospective cohort study with quantitative olfaction testing comparing 79 patients with a confirmed VOC-Delta (n=21) or wild-type (WT) SARS-CoV-2 infection. Acute SARS-CoV-2 infection led to significant decrease of olfactory function in both cohorts. A majority of patients suffered from hyposmia or anosmia at inclusion with only 26 individuals performing normosmic. Sniffin'Sticks total scores were significantly higher for VOC-Delta patients at onset of illness, compared to WT patients (p<0.001). At 4 weeks follow-up, olfaction scores recovered only partially for WT patients, thus odds of recovery were stronger in VOC-Delta patients. Also, subjective self-rating of chemosensory function was lower in WT, compared to VOC-Delta patients. The need for ongoing olfaction studies and their prognosis in SARS-CoV-2 background remains urgent, also in the light of increasing numbers of olfaction-related patient presentations.

Olfactory dysfunction is common in COVID-19, and sudden-onset dysosmia is an early marker 21 for SARS-CoV-2 infection [1] [2] [3] . This finding was confirmed during the early stages of the 22 pandemic. However, over 10,000 mutations of SARS-CoV-2 have been registered with an 23 increased chance of having an altered phenotype of illness 4 . Some mutants give the virus 24 selective advantages and accelerate the pandemic progression. The multiple variants of 25 concern (VOCs; WHO nomenclature) are particularly under observation by the World Health 26

Organization. In the VOC-Delta (B.1.617.2), first described in India, spike protein mutations 27 induce an increased transmission rate 5 . 28

The mechanisms for long-term olfactory impairment beyond acute olfactory epithelial 29 damage are still unclear 6 . Psychophysical testing is a common standard for the reliable 30 evaluation of olfaction in COVID-19 1, 7 . Based on previous studies, despite methodologic 31 differences, different SARS-CoV-2 variants may differ in terms of olfaction disturbance 1, 8 . To 32 the best of our knowledge, no psychophysical quantitative measures of olfaction have yet 33 compared wild-type SARS-CoV-2 infections with any other VOCs, particularly the VOC-Delta. 34

We report a telemedicine-based 7,9 , multicentre, prospective cohort study with quantitative 35 olfaction testing comparing 79 patients with a confirmed VOC-Delta or wild-type SARS-CoV-2 36 infection. 37

The study respected the Declaration of Helsinki, approval was obtained from the Ethics 39

Committee ([blinded] No.14943), and all participants provided written informed consent. 40 COVID-19 was defined by a positive SARS-CoV-2 RT-PCR on nasopharyngeal and pharyngeal 41 swab tests. The wild-type variant (WTV) and VOC-Delta were defined by high-sensitive next-42 generation sequencing (NGS). 43

Inclusion criteria were as follows: positive RT-PCR no later than 5 days after symptom onset, 44 no other olfaction pathology, willingness to participate, age > 18 years, intellectual and clinical 45 ability to self-perform a full Sniffin´Sticks olfaction test, visual analogue scales (VASs, range 1-46 100 min-max), and temperature measurement. The use of language-based questionnaires 47 was avoided due to the mixed primary language background of patients. All subjects were 48 given standardised test kits and instructions for psychophysical olfactory function tests 10 49 (Sniffin´Sticks, Burghart, Holm, Germany). These tests were to be performed via telemedicine 50 consultation with a re-evaluation after 4 weeks. Prior subjective or diagnosed olfaction 51 impairment and chronic rhinitis led to exclusion in the screening process. Patients were 52 screened for participation at a regional COVID testing facility. 53

Statistical analysis was performed with GraphPad Prism v6 (GraphPad Software, San Diego, 54 USA) and included t-tests and ANOVA analyses after normality testing. See Online supplement 55 for full data table. 56

Among the 79 patients (44 males, mean age 40.4 years (range 18-79)), 21 had an NGS-58 confirmed VOC-Delta (B.1.617.2) infection (Suppl. Table 1 ). The course of the disease was mild 59 in both cohorts, and hospital admission was not necessary. Of note, fever did not occur in the 60 VOC-Delta cohort ( Figure 1A , p<0.05). 61

Acute SARS-CoV-2 infection led to a significant decrease of olfactory function in both cohorts. 62

The majority of patients suffered from hyposmia or anosmia at inclusion, with only 26 63 J o u r n a l P r e -p r o o f normosmic cases (Suppl. Table 1 ). At inclusion, the Sniffin'Sticks total combined scores were 64 significantly higher for VOC-Delta patients compared to wild-type variant (WTV) patients 65 (29.5 vs. 21.2, p>0.001, Figure 1A ). The "identification" and "discrimination" subtests were 66 drivers of this effect: identification and discrimination scores were 3.6 or 2.8 lower for WTV 67 patients at inclusion, compared to VOC-Delta cases (Suppl. Table 1) . Threshold values were 68 non-significantly lower for the WTV (7.2 vs. 9.0, p=0.15). Since VOC-Delta patients were 69 younger, this finding was confirmed in subgroups of equal age (44 and younger), with total 70 combined score means of 29.5 vs. 20.6, p<0.001 ( Figure 1A) . 71

At follow-up, olfaction scores recovered only partially for WTV patients. For the entire period, 72 a 2-way ANOVA confirmed that the VOC-Delta caused significantly less olfactory loss 73 (p<0.001). Odds of recovery within four weeks (equal-age subgroups) were stronger in the 74 VOC-Delta patients (odds ratio 2525.0, 95CI: 11.39-449449.5), and all of the VOC-Delta 75 patients had normosmia at follow-up. 76

Global nasal symptoms, obstruction and chemosensory function were all assessed with visual 77 analogue scales (VASs). The subjective self-rating of those symptoms was diminished in both 78 cohorts (Suppl. Table 1 ). Self-rating of both olfaction and gustation function showed 79 significantly lower scores in WTV compared to VOC-Delta ( Figure 1B, p<0.001) . 80

For the first time, quantitative psychophysical analyses of olfaction have been compared in 82 different SARS-CoV-2 variants at several time points. Our data suggest that: 1) functional 83 anosmia in COVID-19 is more frequent in WTV patients than in those with the VOC-Delta, 2) 84 the likelihood of long-term olfaction impairment appears to be substantially lowered in the 85 J o u r n a l P r e -p r o o f VOC-Delta, and 3) as shown before, telemedicine consultations allow safe testing for patients 86 and staff. 87

Recent observations have suggested that VOC patients are more likely to suffer from 88 moderate and severe infections than WTV patients 11 . SARS-CoV-2-induced olfaction 89 impairment seems to occur in a similar way to that of other upper respiratory tract viruses, 90 despite significant differences with regards to nasal congestion and secretion 12 . The precise 91 mechanism of action on olfaction neurons or central nervous system has not yet been 92 determined. However, viral strain alterations may also change the destructive impact on 93 olfaction. In our cohort, regardless of the variants, acute infection had a severe impact on all 94 three capacities tested for by the Sniffin'Sticks psychophysical test. Correlating strongly with 95 the patient's subjective impression of chemosensory performance, identification and 96 discrimination of odours as well as olfactory threshold were impaired upon SARS-CoV-2 97 infection. Strikingly, VOC-Delta patients performed significantly better in psychophysical 98 testing at inclusion, with significantly higher testing scores in odour identification and 99 discrimination. To correct for age differences between cohorts, subgroups of equal age were 100 built, and results were uniformly confirmed. Thus, the more pronounced SARS-CoV-2-101 dependent olfaction loss was not caused by older age, but occurred in all age groups, 102 significantly more frequently in the WTV patients. Notably, all VOC-Delta patients recovered 103 to normal test scores at follow-up, which may well be biased by the age difference between 104 both groups. We can correct these results for age inequality and still see statistical 105 significance; however there is clear need of further studies for confirmation in larger samples. 106

Further limitations of this cohort study arise from the small cohort size and from the lack of 107 means to characterise nasal status more thoroughly, e.g. by nasal endoscopy. Despite an 108 increasing proportion of VOC cases relative to total infections, next-generation sequencing is 109 not standard in all regions and test facilities, which raises problems in the recruiting of 110 patients. 111

Up until now, current vaccination programmes have been effective against wild-type and VOC 112 coronaviruses. This is vitally important for decreasing numbers of SARS-CoV-2-related 113 olfaction disorders 13 . Further studies are urgently required to characterise this bothersome 114 secondary symptom of COVID-19. With virtually few options to treat the increasing number 115 of patients presenting with long-term olfaction impairment, but also in the light of increasing 116 numbers of occupational illness insurance claims, further knowledge about COVID-related 117 olfactory impairment and its severity will be of great interest in the future. 118 

Olfactory and gustatory 126 dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease 127 (COVID-19): a multicenter European study

Anosmia and Ageusia: Common Findings in 130 COVID-19 Patients

Association of chemosensory 132 dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int Forum 133 Allergy Rhinol

Increased mortality in community-tested 135 cases of SARS-CoV-2 lineage B.1.1.7. Nature

Increased household transmission of COVID-19 cases associated 139 with SARS-CoV-2 Variant of Concern B.1.617.2: a national case-140 control study

The mechanisms of smell loss after SARS-CoV-2 infection

Telemedicine allows quantitative measuring of 144 olfactory dysfunction in COVID-19

Neurologic Manifestations of Hospitalized Patients 146

With Coronavirus Disease

Telemedicine in allergology: practical aspects: 149 A position paper of the Association of German Allergists (AeDA)

Sniffin' sticks': olfactory 152 performance assessed by the combined testing of odor identification, odor discrimination 153 and olfactory threshold

The Disease Severity and Clinical Outcomes of the SARS-155

CoV-2 Variants of Concern. Front Public Health

Differentiation of COVID-19 signs and 158 symptoms from allergic rhinitis and common cold: An ARIA-EAACI-GA(2) LEN consensus

Effectiveness of Covid-19 Vaccines against the 161

2 (Delta) Variant

We would like to formally acknowledge our study assistants and nurses and thank Anna Bedbrook in particular for proof-reading.

LK, JB and JH drafted the study. All authors contributed to data collection and executed the