Study population
A total of 467 out of the 569 participants who enrolled and underwent a SARS-CoV-2 antibody test completed the follow-up questionnaire, yielding a follow-up rate of 82.1%. The demographics of the entire study cohort can be seen in Additional File 2. Out of the cohort of 467 who completed the follow-up questionnaire, participants with positive and negative SARS-CoV-2 antibodies were comparable in terms of age, gender, smoking status and ethnicity (Table 1). Admission to hospital was reported by 1.6% (n=7) of participants in the antibody positive group vs. 3.1% (n=4) in the antibody negative group (p=0.097).
Table 1: Demographics of participants followed up after 4-6 weeks with positive and negative SARS-CoV-2 antibodies
Demographics
|
SARS-CoV-2 IgG/IgM positive (n=381)
|
SARS-CoV-2 IgG/IgM negative (n=86)
|
p-value
(0.05)
|
Gender
|
Female
|
70.9% (n=270)
|
66.3% (n=57)
|
0.382
|
Male
|
28.8% (n=110)
|
33.7% (n=29)
|
Other
|
0.3%
(n=1)
|
0
|
0.450
|
Age (years)
|
39.67±12.12
|
40.25±12.33
|
0.689
|
Ethnicity *
|
|
White
|
83.7% (n=319)
|
81.4% (n=70)
|
0.600
|
Mixed/Multiple Ethnicities
|
5.5% (n=21)
|
4.7% (n=4)
|
0.749
|
Asian/Asian British
|
5% (n=19)
|
4.7% (n=4)
|
0.897
|
Black/African/Caribbean/Black British
|
1.6% (n=6)
|
2.3% (n=2)
|
0.628
|
‘Other’
|
3.7% (n=14)
|
3.5% (n=3)
|
0.933
|
Smoking status
|
|
Current/ Ex-smoker
|
42% (n=160)
|
44.2% (n=38)
|
0.710
|
Never smoked
|
58% (n=221)
|
55.8% (n=48)
|
Figures presented as % with total number (n). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
*5 participants opted not to disclose their ethnicity.
Smell and taste loss and resolution at 4 -6 weeks follow-up
The frequency of reported smell and/or taste loss at baseline can be seen in Table 2.
Table 2: Loss of smell and/or taste in SARS-CoV-2 IgG/IgM positive and negative participants
|
SARS-CoV-2 IgG/IgM positive (n=443)
|
SARS-CoV-2 IgG/IgM negative (n=126)
|
p-value (0.05)
|
Sense of smell
|
|
Loss of sense of smell (complete and partial)
|
93.5%
(n=414)
|
79.4%
(n=100)
|
<0.001
|
Partial loss of smell
|
24.4%
(n=108)
|
39.7%
(n=50)
|
<0.001
|
Complete loss of smell
|
69.1%
(n=306)
|
39.7%
(n=50)
|
Parosmia (distorted sense of taste)
|
30%
(n=133)
|
21.4%
(n=27)
|
0.245
|
Sense of taste
|
|
Loss of sense of taste (complete and partial)
|
90.1%
(n=399)
|
88.9%
(n=112)
|
0.700
|
Partial loss of taste
|
42.7%
(n=189)
|
61.9%
(n=78)
|
<0.001
|
Complete loss of taste
|
47.4%
(n=210)
|
27%
(n=34)
|
Dysgeusia (distorted sense of taste)
|
44.7%
(n=198)
|
42.9%
(n=54)
|
0.856
|
Experience of taste without eating/drinking
|
21.4%
(n=95)
|
24.6%
(n=31)
|
0.374
|
Only loss of smell
|
9.9%
(n=43)
|
11.1%
(n=14)
|
0.643
|
Only loss of taste
|
6.5%
(n=28)
|
20.6%
(n=27)
|
<0.001
|
Loss of sense of smell and taste (partial and complete)
|
83.6%
(n=371)
|
68.3%
(n=86)
|
<0.001
|
Out of 467 patients followed up at 4-6 weeks, 57.7% (n=206) of participants with positive SARS-CoV-2 antibodies reported full resolution of their smell loss, compared to 72.1% (n=49) of participants with a negative antibody test (p=0.027). Out of the participants with positive SARS-CoV-2 antibodies, 38.4% (n=137) reported partial and 3.9% (n=14) reported no resolution of their smell loss at the time of follow-up. Out of participants with negative SARS-CoV-2 antibodies 25.0% (n=17) reported partial and 2.9% (n=2) no resolution of their smell loss. Figure 1 shows the resolution of smell and taste loss reported at the time of follow-up.
Full resolution of taste loss was reported by 66.2% (n=227) of participants with SARS-CoV-2 antibodies and 80.3% (n=61) of participants with negative SARS-CoV-2 antibodies (p=0.017). Out of participants with positive SARS-CoV-2 antibodies, 31.2% (n=107) reported partial and 2.6% (n=9) no resolution of their taste loss at the time of follow up. Out of participants with negative SARS-CoV-2 antibodies, 19.7% (n=15) reported partial resolution of their taste loss (0 participants reported ‘no resolution’ of taste loss). Out of participants with positive SARS-CoV-2 antibodies, only 24 experienced a loss of their sense of taste in the absence of a loss of smell. The demographics were comparable to those of the entire SARS-CoV-2 positive cohort, with a mean age of 38.4 ±14.21 years and 70.8% (n=17) of participants of female sex.
For subsequent analyses participants with partial and no resolution were grouped together in order to enable comparison between participants who achieved full resolution versus those who had ongoing smell and/or taste impairment at the time of follow-up. Table 3 shows results regarding resolution vs. no resolution of smell loss, taste loss and combined smell/taste loss in participants with positive and negative SARS-CoV-2 antibodies. A higher percentage of participants without SARS-CoV-2 antibodies fully recovered their sense of smell (72.1% vs 57.7%. p=0.027), their sense of taste (80.3% vs 66.2%, p=0.017) and both their senses of smell and taste (79.6% vs 64.0%, p=0.026).
Table 3: Smell and/or taste loss resolution in SARS-CoV-2 IgG/IgM positive and negative participants
Pattern of resolution
|
SARS-CoV-2 IgG/IgM positive
|
SARS-CoV-2 IgG/IgM negative
|
p-Value (0.05)
|
Smell loss
|
Total (n=357)
|
Total (n=68)
|
|
No/partial resolution
|
42.3%
(n=151)
|
27.9%
(n=19)
|
0.027
|
Full resolution
|
57.7%
(n=206)
|
72.1%
(n=49)
|
Taste loss
|
Total (n=343)
|
Total (n=76)
|
|
No/partial resolution
|
33.8%
(n=116)
|
19.7%
(n=15)
|
0.017
|
Full resolution
|
66.2%
(n=227)
|
(80.3%)
(n=61)
|
Combined smell and taste loss
|
Total (n=261)
|
Total (n=54)
|
|
No/partial resolution
|
36.0%
(n=94)
|
20.4%
(n=11)
|
0.026
|
Full resolution
|
64.0%
(n=167)
|
79.6%
(n=43)
|
In participants with SARS-CoV-2 antibodies who reported full resolution of their smell loss, a full recovery of the sense of smell was reported to have occurred within one week in 11.7%, within 1-2 weeks in 26%, within 2-4 weeks in 26.5% and within >4 weeks in 35.8%.
The effects of smell loss pattern and presence of parosmia on recovery of the sense of smell in participants with SARS-CoV-2 IgG/IgM antibodies
The effect of complete vs. partial smell loss and the presence of parosmia on smell recovery in participants with positive SARS-CoV-2 antibodies was investigated. In participants who experienced complete loss of their sense of smell, full sense of smell recovery was reported by 54.5% compared to 67.4% in participants who reported a partial loss of their sense of smell (54.5% vs 67.4%, p=0.032).
Out of participants who reported parosmia at the time of their smell loss, full recovery was reported by 41.4% compared to 65% in participants with smell loss who did not experience parosmia (41.4% vs. 65%, p<0.001).
The effects of taste loss pattern and presence of dysgeusia on recovery of the sense of taste in participants with SARS-CoV-2 IgG/IgM antibodies
The effect of complete vs. partial taste loss and the presence of dysgeusia on smell recovery in participants with positive SARS-CoV-2 antibodies was investigated. There was no significant difference in the reported rates of recovery of taste loss in participant who reported complete vs. partial loss of their sense of taste (64.7% vs. 67.9%, p=0.525).
Out of participants who experienced dysgeusia at time of their loss of taste, a significantly lower proportion reported full resolution of their taste loss, compared to participants who did not experience dysgeusia (60.7% vs. 71.4%, p=0.036).
Participants who experienced taste sensations in the absence of eating or drinking reported lower resolution rates compared to participants who did not (51.2% vs 71.0%, p=0.001).
The effect of sex and age on the recovery of the sense of smell and taste in participants with SARS-CoV-2 IgG/IgM antibodies
Full recovery of sense of smell was more prevalent among males compared to females (72.8% in males vs. 51.4% in females, p<0.001). Similarly, full taste loss resolution was more common in males vs. females (80.8% vs. 60.1%, p<0.001) as was full resolution of combined smell/taste loss (69.6% vs. 4.1%, p<0.001); Table 4.
Table 4: Resolution of loss of smell, loss of taste and combined loss of smell and taste in female vs. male participants with SARS-CoV-2 IgG/IgM antibodies.
|
Female
|
Male
|
p-value (0.05)
|
Smell loss resolution
|
Full resolution
|
51.4% (n=130)
|
72.8%
(n=75)
|
<0.001
|
No/partial resolution
|
48.6%
(n=123)
|
27.1%
(n=28)
|
Taste loss resolution
|
Full resolution
|
60.1%
(n=146)
|
80.8%
(n=80)
|
<0.001
|
No/partial resolution
|
39.9%
(n=97)
|
19.2%
(n=19)
|
Combined smell and taste loss resolution
|
Full resolution
|
45.1%
(n=102)
|
69.6%
(n=64)
|
<0.001
|
No/partial resolution
|
54.9%
(n=124)
|
30.4%
(n=28)
|
The effect of age on resolution of smell and taste loss was evaluated. Mean age of male and female participants was comparable for participants who experienced full resolution of the loss in their sense of smell (40.4 ± 13.2 years in males vs. 38.1 ± 11.3 in females, p=0.333), their sense of taste (40.3 ±13.4 vs .37.1 ± 10.7 p=0.153) and combined loss of smell and taste (40.0 ± 12.6 vs. 37.1 ± 11.0, p=0.122). In participants with loss of their sense of taste that did not resolve at the time of follow-up, mean age was significantly higher in females compared to males (42.7 ± 12.5 years vs. 37.6 ± 12.6 years, p=0.030). Mean age was also significantly higher in female participants with unresolved combined loss of smell and taste loss compared to male participants (42.8 ± 12.5 vs. 34.6 ± 10.4, p=0.001). Mean age of female participants with unresolved smell loss was 41.6 ± 11.7 years compared to 37.4 ± 12.7 years in male participants, however this borderline difference did not reach statistical significance (p=0.053) (Figure 2).
In light of the above findings, we further evaluated the effect of age on smell and/or taste loss resolution in female participants. A significantly higher age was observed in female participants without resolution compared to those with full resolution of the loss of their sense of smell (41.6 ± 11.7 yrs vs. 38.1 ± 11.3 yrs, p=0.010), their sense of taste (42.7 ± 12.5 yrs vs. 37.1 ± 10.7 yrs, p<0.001) and combined smell and taste (42.8 ± 12.5 yrs vs. 37.1 ± 11.0 yrs, p<0.001).
Predictors of persisting smell loss in a community population with SARS-CoV-2 antibodies and acute loss of their sense of smell
Logistic regression was used to explore the relative importance of participant’s age, sex, ethnicity, smoking status, presence of parosmia and smell loss pattern as risk factors for persistent smell loss at >4 weeks from onset.
Female participants were almost 2.5 times more likely to have ongoing smell loss after 4 weeks compared to participants of male sex (OR 2.46, 95% CI 1.47 to 4.13, p=0.001). Parosmia was also shown to have a significant association with unresolved smell loss at 4-6 week follow-up (OR 2.47, 95%CI 1.54 to 4.00, p<0.001), in a model adjusting for the age, ethnicity, patterns of smell loss (complete vs partial) and smoking; Table 5.
Table 5: Logistic regression exploring the association between age, sex, ethnicity, smoking status, presence of parosmia and smell loss pattern (complete vs partial) and no resolution of smell loss at 4 weeks follow up.
Variable
|
B
|
OR
|
95% CI (lower)
|
95% CI (upper)
|
p value
|
Age
|
0.13
|
1.013
|
.994
|
1.032
|
0.172
|
Ethnicity
|
0.96
|
1.101
|
.595
|
2.034
|
0.760
|
Complete anosmia
|
0.529
|
1.697
|
0.998
|
2.884
|
0.051
|
Parosmia
|
0.904
|
2.470
|
1.539
|
3.966
|
<0.001
|
Sex (Female)
|
0.901
|
2.461
|
1.468
|
4.126
|
0.001
|
Smoking
|
0.303
|
1.355
|
0.604
|
3.038
|
0.462
|
Persistent smell and/or taste loss as a manifestation of long COVID.
At the end of the 4-6 week follow-up period 42.3% (n=151) of participants with positive SARS-CoV-2 antibodies had ongoing smell loss, 33.8% experienced ongoing taste loss and 36% had ongoing taste and smell loss. We also evaluated the resolution of other symptoms of COVID-19 at the end of the follow-up period in participants positive for SARS-CoV-2 antibodies. Out of 134 participants with unresolved smell loss who reported additional COVID-19 symptoms on their original questionnaire, 29.1% (n=39) had at least 1 additional unresolved symptom at the time they completed their follow-up questionnaire, compared to 19.9% (n=35) of participants with full resolution of their smell loss (29.1% vs 19.9%, p=0.059). The most commonly reported unresolved symptoms were shortness of breath, chest pain and muscle/joint pains.
Objective smell testing in a subsample of participants and correlation with perceived smell function
A subsample of 50 participants underwent objective olfactory testing using the UPSIT. 84% were female (n=42) and 16% (n=8) male. The mean age was 39.6 ±13.5 years and mean duration of test date from the onset of symptoms was 21.6 ±4.7 weeks. 76% (n=38) participants had complete loss of their sense of smell at the time of the original questionnaire and 24% (n=12) partial loss of smell. At the time of the follow-up questionnaire 16% (n=8) reported their smell loss ‘did not resolve’, 42% (n=21) reported their smell loss ‘resolved partially’ and 42% (n=21) reported their smell loss ‘resolved fully’.
The mean UPSIT test score was 29.1 ±7.5 points. In view of the time elapsed between the completion of the follow-up questionnaire and the UPSIT testing, prior to testing, participants were asked how they perceived their smell function. Their answers were grouped into: ‘No or minimal sense of smell’, ‘Sense of smell improved but not fully recovered’ or ‘Sense of smell fully recovered’. Table 6 illustrates a comparison of participants’ perceived smell function and their UPSIT test result, by test result category. A Spearman rank correlation analysis found a significant correlation between perceived smell function and UPSIT test result category (r=0.84 ± 0.71 to 0.90, p<0.001).
Table 6: Comparison between UPSIT test result and perceived smell function in a study subgroup of 50 participants
|
Minimal/no sense of smell (n=11)
|
Improved sense of smell, not fully recovered (n=9)
|
Fully recovered
(n=30)
|
Total anosmia
|
45.5% (5)
|
0%
|
0%
|
Severe microsmia
|
45.5% (5)
|
0%
|
0%
|
Moderate microsmia
|
9.0% (1)
|
77.8% (7)
|
0%
|
Mild microsmia
|
0%
|
11.1% (1)
|
16.7% (n=5)
|
Normosmia
|
0%
|
11.1% (1)
|
83.3% (n=25)
|
Spearman r
|
0.95
|
-0.63
|
-0.89
|