Clinical characteristics associated with persistent olfactory and taste alterations in COVID-19: A preliminary report on 121 patients.

To the Editor,

many patients infected by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) reported olfactory and taste dysfunction [1,2]. Anosmia and hypogeusia were recognized as presenting clinical symptoms of Coronavirus Disease 2019 (COVID-19) [3]. Sungnak et al. [4] investigated the expression of SARS-CoV-2 entry-associated genes in multiple tissues from healthy human donors. They found that these genes were expressed in nasal epithelial cells, highlighting the cells' potential role in initial viral infection. A multicenter European study enrolling 417 mild-to-moderate COVID-19 patients found olfactory/taste alterations in >80% of cases [5]. The early follow up of these patients (14 days) showed that olfactory dysfunction persisted in 56% of cases [5]. In the present investigation, our primary aim was to evaluate olfactory/taste alterations one month after COVID-19 diagnosis. The secondary aim was to search clinical characteristics associated with the persistence of sensory dysfunctions.

Three international ethics committees (HAP2020–011; CHUSP20032020; EpiCURA-2020-2303) and the Italian committee of Veneto region (protocol n°: 0171064) approved the study protocol. Informed consent was obtained verbally during telephone interviews. Inclusion criteria were: i) ≥ 18 years old; ii) laboratory-confirmed COVID-19 infection (reverse transcription polymerase chain reaction on nasopharyngeal swab) at least one month before inclusion; iii) olfactory and/or taste dysfunction. Exclusion criteria: i) patients with olfactory/gustatory alterations before the epidemic; ii) patients who were in the intensive-care unit at the time of the study (due to their health status). Thus, we included mild-to-moderate COVID-19 patients, defined as patients without need of intensive cares.

During the telephonic survey, we used the questionnaire proposed by the COVID-19 Task Force of YO-IFOS5. We classified the outcome of olfactory/taste dysfunction as persistence (1) or resolution (0). We used Fisher exact test and Mann-Whitney U test as needed. For significant association at Fisher exact test, we calculated odds ratio (OR) and 95% confidence interval (CI). A multivariate logistic regression was calculated, adding only the clinical parameters with a p value ≤0.05, as disclosed by Fisher exact test at univariate analysis. The results were expressed as ORs, p values, and 95% CI. A p value <0.05 was considered significant.

We included 121 COVID-19 patients with olfactory and/or taste alterations; the mean follow up time from diagnosis was 38.2 days (standard deviation [SD] 3.0 days). Table 1 summarized clinical characteristics and treatments. General symptoms resolved in all but 5 patients (3 had dry cough and 2 fatigue). Persistence of sensory dysfunction was reported by 26 subjects (21.5%). The duration of smell and gustatory symptoms was significantly longer (p < 0.00001; Mann-Whitney U test) in patients with persistence (mean 39.1 days) when compared with those with resolution (mean 15.6 days). At univariate analysis, patients without fever (OR 6.26; 95% CI = 2.45–15.99; p = 0.0001) and with olfactory/taste alterations before general symptoms (OR 3.36; 95% CI = 1.32–8.59; p = 0.01) were at higher risk of persistent complaints. Only absence of fever (OR 5.29; 95% CI = 2.02–13.89; p = 0.0007) was an independent prognostic factor (olfactory and taste dysfunction before general symptoms; OR 2.38; 95% CI = 0.86–6.58; p = 0.09) at multivariate analysis.

Table 1

Clinical characteristics and therapy of COVID-19 patients with resolved or persistent olfactory/taste alterations.

	Total	Resolution	Persistence	p value⁎
N.° of patients	121	95	26
Female/male	72/49	55/40	17/9	0.65
Mean age	46.7	48.2	46.1	0.9
Symptoms
Anosmia/Hyposmia	50/64	42/46	8/18	0.37
Ageusia/Hypogeusia	45/71	31/59	14/12	0.11
Nasal Congestion yes/no	19/102	14/81	5/21	0,55
Rhinorrhoea yes/no	27/94	20/75	7/19	0,6
Fever yes/no	89/32	78/17	11/15	0.0002
Cough yes/no	76/45	58/37	18/8	0.5
Fatigue yes/no	83/38	63/32	20/6	0.35
Myalgia yes/no	46/75	32/63	14/12	0.07
Relationship between onset of olfactory/taste dysfunction and general symptoms
Before/together or after general symptoms	28/93	17/78	11/15	0.01
Associated chronic medical illness
Allergic rhinitis yes/no	31/90	27/68	4/22	0.21
Hypertension yes/no	15/106	12/83	3/23	1.0
Asthma yes/no	11/110	8/87	3/23	0.7
Diabetes yes/no	3/118	3/92	0/26	1.0
Therapy
Nasal saline irrigations yes/no	48/73	42/53	6/20	0.07
Nasal steroids yes/no	39/82	29/66	10/16	0.49
Hydroxychloroquine yes/no	7/114	7/88	0/26	0.34

Fisher exact test and Mann-Whitney U test as needed; Bold = p value inferior to 0.05.

Previous studies have already shown the ability of SARS coronavirus to cause neuronal death in mice by invading the brain via the nose close to the olfactory epithelium [1]. We could hypothesize that SARS-CoV-2 has a similar behavior, given the well-known genetic similarity with other coronaviruses [3]. In a recent clinical study, Vaira et al. [6] considering 72 COVID-19 cases, found in 34% a persistence of alterations in taste and olfaction. Also in our series of 121 COVID-19 patients olfactory and taste alterations lasted more than one month in 21.5% of cases. However, most of patients reported resolution of symptoms after a mean of 15 days, and this confirmed the data from previous survey [5]. In the present investigation, absence of fever was an independent prognostic factor of persistent olfactory/taste dysfunction in COVID-19 patients. A survey on 1420 COVID-19 patients found that fever was less frequent in patients with olfactory and taste dysfunctions [7]. Fever was considered a risk factor for severe COVID-19 [3]. Anosmia was recently associated with mild-to-moderate COVID-19 and outpatient care [6,8]. Considering our results and previous evidences, we could hypothesize that patients with olfactory/taste alterations and without associated fever would experience a mild-to-moderate COVID-19, but persistent sensory reduction. Our hypothesis was limited by the absence of severe COVID-19 in our case series.

In conclusion, olfactory and taste dysfunction may be persistent in COVID-19. There is an urgent need for randomized-controlled clinical trials focus on treatment of COVID-19 olfactory and taste alterations.

Conflicts of interest and source of funding

This was not an industry-supported study. The authors have no conflicts of interest to disclose.