key: cord-0786797-s90zm901
authors: Fantozzi, Paolo J.; Pampena, Emanuele; Di Vanna, Domenico; Pellegrino, Eugenia; Corbi, Daniele; Mammucari, Stefano; Alessi, Federica; Pampena, Riccardo; Bertazzoni, Giuliano; Minisola, Salvatore; Mastroianni, Claudio Maria; Polimeni, Antonella; Romeo, Umberto; Villa, Alessandro
title: Xerostomia, gustatory and olfactory dysfunctions in patients with COVID-19()()
date: 2020-09-10
journal: Am J Otolaryngol
DOI: 10.1016/j.amjoto.2020.102721
sha: ba90a571c7c176361806198408c38fe27e1085b0
doc_id: 786797
cord_uid: s90zm901

BACKGROUND: The novel Coronavirus Disease-19 (COVID-19) continues to have profound effect on global health. Our aim was to evaluate the prevalence and characterize specific symptoms associated with COVID-19. METHODS: This retrospective study included 326 patients with confirmed SARS-CoV-2 infection evaluated at the Emergency Department of the Umberto I Polyclinic Hospital, Rome, Italy between March 6th and April 30th, 2020. In order to assess xerostomia, olfactory and gustatory dysfunctions secondary to COVID-19, a telephone-based a modified survey obtained from the National Health and Nutrition Examination Survey (NHANES) 2013–2014 for taste and smell disorders and the Fox Questionnaire for dry mouth were administered to 111 patients (34%) after discharge between June 4th and June 12th. RESULTS: Taste dysfunction was the most common reported symptom (59.5%; n = 66), followed by xerostomia (45.9%; n = 51) and olfactory dysfunctions (41.4%; n = 46). The most severe symptom was olfactory dysfunction with a median severity score of 8.5 (range: 5–10). Overall 74.5% (n = 38) of patients with xerostomia, 78.8% (n = 52) of patients with gustatory dysfunctions and 71.1% (n = 33) of patients with olfactory dysfunctions reported that all symptoms appeared before COVID-19 diagnosis. Overall, the majority of patients reported one symptom only (45.9%, n = 51), 37 (33.3%) reported the association of two symptoms, and 23 (20.7%) patients reported the association of three symptoms at the same time. CONCLUSION: Xerostomia, gustatory and olfactory dysfunctions may present as a prodromal or as the sole manifestation of COVID-19. Awareness is fundamental to identify COVID-19 patients at an early stage of the disease and limit the spread of the virus.

The recent Coronavirus Disease-19 (COVID-19) pandemic continues to have profound social and economic effects, with more than twelve millions infections and more than half a million deaths reported globally by July 1 st ,2020 [1] , [2] . Patients affected by COVID-19 may present with a variety of conditions that usually start from two to 14 days after exposure, and range from a mild flu-like condition to a life-threatening multi-organ failure with mortality being significantly higher among those having co-morbidities, older individuals and among those who require hospital admission and ventilation support in intensive care units [3] .

Interestingly, a significant number of patients reported taste and smell dysfunction as a prodromal, concomitant or as the sole manifestation of COVID-19 infection [4] , [5] , [6] . A recent systematic review and meta-analysis showed that 1627 patients had a prevalence of 52.7% of olfactory dysfunction and 1390 patients had a prevalence of 43.9% of gustatory changes, respectively [7] . On the other hand, oral complications secondary to COVID-19 have been poorly described, with one study reporting dry mouth and taste changes in 46.3% and 47.2% of COVID-19 patients (n=108), respectively [8] . While the pathobiology of dysgeusia, hyposmia/anosmia and xerostomia secondary to the COVID-19 is yet to be determined, it is wellreported that angiotensin-converting enzyme II (ACE2) may represent the novel coronavirus (2019-nCoV) cell receptor. In fact, recent studies showed that 2019-nCoV may specifically target ACE2-expressing olfactory/trigeminal and salivary glands cells following inoculation, or induce such manifestations as a consequence of the central nervous system involvement through the invasion of the olfactory/trigeminal bulb [7] , [9] , [10] .

This was a retrospective cohort study of adult patients ( 18 years) who were evaluated at the Emergency Department (ED) of the Umberto I Polyclinic Hospital, Rome, Italy between March 6 th and April 30 th , 2020 with confirmed SARS-CoV-2 infection. SARS-CoV-2 testing was obtained by sampling both the nasal and oropharyngeal mucosa and analyzed with real-time polymerase chain reaction (rtPCR) according to the WHO interim guidance [11] . Demographic data, co-morbidities, SARS-CoV-2 Polymerase Chain Reaction (PCR) results, additional laboratory tests (including Complete Blood Count (CBC), Lactate Dehydrogenase (LDH), Creatinine, C-Reactive Protein (CRP), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Ddimer, fibrinogen, and International Normalized Ration (INR)), home medications, and outcomes data of patients with a diagnosis of COVID-19 were abstracted from electronic medical records and entered into a de-identified electronic spreadsheet. This study was reviewed and approved by the Sapienza University/Umberto I Polyclinic Hospital Institutional Review Board.

All patients were queried on xerostomia, dysgeusia and hyposmia/anosmia, using a modified survey obtained from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 for taste and smell disorders [12] and the Fox Questionnaire for dry mouth [13] . The survey consisted of a total of ten questions divided into five sections; the first section assessed the patients' demographic information (gender and age) and date when the survey was administered. The second, third and fourth sections focused on the onset, duration and characterization of xerostomia, dysgeusia and hyposmia/anosmia. Patients rated their level of xerostomia, dysgeusia and hyposmia/anosmia on a 11-point scale (from 0=absent to 10=severe). The last section of the survey assessed the patients' tobacco and alcohol consumption (appendix 1). The survey was administered by phone by five investigators (DDV, EP, SM, EP, PJF) after discharge between June 4 th and June 12 th . Informed consent was obtained verbally as per protocol. Responses to the survey were recorded in an electronic spreadsheet for statistical analysis. The intensity of xerostomia, taste and smell dysfunctions was registered using a numeric rating scale (NRS) which ranged from 0 (absent) to 10 (maximum intensity). After assessing the normal distribution, median values and interquartile ranges (IQRs) were calculated for the NRS scores. Qualitative variables were assessed using chi-square test, while quantitative variables were firstly assessed for normal distribution and then compared through the Mann-Whitney U test.

In order to describe the presence of multiple oral symptoms and their different intensity levels in our study population, a k-means clusters analysis was performed [14] . The clustering process was determined considering xerostomia, gustatory and olfactory dysfunction scores, which were graded as absent (0), very low (1-2), low (3) (4) , intermediate (5) (6) , high (7-8) and very high (9) (10) . To determine the optimal number of clusters we used the Calinski and Harabasz stopping method; specifically, larger pseudo-F index values indicated a more distinct clustering [15] (Supplementary Table 2 ). The interpretation of clustering in the clinical context was assessed by an Oral Medicine specialist (AV) and expert oral health providers (EP, PJF, UR). Finally, clusters were compared according to the same variables previously considered for xerostomia, gustatory and olfactory dysfunction. All P values were considered statistically significant at P < .05. Data were 

A total of 326 patients tested positive for SARS-CoV-2 in the ED. Among these, 40 (12.2%) deceased before discharge, and were therefore ineligible to participate to the survey. A total of 157 patients were contacted via phone; 111 agreed to participate and completed the questionnaire (34.0%). Most patients were males (52.3%) with a median age of 57 (range: 48-67) ( Table 1) ; 38 patients reported being former (34.2%) and 7 patients current (6.3%) tobacco smokers, while 44.1% (n=49) of patients reported to be social alcohol consumers. Common signs and symptoms at ED presentation included fever (n=101, 90.9%), cough (n=52,46.8%), and dyspnea (n=38, 34.3%). Hypertension (n=29; 26.1%) and chronic pulmonary disease (n=11; 9.9%) were the most common co-morbidities. Of all queried patients (n=111), 5.4% (n=6) were admitted in the ICU, spending a median number of days of 12.5 (range: 5-22) (Supplementary table 1). All of them were males and had a median age of 60 (range: 54-82).

Xerostomia was reported by 51 (45.9%) patients with a median dryness score of five (range: 3-8) and

with 39/51 (76.5%) patients mentioning that it was their first-time experiencing xerostomia in their lifetime (Table 2) 

In order to evaluate the distribution between xerostomia, taste and smell dysfunction, a K-means cluster analysis was performed (table 3) , with three-cluster solution selection (cluster 1, cluster 2, cluster 3) to show the largest pseudo-F statistics. (Supplementary Table 2 of which had anosmia. The onset time was only considered for olfactory changes, which began before (11.8%), after (65.4%) or at the same time as the general or ENT symptoms associated with COVID-19 (22.8%). No onset presentation time was reported for gustatory changes [5] . In terms of prevalence and distribution, our work showed similar results with the studies mentioned above; however, we also described in detail the clinical characterization and onset time of such complications, which in several cases were the first symptoms of SARS-CoV-2 infection.

Our study had some limitations. First, the sample size was relatively small and therefore the findings may not be generalizable to all COVID-19 patients. Second, the survey was administered a few days after the diagnosis of COVID-19 and some responses may not be as accurate. Nonetheless, the information provided on xerostomia, olfactory and gustatory dysfunctions were obtained using validated scales and questionnaires in a standardized manner, which may have improved the accuracy of the results. Finally, only 34% of all COVID-19 patients included in the initial cohort (n=326) responded and participated to the survey, which mostly consisted of patients with mild to moderate COVID-19, with few co-morbidities and good prognosis, therefore not representative of the entire COVID-19 population.

In summary, we showed that xerostomia, olfactory and gustatory dysfunctions are common symptoms reported as concomitant, and in some cases the sole manifestation of COVID-19. Oral health and J o u r n a l P r e -p r o o f 

None or any oral symptom <5* Xerostomia 5* Dysgeusia 5* Hyposmia 5* Dysgeusia 5* + Xerostomia  5* Dysgeusia 5* + Hyposmia 5* Dysgeusia 5* + Xerostomia 5*+ Hyposmia 5* 1 Mainly prevalent xerostomia cluster: 97.9% of the patients had one symptom, all of them with a severity score < than 5 (0-10) 2 Mainly prevalent dysgeusia cluster with or without xerostomia cluster: more than 60% of the patients had two symptoms, most of them with a severity score > 5 (0-10) 3 Oral symptoms with or without olfactory alteration cluster: 50% of the patients had two symptoms, 50% had three symptoms, all of them with a severity score > than 5 (0-10) J o u r n a l P r e -p r o o f

COVID-19 Dashboard by the Center for Systems Science and Engineering

Public Health Interventions for COVID-19: Emerging Evidence and Implications for an Evolving Public Health Crisis

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Contribution of anosmia and dysgeusia for diagnostic of COVID-19 in outpatients

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

Olfactory Dysfunction in COVID-19: Diagnosis and Management

The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis

Detection of 2019-nCoV in Saliva and Characterization of Oral Symptoms in COVID-19 Patients

Smell and taste dysfunction in patients with COVID-19

Dysgeusia in COVID-19: Possible Mechanisms and Implications. Oral Surg Oral Med Oral Pathol Oral Radiol 2020

Clinical management of severe acute respiratory infection ( SARI ) when COVID-19 disease is suspected. Interim guidance

National Health and Nutrition Examination Survey 2013-2014. Data Documentation, Codebook, and Frequencies Taste & Smell (CSX_H). Centers Dis Control Prev

Subjective reports of xerostomia and objective measures of salivary gland performance

Automatic detection of erythemato-squamous diseases using k-means clustering

A dendrite method for cluster analysis

Olfactory and Oral Manifestations of COVID-19: Sex-Related Symptoms-A Potential Pathway to Early Diagnosis

Symptomatology in head and neck district in coronavirus disease (COVID-19): A possible neuroinvasive action of SARS-CoV-2

Olfactory and taste disorders in COVID-19: a systematic review

Smell dysfunction: a biomarker for COVID-19