10.14639/0392-100X-N1038
Objectives. Patients with coronavirus disease-19 (COVID-19) caused by severe acute res- piratory syndrome coronavirus 2 (SARS-CoV-2) may present with a wide range of symp- toms. In this paper, a detailed characterisation of mild-to-moderate ear, nose nd throat (ENT) symptoms is presented with the aim of recognising the disease early to help reduce further spread and progression.Methods. A total of 230 cases testing positive for SARS-CoV-2 and 134 negative controls were recruited for a case-control analysis. Symptoms were analysed using the Acute Respiratory Tract Infections Questionnaire, while other symptoms were investigated by ad hoc questions. Results. Among the study samples (n = 364), 149 were males and 215 were females with age ranging from 20 to 89 years (mean 52.3). Four main groups of symptoms were ob- tained: influenza-like symptoms, ENT-symptoms, breathing issues and asthenia-related symptoms, representing 72%, 69%, 64% and 53% of overall referred clinical manifesta- tions, respectively. ENT symptoms, breathing issues and influenza-like symptoms were as- sociated with positivity to SARS-CoV-2, whereas asthenia-related symptoms did not show a significant association with SARS-CoV-2 infection after controlling for other symptoms, comorbidities and demographic characteristics.Conclusions. ENT symptoms are equally represented with influenza-like ones as present- ing symptoms of COVID-19. Patients with ENT symptoms should be investigated for early identification and prevention of SARS-CoV-2 spread.
application/xml
1827-675X
1038
en
Paolo Boscolo-Rizzo
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
ENT symptoms
The importance of early detection of ENT symptoms in mild-to-moderate COVID-19
Text.Serial.Journal
https://www.actaitalica.it/
41
COVID-19
2021-05-14
2020-08-03
2021-05-17
2021-05-17
101-107
1
Paolo Boscolo-Rizzo
2021/05/14
10.14639/0392-100X-N1038
101
Department of Neurosciences, Section of Otolaryngology and Regional Centre for Head and Neck Cancer, University of Padua, Treviso, Italy
1827-675X
ENT symptoms
107
The importance of early detection of ENT symptoms in mild-to-moderate COVID-19
https://www.actaitalica.it/article/download/1038/572
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:101-107; doi: 10.14639/0392-100X-N1038




COVID-19


The importance of early detection of ENT symptoms
in mild-to-moderate COVID-19
Importanza del rilevamento precoce dei sintomi ORL nella COVID-19 lieve-moderata
Giacomo Spinato1,2, Giulio Costantini3, Cristoforo Fabbris1, Anna Menegaldo1, Francesca Mularoni1,
Piergiorgio Gaudioso1, Monica Mantovani1, Daniele Borsetto4, Ananth Vijendren5, Maria Cristina Da Mosto1,
Paolo Boscolo-Rizzo1
1
 Department of Neurosciences, Section of Otolaryngology and Regional Centre for Head and Neck Cancer, University of Padova,
Treviso, Italy; 2 Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova,
Padova, Italy; 3 Psychology Department, University of Milano-Bicocca, Milano, Italy; 4 Guy’s and St Thomas’ Hospitals, London,
United Kingdom; 5 ENT Department, Lister Hospital, Stevenage, United Kingdom


SUMMARY
Objectives. Patients with coronavirus disease-19 (COVID-19) caused by severe acute res-
piratory syndrome coronavirus 2 (SARS-CoV-2) may present with a wide range of symp-
toms. In this paper, a detailed characterisation of mild-to-moderate ear, nose nd throat
(ENT) symptoms is presented with the aim of recognising the disease early to help reduce
further spread and progression.
Methods. A total of 230 cases testing positive for SARS-CoV-2 and 134 negative controls were
recruited for a case-control analysis. Symptoms were analysed using the Acute Respiratory
Tract Infections Questionnaire, while other symptoms were investigated by ad hoc questions.
Results. Among the study samples (n = 364), 149 were males and 215 were females with
age ranging from 20 to 89 years (mean 52.3). Four main groups of symptoms were ob-
tained: influenza-like symptoms, ENT-symptoms, breathing issues and asthenia-related                Received: August 3, 2020
symptoms, representing 72%, 69%, 64% and 53% of overall referred clinical manifesta-                Accepted: September 6, 2020
tions, respectively. ENT symptoms, breathing issues and influenza-like symptoms were as-
sociated with positivity to SARS-CoV-2, whereas asthenia-related symptoms did not show              Correspondence
a significant association with SARS-CoV-2 infection after controlling for other symptoms,           Cristoforo Fabbris
comorbidities and demographic characteristics.                                                      piazzale Ospedale 1, 31100 Treviso, Italy
                                                                                                    Tel. +39 0422 322324. Fax +39 0422 2374
Conclusions. ENT symptoms are equally represented with influenza-like ones as present-
                                                                                                    E-mail: cristoforo.fabbris@gmail.com
ing symptoms of COVID-19. Patients with ENT symptoms should be investigated for early
identification and prevention of SARS-CoV-2 spread.
                                                                                                    Funding
KEY WORDS: COVID-19, SARS-CoV-2, early diagnosis, ENT symptoms                                      None.

                                                                                                    Conflict of interest
RIASSUNTO                                                                                           The Authors declare no conflict of interest.
Obiettivo. I pazienti con malattia da Coronavirus-19 (COVID-19) causata dal Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) possono presentare una vasta gamma
di sintomi. In questo articolo, è mostrata una caratterizzazione dettagliata dei sintomi nei          How to cite this article: Spinato G, Costantini G,
                                                                                                      Fabbris C, et al. The importance of early detection
pazienti con malattia lieve-moderata, al fine di riconoscere precocemente la malattia e
                                                                                                      of ENT symptoms in mild-to-moderate COV-
ridurne l’ulteriore diffusione.                                                                       ID-19.Acta Otorhinolaryngol Ital 2021;41:101-
Metodi. Un totale di 230 pazienti risultati positivi per infezione da SARS-CoV-2 e 134 sog-           107. https://doi.org/10.14639/0392-100X-N1038
getti risultati invece negativi sono stati reclutati per questa analisi caso-controllo. I sintomi
sono stati analizzati utilizzando l’Acute Respiratory Tract Infections Questionnaire, mentre        © Società Italiana di Otorinolaringoiatria
altri, sono stati indagati mediante domande ad hoc.                                                 e Chirurgia Cervico-Facciale
Risultati. La popolazione oggetto dello studio era composta da 364 soggetti; 149 erano
maschi e 215 femmine con età compresa tra 20 e 89 anni (media 52,3). Sono stati identifi-                          OPEN ACCESS
cati quattro gruppi di sintomi: sintomi simil-influenzali, sintomi ORL, problemi respiratori        This is an open access article distributed in accordance with
e sintomi astenia-correlati che rappresentavano rispettivamente il 72%, 69%, 64% e 53%              the CC-BY-NC-ND (Creative Commons Attribution-Non-
delle manifestazioni cliniche. Sintomi ORL, problemi respiratori e sintomi simil-influenzali        Commercial-NoDerivatives 4.0 International) license. The
                                                                                                    article can be used by giving appropriate credit and mentio-
erano associati a positività a SARS-CoV-2, mentre i sintomi correlati all’astenia non mo-
                                                                                                    ning the license, but only for non-commercial purposes and
stravano un’associazione significativa con l’infezione da SARS-CoV-2 dopo il controllo di           only in the original version. For further information: https://
altri sintomi, co-morbidità, e caratteristiche demografiche.                                        creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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G. Spinato et al.




Conclusioni. I sintomi ORL sono ugualmente rappresentati rispetto a quelli simil-influenzali nell’esordio della COVID-19. I pazienti con sin-
tomi ORL devono essere studiati per l’identificazione precoce e la prevenzione della diffusione del SARS-CoV-2.
PAROLE CHIAVE: COVID-19, SARS-CoV-2, diagnosi precoce, sintomi ORL



Introduction                                                            The study was approved by the ethics committee of Treviso
                                                                        and Belluno provinces, and informed consent was obtained
In December 2019, a world pandemic was caused by the
                                                                        verbally for telephone interviews.
severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) which originated in China 1. The virus belongs
                                                                        Questionnaire
to the beta coronavirus genus which has resulted in prior
                                                                        The Acute Respiratory Tract Infections Questionnaire
epidemics, notably the severe acute respiratory syndrome
                                                                        (ARTIQ) 9, a questionnaire commonly used to investigate
(SARS-CoV) and Middle East respiratory syndrome
                                                                        symptoms of respiratory infections, was employed as well
(MERS-CoV) 2. The virus has been noted to infect target
                                                                        as ad hoc questions. Questionnaires were administered by
cells by binding to the angiotensin-converting enzyme 2
                                                                        the authors G.S., C.F., A.M., F.M., and P.G. by telephone
(ACE2), which is overexpressed in patients affected by hy-
                                                                        interview. The ARTIQ questionnaire contains symptoms
pertension and diabetes who are treated with ACE inhibi-
                                                                        belonging to five subscales: Physical-upper respiratory
tors and angiotensin II receptor blockers 3,4.
                                                                        tract symptoms (13 items; e.g., “Dry Cough”), Physical-
The resultant syndrome has been called coronavirus dis-
                                                                        lower respiratory tract symptoms (8 items; e.g., “Sweat-
ease-19 (COVID-19) and has an incubation period ranging
                                                                        ing”), symptoms connected to sleep quality (4 items; e.g.,
from 2 to 14 days with a variety of potentially exhibited
                                                                        “Poor quality of sleeping”), psychological symptoms (5
symptoms 5. This can include asymptomatic patients as
                                                                        items; e.g., “Difficulty in thinking clearly”), and medica-
well as those with mild to moderate cases of influenza-like
                                                                        tion usage (8 items; e.g., “Taken eye drops”). It also has 8
illnesses, without the need for hospitalisation 6-8.
                                                                        items that were not part of any specific subscale: 5 of them
In this paper, we present a case-control series focusing on
                                                                        investigated other physical or psychological symptoms
mild to moderate symptoms to formulate a general over-
                                                                        (e.g., “Joint pains”, “Felt dizzy”), whereas three investigat-
view of COVID-19. Our study has two main goals: to char-
acterise the symptom structure of COVID-19, focusing on                 ed other experiences that did not directly assess symptoms
those that may be encountered by an otolaryngologist and                (e.g., “Cancelled leisure activities”, “Taken painkillers”).
to identify symptoms that could be used for early diagnosis             Participants indicated the experience of each symptom on a
of SARS-CoV-2 infection.                                                three-point scale (0 = No, 1 = Yes – some, and 2 = Yes – a
                                                                        lot). We investigated five additional symptoms (diarrhoea,
                                                                        nausea, vomiting, abdominal pain, and dizziness) by ad
Materials and methods                                                   hoc questions using the same response scale, for a total of
Participants and procedure                                              51 items. However, the analyses focused on a subset of 40
Participants were recruited from those who were tested posi-            items to better examine the configuration of the physical
tive for SARS-CoV-2 RNA by polymerase chain reaction                    and psychological symptoms of SARS-CoV-2 infection,
(PCR) on nasopharyngeal and oropharyngeal swabs. Patients               excluding those related to use of medicines and other ex-
underwent nasal swabs at Treviso General Hospital (Italy)               periences.
and were living in the same geographical area. These patients           Participants also indicated their smoking status (current,
had undergone swab tests as they were either symptomatic,               former, never), and isolated or associated comorbidities
or had been in close contact with SARS-CoV-2 positive pa-               [hypertension, cardiovascular disease, diabetes, chronic
tients, or were healthcare professionals, and were all per-             obstructive pulmonary disease (COPD), renal disease, liver
formed in-line with the local healthcare system COVID-19                disease, cancer, cerebrovascular disease].
guidelines. Only adults (≥ 18 years old) and non-hospitalised           All analyses were performed using package psych 10 in the
subjects were included to represent a mild-moderate spec-               software R 4.0.0. 11.
trum of affected COVID-19 individuals, amounting to 230
patients who were self-isolating at home. We also recruited             Characterisation of symptoms
age- and sex-matched 134 controls that had negative SARS-               The first goal of this study was to characterise the symptoms
CoV-2 PCR swabs as part of our case-control study design.               of infection with SARS-CoV-2. We used principal compo-
Stratification of this group was not considered, in order to            nent analysis as implemented in the psych R package 10 to
obtain the most general results as possible.                            examine the structure of the 40 symptoms in the overall



102
                                                                                                                   ENT symptoms in COVID-19




sample. Since symptoms were rated on an ordinal response       Table I. Comorbidities.
scale, we analysed the polychoric correlation matrix. The                                              Cases            Controls         p-value
scree-plot and parallel analysis 12 converged in indicating     Hypertension                        67 (29.1%)         12 (9.0%)         < .001
that four components provided an adequate description           Cardiovascular diseases             26 (11.3%)          8 (6.0%)          .003
of the symptom structure (the first six eigenvalues were        Diabetes                             21 (9.1%)         3 (2.2%)          < .001
18.34, 2.86, 2.08, 2.00, 1.65 and 1.47; the first six eigen-    COPD                                 10 (4.3%)         7 (5.2%)           .629
values extracted from randomly resampled data were 2.94,        Tumours                              9 (3.9%)          5 (3.7%)           .424
2.23, 2.06, 1.94, 1.84 and 1.76). Through an inspection of      Renal diseases                       7 (3.0%)          3 (2.2%)           .344
component loadings, we identified the first component as        Cerebrovascular diseases             5 (2.2%)          1 (0.7%)           .219
asthenia-related symptoms, combining both psychological         Hepatic diseases                     1 (0.4%)            0 (0%)             -
symptoms and sleeping issues of the ARTIQ. The second          COPD: chronic obstructive pulmonary disease. A series of exact binomial tests revealed
component, i.e. Ear, Nose, Throat (ENT) symptoms, main-        that, when examined individually, hypertension, cardiovascular diseases, and diabetes
                                                               were significantly associated to SARS-CoV-2.
ly reflected physical-upper respiratory tract symptoms.
The third component (influenza-like) included mostly
influenza-like symptoms, also including gastrointestinal       Symptoms in SARS-CoV-2 positive subjects
symptoms, whereas the last component (breathing-issues)        Component loadings are reported in Table II. First we fo-
received the highest loadings by symptoms connected with       cused on the mere presence of any of the marker symptoms
breathing issues. The four components all correlated with      for each cluster and overall. Table III shows the propor-
each other (RS ranging between 0.31 and 0.46). We saved        tion of cases and controls who reported none of the mark-
component scores to use in subsequent analyses.                er symptoms (column “Absent”), the proportion of those
For each symptom component, we defined a set of marker         who reported at least one marker symptom, independent of
symptoms, symptoms that showed a primary loading > 0.40        whether it was reported as mildly present (Yes – some) or
on that component and whose remaining loadings were at         severely present (Yes – a lot; column “At least one”), and
most half of their primary one. These symptoms were thus       the proportion of those who reported at least one marker
those more clearly connected with a certain component,         symptom as severely present (column “At least one se-
and not being as strongly connected to other components.       vere”). Most patients reported at least one of the marker
We further investigated whether marker symptoms would          symptoms as at least mildly present (92%), whereas most
allow the identification of SARS-CoV-2 infection. We per-      controls (80%) did not report any marker symptom.
formed logistic regression analysis in which we regressed      Second, we inspected the number of reported symptoms.
the diagnosis (1 = positive vs 0 = negative) on age, gender,   For each symptom component, we computed the average
smoking status, the three most frequent health conditions      number of marker symptoms, independent of whether a
(hypertension, cardiovascular diseases and diabetes), and      symptom was reported as mild or severe, and also com-
the principal component scores for each symptom compo-         puted the average number of severely present symptoms
nent.                                                          (Tab. IV). On average, cases reported more than one symp-
                                                               tom for each cluster as mild or severe, whereas controls
Results                                                        reported on average less than one symptom. A series of
                                                               Welch independent samples t-tests indicated that differ-
Baseline characteristics                                       ences among cases and controls were higher when examin-
A total of 364 individuals (149 males and 215 females)         ing reporting symptoms independent of their severity, then
were recruited for the study with ages ranging from 20 to      when focusing on symptoms reported as severe.
89 years (mean 52.3, SD = 15.8). 217 cases (94.3%) and
110 controls (82.1%) were never/former smokers, while 11       Indicators of SARS-CoV-2 infection
patients (4.8%) and 24 controls (17.9%) were ever smok-        Since data were not randomly sampled from the popula-
ers, respectively (P < 0.001). Comorbidities were observed     tion but were obtained using a case-control strategy, aimed
in 146 cases (63.3%) and 39 controls (29.0%) (Tab. I). Even    at balancing the number of positive and negative subjects,
if hypertension, cardiovascular diseases and diabetes were     positive patients were overrepresented compared to the
significantly more prevalent in cases (Tab. I), a chi-square   general population. We controlled for potential biases by
test for independence showed that the pattern of comor-        applying the corrections for rare-event logistic regression
bidities was not significantly different between cases and     suggested by King and Zeng 13,14, as implemented in the
controls, χ2(7) = 9.58, P = 0.222.                             relogit module of the R package Zelig 15. Using public-



                                                                                                                                               103
G. Spinato et al.




Table II. Principal component analysis (PCA) of 51 symptoms.
 Variable                                                                       Asthenia-related          ENT-symptoms             Influenza-like         Breathing issues
                                                                                   symptoms                                          symptoms
 Been awake most of the night                                                          0.91
 Difficulty falling asleep                                                             0.91
 Waking up several times at night                                                      0.79
 Poor quality of sleeping                                                              0.78
 Been irritable                                                                        0.68                                             0.21
 Been in a bad mood                                                                    0.64                                             0.26
 Not feeling yourself                                                                  0.45                                             0.32                     0.33
 Vertigo                                                                               0.34                     0.21                    0.24
 Swollen glands                                                                        0.28                     0.26                                             0.24
 Blocked nose                                                                                                   0.86
 Runny nose                                                                                                     0.84
 Sneezing                                                                                                       0.73
 Muscle pain                                                                                                    0.67                    0.32
 Joint pain                                                                                                     0.59                    0.30                    0.21
 Painful sinuses                                                                       0.38                     0.58                                            -0.25
 Painful pressure in ears                                                              0.27                     0.58
 Sore throat                                                                           0.25                     0.56
 Tickles in the throat                                                                 0.21                     0.51
 Watery eyes                                                                                                    0.42                                             0.27
 Hoarseness                                                                                                     0.38
 Vomiting                                                                                                                               0.86                    -0.20
 Nausea                                                                                                                                 0.78
 Chills                                                                                                         0.28                    0.64
 Feeling feverish                                                                                                                       0.63                     0.24
 Diarrhoea                                                                                                                              0.59                     0.20
 Abdominal pain                                                                        0.24                                             0.58
 Headache                                                                                                       0.44                    0.51
 Sweating                                                                                                                               0.48                     0.28
 Loss of appetite                                                                      0.30                                             0.48
 Felt tired                                                                            0.33                                             0.38                     0.38
 Difficulty in thinking clearly                                                        0.26                                             0.38                     0.30
 Felt dizzy                                                                            0.32                                             0.34                     0.27
 Shortness of breath                                                                                                                                             0.92
 Problems breathing                                                                                                                                              0.91
 Wheezing                                                                                                                                                        0.90
 Being so unwell you had to stay in bed                                                0.37                                             0.32                     0.48
 Dry cough                                                                                                                                                       0.46
 Difficulty in going about your daily business                                          0.35                                            0.38                     0.41
 Coughing up mucus                                                                     -0.30                    0.23                    0.33                     0.40
 Chest pain                                                                             0.25                    0.20                                             0.27
 Correlation among rotated components
    Asthenia-related symptoms                                                          1.00
    ENT symptoms                                                                       0.46                     1.00
    Influenza-like symptoms                                                            0.45                     0.36                    1.00
    Breathing issues                                                                   0.42                     0.31                    0.39                     1.00
The first panel reports oblimin-rotated component loadings, the second panel reports correlations among components. PCA was performed on the smoothed polychoric correlation
matrix among symptoms. A continuity correction of 0.50 was applied to empty cells when computing polychoric correlations (9). Loadings smaller than 0.20 in absolute value are
not shown. Primary loadings larger than 0.40 are shown in bold when no other loading was larger than half the primary loading.


104
                                                                                                                                                        ENT symptoms in COVID-19




Table III. Presenting symptoms in cases and controls.
                                                                                             Cases                                                      Controls
    Symptom                                                            Absent          At least one        At least one            Absent          At least one        At least one
                                                                                                              severe                                                      severe
    Asthenia-related symptoms (6 marker symptoms)                    109 (47%)            121 (53%)          38 (17%)             120 (90%)            14 (10%)            8 (6%)
    ENT symptoms (7 marker symptoms)                                 72 (31%)             158 (69%)          56 (24%)             110 (82%)            24 (18%)           12 (9%)
    Influenza-like symptoms (6 marker symptoms)                      64 (28%)             166 (72%)          72 (31%)             114 (85%)            20 (15%)           8 (6%)
    Breathing issues (4 marker symptoms)                             83 (36%)             147 (64%)          44 (19%)             117 (87%)            17 (13%)           5 (4%)
    Total (23 marker symptoms)                                        19 (8%)             211 (92%)         122 (53%)             107 (80%)            27 (20%)          13 (10%)
For each symptom component, column “Absent” reports the proportion of participants without any of the marker symptoms. Column “At least one” reports the proportion of
participants with at least one marker symptom (independent of whether the symptom was indicated as mildly or severely present). Column “At least one severe” reports the
proportion of participants who reported at least one marker symptom as severe.



Table IV. Prevalence of symptoms by component.
                                                                      Mild or severe                                                              Severe
    Symptom                                     M (SD)             M (SD)             t         df          p           M (SD)             M (SD)            t          df          p
                                               controls           patients                                             controls           patients
    Asthenia-related symptoms                 0.38 (1.26)       1.47 (1.85)        6.69      353.91 < .001           0.15 (0.71)        0.39 (1.04)        2.63      353.26       .009
    (6 marker symptoms)
    ENT-symptoms                              0.51 (1.37)       1.86 (1.77)        8.10      333.82 < .001           0.24 (0.94)        0.38 (0.77)        1.46      237.50       .145
    (7 marker symptoms)
    Influenza-like symptoms                   0.43 (1.18)       1.69 (1.51)        8.86       332.31 < .001          0.12 (0.54)        0.53 (0.93)        5.40      361.94 < .001
    (6 marker symptoms)
    Breathing issues                          0.23 (0.70)       1.37 (1.41)        10.19      354.74 < .001          0.05 (0.31)        0.34 (0.84)        4.74      317.73 < .001
    (4 marker symptoms)
    Total (23 marker symptoms)                1.55 (3.82)       6.39 (4.38)        11.03      309.81 < .001          0.56 (2.08)        1.65 (2.37)        4.57      308.79 < .001
For each symptom component, the table reports the average number of marker symptoms indicated as mild / severe (left panel) or severe (right panel) for patients and control. The table
reports also the standard deviations (SD) and a Welch t-test for independent samples comparing the prevalence of symptoms in patients and controls. df = degrees of freedom.



domain data from the Italian Civil Protection in the Veneto                                     Therefore, we estimated that the probability of testing posi-
region on 497,045 swabs (updated to May 16th 2020) 16, we                                       tive by a swab without being hospitalised, was about 3.1%.
estimated that the proportion of positive cases over swabs                                      We used this as the estimate of the tau parameter for the
was 3.8%. About 17% of positive subjects were hospital-                                         rare-event logistic regression 13. The results are reported in
ised with symptoms, whereas 83% were not hospitalised.                                          Table V and show that males and non-smokers were more

Table V. Rare-event logistic regression predicting SARS-CoV-2.
 Predictor                                               b                                  Exp(b)                     S.E.                        Z                         p
    (Intercept)                                                  -4.463                      0.012                    0.556                     10.56                   < 0.001
    Age                                                           0.017                      1.017                    0.011                      1.49                    0.105
    Gendera                                                       1.009                      2.744                    0.295                     2.93                    < 0.001
    Smoking statusb                                              -1.598                      0.202                    0.491                      2.94                    0.001
    Hypertensionc                                                 0.748                      2.112                    0.426                     2.03                     0.079
    Cardiovascular diseasesc                                     -0.035                      0.965                    0.532                      0.14                    0.947
    Diabetesc                                                    -0.056                      0.946                    0.708                      0.06                    0.937
    Asthenia-related symptoms                                     0.196                      1.216                    0.222                      0.82                    0.377
    ENT-symptoms                                                  0.696                      2.007                    0.212                      3.29                    0.001
    Influenza-like symptoms                                       0.647                       1.91                    0.228                      1.98                    0.004
    Breathing issues                                              0.824                       2.28                    0.259                      2.98                    0.001
a
 Gender was coded as 0 for females and 1 for males. b Smoking status was coded as 0 for never or former, and 1 for current smokers. c Hypertension, cardiovascular diseases and
diabetes were coded as 0 for absent and 1 for present. S.E.: Standard Error.




                                                                                                                                                                                    105
G. Spinato et al.




likely to be diagnosed as positive. Crucially, of the four       headache (46.4%), cough (44.9%) and dizziness (43.5%),
symptom components, ENT-symptoms, breathing issues               with diarrhoea present in only a few cases (4.3%) 20,21. An
and influenza-like symptoms were associated with positiv-        analysis of the commonest MERS symptoms by Assiri et
ity for SARS-CoV-2, whereas asthenia-related symptoms            al. 22 found that fever was present in 98% of cases, nasal
did not show a significant association with SARS-CoV-2           symptoms in 87%, dyspnoea in 72%, cough in 47%, diar-
infection after controlling for other symptoms, comorbidi-       rhoea in 26% and headache in 13%.
ties and demographic characteristics.                            A comparison between components of the three SARS-
                                                                 CoV-2 subtypes revealed that ENT symptoms are present
Discussion                                                       in less than 50% of SARS and MERS patients (mean rates
                                                                 44.7% and 49%, respectively), whereas they account for
According to CDC guidelines 17, COVID-19 must be sus-            almost 70% in COVID-19. Conversely, influenza-like com-
pected in case of fever or chills, cough, shortness of breath,   ponents are present in 51% of SARS, 62% of MERS and
fatigue, muscle or body aches, headache, new loss of taste or    72% of COVID-19 patients. On the other hand, breathing
smell, sore throat, congestion or runny nose, nausea or vom-     issues are slightly higher, with 70% of presentations in
iting, or diarrhoea. Among the 364 patients recruited in this    SARS and MERS (mean rates 71% and 72%, respectively),
study, 230 tested positive for SARS-COV-2 via nasopharynx        and only 64% in mild-to-moderate COVID-19. There was a
and oropharynx swabs. Statistical analysis of data underlined    high rate of discrepancy in asthenic-symptom components
that, in mild-to-moderate COVID-19, four main symptom            with rates of 78% in SARS and 53% in COVID-19.
groups may be identified using principal component analy-        ENT symptoms accounted for 69% of overall mild-to-mod-
sis. These components are influenza-like symptoms, general       erate symptoms in our case series of positive cases. These
ENT-symptoms, breathing and asthenia-related issues. In-         comprised of nasal obstruction, rhinorrhoea, sneezing, ear
terestingly, the two latter components did not clearly mirror    fullness, sore throat, tearing, neck swelling, hoarseness and
components identified by Aabenhus et al. 9.                      dizziness. In particular, among these clinical manifesta-
In contrast to 80% of negative-swab subjects who did not         tions, it is worth noting that some of these symptoms (i.e.
exhibit any symptom, 92% of positive-swab patients pre-          nasal obstruction, rhinorrhoea, sneezing, ear fullness, sore
sented with at least one symptom. Specifically, 72% of pa-       throat, throat discomfort) were significantly more prevalent
tients showed influenza-like symptoms, 69% showed ENT            compared to other comparable ENT ones (e.g., vertigo,
symptoms, 64% showed breathing issues and 53% asthe-             chills, headache, swollen glands).
nia-related symptoms.                                            Alterations of smell and taste were previously widely
When examined individually, hypertension, cardiovascular         evaluated by our research group. We analysed 202 patients
diseases and diabetes were significantly associated with         with positive COVID-19 swabs and showed that 65% re-
SARS-CoV-2 infection. These few correlations may derive          ported smell and taste alterations in addition to the other
from the number of the cases analysed, which had mild-to-        ENT symptoms reported above 23. These patients were re-
moderate symptoms. On the other hand, other comorbidi-           viewed 4 weeks after onset of their sensory changes: 50%
ties may have a greater impact in patients showing severe        m recovered completely, 40% had improvement and 10%
clinical manifestations 18.                                      had unchanged or worsened symptoms 24-26. Reports from a
Moreover, our results show a significant lower prevalence of     different study on household members with positive COV-
COVID-19 in females and current smokers. This significant-       ID-19 swabs found that 38% showed typical COVID-19
ly reduced risk of SARS-CoV-2 infection among smokers is         symptoms and 22% had these symptoms in association
quite intriguing considering that smokers are usually more       with altered sense of smell and taste, while 4% only had al-
prone to respiratory infections. According to the authors’       teration of smell and taste as an isolated symptom 27. These
personal experience, even if not validated, there is a para-     data sets are consistent with a recent systematic review and
doxical protective role of current smoking on COVID-19.          meta-analysis on 3563 patients who had positive swab for
Viruses of the SARS-CoV-2 family have been known to              SARS-CoV-2. The authors found that 67% of mild to mod-
cause prior pandemics; the SARS coronavirus in 2002-             erate cases had smell or taste loss, whereas the rates among
2003 and Middle East respiratory syndrome (MERS) coro-           hospitalised patients was 31% 28.
navirus in 2012. These two viruses mainly resulted in res-
piratory symptoms, as the infection tended to be localised
in the lower airway tract 19. Literature published on SARS
                                                                 Conclusions
showed that the most frequent symptoms were persistent           ENT symptoms during the COVID-19 pandemic should
fever (99%), nasal symptoms (15-73%), dyspnoea (71%),            be treated with caution and not underestimated. Patients



106
                                                                                                                              ENT symptoms in COVID-19




with new onset nasal obstruction, sore throat and ear full-                    12
                                                                                    Horn JL. A Rationale and test for the number of factors in factor
                                                                                    analysis. Psychometrika 1965;30:179-185. https://doi.org/10.1007/
ness should lead to a suspicion of COVID-19, with cas-                              BF02289447
es of sudden loss of smell and taste raising further alarm                     13
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of mild to moderate SARS-CoV-2 infection. Further high-                             pan.a004868
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                                                                               15
                                                                                    Christine C, Honaker J, Imai K, et al. Zelig: Everyone’s Statistical
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to help us identify if these ENT symptoms should form part                     16
                                                                                    Ministero della salute. http://www.salute.gov.it/
of the screening pathway for COVID-19 to be adopted by                         17
                                                                                    Centers for Disease Control and Prevention; https://www.cdc.gov/
nations faced with the pandemic.                                                    coronavirus/2019-ncov/symptoms-testing/symptoms.html
                                                                               18
                                                                                    Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its
                                                                                    effects in patients infected with SARS-CoV-2: a systematic re-
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