10.14639/0392-100X-suppl.1-42-2022-02
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coro- navirus 2 (SARS-CoV-2) is characterised by a wide spectrum of disease severity ranging from asymptomatic or oligosymptomatic cases to severe and life-threatening forms. As this new coronavirus is a respiratory virus, it is not surprising that many symptoms caused by SARS-CoV-2 infection are related to the involvement of the upper respiratory tract. In ad- dition the most pathognomonic of symptoms, i.e. the alteration of smell, nasal obstruction, sore throat and cough have been consistently described as early symptoms of the disease. However, for other ENT symptoms, such as oral lesions and audio-vestibular changes, a causal relation is far from proven. The rapid and extensive spread of COVID-19 makes it difficult to demonstrate a causative link between several ENT symptoms and SARS-CoV-2 infection and it is reasonable to assume that at least in some cases this link is actually coincidental in some cases. Moreover, following the phenomenon of the race to publish, there has been an uncontrolled release of poor-quality articles showing the most disparate associations mainly based on a temporal association between SARS-CoV-2 infection and symptoms of various types including those of the ENT area. In this narrative review of the literature, we will critically describe the ENT symptoms of COVID-19.
text/xml
1827-675X
2106
en
Paolo Boscolo-Rizzo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
symptoms
ENT symptoms in acute COVID-19: a narrative review
Text.Serial.Journal
https://www.actaitalica.it/
42
Annual congress report
2022-04-26
2022-04-06
2022-04-28
2022-04-28
S14-S19
1
Paolo Boscolo-Rizzo
2022/04/26
10.14639/0392-100X-suppl.1-42-2022-02
S14
Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, Trieste, Italy
1827-675X
symptoms
S19
ENT symptoms in acute COVID-19: a narrative review
https://www.actaitalica.it/article/download/2106/764
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42(SUPPL.1):S14-S19; doi: 10.14639/0392-100X-suppl.1-42-2022-02




ENT symptoms in acute COVID-19: a narrative review
Sintomi ORL durante la fase acuta della COVID-19: una revisione narrativa
Giancarlo Tirelli, Paolo Boscolo-Rizzo
Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, Trieste, Italy


SUMMARY
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coro-
navirus 2 (SARS-CoV-2) is characterised by a wide spectrum of disease severity ranging
from asymptomatic or oligosymptomatic cases to severe and life-threatening forms. As this
new coronavirus is a respiratory virus, it is not surprising that many symptoms caused by
SARS-CoV-2 infection are related to the involvement of the upper respiratory tract. In ad-
dition the most pathognomonic of symptoms, i.e. the alteration of smell, nasal obstruction,
sore throat and cough have been consistently described as early symptoms of the disease.
However, for other ENT symptoms, such as oral lesions and audio-vestibular changes, a
causal relation is far from proven. The rapid and extensive spread of COVID-19 makes it
difficult to demonstrate a causative link between several ENT symptoms and SARS-CoV-2
infection and it is reasonable to assume that at least in some cases this link is actually
coincidental in some cases. Moreover, following the phenomenon of the race to publish,
there has been an uncontrolled release of poor-quality articles showing the most disparate
associations mainly based on a temporal association between SARS-CoV-2 infection and
symptoms of various types including those of the ENT area. In this narrative review of the
literature, we will critically describe the ENT symptoms of COVID-19.
KEY WORDS: coronavirus, COVID-19, ear nose throat, manifestation, otolaryngologic,
SARS-CoV-2, symptoms

RIASSUNTO
La malattia da coronavirus 2019 (COVID-19) causata dal coronavirus 2 della sindrome respi-
ratoria acuta grave (SARS-CoV-2) può essere caratterizzata da un ampio spettro di gravità che
va da casi asintomatici o pauci-sintomatici a forme gravi e letali. Poiché il nuovo coronavirus
è un virus respiratorio, non sorprende che molti sintomi causati dall’infezione da SARS-CoV-2
                                                                                                    Received: January 19, 2022
siano legati al coinvolgimento delle prime vie respiratorie. Oltre al più patognomonico dei
                                                                                                    Accepted: February 2, 2022
sintomi, ovvero l’alterazione del senso dell’olfatto, ostruzione nasale, mal di gola e tosse sono
stati costantemente descritti come primi sintomi della malattia. Tuttavia, per altri sintomi ORL,
                                                                                                    Correspondence
come lesioni del cavo orale e alterazioni audio-vestibolari, una relazione causale è tutt’altro
                                                                                                    Paolo Boscolo-Rizzo
che dimostrata. L’estrema diffusione della COVID-19 rende spesso difficile dimostrare un nes-       University of Trieste, strada di Fiume 447, 34149
so causale tra diversi sintomi ORL e l’infezione da SARS-CoV-2 ed è ragionevole presumere           Trieste, Italy
che almeno in alcuni casi questo legame sia effettivamente casuale. Inoltre, a seguito di un        Tel. + 39 040 394450
fenomeno di vera e propria corsa alla pubblicazione, c’è stato un rilascio incontrollato di         E-mail: paolo.boscolorizzo@units.it
articoli di scarsa qualità che mostravano le associazioni più disparate basate principalmente
su un’associazione temporale tra infezione da SARS-CoV-2 e sintomi di vario tipo, compresi
                                                                                                      How to cite this article: Tirelli G, Boscolo-
quelli dell’area ORL. In questa revisione narrativa della letteratura descriveremo in modo            Rizzo P. ENT symptoms in acute COVID-19:
critico i sintomi ORL della COVID-19.                                                                 a narrative review. Acta Otorhinolaryngol Ital
PAROLE CHIAVE: coronavirus, COVID-19, orecchio naso gola, manifestazioni,                             2022;42(SUPPL.1):S14-S19.          https://doi.
                                                                                                      org/10.14639/0392-100X-suppl.1-42-2022-02
otorinolaringoiatrico, SARS-CoV-2, sintomi
                                                                                                    © Società Italiana di Otorinolaringoiatria
Introduction                                                                                        e Chirurgia Cervico-Facciale


Since December 2019, a pandemic of coronavirus disease 2019 (COVID-19)                                             OPEN ACCESS
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)                              This is an open access article distributed in accordance with
                                                                                                    the CC-BY-NC-ND (Creative Commons Attribution-Non-
has spread globally 1,2. A wide spectrum of disease severity has been reported                      Commercial-NoDerivatives 4.0 International) license. The
ranging from asymptomatic or oligosymptomatic cases to severe and life-                             article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
threatening forms of interstitial pneumonia, which can develop into acute res-                      only in the original version. For further information: https://
piratory distress syndrome and death.                                                               creativecommons.org/licenses/by-nc-nd/4.0/deed.en




S14
                                                                                                         ENT symptoms in COVID-19




As the new coronavirus is a respiratory virus which spreads        In a consecutive series of 202 home-isolated patients with
primarily through droplets generated when an infected per-         PCR-confirmed SARS-CoV-2 infection, using a validated
son coughs or sneezes, it is not surprising that a wide range      structured questionnaire, we observed the following preva-
of symptoms caused by SARS-CoV-2 infection are related             lence of non-chemosensory ENT symptoms: cough 60%,
to the involvement of the upper respiratory tract. Conse-          blocked nose 31%, sore throat 31% and sinonasal pain
quentially, ENT symptoms are among the most common in              17% 6.
COVID-19. In our original investigation, upper respiratory         A recent meta-analysis reported a pooled prevalence of
tract symptoms accounted for 69% of overall symptoms               cough and nasal obstruction of 53 and 26%, respectively,
in patients with mild-to-moderate COVID-19 and were                followed by sore throat (18%) and rhinorrhoea (13%).
comprised of nasal obstruction, rhinorrhoea, sneezing, ear         While symptoms like fever, cough, fatigue, vomiting/diar-
fullness, sore throat, tearing, neck swelling, hoarseness          rhoea, and dyspnoea were most common among hospital-
and dizziness 3. However, following the phenomenon of              ised patients, nasal obstruction, sore throat and rhinorrhea
the race to publish about coronavirus, there has been an           were conversely most prevalent in patients with mild-to-
uncontrolled release of poor-quality articles showing the          moderate COVID-19 15.
most disparate associations between SARS-CoV-2 infec-              Outstandingly, ENT symptoms are among the first to mani-
tion and symptoms of various types including those of the          fest, and thus their prompt identification can dramatically
ENT area 4,5.                                                      prevent the spread of the infection 6,16. Furthermore, olfac-
We have already reported how smell and taste alterations           tory loss and nasal obstruction are often dissociated symp-
are among the most frequent symptoms at the onset of the           toms and, if they coexist, the evolution of one is independ-
disease affecting around two-third of patients with mild-          ent of the other 7.
moderate disease 6, as they are among the most persistent
symptoms 7,8, and they are predominant in long-COVID               Oral manifestations of COVID-19
syndrome 9,10, as they can be an indication of infection in
the context of patients in home isolation 11, since the self-      Although the detection of SARS-CoV-2 in saliva reveals
reported alterations of the olfactory function underestimate       the presence of the virus in the oral cavity, the impact of
the real prevalence and persistence that emerges through           SARS-CoV-2 on oral diseases is still poorly studied 17. Nu-
psychophysical tests 12,13. As this topic will be the subject of   merous studies have described different types of lesions
a separate discussion in this special issue, in this review we     affecting the oral cavity in COVID-19 patients. While for
will limit the description to non-chemosensory ENT symp-           many of these a coincidental relationship is rather prob-
toms of SARS-CoV-2 infection.                                      able, while for others lesions a direct or indirect link with
                                                                   COVID-19 seems established 18.
                                                                   Oral cavity findings, including lingual papillitis, glossitis,
Upper airway-related general symptoms                              aphthous stomatitis, xerostomia and mucositis were ob-
The correct definition of the ENT symptomatology in                served up to 26% of patients with COVID-19 19. Aragone-
COVID-19 is hampered by two main factors. On one hand,             ses et al. 18, in a very comprehensive review and meta-anal-
many of the clinical studies aimed at describing the clinical      ysis, classified oral manifestations in COVID-19 according
features of COVID-19 are focused on the more severe signs          to the putative aetiology. Aphthous lesions and oral ulcers
and symptoms of involvement of the lower airways, while            are among the most consistently observed manifestations
completely or partially ignoring upper airway involvement.         for which a direct aetiological role of SARS-CoV-2 is
On the other hand, the extreme spread of COVID-19 makes            likely 19,20. These lesions can affect any sub-site of the oral
it difficult to demonstrate a causal link between atypical         cavity, although the tongue is more frequently involved. A
ENT symptoms and SARS-CoV-2 infection and it is rea-               variable prevalence of oral manifestations including oral
sonable to assume that at least in some cases this link is         ulceration, cheilitis and glossitis were observed in the con-
actually coincidental.                                             text of multi-organ involvement, i.e. multisystem inflam-
Many studies have consistently described cough and nasal           matory syndrome and Kawasaki-like disease in children
obstruction as the most common non-chemosensory ENT                with COVID-19 21-23. Furthermore, a substantial group of
symptoms of COVID-19. Due to the retrospective design              oral lesions are attributable to iatrogenic lesions, such as
of many studies, the prevalence of ENT symptoms such as            intubation injuries, drug reactions and opportunistic infec-
cough, sore throat, runny nose and nasal obstruction in the        tions during SARS-CoV-2 infection 24,25.
different studies is highly variable with rates ranging from       In addition, periodontal disease may increase during COV-
3 to 90% 14.                                                       ID-19 26 and on the other hand, a poor periodontal state can



                                                                                                                             S15
G. Tirelli, P. Boscolo-Rizzo




favour a vicious circle with an increase in the indexes of in-    CoV-2 virus, and the transmembrane protease serine 2 and
flammation, aspiration of bacteria and consequent increased       FURIN cofactors required for virus entry 35. However, data
risk of pneumonia. Although it is difficult to state which        about possible audio-vestibular dysfunction secondary to
of the various oral lesions associated with COVID-19 are          SARS-CoV-2 infection are mainly based on case reports
the most prevalent, it seems that a higher frequency can be       and small case series 36,37.
found in older, hospitalised patients with severe infection 27.   While generic dizziness was self-reported by 14% of pa-
The hypothesis that the oral manifestations are secondary         tients with mild-to-moderate COVID-19 6, more specific
lesions resulting from the deterioration of systemic health       audio-vestibular symptoms, i.e. sensorineural hearing loss
or treatments for COVID-19 is most probably correct. The          and vertigo, were indeed anecdotally described with au-
pharmacological agents against COVID-19 are related to            thors theorising a direct correlation to SARS-CoV-2 infec-
several adverse reactions, including oral lesions 28.             tion mainly based on a temporal association 38.
                                                                  A more recent study compared evolution of incidence of
Salivary alterations                                              sudden sensorineural hearing loss and Meniere’s disease
Xerostomia was reported by 50% of patients with a me-             from 2016 to 2020 and observed a decrease in the inci-
dian dryness score of 5 (range: 3-8) and for 76.5% patients       dence of Meniere’s disease, while the incidence of sud-
mentioning that it was their first-time experiencing xeros-       den sensorineural hearing loss remained unchanged from
tomia in their lifetime 29. The hypothesis is that the xeros-     2016 to 2020 indicating that audio-vestibular symptoms in
tomia reported in patients with the COVID-19 occurs due           COVID-19 patients are probably coincidental rather than
to the neuro-invasive and neurotropism potential of SARS-         causal 39. However, one should consider that the restrictive
CoV-2 30. In fact, angiotensin-converting enzyme 2 (ACE-          measures implemented during the pandemic could have
2), reported to be the main site of entry of SARS-CoV-2           reduced exposure to triggers of audio-vestibular diseases
into the cell, was found to be present in the ductal elements     and counterbalanced any increase related to SARS-CoV-2
of the salivary glands 31. Overall, studies are still neces-      infection.
sary to unveil the precise pathophysiological mechanism           Thus, based on the current literature, no definitive conclu-
by which SARS-CoV-2 causes the reported xerostomia and            sions can be drawn about the possible clinical impact of
taste disturbances 32.                                            SARS-CoV-2 on the inner ear and large case-control stud-
                                                                  ies are necessary to clarify the effect of SARS-CoV-2 in-
Oropharynx                                                        fection in the onset of audio-vestibular symptoms.
The oropharyngeal tissue is one of the main harbour sites         Regarding hearing disorders, it seems that SARS-CoV-2
of the infection, main site of taking the sample for testing      infection may cause a worsening of symptoms in pa-
and a main source of transmission of infection. However, it       tients already suffering from tinnitus. This highlights the
was reported that pharyngeal erythema and tonsil enlarge-         diverse response that both internal and external factors
ment are not common manifestations of SARS-CoV-2 in-              have on tinnitus levels. Some authors stated that clinical
fection, and these signs are present in only about 5 and 1%       services should be mindful that tinnitus may be caused
of cases, respectively 33. However, sore throat is referred by    by contracting COVID-19 and pre-existing tinnitus may
around one-third of patients 6.                                   be exacerbated 40. However, little evidence has been
                                                                  found regarding the onset of new tinnitus contextual to
Temporomandibular disorders                                       SARS-CoV-2 infection 41 and it is not clear if this could
Indirectly caused by the coronavirus due to the stress relat-     be a direct viral effect or the consequence of ototoxicity
ed to the pandemic situation and the governmental choices         of drugs used during hospitalization of patients 42.
of the various countries in its management, reports have
noted an increased number of people experiencing teeth            COVID-19 and acute otitis media
grinding and oral pain during the COVID-19 pandemic as a          Concerning a hypothetical link between SARS-CoV-2 in-
consequence of increased stress. On the other hand, stress,       fection and otitis media, the literature includes small case
anxiety and depression due to COVID-19 lead to increased          series and case reports 43,44. Although researchers have
orofacial pain, TMD and bruxism 34.                               found the presence of virus in the middle ear of subjects
                                                                  who died from COVID-19, a direct role of SARS-CoV-2
                                                                  in the aetiopathogenesis of otitis media has not been dem-
Audio-vestibular symptoms                                         onstrated 45.
Adult human inner ear tissue has been shown to co-express         It is reasonable to hypothesise that a viral infection of the
the angiotensin-converting enzyme 2 receptor for SARS-            upper airways such as that caused by SARS-CoV-2, in con-



S16
                                                                                                                        ENT symptoms in COVID-19




Table I. Definitive, probable, possible and complication-related ENT symptoms of COVID-19.
 Definitive symptoms                            Probable symptoms                     Possible symptoms          COVID-19 complication-related
                                                                                                                          symptoms
Cough 6,14,15,16                           Aphthous stomatitis 18,19,20          Sudden hearing loss 36,37,38           Intubation injuries 24
Sore throat 6,14,15,16                          Cheilitis 21,22,23                     Vertigo 36,37                   Periodontal disease 26
Nasal obstruction 6,7,14,15,16                  Glossitis 21,22,23                  Facial palsy 47,48,49                 Drug reactions 28
Rhinorrhea 6,14,15,16                          Xerostomia 29,30,31                                                            Bruxism 34
Hyposmia/Anosmia 6,7,8,9,10,11,12,13               Dizzness 6                                                     Temporomandibular disorders 34
Hypogeusia 6,7,8,9,10,11,12,13                    Tonsillitis 33                                                 Nasal swab complications 50,51,52,53
Sinonasal pain 6,10                                                                                                      Otitis media 43,44,45



junction with Eustachian tube dysfunction, may be compli-                    and atypical ENT symptoms can be coincidental.
cated with acute or effusive otitis media, similar to what is                Furthermore, there has been an uncontrolled release
observed in rhinitis or nasopharyngitis caused by common                     of poor-quality articles showing the most disparate
respiratory viruses 46. Thus, the concomitant occurrence of                  associations mainly based on a temporal association
otitis media and COVID-19 should be considered a compli-                     between SARS-CoV-2 infection and symptoms of various
cation rather than a manifestation of COVID-19.                              types including those of the ENT area. Finally, the
                                                                             evaluation of the incidence trends in ENT diseases during
COVID-19 and facial palsy                                                    the COVID-19 pandemic in order to generate hypotheses
Different clinical series on the prevalence of Bell’s palsy                  on the direct role of SARS-CoV-2 in some ENT diseases
(BP) in the pandemic are emerging in the literature. Even                    is complicated by the fact that the restrictive measures
if some authors sustained a direct correlation between sars-                 implemented during the pandemic may have modulated
CoV-2 infection and Bell’s palsy in the first phase of the                   the onset of ENT symptoms in the opposite direction.
pandemic 47,48, the most recent epidemiological data have
reduced the causal relationship 49 and there seems to be no                  Conflict of interest statement
association other than mere chance.                                          The authors declare no conflict of interest.
Complications of nasal swab                                                  Funding
In addition to the more common symptoms treated above,
                                                                             This research did not receive any specific grant from
it should be mentioned that indirectly the need to perform
                                                                             funding agencies in the public, commercial, or not-for-
frequent nasal swabs for health surveillance during COV-
                                                                             profit sectors.
ID pandemic implies a, albeit minimal, rate of complica-
tions, like nasal bleeding, foreign body retention (broken
                                                                             Authors’ contributions
swab) 50,51 and cases of cerebrospinal fluid leak 52,53.
                                                                             Both authors played a substantial role in conception,
                                                                             literature searching, drafting and revision of the manuscript.
Conclusions
Consistent with the fact that SARS-CoV-2 is a respiratory                    Ethical consideration
virus, many symptoms observed during the acute phase                         Ethics approval was not required for this study because it
reflect active upper airway infection. Importantly, upper                    was based on published studies.
airway symptoms, i.e. dry cough or coughing up mucus,
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