10.14639/0392-100X-suppl.1-42-2022-10
Objective. The persistence of auditory, vestibular, olfactory, and gustatory dysfunction for an extended time after COVID-19 has been documented, which represents an emerging challenge of which ENT specialists must be aware. This systematic review aims to evaluate the prevalence of persistent audiovestibolar and olfactory/gustatory symptoms in patients with “long-COVID”. Methods. The literature was systematically reviewed according to PRISMA guidelines; PubMed, Scopus and Google Scholar were screened by searching articles on audiovestibular symptoms and olfactory/gustatory dysfunction after SARS-CoV-2 infection. The keywords used were hearing loss, tinnitus, vertigo, smell disorders, parosmia, anosmia, hyposmia, dysgeusia combined with COVID-19 or SARS-CoV-2. Results. 1100 articles were identified. After removal of duplicates (382), 702 articles were excluded, and 16 were included in the systematic review. All articles included identified an association between SARS-CoV-2 infection and persistent hearing or chemosensory impairment. The studies were published over a period of 2 years, between 2019 and 2021. Conclusions. The likelihood of patients with persistent audiovestibular symptoms related to COVID-19 was different among the articles; however, olfactory and gustatory disturbances were more consistently reported. Studies with longer follow-up are required to fully evaluate the long-term impact of these conditions.
text/xml
1827-675X
1886
en
Ettore Cassandro
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
anosmia
Long COVID, audiovestibular symptoms and persistent chemosensory dysfunction: a systematic review of the current evidence
Text.Serial.Journal
https://www.actaitalica.it/
42
Annual congress report
2022-04-26
2021-10-31
2022-04-28
2022-04-28
S87-S93
1
Ettore Cassandro
2022/04/26
10.14639/0392-100X-suppl.1-42-2022-10
S87
Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy; * These authors share last authorship as Senior Authors
1827-675X
anosmia
en
S93
Long COVID, audiovestibular symptoms and persistent chemosensory dysfunction: a systematic review of the current evidence
https://www.actaitalica.it/article/download/1886/780
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42(SUPPL.1):S87-S93; doi: 10.14639/0392-100X-suppl.1-42-2022-10




Long COVID, audiovestibular symptoms
and persistent chemosensory dysfunction:
a systematic review of the current evidence
Sindrome “Long COVID”, sintomi otovestibolari e disturbi chemosensoriali persistenti:
revisione sistematica delle attuali evidenze scientifiche
Pietro De Luca1, Arianna Di Stadio2, Vito Colacurcio3, Pasquale Marra1, Alfonso Scarpa1, Filippo Ricciardiello4,
Claudia Cassandro5, Angelo Camaioni6*, Ettore Cassandro1*
1
  Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy; 2 Department of Surgery and Biomedical
Sciences, Section of Otorhinolaryngology, “Santa Maria della Misericordia” University Hospital, Perugia, Italy; 3 Department of
Otolaryngology, University of Modena, Modena, Italy; 4 Otolaryngology Department, AORN Cardarelli, Naples, Italy; 5 Department of
Surgical Sciences, University of Turin, Turin, Italy; 6 Otolaryngology Department, San Giovanni-Addolorata Hospital, Rome, Italy
*
  These authors share last authorship as Senior Authors.


SUMMARY
Objective. The persistence of auditory, vestibular, olfactory, and gustatory dysfunction for
an extended time after COVID-19 has been documented, which represents an emerging
challenge of which ENT specialists must be aware. This systematic review aims to evaluate
the prevalence of persistent audiovestibolar and olfactory/gustatory symptoms in patients
with “long-COVID”.
Methods. The literature was systematically reviewed according to PRISMA guidelines;
PubMed, Scopus and Google Scholar were screened by searching articles on audioves-
tibular symptoms and olfactory/gustatory dysfunction after SARS-CoV-2 infection. The
keywords used were hearing loss, tinnitus, vertigo, smell disorders, parosmia, anosmia,
hyposmia, dysgeusia combined with COVID-19 or SARS-CoV-2.
Results. 1100 articles were identified. After removal of duplicates (382), 702 articles were
excluded, and 16 were included in the systematic review. All articles included identified an
association between SARS-CoV-2 infection and persistent hearing or chemosensory im-                Received: October 31, 2021
pairment. The studies were published over a period of 2 years, between 2019 and 2021.              Accepted: January 3, 2022
Conclusions. The likelihood of patients with persistent audiovestibular symptoms related
to COVID-19 was different among the articles; however, olfactory and gustatory distur-             Correspondence
bances were more consistently reported. Studies with longer follow-up are required to fully        Pietro De Luca
                                                                                                   Department of Medicine, Surgery and Dentistry,
evaluate the long-term impact of these conditions.
                                                                                                   University of Salerno, via Giovanni Paolo II 132,
KEY WORDS: Long-COVID, post-acute COVID, PASC, COVID-19 pandemic, anosmia                          84084 Fisciano (SA), Italy
                                                                                                   E-mail: dr.dlp@hotmail.it

RIASSUNTO
Obiettivi. La persistenza di disfunzioni uditive, vestibolari, gustative e olfattive persistenti     How to cite this article: De Luca P, Di Stadio
dopo la risoluzione del COVID-19 è stata documentata in letteratura, e rappresenta una               A, Colacurcio V, et al. Long COVID, audi-
                                                                                                     ovestibular symptoms and persistent chem-
sfida emergente che necessita di una risposta adeguata da parte dello specialista otorino-
                                                                                                     osensory dysfunction: a systematic review of
laringoiatra. Lo scopo di questa revisione sistematica è rivedere le attuali conoscenze sulla        the current evidence. Acta Otorhinolaryngol
persistenza di questi sintomi.                                                                       Ital 2022;42(SUPPL.1):S87-S93. https://doi.
Metodi. È stata effettuata una revisione sistematica della letteratura disponibile, in accor-        org/10.14639/0392-100X-suppl.1-42-2022-10
do con le linee guida PRISMA; PubMed, Scopus e Google Scholar sono stati sottoposti a
screening cercando articoli sui sintomi audiovestibolari e sulla disfunzione olfattiva/gusta-      © Società Italiana di Otorinolaringoiatria
tiva dopo l’infezione da SARS-CoV-2. Le parole chiave utilizzate sono state perdita dell’u-        e Chirurgia Cervico-Facciale
dito, tinnito, vertigini, disturbi dell’olfatto, parosmia, anosmia, iposmia, disgeusia sempre
in combinazione con il termine COVID-19 o Sars-CoV-2. D                                                           OPEN ACCESS
Risultati. Sono stati identificati 1.110 articoli; dopo la rimozione dei duplicati (382), 702      This is an open access article distributed in accordance with
articoli sono stati esclusi, e 16 articoli, che identificavano l’associazione tra il SARS-CoV-2    the CC-BY-NC-ND (Creative Commons Attribution-Non-
e la persistenza di disturbi uditivi, vestibolari e chemosensoriali, e pubblicati tra il 2019 e    Commercial-NoDerivatives 4.0 International) license. The
                                                                                                   article can be used by giving appropriate credit and mentio-
il 2021, sono stati inclusi nella revisione sistematica.
                                                                                                   ning the license, but only for non-commercial purposes and
Conclusioni. La percentuale di pazienti che mostrano una persistenza di sintomi audio-             only in the original version. For further information: https://
vestibolari dopo COVID-19 è risultata variabile tra i diversi articoli, mentre le anomalie         creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                           S87
P. De Luca et al.




olfattive e gustative sono riportate più costantemente. In futuro saranno necessari studi con follow-up più lungo, in modo da valutare l’impatto,
a lungo termine, di questi disturbi.
PAROLE CHIAVE: Long-COVID, post-acute COVID, PASC, pandemia COVID-19, anosmia



Introduction                                                                   tory tract in COVID-19, otolaryngologists have assumed a
                                                                               prominent role in both the early fighting of the disease 3 and
Since February 2020, the SARS-CoV-2 pandemic (COV-
                                                                               in treatment of post-COVID-19 sequalae 4. Considering the
ID-19) has affected tens of millions of people worldwide;
                                                                               increase of post-COVID-19 symptoms and that most of
although initially identified as respiratory disease, today
                                                                               these are in the ENT district, the awareness of the different
it is clear that SARS-CoV-2 infection is a multi-organ,
                                                                               and possible symptoms related to SARS-CoV-2 is some-
multi-systemic disease, which affects organs and appara-                       thing to keep in mind.
tus such as the inner ear and cochlea, liver, kidneys, heart                   The present systematic review aims to summarize and dis-
and brain 1. Although symptoms generally disappear in few                      cuss the evidence regarding the presence of audio, vestibu-
weeks, about one-third of patients continues to suffer from                    lar and chemosensory sequelae of COVID-19, of which the
one or more persistent symptoms for long time after reso-                      otolaryngologist should be aware for correct management
lution of infection; this condition has been termed “long-                     and treatment of such patients.
COVID” 2, and recently renamed syndrome of “post-acute
sequelae of SARS-CoV-2 infection” (PASC). The patho-
genesis of PASC is still unclear, but reasonably it is a multi-                Materials and methods
factor event (Fig. 1).                                                         This study was performed in accordance with the Preferred
Due to the prominent involvement of the upper respira-                         Reporting Items for Systematic Reviews and Meta-analy-




Figure 1. Multi-factorial pathogenesis of post-acute sequelae of SARS-CoV-2 infection (PASC).



S88
                                                               Persistence of audivestibular, olfactory and gustatory symptoms in long-COVID syndrome




sis (PRISMA) 5 checklist and statement recommendations                     tory symptoms”, OR “ageusia” AND “SARS-CoV-2” OR
(Fig. 2).                                                                  “COVID-19”. Only articles in English were considered for
                                                                           the analysis.
Search strategy                                                            Two independent investigators (P.D.L. and A.D.S.) re-
A comprehensive search strategy, developed in partner-                     viewed the articles extracted from the literature review. Du-
ship with a medical librarian, was performed on PubMed,                    plicates were removed, and each reviewer then individually
Scopus, and Google Scholar without time restrictions. The                  filled in an Excel data sheet (Microsoft Corporation, USA)
keywords used were: “persistent”, OR “persistence”, AND                    including information extracted from the articles in agree-
“hearing loss,” OR “hearing impairment”, OR “tinnitus”,                    ment with inclusion and exclusion criteria (see below).
OR “audio and vestibular symptom”, OR “sudden hearing                      The datasheets were compared, and disagreements were
loss”, OR “olfactory symptoms”, OR “smell symptoms”,                       debated until complete agreement by both researchers.
OR “anosmia”, OR “hyposmia” OR “ parosmia OR “gusta-                       Only papers that received full consensus were considered.




Figure 2. Systematic reviews and meta-analysis (PRISMA) diagram.



                                                                                                                                               S89
P. De Luca et al.




PRISMA guidelines were followed to conduct the system-            emissions (DPOAE) responses. One limitation of this study
atic review and the full list of references was screened for      is that among admission criteria there was current normal
potentially relevant articles. Selected articles were read in     hearing and absence of audiological complaints.
full to assess the study objectives and the level of evidence.    In assessing the presence of persistent audio and vestibular
Inclusion criteria: patients (0-99 years) affected by persis-     damage in healed COVID-19 patients, Gallus et al. 9 tested
tent hearing deterioration, gustatory or olfactory symptoms       48 patients within 2 weeks from the second negative swab
after SARS-CoV-2 infection, written in English language,          with pure tone audiometry (PTA), video-Head Impulse Test
with full-text available. There were no restrictions in terms     (vHIT) and suppression head impulse test (SHPIMP) and
of diagnostic tools used to detect SARS-CoV-2.                    compared them with 28 age-sex matched voluntary con-
Exclusion criteria: studies that contain information about        trols. The difference between the two groups appeared to
suspected/unconfirmed COVID-19, articles that included            be minimal, and all patients fell within the normal range
patients affected by auditory/vestibular/ olfactory/taste dis-    for the explored frequencies. Moreover, in this study most
orders before COVID-19 infection or lacked previous clini-        vestibular symptoms reported were transient and resolved
cal history and case reports.                                     at the time of the screening and vHIT gain was within the
                                                                  normal range. One only case reported a persistent sensation
Results                                                           of isolated static imbalance.
                                                                  Kökoğlu et al. 10 in 101 healed COVID-19 patients who
Study selection                                                   did not require hospitalization, identified the following as
A total of 1100 articles were identified (Tab. I). After remov-   otologic symptoms during mild and moderate COVID-19:
al of duplicates, 702 articles were excluded. Twenty-nine         ear fullness (20%), otalgia (11%), tinnitus (10%), dizziness
full-text articles matched the inclusion/exclusion criteria; of   (6%) and hearing loss (5%). However, none of the neuro-
these 13 were excluded because at high-risk of bias and the       otological symptoms was permanent, and audiological
remaining 16 were included in the systematic review 4-19. The     evaluation via PTA found no persistent impairment. Thrane
articles identified an association between SARS-CoV-2 and         et al. 11 administered an ear-symptom questionnaire to a
persistent hearing or chemosensory impairment. All stud-          group of healed COVID-19 patients with reported audio-
ies were published over a period of 2 years, between 2019         logical symptoms (mean follow-up range 209-318 days).
and 2021. Across the studies, 5582 patients recovered from        Of the 17 patients with hearing loss, two reported normal-
SARS-CoV-2 infection were evaluated.                              ised hearing, 10 reported improvements but not yet at the
                                                                  same level as before COVID-19, and 5 patients had not ex-
Audio and vestibular symptoms                                     perienced improved function at the time of follow-up. Of
The presence and the persistence of audiovestibular disor-        the 21 patients with tinnitus, 7 reported recovery, 7 reported
ders in COVID-19 were reported in 7 studies.                      reduction of symptoms, and 7 reported no decrease in tin-
Vertigo prevalence was 7.2% 1. In a questionnaire adminis-        nitus since onset at the time of follow-up.
tered to 185 patients who recovered from COVID-19, Viola          In another study 12, the authors investigated the effects of
et al. 6 found that 34 patients (18.4%) reported equilibrium      COVID-19 on the hearing system by administering PTA,
disorders after COVID-19 diagnosis. Of these, 32 patients         speech audiometry, extended high-frequency audiometry,
reported dizziness (94.1%) and 2 (5.9%) reported acute            otoacoustic emissions (OAE) testing and auditory brain-
vertigo attacks; 14 (7.6%) patients reported equilibrium          stem response (ABR) testing. This study enrolled 27 pa-
disorders associated with tinnitus.                               tients diagnosed with COVID-19 at least one month (mean
Regarding the persistence of audio and vestibular dys-            3.81 ± 2.11 months) earlier and treated at home and a con-
function, Bhatta et al. 7 evaluated 331 COVID patients            trol group of 20 individuals without history of COVID-19.
at the time of diagnosis and at 3 months follow-up, and           A small but significant difference was observed in air and
failed to show any significant change in hearing status of        bone conduction thresholds between the two groups in
COVID-19 patients compared to a control group. Moreo-             terms of mean low and high frequencies. Speech audiome-
ver, 3.2% patients had mild conductive hearing loss corre-        try recognition thresholds were significantly higher in both
lated with nasopharyngeal inflammation, which improved            ears in patients with COVID-19 compared to the control
over the course of follow-up. In a cross-sectional study by       group at 2 kHz only, in the right ear. The ABR results dem-
Dror et al. 8, no cochlear or retrocochlear dysfunction was       onstrated that only the interpeak latencies of waves III-V
found in recovered COVID-19 patients analysing auditory           were significantly longer in the study group compared to
brainstem response (ABR), transiently evoked otoacoustic          the control group. The authors noted that even if further
emissions (TEOAE) and and distortion product otoacoustic          research is needed there is the possibility that SARS-CoV-2



S90
                                                         Persistence of audivestibular, olfactory and gustatory symptoms in long-COVID syndrome




infection may cause damage to the hearing system, particu-           from which both auditory and smell disorders can arise de-
larly in high frequencies.                                           pending of the areas suffering from neuroinflammation 23.
                                                                     Another possible mechanism is an abnormal immune re-
Smell and taste alterations                                          sponse, with the production of a large number of autoan-
Spontaneous recovery rates of smell and taste symptoms               tibodies, including those directed to cells of the blood
were found to be very high, with a 60-day recovery rate              vessels, which can potentially cause autoimmune thrombo-
ranging from 75% to 85% and a 6-month recovery rate of               cytopenia, and those directed against phospholipids, which
95.3% 13,14, suggesting a remarkable capacity of regenera-           can later result in antiphospholipid antibody syndrome. In
tion for these structures. Nonetheless, a minority of patients       addition, the molecular mimicry of some proteins, such as
will continue to suffer from anosmia and will be referred            OR7DAm, SLC12A6, and PARP9, has been hypothesised
to an ENT specialist, requiring some sort of management.             to be responsible for anosmia, vascular damage, and multi-
This was confirmed by the study from Riestra-Ayora et al. 15         organ damage 24.
in which, at 6-months follow-up, 11% of patients did not             Another hypothesis, specifically focused on the audio and
experience recovery, and partial resolution was reported in          vestibular symptoms, is neuro-inflammation in the inner
30% of patients. The work from Bussiere et al. 16 and Petro-         ear 23. The thrombotic and transient-ischaemic mechanisms,
celli et al. 17 also described a similar percentage (respective-     and the consequent prolonged hypoxia of the auditory
ly, 27% and 19.5 %) of persistent smell alterations at 6 and         pathways, could be responsible for persistent audiological
7 months after testing negative for infection. A higher rate         symptoms in long-COVID-19 patients. Although vertigo
of smell alterations was reported by Biadsee et al. 18 who           and dizziness are very uncommon, the same aetiopatho-
reported that 48% of subjects experienced smell alterations          genesis of audiological disorders, especially a thrombosis
at 8 months after the primary infection, and by the work             in the audio-vestibular artery, could be held accountable
from Zayet et al. 19 in which persistent loss of smell was           for the persistence of these symptoms. However, to date
the most prevalent symptom, at 9 months of follow-up in              the most valid theory is the one focusing on the neuroin-
a group of 354 long-COVID French patients. On the other              flammation 5. The inflammation of the auditory, vestibular,
hand, the small cohort (only 26 patients) described by Otte          olfactory and gustatory areas following the spread of the
et al. 20 showed a high percentage (97%) of olfactory func-          virus from the nose (olfactory bulbs) or the extension of
tion improvement after 6 months of COVID-19 infection.               the inflammation from this area to the part of the brain,
An Italian study leaded by Boscolo-Rizzo 21 reported the             might explain the presence of all these otolaryngological
longest follow-up (one-year) in a cohort of 100 patients             symptoms.
who were previously home-isolated for moderate sympto-               Acute olfactory dysfunction (OD) is a key symptom in
matic COVID-19; in this study, 46% of patients showed                COVID-19 disease, and since the first phases of the pan-
persistent olfactory dysfunction, and the authors hypoth-            demic it has been considered a potential discriminatory
esised that this could be associated with emotional distress         symptom, indicating triaging for COVID-19 and allowing
and depression.                                                      early identification.
                                                                     The mechanism by which SARS-CoV-2 could cause long
                                                                     anosmia is not completely defined and is probably related
Discussion
                                                                     to the injury caused by the virus on neuro-olfactory epithe-
The etiopathogenesis of persistence of audio, vestibular             lium, in which the sustentacular cells express the ACE 2
and gustatory symptoms in PASC is still unclear. A series            receptor 200-700 times more than in nasal or tracheal epi-
of hypotheses have been made. The first idea is the crucial          thelia, and consequential spreading to the olfactory bulb.
role of inflammatory cytokines and their over-production             Neuroradiologic findings are consistent with this hypoth-
(cytokine storm) during COVID-19 infection; their in-                esis and MRI studies of patients suffering from olfactory
crease and excessive circulating levels are responsible for          dysfunction after COVID-19 noted a high percentage of
the short effects and perhaps even for the long-term symp-           olfactory cleft opacification, reduction of olfactory bulb
toms. These effects are exemplified by interleukin 6, the            volumes, change in bulb shape and signal abnormalities
main interleukin produced by lymphocytes, fibroblasts, and           suggesting direct/indirect injury to olfactory neuronal path-
bronchial epithelium during SARS-CoV-2 infection, which              ways 5,25.
can regulate synaptic plasticity and change brain blood              Although OD in most cases resolves completely within
flow and local tissue metabolism 22. There is also evidence          30 days, a consistent number of patients may experience
that the SARS-CoV-2 spike protein can directly alter the             longer symptoms. The risk of developing a long-lasting
blood-brain barrier and cause direct brain inflammation,             anosmia is related to the severity of the baseline OD, with



                                                                                                                                         S91
P. De Luca et al.




highly severe cases more likely to experience a persistent       “self-reported symptoms” without objective assessment of
deficit 13; moreover, some authors have speculated that the      hearing or olfactory/gustatory symptoms.
viral load (very high) might cause the persistence of symp-
toms.                                                            Conclusions
Unfortunately, the therapeutic approach for the treatment
of post-COVID-19 smell alteration is not well defined yet.       The available evidence indicates that an inconsistent per-
Current strategies include olfactory training (deliberate        centage of patients show persistence of audio and vestibular
sniffing of a set of odourants 20 sec each at least twice a      symptoms after COVID-19 infection, while notable num-
day for at least 3 months), alpha-lipoic acid and systemic       bers of long-COVID subjects present lasting olfactory and
omega-3 supplementation. Oral and topical corticosteroids        consequent gustatory disturbances. Further studies with
are used to treat inflammatory component in post-infective       longer (more than one-year) follow-up will be required to
OD, but data regarding their efficacy in COVID-19 re-            fully understand the percentage of COVID-19 ‘long haul-
lated anosmia is currently lacking and their usage is not        ers’ who will spontaneously recover from these symptoms.
recommended. Recently, D’Ascanio et al. proposed the
combination of anti-neuroinflammatory drugs and olfac-           Acknowledgements
tory training for treating persistent olfactory disease; the     The authors want to thank Miss Rosalia Di Rienzo for the
authors, in their pilot study, showed that patients treated by   realization of the Figure 1.
combining olfactory training and PeaLut recovered 100%
more than patients who did olfactory rehabilitation only 5.      Conflict of interest statement
The rationale of the study was focused on the treatment of       The authors declare no conflict of interest.
neuro-inflammation to support the recovery of smell. Even
if preliminary, the results of this study are very promising.    Funding
Gustatory impairment is the most common oral manifes-            This research did not receive any specific grant from fund-
tation in COVID-19, affecting 45% of patients. The esti-         ing agencies in the public, commercial, or not-for-profit
mated pooled prevalence of loss of taste in a systematic         sectors.
review was 41.47% 26. The mean duration of these condi-
tions was found to be 15 days, and most patients seemed to       Authors’ contributions
fully recover. Long-lasting gustatory impairment is often        PDL: design, acquisition of data, data analysis and inter-
attributed to concomitant impaired retronasal olfaction (fla-    pretation, drafting, accountability of the work; ADS: data
vour) rather than impaired gustation (sweet, salty, sour, bit-   analysis and interpretation, drafting, accountability of the
ter). However isolated gustatory impairment is described in      work; VC: design, drafting, figure editing; PM: design,
long-COVID patients, although its mechanism is not com-          drafting, table editing; AS: data analysis and interpretation,
pletely understood. Since epithelial cells of the oral cav-      table editing; FR: data anlaysis and interpretation, revising
ity, including taste buds, widely express ACE2 receptors,        the manuscript for important intellectual content; CC: data
this could again represent the key to cellular damage; it is     analysis and interpretation, accountability of the work; AC:
reasonable to assume that in some cases this damage is ir-       revising the manuscript for important intellectual content,
reversible or slow to heal, thus leading to long lasting ageu-   final approval; EC: design, accountability of the work, final
sia. Also, neuronal impairment of the gustatory afferents        approval.
and nuclei could play a role, similarly to how it happens
elsewhere. Data regarding medical treatments specifically        Ethical consideration
aimed at hypogeusia are limited and no specific recommen-        Because of the nature of this work, Institutional Review
dations can be made.                                             Board approval was not requested.

Limits of the study                                              References
This study presents several limitations. First, the quality      1
                                                                     Lv G, Yuan J, Xiong X, et al. Mortality rate and characteristics of
rating of the studies was not always satisfactory; in fact,          deaths following COVID-19 vaccination. Front Med (Lausanne)
                                                                     2021;8:670370. https://doi.org/10.3389/fmed.2021.670370
there are several case reports and the cross-sectional, pro-     2
                                                                     The Lancet. Facing up to long COVID. Lancet 2020;396:1861. htt-
spective observational, and case control studies have un-            ps://doi.org/10.1016/S0140-6736(20)32662-3
controlled designs or provide insufficient details on the        3
                                                                     Bier-Laning C, Cramer JD, Roy S, et al. Tracheostomy during the
control groups. Second, some of these studies described              COVID-19 pandemic: comparison of international perioperative care




S92
                                                                    Persistence of audivestibular, olfactory and gustatory symptoms in long-COVID syndrome




     protocols and practices in 26 countries. Otolaryngol Head Neck Surg             ID-19: 6 months case-control study of health workers. Eur Arch
     2021;164:1136-1147. https://doi.org/10.1177/0194599820961985                    Otorhinolaryngol 2021;278:4831-4837. https://doi.org/10.1007/
4
     D’Ascanio L, Vitelli F, Cingolani C, et al. Randomized clinical trial           s00405-021-06764-y
     “olfactory dysfunction after COVID-19: olfactory rehabilitation            16
                                                                                     Bussière N, Mei J, Lévesque-Boissonneault C, et al. Chemosensory
     therapy vs. intervention treatment with Palmitoylethanolamide                   dysfunctions induced by COVID-19 can persist up to 7 months:
     and Luteolin”: preliminary results. Eur Rev Med Pharmacol Sci                   a study of over 700 healthcare workers. Chem Senses 2021 Jan
     2021;25:4156-4162. https://doi.org/10.26355/eurrev_202106_26059                 1;46:bjab038. https:// doi.org/10.1093/chemse/bjab038
5
     Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020                   17
                                                                                     Petrocelli M, Cutrupi S, Salzano G, et al. Six-month smell and taste
     statement: an up-dated guideline for reporting systematic reviews.              recovery rates in coronavirus disease 2019 patients: a prospective
     BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71                               psychophysical study. J Laryngol Otol 2021;135:436-441. https://doi.
6
     Viola P, Ralli M, Pisani D, et al. Tinnitus and equilibrium disorders in        org/10.1017/S002221512100116X
     COVID-19 patients: preliminary results. Eur Arch Otorhinolaryngol          18
                                                                                     Biadsee A, Dagan O, Ormianer Z, et al. Eight-month follow-up of
     2021;278:3725-3730. https://doi.org/10.1007/s00405-020-06440-7                  olfactory and gustatory dysfunctions in recovered COVID-19 patients.
7
     Bhatta S, Sharma S, Sharma D, et al. Study of hearing status in                 Am J Otolaryngol 2021;42:103065. https://doi.org/10.1016/j.
     COVID-19 patients: a multicentered review. Indian J Otolaryngol                 amjoto.2021.103065
     Head Neck Surg 2021 Jul 12;1-7. https://doi.org/10.1007/s12070-            19
                                                                                     Zayet S, Zahra H, Royer PY, et al. Post-COVID-19 syndrome: nine
     021-02710-w. Epub ahead of print.
                                                                                     months after SARS-CoV-2 infection in a cohort of 354 patients: data
8
     Dror AA, Kassis-Karayanni N, Oved A, et al. Auditory performance                from the first wave of COVID-19 in Nord Franche-Comté Hospital,
     in recovered SARS-COV-2 patients. Otol Neurotol 2021;42:666-670.                France. Microorganisms 2021;9:1719. https://doi.org/ 10.3390/
     https://doi.org/10.1097/MAO.0000000000003037                                    microorganisms9081719
9
     Gallus R, Melis A, Rizzo D, et al. Audiovestibular symptoms and            20
                                                                                     Otte MS, Bork ML, Zimmermann PH, et al. Persisting olfactory dys-
     sequelae in COVID-19 patients. J Vestib Res 2021;31:381-387.                    function improves in patients 6 months after COVID-19 disease. Acta
     https://doi.org/10.3233/VES-201505                                              Otolaryngol 2021;14:626-629. https://doi.org/10.1080/00016489.202
10
     Kökoğlu K, Tektaş N, Baktir-Okcesiz FEM, et al. Mild and moderate               1.1905178
     COVID-19 disease does not affect hearing function permanently: a           21
                                                                                     Boscolo-Rizzo P, Hummel T, Hopkins C, et al. High prevalence of
     cross-sectional study ınvolving young and middle-aged healthcare                long-term olfactory, gustatory, and chemesthesis dysfunction in
     givers. Eur Arch Otorhinolaryngol 2021;278:3299-3305. https://doi.
                                                                                     post-COVID-19 patients: a matched case-control study with one-
     org/10.1007/s00405-021-06883-6
                                                                                     year follow-up using a comprehensive psychophysical evaluation.
11
     Thrane JF, Britze A, Fjaeldstad AW. Incidence and duration of self-             Rhinology 2021;59:517-527. https://doi.org/10.4193/Rhin21.249
     reported hearing loss and tinnitus in a cohort of COVID-19 patients        22
                                                                                     Gruol DL. IL-6 regulation of synaptic function in the CNS.
     with sudden chemosensory loss: a STROBE observational study.
     Eur Ann Otorhinolaryngol Head Neck Dis 2021 Sep 30:S1879-                       Neuropharmacology 2015; 96(pt A):42–54. https://doi.org/10.1016/j.
     7296(21)00224-6. https://doi.org/10.1016/j.anorl.2021.07.012. Epub              neuropharm.2014.10.023
     ahead of print.                                                            23
                                                                                     De Luca P, Scarpa A, Ralli M, et al. Auditory disturbances and
12
     Gedik Ö, Hüsam H, Başöz M et al. The effect of coronavirus disease              SARS-CoV-2 infection: brain inflammation or cochlear affection?
     2019 on the hearing system. J Laryngol Otol 2021;135:810-814.                   Systematic review and discussion of potential pathogenesis. Front
     https://doi.org/10.1017/S0022215121001961                                       Neurol 2021;12:707207. https://doi.org/10.3389/fneur.2021.707207
13
     Lechien JR, Chiesa-Estomba CM, Beckers E, et al. Prevalence and
                                                                                24
                                                                                     Angileri F, Legare S, Marino Gammazza A, et al. Molecular mimicry
     6-month recovery of olfactory dysfunction: a multicentre study of               may explain multi-organ damage in COVID-19. Autoimmun Rev
     1363 COVID-19 patients. J Intern Med 2021;290:451-461. https://                 2020;19:102591. https://doi.org/10.1016/j.autrev.2020.102591
     doi.org/10.1111/joim.13209                                                 25
                                                                                     Kandemirli SG, Altundag A, Yildirim D, et al. Olfactory bulb MRI and
14
     Stavem K, Ghanima W, Olsen MK, et al. Persistent symptoms 1.5-6                 paranasal sinus CT findings in persistent COVID-19 anosmia. Acad
     months after COVID-19 in non-hospitalised subjects: a population-               Radiol 2021;28:28-35. https://doi.org/10.1016/j.acra.2020.10.006
     based cohort study. Thorax 2021;76:405-407. https://doi.org/10.1136/       26
                                                                                     Ibekwe TS, Fasunla AJ, Orimadegun AE. Systematic re-
     thoraxjnl-2020-216377                                                           view and meta-analysis of smell and taste disorders in COV-
15
     Riestra-Ayora J, Yanes-Diaz J, Esteban-Sanchez J, et al. Long-                  ID-19. OTO Open 2020;4:2473974X20957975. https://doi.
     term follow-up of olfactory and gustatory dysfunction in COV-                   org/10.1177/2473974X20957975




                                                                                                                                                    S93
