European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897

https://doi.org/10.1007/s00405-020-05968-y

REVIEW ARTICLE

COVID‑19 in otolaryngologist practice: a review of current knowledge

Joanna Krajewska1   · Wojciech Krajewski2 · Krzysztof Zub1 · Tomasz Zatoński1

Received: 30 March 2020 / Accepted: 6 April 2020 / Published online: 18 April 2020
© The Author(s) 2020

Abstract
Purpose  Otorhinolaryngological manifestations are common symptoms of COVID-19. This study provides a brief and
precise review of the current knowledge regarding COVID-19, including disease transmission, clinical characteristics,
diagnosis, and potential treatment. The article focused on COVID-19-related information useful in otolaryngologist practice.
Methods  The Medline and Web of Science databases were searched without a time limit using terms “COVID-19”, “SARS-
CoV-2” in conjunction with “otorhinolaryngological manifestation”, “ENT”, and “olfaction”.
Results  The most common otolaryngological dysfunctions of COVID-19 were cough, sore throat, and dyspnea. Rhinor-
rhea, nasal congestion and dizziness were also present. COVID-19 could manifest as an isolated sudden hyposmia/anosmia.
Upper respiratory tract (URT) symptoms were commonly observed in younger patients and usually appeared initially. They
could be present even before the molecular confirmation of SARS-CoV-2. Otolaryngologists are of great risk of becoming
infected with SARS-CoV-2 as they cope with URT. ENT surgeons could be easily infected by SARS-CoV-2 during perform-
ing surgery in COVID-19 patients.
Conclusion  Ear, nose and throat (ENT) symptoms may precede the development of severe COVID-19. During COVID-19
pandemic, patients with cough, sore throat, dyspnea, hyposmia/anosmia and a history of travel to the region with confirmed
COVID-19 patients, should be considered as potential COVID-19 cases. An otolaryngologist should wear FFP3/N95 mask,
glasses, disposable and fluid resistant gloves and gown while examining such individuals. Not urgent ENT surgeries should
be postponed. Additional studies analyzing why some patients develop ENT symptoms during COVID-19 and others do not
are needed. Further research is needed to determine the mechanism leading to anosmia.

Keywords  COVID-19 · SARS-CoV-2 · Otolaryngological manifestations · Olfaction · ENT

Introduction subsequent global pandemic [1]. On March 30, 2020, a total

of 638.146 confirmed cases of COVID-19 and 30.039 deaths
At the end of 2019 in Wuhan, a large city in the Hubei Prov- were reported by WHO.
ince of China, a novel coronavirus, Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2), was considered Aim of the study
as the cause of a number of lower respiratory tract infec-
tions [1]. On February 11, 2020, the new disease caused The main aim of this study was to provide a brief and pre-
by the SARS-CoV-2 virus was officially termed “COVID- cise review of the current knowledge regarding COVID-19,
19” by WHO [1]. The high potential of human to human including disease transmission, clinical characteristics, diag-
transmission led to rapid COVID-19 epidemic in China and nosis and potential treatment. The article focused on infor-
mation that, in our opinion, could be useful in otolaryngolo-
gist practice. We emphasized the role of otolaryngologist in
* Joanna Krajewska rapid COVID-19 diagnosis. We also implied the high risk
[email protected] of becoming infected with SARS-CoV-2 as a results of the
1
Department and Clinic of Otolaryngology, Head and Neck
practice of the ENT specialist.
Surgery, Medical University in Wroclaw, Borowska 213
Street, 50556 Wroclaw, Poland
2
Department and Clinic of Urology and Urological Oncology,
Medical University in Wroclaw, Wroclaw, Poland

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1886 European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897

Methods another person. Direct contact with a person with COVID-

19 or a direct contact with the surfaces contaminated with
The Medline and Web of Science databases were searched SARS-CoV-2 with subsequent contact with own nasal
without time limit but focusing on the newest report, using cavity, oral cavity or eyes are also sources of infection
the terms “COVID-19”, “SARS-CoV-2”, “novel coronavi- [1]. Oro-fecal transmission of the virus is presumably also
rus”, and “coronavirus from Wuhan” in conjunction with possible. It was suggested that the two meters distance
“otorhinolaryngological manifestation”, “ENT”, “ear”, between an infected and non-infected person should be
“nose”, “throat’’, “oral cavity”, “pharynx”, “larynx”, enough to avoid infection [2]. Van Doremalen et al. con-
“hearing”, “vertigo”, “head and neck”, and “olfaction”. ducted an experimental study in which they reported that
Boolean operators (NOT, AND, OR) were also used in SARS-CoV-2 was able to remain viable in aerosols for
succession to narrow and broaden the search. Auto alerts 3 h [3]. SARS-CoV-2 survived up to 72 h on plastic and
in Medline were also considered, and the reference lists of stainless steel, on copper the virus was not detected after
original articles and review articles were searched for fur- 4 h, while on cardboard no viable virus was found after
ther eligible sources. Opinions of medical societies were 24 h [3].
also included if applicable. The search included articles The incubation time for COVID-19 since the exposure
without language limitations. to SARS-CoV-2 is believed to reach 14  days, neverthe-
A total of 1790 articles were originally identified using less, the majority of patients develop COVID-19 disease
our search criteria. 1740 articles were excluded after after 4–5 days (range between 2 and 7 days) after being
abstract or full-text analysis because they did not exactly infected [4, 5]. COVID-19 remains contagious even during
address the topic. Therefore, the total number of 50 studies the latency period, thus patients before clinical COVID-19
were finally chosen to prepare this manuscript. Studies on presentation can transfer the virus to others [1].
which this article was prepared were not limited to large It was reported that the median time to no detectable
cohorts, as a vast majority of reports were based on small SARS-CoV-2 RNA in oropharyngeal samples in patients
cohorts. Because of COVID-19 novelty, randomized con- with COVID-19 reached 20  days (range between 8 and
trolled studies and precise recommendations for COVID- 37 days) [6]. Samples obtained from patients with a mild
19 management are not available yet. We presume that or moderate form of the disease more quickly became nega-
even reports based on sparse cohorts could be valuable tive for SARS-CoV-2 than samples obtained from severe
at this time and may lead to further better disease under- COVID-19 cases [6].
standing and treatment.
Clinical manifestation of COVID‑19 – important
knowledge for otolaryngologists
Origin, transmission, and characteristics
of SARS‑CoV‑2 Fever, fatigue and dry cough are considered to be the most
common manifestations of COVID-19 [7–9]. Anorexia,
Human SARS-CoV-2 express 96.2% genomic similarity to dyspnea, sputum production, and myalgias are reported in
bats’ coronavirus. Because of this high genomic similarity more than 25% of cases [7]. Sore throat, rhinorrhea, head-
bats have been considered as a natural virus host. There- aches, nausea, and diarrhea are less frequent and are mainly
fore, it was speculated that human SARS-CoV-2 might be observed in mild or moderate forms of the disease [7].
transmitted to humans from bats through other mammalian Cough, dyspnea, sore throat, rhinorrhea, nasal congestion,
hosts [1]. throat congestion, tonsils edema, enlarged cervical lymph
According to epidemiologic studies, the first human nodes or dizziness are symptoms that otolaryngologist could
SARS-CoV-2 infection presumably took place in Wuhan’s encounter while examining patients with COVID-19.
seafood market where live animals were sold [1]. First It was recently reported that COVID-19 led to hyposmia/
COVID-19 cases were confirmed in individuals who had anosmia and taste disturbances [10]. South Korea, China
previously visited this market [1]. Nevertheless, the fol- and Italy presented that a significant number of individu-
lowing COVID-19 cases were not exposed to this kind of als with COVID-19 was affected by hyposmia/anosmia. A
seafood market- related infection. Therefore, a potential few cases were also detected in Germany, while in South
human to human transmission was suggested to be the Korea 30% of infected individuals developed hyposmia/
main source of the virus spread [1]. The virus is trans- anosmia. There are also reports implying that COVID-19
mitted between individuals through respiratory droplets may present as isolated anosmia [10]. Researches from vari-
that are produced by an infected person while sneezing, ous countries observed patients with COVID-19 presenting
coughing or talking and staying in the short distance from isolated anosmia, without any other symptoms [10]. They
suggested that these individuals could be the hidden carries

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European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897 1887

of SARS-CoV-2 as they do not meet the current criteria for tracheostomy tube insertion into the trachea [28]. Heat and
diagnosing COVID-19. These patients could be the source moisture exchanger (HME) ought to be immediately con-
of the rapid spread of COVID-19. nected with the tracheostomy to reduce the spread of the
Professor Hopkins and Kumar from the Rhinological virus. Subsequently it should not be disconnected [28]. It is
Society recommended that oral corticosteroids should not recommended to avoid humidified closed circuits to mini-
be incorporated in the treatment of the new-onset anosmia mize the chance of the virus-induced space contamination
during the COVID-19 pandemic, as they may exacerbate the in case of the system disjunction [28]. The closed gear used
severity of COVID-19 disease [10]. Nasal steroids are also in patients after tracheostomy should be the same as used for
not recommended for the sudden loss of smell [11]. Accord- patients connected to a mechanical ventilator [29]. After the
ing to the available reports, patients below 40 years of age surgery, the tracheostomy tube should not be changed until
are mostly predisposed to develop the form of COVID-19 patient’s COVID-19 status is positive or unknown [28]. Suc-
that is only manifested by hyposmia/anosmia or taste dis- tion other than closed in line suction must be avoided while
turbances [10, 11]. Patients with sudden anosmia should be performing respiratory tract toilet [28].
tested for SARS-Cov-2 presence and considered as potential Flexible laryngoscopy is another aerosol-generating
individuals with COVID-19 [11]. procedure that exposes otolaryngologists to COVID-19
The prevalence of particular COVID-19 ear, nose and infection [29]. It should be performed only if absolutely
throat (ENT) manifestations in various reports was presented necessary.
in Table 1 [4, 7–9, 12–27]. Additional, crucial information It is recommended that every patient with unknown status
found in these studies was also presented in Table 1. of COVID-19 should be examined by otolaryngologist that
is fully equipped [29]. It is of great importance as the mean
COVID‑19‑related crucial information incubation time reaches 5.2 days, with 95% of the distri-
for otolaryngologists/head and neck surgeons bution at 12.5 days [5]. The minimal personal protective
equipment (PPE) includes FF3/N95 mask, gloves, gown, eye
Otolaryngologists, especially ENT surgeons are at very protection and a cap [29]. If possible, patients not requir-
high risk of SARS-Cov-2 infection as they cope with the ing urgent ENT consult, especially those treated for chronic
upper respiratory tract (URT) which is the main reservoir ENT diseases, should be consulted by phone. Individuals
of SARS-CoV-2. According to current recommendations of requiring ENT visit are obligated to have their body tem-
European Rhinologic Society, all non-urgent ENT surgeries perature measured before entering the outpatient clinic [29].
should be postponed because of COVID-19 pandemic [11]. Additionally, their recent travel status should be assessed as
For patients requiring urgent surgery or ENT consult, oto- the patients could be asymptomatic during the first several
laryngologist should wear fluid-resistant FFP3/N95 mask, days after SARS-CoV-2 infection [29].
disposable and fluid resistant gloves and gown, glasses or Currently, there is no evidence against topical corticos-
full face shield. Double-gloving during operation is recom- teroids use in patients with chronic nasal corticosteroids use
mended for surgeons [2]. A number of staff attending the OR for rhinosinusitis or allergic rhinitis [11].
during urgent ENT surgery should be limited to minimum
[2]. COVID‑19 diagnosis
Tracheostomy is one of the most frequent urgent ENT sur-
gery. Currently, during COVID-19 pandemic, every patient Symptoms including fever, unproductive cough and dyspnea
requiring emergency tracheostomy should be considered as a in combination with a history of travel to areas with con-
COVID-19 positive as delaying the surgery while waiting for firmed COVID-19 cases strongly suggest COVID-19 disease
SARS-CoV-2 detection test may lead to patient’s death [28]. [30]. Currently, patients with severe lower respiratory tract
For patients with intermittent dyspnea that is potentially infection should be considered as potential SARS-CoV-2
reversible, intubation rather than tracheostomy should be carriers [30]. Nevertheless, to confirm the diagnosis of
performed [28]. High flow oxygen/AIRVO should not be COVID-19 molecular test must detect SARS-CoV-2 pres-
used in these cases [28]. For individuals with constant dysp- ence [30]. The specific test for SARS-CoV-2 detection is
nea, in whom irreversible cause of dyspnea is strongly sus- the real-time reverse transcriptase-polymerase chain reac-
pected, tracheostomy is required [28]. In patients positive tion (RT-PCR) test. Presently, it is the recommended test to
for COVID-19 or in those with unknown COVID-19 status, diagnose SARS-Cov-2 infection. A positive RT-PCT test for
cuffed and non-fenestrated tracheostomy tube should be used SARS-CoV-2 confirms the diagnosis of COVID-19 in the
to prevent SARS-Cov-2 from aerosolizing [28]. The cuff of vast majority of cases, nevertheless, false-positive results
the endotracheal tube should not be perforated during the can also occur [30]. RT-PCR is considered as highly specific,
procedure. The mechanic ventilation should be suspended however, in a number of cases its sensitivity seemed not to
while making the opening in the trachea and during the be enough to diagnose the disease. RT-PCR sensitivity range

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Table 1  ENT symptoms of COVID-19 reported in observational studies

1888

Study Number Population ENT symptoms Additional information

of studied

13
patients

Team C-NIRS [12] 295 Australian – Cough in 54% – Criteria for confirmed COVID-19 case:
– Sore throat in 46% A patient who tested positive to a
– Runny nose in 40% validated specific SARS-CoV-2 nucleic
– Dyspnea in 35% Acid examination or has the
Virus identified by electron microscopy or viral culture
– A suspected case should fulfil following criteria:
(1) Epidemiological criteria
– International travel in the 14 days before COVID-19 onset
or
– Close contact with a patient with COVID-19 within 14 days
before disease development
(2) Clinical criteria:
– Fever
or
– Acute respiratory infection (dyspnea, cough, sore throat)
with or without fever
Guan et al. [4] 1099 Chinese – Cough in 67.8% – Cough and dyspnea were more commonly observed in
– Dyspnea in 18.7% patients with severe disease, while nasal congestion and sore
– Sore throat in 13.9% throat in individuals with non-severe form of COVID-19
– Nasal congestion in 4.8%
– Throat congestion in 1.7%
– Tonsil edema in 2.1%
– Enlargement of lymph nodes in 0.2%
Zhang et al. [15] 140 Chinese – Cough 75% – Allergic diseases and smoking history may potentailly not
– Dyspnea in 36.7% predispose to COVID-19
– Eosinopenia along with lymphopenia could be a useful tool
in diagnosing COVID-19 in individuals with typical clinical
symptoms and CT chest abnormalities
Wang et al. [23] 138 Chinese – Dry cough in 59.4% – The mean time from
Disease onset to dyspnea was 5 days; 7 days to hospital admis-
sion, 8 days to ARDS development
– Dry cough was a common initial symptom
Liu et al. [8] 137 Chinese – Cough in 48.2% – Middle-aged and elderly patients with coexisting chronic
diseases were susceptible to respiratory failure
Zhu et al. [19] 116 Chinese – Cough in 66% – The majority of patients presented mild form of the disease
Zhao et al. [17] 101 Chinese – Cough in 62% – 70.2% of patients were 21–50 years old
– Sore throat in 12% – Majority of patients with COVID-19 had typical chest CT
abnormalities (GGO, mixed GGO and consolidation,
Vascular enhancement in the lesion, traction bronchiectas)
European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897
 Table 1  (continued)
Study Number Population ENT symptoms Additional information
of studied
patients

Chen et al. [18] 99 Chinese – Cough in 82% – The majority of patients were men
– Dyspnea in 31% – It was reported that the lower susceptibility of women to
– Sore throat in 5% develop viral infections could result from the protection of X
– Rhinorrhea in 4% chromosome and sex hormones, which have a significant role
in innate and adaptive immunity
Xu et al. [14] 90 Chinese – Cough in 63% – Chest CT could detect minor pulmonary abnormalities in
– Sore throat in 26% patients at an early stage of COVID-19
– Initial presentation of bilateral, multifocal, and peripheral
ground-glass opacities detected in chest CT might strongly
suggest COVID-19
Yang et al. [21] 85 Chinese – Cough in 58.4% – 10.06% of patients had no contact with Hubei Province
– Dyspnea in 1.3%
Huang et al. [20] 84 Chinese – Cough in 50% – Patients with atypical or mild symptoms may not present
pulmonary changes during disease appearance. Development
of pulmonary infiltrates in CT scan might be delayed and it
does not suggest that pneumonia will not develop later
European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897

Wu et al. [26] 80 Chinese – Cough in 63.75% – 35% of patients presented a mild form of COVID-19; 61.25%
– Dyspnea in 37.5% had moderate form; 3.75% of patients suffered from the
severe type; nobody was critically ill
– 51.25% of patients were diagnosed after the positive result in
the first test; 37.5% were tested positive in the second test;
11.25% remained negative until a third test
Xu et al. [9] 62 Chinese – Cough in 81% – The median time from exposure to SARS-CoV-2 to the onset
of COVID-19 reached 4 days (range: 3–5 days)
Song et al. [24] 51 Chinese – Cough in 47% – All patients except one reported a history of Wuhan contact
– Dizziness in 16%
Xu et al. [22] 50 Chinese – Cough in 40% – Patients with mild form of the disease were significantly
– Sore throat in 8% younger (mean age 29 years) than those with moderate or
– Dyspnea in 8% severe form
Huang et al. [7] 41 Chinese – Cough in 76% – Patients requiring hospitalization in an intensive care unit
– Dyspnea in 55% expressed higher plasma levels of IL-2, IL-7, IL-10, GSCF,
IP10, MCP1, MIP1A, and TNFα
– Majority of patients were men (73%)
– 32% had underlying diseases: 20% had diabetes, 15% had
hypertension,
15% had cardiovascular disease
– 66% had direct exposure to Huanan seafood market
Covid-19 National Emer- 28 Korean – Sore throat in 32.1% – Secondary COVID-19 infection developed in patients
gency Response Center – Cough in 17.9% from close contact with an infected individual after staying
[13] together for a considerable amount of time

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1890 European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897

differed between reports from various counties. It could be

CT computed tomography, GGO ground glass opacities, IL-2 interleukin 2, IL-7 interleukin 7, IL-10 interleukin 10, GSCF granulocyte-colony stimulating factor, IP10 interferon gamma-
induced protein 10, MCP1 monocyte chemoattractant protein 1, MIP1A macrophage Inflammatory protein 1alpha, and TNFα tumor necrosis factor alpha; ARDS – acute respiratory distress
– Majority of the patients with COVID-19 were healthy adults;

– Two cases were asymptomatic and remained so until became

– Median hospitalization time was 13 days (range: 8–23 days)

did not significantly improve patient’s condition. LPV-RTV

– Methylprednisolone in combination with interferon therapy
1 patient was older than 50 years; 1 was younger than 5 years

– Chest CT imaging accompanied by the detection of SARS-

as low as 60–70% [31] or as high as 97% [32]. Keeping in
mind such detection discrepancies, doctors should repeat the

incorporation led to quick improvement of the clinical

test after several days.
Molecular examination is performed on specimens
obtained mainly from the respiratory tract and sometimes

RNA is helpful for the COVID-19 diagnosis

from stool [30]. In severe form of the disease, blood is tested
for SARS-CoV-2 presence [30]. Nasopharyngeal swabs,
oropharyngeal swabs, bronchoalveolar lavage, endotracheal
aspirates or sputum could be taken for testing [30].
Nasopharyngeal swabs are most commonly taken for
SARS-CoV-2 negative

SARS-CoV-2 examination.
Additional information

Nasopharyngeal and oropharyngeal swabs are currently

recommended for detecting SARS-CoV-2 and diagnosing
symptoms COVID-19, nevertheless obtaining specimens from this sites
may be harmful and may lead to bleeding that is especially
CoV-2

important in cases where recurrent analysis is required [33].

Additionally, it was also reported that swabs taken from
URT, especially from nasopharynx or oropharynx might not
charge, stuffy and runny nose and vertigo

be enough sensitive to detect SARS-CoV-2 [34].

Patient presented cough with white dis-

According to current recommendations, two negative tests

conducted in at least 24-h interval could exclude COVID-
19. Nevertheless, Wu et al. presented a case of COVID-
– Nasal congestion in 7.7%

19 with double negative SARS-CoV-2 tests obtained from

nasopharyngeal swabs [35]. The authors suggested that in
– Rhinorrhea in 6.4%
– Sore throat in 6.4%

patients with clinical symptoms strongly suggesting COVID-

– Dyspnea in 6.4%
– Cough in 46.2%

World Health Organization European – Cough in 45%

19 disease, sputum or bronchoalveolar lavage fluid (BALF)

ENT symptoms

should be taken for examination [35]. The patient presented

altogether

in this case was co-infected by influenza A virus that was

detected in the nasopharyngeal swab. Simultaneously, the
patient was negative for SARS-CoV-2 [35]. This report high-
lights the possibility of false-negative results for samples
Region (excluding United King-

obtained from URT while diagnosing COVID-19 [35].

Sputum could be analyzed for SARS-CoV-19 presence
however it may be difficult to obtain in non-productive
patients [33]. It was speculated that saliva may serve as a
potential, non-invasive material for diagnosing COVID-19
[33]. Saliva could be self-collected by a patient by spitting
into a sterile container. That could eliminate the exposure of
Population

Chinese

Chinese

healthcare service to close contact with a patient while tak-

dom)

ing naso- or oropharyngeal swabs [33]. It was also reported

that in several cases saliva was more accurate material to
detect coronavirus than nasopharyngeal swab [34]. Authors
of studied

from China reported that SARS-CoV-2 was detected in

Number

patients

saliva specimens obtained from 91.7% of patients with

13

COVID-19 [33]. Saliva was taken into a sterile container

from patients while spitting saliva from throat and subse-
quently analyzed using nucleic acid extraction and RT-PCR
Table 1  (continued)

test [33].
Spiteri et al. [27]
Chang et al. [25]

Han et al. [16]

According to studies, computed tomography (CT) of the

chest seemed to be very useful in diagnosing COVID-19. It
syndrome

was suggested that chest CT could be even more sensitive

Study

in detecting COVID-19 than repeated RT-PCR test. Ai et al.

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European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897 1891

conducted a large cohort study performed on patients with hospitalization in the intensive care unit (ICU), expressed
positive RT-PCR test revealing that the sensitivity of chest high levels of granulocyte-colony stimulating factor (GCSF),
CT in implying the presence of COVID-19 reached 97% IP10, MCP1, macrophage Inflammatory protein 1alpha
[32]. The sensitivity of RT-PCR tests and chest CT for diag- (MIP1A), and tumor necrosis factor alpha (TNFα) [7]. Con-
nosing COVID-19 in suspected individuals reached 59% and centrations of these molecules were significantly higher than
88%, respectively [32]. 60% to 93% of patients in this cohort in patients with less severe disease [7]. The authors specu-
presented initial positive chest CT suggesting COVID-19 lated that these molecules may potentially reflect a severe
before the initial RT-PCR test detected SARS-CoV-2 [32]. form of COVID-19 [7].
42% of patients with COVID-19 presented improvement in
the follow-up chest CT before the test based on RT-PCR Vaccine
results turned negative [32]. The authors suggested that
chest CT could be considered as a sensitive and useful test Vaccine against SARS-CoV-2 is not available yet. The most
in detecting COVID-19 in the areas affected by COVID-19 promising target in developing a vaccine against SARS-
epidemic [32]. CT of the thoracic cavity revealing ground- CoV-2 seems to be the viral spike protein (S protein) [37].
glass opacities, infiltrates and bronchovascular thickening The first vaccine is examined in the clinical trial (Phase 1) in
consolidations strongly suggest SARS-CoV-2 infection [23]. human beings in the United States [37]. It uses a messenger
According to previous reports, we speculate that during RNA platform to achieve S protein expression to stimulate
COVID-19 pandemic, chest CT should be performed in an immune response [37].
patients before ENT operations. It could be of great value
in individuals with negative RT-PCR. Therapy for COVID‑19 (Fig. 1)
There are currently no laboratory abnormalities specific
for COVID-19 diagnosis. According to various authors, Previously known SARS-CoV, and novel SARS-CoV-2
complete blood count usually revealed the normal or express genomic similarity (approximately 82% similar-
decreased level of white blood cells and thrombocytes, and ity), thus therapeutic option used for SARS-CoV could
reduced number of lymphocytes [30]. The levels of erythro- potentially be useful in treating SARS-CoV-2 infection [1,
cyte sedimentation rate and C-reactive protein were mainly 36]. Partial genomic similarity was also observed between
increased, while procalcitonin remained normal in the SARS-CoV-2 and Middle East Respiratory Syndrome coro-
majority of cases [30]. Increased levels of D-dimer, serum navirus (MERS-CoV).
creatinine, creatinine phosphokinase, lactate dehydrogenase, No therapeutic agent has already been proven to be effi-
prothrombin time, and aminotransferases namely alanine cient in SARS-Cov-2 infection treatment. No drug is cur-
transaminase and aspartate transaminase, usually indicated rently approved for COVD-19. However, several agents are
severe form of COVID-19 [30]. High D-dimer concentra- currently investigated in clinical trials [1].
tion and significant lymphopenia were correlated with
higher mortality [30]. Patients with ENT manifestations of Agents being investigated in COVID‑19
COVID-19 may present similar laboratory abnormalities to
individuals in alike disease stage but with other COVID-19 There are currently several agents used in COVID-19 ther-
symptoms. apy. Randomized controlled studies analyzing their poten-
It was implied that the loop-mediated isothermal ampli- tial positive effects in COVID-19 management are lacking.
fication (LAMP) assay could be a potentially useful tool in Reports on these agents’ use in COVID-19 are mainly based
diagnosing COVID-19 because of its diagnostic sensitiv- on in vitro or extrapolated evidence. Clinical usefulness of
ity exceeding 95% [36]. LAMP reaction is a novel nucleic these drugs appeared in case reports.
acid amplification analysis that amplifies DNA [36]. It is
characterized by very specific, efficient and quick test [36]. Lopinavir (LPV)‑Ritonavir (RTV)
LAMP technology is believed to be of higher stability and
sensitivity than PCR [36]. Therapy based on combined LPV and RTV, protease inhibi-
High levels of interleukin-1B (IL-1B), interferon- γ tors recommended for HIV-1 treatment, showed antiviral
(IFN-γ), interferon gamma-induced protein 10 (IP10), and activity against SARS-CoV in in vitro study [38]. Promising
monocyte chemoattractant protein 1 (MCP1) were found in effects were also found in managing MERS-CoV with LPV-
patients with COVID-19. T-helper-1 (Th1) cell response RTV in a study on animals [39].
was potentially dominant in infected individuals [7]. Nev- The efficiency of LPV-RTV use for COVID-19 treatment
ertheless, the levels of IL-4 and IL-10 that are related to has not already been established. Further clinical studies
T-helper-2 (Th2) cell response, were also elevated [7]. Addi- are required to assess the potential benefits of these agents
tionally, patients with severe form of the disease, requiring in COVID-19.

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1892 European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897

Fig. 1  Potential therapeutic
options for COVID-19 Potential
therapeutic
options for
COVID-19

Investigational Other potentially

agents useful agents

Lopinavir- Convalescent
Ritonavir serum

Interferon-
Remdesivir
alpha

Thymosin
Chloroquine/h alpha-1
ydroxychloroq
uine
Cyclosporine A

Favipiravir Chymotrypsin-like and

papain-like protease
inhibitors
Tocilizumab

Angiotensin-converting
enzyme-2 inhibitor

Nelfinavir

Glucocorticosteroids

Supplements:
-Vit. A, B, C, D, E
-Selenium
-Zinc
-Iron
-Omega-3
polyunsaturated
fatty acids

Cao et  al. conducted a study on 199 patients with Remdesivir

COVID-19 [40]. The authors reported that LPV-RTV ther-
apy was not effective in adults with severe COVID-19. The Remdesivir, a novel nucleotide analogue could be a poten-
use of LPV-PTV (dosage 400 and 100 mg, respectively) tial therapeutic option for COVID-19 [42]. It appeared
two times a day for two weeks showed no significant dif- to have activity against SARS-CoV-2 in in  vitro study
ference in the time to clinical improvement, duration of [42]. Remdesivir was clinically used for the first time in
the stay in ICU, duration of mechanical ventilation, dura- 35-years old American with COVID-19 when the patient’s
tion of oxygen support, or in mortality rate from patients clinical status started to exacerbate [43]. Currently, there
undergoing standard care without LPV-RTV under the are two ongoing large cohort clinical trials designed to
observation for 28 days [40]. analyze the efficiency and safety of remdesivir in patients
Deng et al. found that therapy based on LPV-RTV in with mild, moderate, and severe COVID-19 [44]. Prelimi-
combination with Arbidol, a drug used against influenza nary results of these studies have not been reported yet.
virus, was more efficient than LPV-RTV use only in con-
firmed COVID-19 cases [41].

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European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897 1893

Chloroquine/hydroxychloroquine Other potentially useful agents in COVID‑19

Chloroquine/hydroxychloroquine expressed promising Convalescent serum

results in COVID-19 treatment in various studies [45,
46]. Chloroquine and hydroxychloroquine presented anti- Sera obtained from convalescent patients could poten-
viral activity against SARS-CoV-2 in in vitro and in vivo tially be used in COVID-19 therapy in subjects with early
studies [46, 47]. Stronger antiviral function was observed symptoms [50]. It could prevent COVID-19 development
for hydroxychloroquine than for chloroquine [46]. Chlo- in exposed individuals [50].
roquine was able to decrease the length of hospitaliza-
tion and to improve COVID-19 pneumonia therapy. It Interferon‑alpha (INF‑alpha)
expressed positive results with potential safety in fighting
COVID-19-associated pneumonia in the Chinese multi- Zhang et al. reported the potential therapeutic effect of
center clinical trials [48]. In a study conducted by Gautret INF-alpha and combined INF-alpha-2a with ribavirin in
et al., 100% of individuals with COVID-19 undergoing patients with SARS and severe MERS-CoV, respectively
therapy based on hydroxychloroquine and azithromycin [47].
were healed, while only 57.1% of patients on hydroxychlo-
roquine alone and only 12.5% of individuals from control
group improved after the therapy [45]. Chloroquine is cur- Thymosin alpha‑1
rently recommended to be incorporated in the upcoming
version of the “Guidelines for the Prevention, Diagnosis, Thymosin alpha-1 express the ability to elevate the resist-
and Treatment of Pneumonia Caused by COVID-19” ance to glucocorticosteroids-induced death of thymocytes.
issued by the National Health Commission of the People’s It was observed that thymosin alpha-1 acted as an immune
Republic of China [48]. booster in patients with SARS and was able to restrain the
spread of the infection [47]. In patients with COVID-19
Favipiravir in whom incorporating glucocorticosteroids is planned,
thymosin alpha-1 should be considered before glucocorti-
Favipiravir is a novel RNA-dependent RNA polymerase costeroid use to prevent glucocorticosteroid-induced death
inhibitor [49]. It was approved for novel influenza virus of thymocytes [47].
in China [49]. Favipiravir expresses its inhibiting activity
against viral RNA polymerase after initially being trans- Cyclosporine A
formed to an active phosphoribosylated form (favipiravir-
RTP) in cells, where it is identified as a substrate by the It was speculated that non-immunosuppressive derivatives
viral RNA polymerase [49]. It could potentially be useful of cyclosporine A might act as COVID-19 inhibitors [47].
in COVID-19 treatment as SARS-CoV-2 is a RNA virus
[49]. Encouraging results were already achieved by a clini-
cal trial conducted in the Clinical Medical Research Center Chymotrypsin‑like (3C‑like) and papain‑like protease (PLP)
of the National Infectious Diseases and the Third People’s inhibitors
Hospital of Shenzhen [49]. Authors of this trial reported
that favipiravir expressed stronger antiviral activity than Therapy targeting coronavirus proteases, namely chymot-
LPV-RTV with significantly less adverse effects [49]. rypsin-like (3C-like) and papain-like protease (PLP) could
potentially be useful in COVID-19 treatment [47]. 3C-like
protease was observed to be encoded in COVID-19 [47].
Tocilizumab
Cinanserin express the ability to suppress 3C-like protease
subsequently implying its potential usefulness in facing
Tocilizumab is a recombinant humanized monoclonal anti-
COVID-19 [47]. Cinanserin was able to suppress SARS-
body against the interleukin-6.
CoV replication [47]. Flavonoids presented the inhibitory
(IL-6) receptor [44]. It showed promising results in
effects against MERS-CoV and SARS-CoV chymotrypsin-
treating severely or critically ill individuals with COVID-
like proteases [47]. Diarylheptanoid, a PLP inhibitor,
19 with coexisting massive changes in lungs and signifi-
expressed the ability to inhibit SARS-CoV PLP [47]. Tar-
cantly elevated levels of IL-6 [44].
geting coronavirus proteases could potentially be useful in
facing COVID-19 [47].

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1894 European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897

Angiotensin‑converting enzyme‑2 (ACE2) inhibitors in patients infected with SARS-CoV-2 are cough, mainly
dry, sore throat and dyspnea. Rhinorrhea, nasal congestion
ACE2 was found to be a critical receptor of SARS-CoV-2 and dizziness may also be present. COVID-19 could also
invasion [1]. SARS-CoV-2 Spike (S) glycoprotein bind- manifest as a sudden hyposmia or anosmia not accompa-
ing with host ACE2 enables the virus to invade the human nied by any other symptom. Whether SARS-CoV-2-induced
organism [1]. Suppressing SARS-CoV-2 S glycoprotein hyposmia/anosmia is reversible remain unknown. URT
from linking with ACE2 could be a promising therapeutic symptoms are commonly observed in younger patients and
option for SARS-CoV-2 infection development [1]. usually appear initially. They may precede the development
Recombinant human monoclonal antibody scFv80R of severe COVID-19. Mild cases of COVID-19 without clin-
against S1 domain of the SARS-CoV was found [47]. It was ical pneumonia could represent the clinical presentation of
reported that this antibody was able to suppress SARS-CoV the disease in young, healthy individuals. ENT symptoms
S glycoprotein from binding to ACE2 and counteract SARS- may be present before the patient tested positive for SARS-
CoV [47]. CoV-2 in molecular analysis.
Emodin expressed antiviral activity [47]. It suppressed Otolaryngologist is of great risk of becoming infected
SARS-CoV and ACE2 fusion because of its ability to com- with SARS-CoV as they cope with URT during performing
pete with SARS-CoV S glycoprotein [47]. This observation a consult, clinical examination, sample taking and a sur-
implied the potential usefulness of emodin in COVID-19 gery. ENT specialist is one of the specialists that patients
therapy [47]. Similar competition with SARS-CoV S gly- with COVID-19 contact most commonly. During COVID-
coprotein for connection to the ACE2 receptor was also 19 pandemic, every patient with cough, sore throat, dysp-
observed for promazine [47]. nea, hyposmia/anosmia and a history of travel to the region
with confirmed COVID-19 cases, should be considered as
a potential COVID-19 case. Otolaryngologist should wear
Nelfinavir
fluid-resistant FFP3/N95 mask, disposable and fluid resistant
gloves and gown, glasses or a full face shield when examin-
Nelfinavir, a HIV protease inhibitor, was able to inhibit
ing such individual. According to previous reports, we spec-
SARS-CoV, thus it could be also considered as a potential
ulate that during COVID-19 pandemic, chest CT should be
therapeutic option for SARS-CoV-2 [47].
performed in patients before ENT operations. It could be of
great value in individuals with negative RT-PCR.
Glucocorticosteroids
Additional studies analyzing why not all patients
develop ENT symptoms during SARS-CoV-2 infection
World Health Organization (WHO) and the Centers for
are needed. Further research is needed to determine the
Disease Control and Prevention (CDC) recommended that
mechanism leading to loss of smell.
glucocorticosteroids should not be commonly administered
in individuals with COVID-19 for managing SARS-CoV-
2-induced pneumonia or acute respiratory distress syndrome Author contributions  JK: Substantial contribution to the design of the
(ARDS) unless required for another reason, like worsen- manuscript, literature search, data analysis and interpretation. Prepar-
ing of the chronic obstructive pulmonary disease, asthma ing the main paper. WK: Substantial contribution to literature search,
or septic shock [44]. Nevertheless, it was reported that in data analysis and interpretation. KZ: Substantial contribution to lit-
erature search. TZ: Drafting the manuscript and revising it critically
patients with COVID-19 pneumonia who progressed to for important intellectual content. Final approval of the manuscript.
ARDS, methylprednisolone brought favorable results [44]. All authors read and approved the final manuscript. All listed authors
have approved the manuscript before submission, including the names
Supplements and order of authors.

Funding  Not applicable.

It was speculated that Vitamin A, B, C, D, E, omega-3 poly-
unsaturated fatty acids, selenium, zinc and iron supplemen-
Compliance with ethical standards 
tation could be beneficial in COVID-19 management [47].
All the research included in this manuscript meet the ethical guidelines,
including adherence to the legal requirements of the study country. The
Conclusion study protocol complied with the 1964 Helsinki declaration and its later
amendments. I confirm that the manuscript has not been published or
submitted for publication to any other journal.
Otorhinolaryngological manifestations are not rare symp-
toms of COVID-19, especially in mild or moderate form of Conflicts of interests  The authors declare that they have no conflicts
the disease. The most common ENT dysfunctions observed of interests.

13
European Archives of Oto-Rhino-Laryngology (2020) 277:1885–1897 1895

Informed consent  Not applicable. 8. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W,
Wang YN, Zhong MH, Li CH, Li GC, Liu HG (2020) Clinical
characteristics of novel coronavirus cases in tertiary hospitals
Open Access  This article is licensed under a Creative Commons Attri- in Hubei Province. Chin Med J (Engl). https​://doi.org/10.1097/
bution 4.0 International License, which permits use, sharing, adapta- CM9.00000​00000​00074​4
tion, distribution and reproduction in any medium or format, as long 9. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, Li SB,
as you give appropriate credit to the original author(s) and the source, Wang HY, Zhang S, Gao HN, Sheng JF, Cai HL, Qiu YQ, Li
provide a link to the Creative Commons licence, and indicate if changes LJ (2020) Clinical findings in a group of patients infected with
were made. The images or other third party material in this article are the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan,
included in the article’s Creative Commons licence, unless indicated China: retrospective case series. BMJ 368:m606. https​://doi.
otherwise in a credit line to the material. If material is not included in org/10.1136/bmj.m606
the article’s Creative Commons licence and your intended use is not 10. Hopkins C, Kumar N (2020) Loss of sense of smell as marker
permitted by statutory regulation or exceeds the permitted use, you will of COVID-19 infection (letter). ENT UK website. https​://www.
need to obtain permission directly from the copyright holder. To view a entuk​. org/sites​/ defau​l t/files​/ files​/ Loss%20of%20sen​s e%20
copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. of%20sme​ll%20as%20mar​ker%20of%20COV​ID.pdf Accessed
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