Otorhinolaryngological manifestations of COVID-19-A systematic review

Background: In early December 2019, an outbreak of COVID-19, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in Wuhan City, Hubei Province, China causing havoc all over the world. As clinicians, recognition of this disease is necessary to isolate these patients to prevent further human to human transmission. Due to its a�nity to the respiratory tract and increased viral load in the nose and throat, we as practising otorhinolaryngologists are at increased risk of exposure to this life-threatening virus and warrants an in-depth knowledge on the symptomatology of this disease. This systematic review is intended to highlight the otorhinolaryngological manifestations of COVID-19. Methodology: The literature search was performed on PubMed database using Boolean operators ‘and ‘, ‘or’ as “otorhinolaryngological manifestations” or “rhinology” or “otology” or “larynx” or “hearing” or “olfaction” and “covid19” or “novel corona virus” or “SARS-CoV” with �lters as ‘2020’ year of study on 7/08/2020 at 11.30 Am. Review Results: Total of 357 articles were obtained on search and the �nal 12 articles extracted based on our selection criteria were reviewed. The studies included 6825 laboratory con�rmed COVID -19 patients with varying severity of disease. Olfactory dysfunction and taste dysfunction were noted in 2355 and 2224 patients respectively. Nasal obstruction was reported in 323 patients and sore throat in 261 patients. Rhinorrhoea was reported in 209 patients .158 patients complained of post nasal drip and 152 patients presented with facial pain. Conclusion: As a practising otorhinolaryngologist, a good insight into the otorhinolaryngological manifestations of COVID-19 is essential to differentiate between the prodromal symptoms of COVID-19 and non-COVID viral upper respiratory tract infection.


Background
Coronaviruses are enveloped positive stranded RNA viruses belonging to the family Coronaviridae and the order Nidovirales, with spikes on its surface giving it a crown like ultrastructural appearance; hence was named coronavirus.The 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) as it is now called, has swiftly spread from its origin in Wuhan City of China to all around the globe.As on 14/09/2020 there has been 29 million cases with reported deaths around 9,25,000 worldwide.India ranks second in the case burden with 4.85 million cases and 79,722 deaths till then.
The incubation period for COVID-19 is believed to reach 14 days, nevertheless, most of the patients develop symptoms of COVID-19 disease after 4-5 days post infection.COVID-19 remains contagious even during the incubation period, thus patients before clinical COVID-19 presentation can spread the virus to others.Infection with 2019-nCoV presents with non-speci c features such as malaise, fever, and dry cough at the prodromal phase.Symptoms of COVID-19 ranges from no symptoms, mild upper respiratory tract infection to very severe lower respiratory tract infection with bilateral lung in ltrates.Despite respiratory symptoms, COVID-19 presents with a plethora of other systemic features.
Due to its a nity to the respiratory tract, we as practising otorhinolaryngologists are at increased risk of exposure to this life-threatening virus and demands an in-depth knowledge on the symptomatology of this disease.This systematic review is intended to highlight the otorhinolaryngological manifestations of COVID-19.

Methodology
Search strategy and selection criteria: The literature search was performed on PubMed database using Boolean operators 'and ', 'or' as "otorhinolaryngological manifestations" or "rhinology" or "otology" or "larynx" or "hearing" or "olfaction" and "covid19" or "novel corona virus" or "SARS-CoV" with lters as '2020' year of study.There were no restrictions on the language of articles published.After eliminating duplicates, three investigators independently reviewed all article title: the full texts of articles considered as eligible for review were extracted for further analysis.Thereafter, eligible articles were selected for nal analysis according to prede ned inclusion and exclusion criteria.Difference of opinion between the authors were solved by consensus.We included only human studies and articles with clearly de ned clinical outcome.The exclusion criteria included animal studies, single case reports and review articles.The search was performed at speci ed date and time on 7/08/2020 at 11.30 Am.

Results
Total of 357 studies were obtained on PubMed database search, out of which 329 studies were excluded after checking the relevance of title.Full text article of the remaining 28 articles were read thoroughly and 16 out of them were excluded due to various reasons (two studies were guidelines for otorhinolaryngological practice, seven studies were review articles,2 were related to anosmia in COVID era in patients not con rmed with COVID infection, one study was on recovery of anosmia post-COVID, three studies were case reports and one another study was on the pathophysiology of anosmia in COVID).Search was done strictly adhering to the PRISMA guidelines, as depicted in Chart 1.
We reviewed the nal 12 articles based on our selection criteria to extract the following information from each: rst author, study design, number of patients, demographic data of study population, otorhinolaryngological manifestations of COVID 19 and drawbacks of study if any.The studies included for this review collectively included 6825 laboratory con rmed COVID -19 patients with varying severity of disease.The extracted data is jotted in Table 1.
4123 females and 2647 males were included (gender distribution was not elaborated in two studies).Olfactory dysfunction and taste dysfunction was noted in 2355 and 2224 patients respectively.In the studies performed by Lauren T Roland et al 4 and Antje Haehner et al 9 Anosmia or ageusia were reported in 95 and 22 patients respectively.Nasal obstruction was reported in 323 patients followed by next common symptom sore throat in 261 patients.Rhinorrhoea was reported in 209 patients .158patients complained of post nasal drip and 152 patients presented with facial pain.Dysphagia was reported by 42 patients and 61 patients had ear pain.Mucus production was one of the presenting symptoms in 36 patients.Table 2.

Discussion
In most of the studies included in our review females were most commonly affected than males.Most of the available literature suggest a contrary observation indicating males have more susceptibility that females due to the fact that there are many differences between men and women in the immune response to Covid-19 infection.Women, compared to men, are less prone to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes.The presence of two X chromosomes in women emphasizes the immune system even if one is inactive.The immune regulatory genes encoded by X chromosome in female gender causes lower viral load levels, and less in ammation than in man, while CD4+ T cells are higher with better immune response.In addition, women generally produce higher levels of antibodies which remain in the circulation longer. 13VID-19 and its relation with olfactory and gustatory dysfunction is a well-known fact and there have been abundant literature on the same.Olfactory and gustatory dysfunction are more prevalent in patients with mild to moderate disease probably due to the fact that in patients with severe disease these symptoms are commonly overlooked and less reported.In our review we noted that anosmia and ageusia are the most common otorhinolaryngological manifestation of COVID-19.
Due to the a nity of coronavirus towards upper respiratory mucosa, nasal obstruction seems to be a common symptom next only to anosmia and ageusia.
Rhinorrhoea and sore throat are common observations in patients with COVID-19 infection.The prodromal symptoms of COVID 19 infection and non COVID Upper respiratory viral infection include nasal obstruction and sore throat, therefore differentiating between both becomes a challenging task.Hence at our institution we have a u OPD (with necessary safety precautions), where patients with URI and Pharyngitis (sore throat) undergo thermal screening, vitals assessment, Chest X ray and rapid antigen testing to rule out COVID-19 infection.After ruling out COVID-19 infection patient is referred to Otorhinolaryngologist for de nitive management.This practise ensures safety at workplace for Otorhinolaryngologist in routine OPD and similar practise is recommended by the authors.
Facial pain and post nasal drip were recorded in 152 and 158 patients respectively, in the study performed by Jerome R. Lechien et al 2 indicating that sinusitis frequently occurs in concordance with COVID-19 infection, other studies included in our review did not indicate such association.This indicates that there is a lacuna in literature regarding the incidence of sinusitis in COVID-19 patients.Sneezing was not reported in any of the included study.
Otological symptoms seems to be less common in COVID-19 patients.In the study performed by Jerome R. Lechien et al 2 ear pain was documented in 61 patients.In the study performed by Mustafa et al 7 , they observed that the high frequency pure-tone thresholds as well as the TEOAE amplitudes were signi cantly worse in the test group.The results of their study showed that COVID-19 infection had deleterious effects on the hair cell of cochlea.The drawback of this particular study is the small cohort.In a case reported by Osman Kilic et al 14 they noted sudden sensorineural hearing loss in a 29-year-old patient.Studies on large population is required to con rm the deleterious effect of COVID-19 infection on the hair cells of cochlea.

Conclusion
As a practising otorhinolaryngologist, a good insight into the otorhinolaryngological manifestations of COVID-19 is essential to differentiate between the prodromal symptoms of COVID-19 and non-COVID viral upper respiratory tract infection.Patients of COVID-19 tend to frequently present with anosmia and ageusia which is common in mild to moderately severe disease.Despite this, frequently they present with nasal obstruction, sore throat, rhinorrhoea, postnasal drip, facial pain, nasal congestion and ear pain in decreasing order of frequency.AUTHOR

Table 2 :
Number of patients with various otorhinolaryngological symptoms from the included studies.