Original articleOlfactory and taste dysfunction in Coronavirus disease 2019 Pandemic- A Study of 42 cases .Background: This study is done to raise awareness of olfactory and taste dysfunction association in COVID-19 pandemic, urging early detection and isolation of COVID-19 positive patients thus breaking the chain of transmission of disease.Materials and Method : This is a cross-sectional observational study of COVID-19 positive patients having olfactory and or taste dysfunction, attending Otorhinolaryngology outpatient department of tertiary care hospital in Mumbai, West India from 1st May 2020 to 1st August 2020. Study was conducted by taking proper history, an OPD examination and a meticulous follow up of the patients. Results: The study comprises of 42 COVID-19 patients having olfactory and or taste dysfunction. 62 % were males and 38 % were females. 57.14 % patients were known contact with COVID-19 positive individuals, the mean incubation period of these patients were 3.79 days. Reduction in smell and taste occurred in 88 % and 83.33 % patients respectively. 71.43 % presented with both olfactory and taste dysfunction, while 16.67 % presented with only olfactory dysfunction and 7.14 % presented with only taste dysfunction. In both cases of olfactory and taste dysfunction, the mean onset of symptoms occurred at fourth to sixth day after being tested positive for COVID-19.The mean duration of total anosmia was two weeks. Out of 37 patients having anosmia, 94.6 % recovered to normal levels and 5.4 % did not show appreciable recovery. The mean duration of hyposmia was around 5 weeks. Out of 35 patients having hyposmia, 94.3 % recovered and 5.7 % did not have appreciable recovery. Ageusia collaborated with the duration of anosmia. The mean duration of reduced taste sensation was 6 weeks. Out of 35 patients having taste dysfunction, 88.6 % recovered and 11.4 % did not recover. The unrecovered patients in smell, also showed poor recovery in taste. Patients who did not recover are still under follow up.Conclusion: Olfactory and taste dysfunction are very important clinical features of COVID-19 positive patients with anosmia being the most prominent symptom. All patients coming with smell and or taste dysfunction should be screened for COVID-19 to avoid delay in diagnosis of the disease.Keywords: SARS-CoV-2, COVID-19, Pandemic, olfactory dysfunction, Anosmia, Ageusia.Background:Severe Acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) is the causative agent for Coronavirus disease 2019 ( COVID-19 ).1 Corona virus causes respiratory tract infections. The severity can be mild like common cold, and can be even lethal, like SARS ( Severe acute respiratory syndrome ), MERS ( Middle East respiratory syndrome ), and COVID-19 ( Corona virus disease 2019 ). COVID-19 disease was first identified in December 2019 in Wuhan, the capital of China's Hubei province and later caused a worldwide pandemic.2, 3 The virus mainly spreads by close contact via small droplets produced while coughing, sneezing and talking.4,5 Bioaerosol transmission occurs while doing intubation, tracheostomy and cardiopulmonary resuscitation. Fomite transmission is also possible.4 The virus is most contagious when people are symptomatic; although spread is possible even before symptoms appear.4 The incubation period is 5 to 6 days but may range from 2 to 14 days. The virus survives for hours to days on surfaces. The patient may be totally asymptomatic or present with flu like symptoms like fever, cough, sneezing, fatigue and shortness of breath. Blood investigations often revels lymphocytopenia and ground glass appearance is commonly seen in HRCT of chest. The disease may progress to pneumonia, multi-organ failure, and even death.8,9,10,11 Of recent there is increasing evidence of olfactory dysfunction in COVID-19 patients. Anosmia can solely be the presenting symptom or associated with dry cough or Ageusia.14Otolaryngologists and health care staff are at high risk of COVID-19 infection, hence appropriate protective and hygiene measures are of utmost improtance.6,7 The risks seem to be more high in the field of rhinology, neuro-oncology and endoscopic endonasal surgery.12,13 Genuine concerns are raised for nasal endoscopy and flexible laryngoscopic examination of patients in out patient clinic and during surgery as virus resides primarily in the nasal cavity and nasopharynx. Materials and Methods: Amidst the COVID-19 pandemic in Mumbai this is a cross-sectional observational study of patients, who are confirmed positive for COVID-19 by real-time reverse transcription polymerase chain reaction ( rRT-PCR ) and having olfactory dysfunction and or taste disorders, attending Outpatient department of tertiary care hospital in Mumbai, west India from 1st May 2020 to 1st August 2020. This study excludes subjects having additional comorbidities or had complication due to COVID-19 disease. Study includes subjects who were under regular follow up in ENT department and also under the guidance of physician to keep a check to any complication due to Coronavirus disease. Study was conducted by taking proper history, an OPD examination and a meticulous follow up of the patient. The olfactory dysfunction for each patient was tested by using vial containing easily available, non-irritating substance like vanilla, lemon, freshly ground coffee and scented soap, which stimulate the olfactory receptors. Irritating odors such as camphor or menthol which stimulate the trigeminal sensory receptors in addition to the olfactory receptors were not used in this study to avoid any false positive result. All patients were informed about the test. The patient was asked to place an index finger over one nostril to block it ( example, right index finger over right nostril ). He or she then closes the eyes. The patient is asked to sniff repetitively and tell when an odor is detected and if the odor is recognized. The test odor was brought up-to within 30 cm or less of the nose. No auditory clue was given. The same process was repeated with the other nostril. Smell sensation was intact when patient detected the odor. The degree of smell sensation gives an idea if the patient has anosmia or hyposmia. The patients who are under home quarantine are explained the procedure and they were advised to repeat this test every 4 days, hence we can measure the recovery. The taste dysfunction for each patient was tested by sugar, salt and vinegar using different concentrations. The patient was asked to rinse the mouth with plain water and wipe the tongue dry with a clean paper towel. A clean cotton swab was dipped in 10 percent sugar solution and smeared all around the surface of the tongue. Patient was asked whether he or she can taste the sweetness. The previous step was repeated to test the 1% , 0.1% and 0.01 % sugar solutions, rinsing the mouth and wiping the tongue before testing each solution. This gave an approximate taste threshold for sugar. The same is repeated with salt and vinegar with 10, 1, 0.1 and 0.01 % and assess the taste dysfunction and threshold. The patients who are under home quarantine are explained the procedure and they were advised to repeat this test every 4 days, hence we could assess the recovery.Results Out of 42 patients, 26 ( 62 % ) were males and 16 ( 38 % ) were females. The males belonged to the age group of 24 to 68 years ( mean age 42.65 years ). The females belonged to the age group of 21 to 60 years ( mean age 38.56 years ). 24 out of 42 patients ( 57.14 % ) had confirmed contact with COVID-19 positive individuals. The incubation period of these 24 patients was 0 to 8 days ( mean 3.79 days ). Reduction in smell occurred in 37 patients out of 42 ( 88 % ). Reduction in taste occurred in 35 out of 42 patients ( 83.33 % ). 30 out of 42 patients ( 71.43 % ) presented with both olfactory and taste dysfunction, while 7 patients ( 16.67 % ) presented with only olfactory dysfunction and 3 patients ( 7.14 % ) presented with only taste dysfunction. In both the cases of olfactory and taste dysfunction, the mean onset of symptoms occurred at around 4th day, but most patients appreciated the distinct anosmia and taste disorder after 7 to 10 days from the onset of symptoms. In our study 5 patients ( 11.9 % ) had reduced olfaction and taste sensation together from the 1st day. Two patients had reduced sense of taste alone on the 1st day before the patients realized any other symptoms.All the patients were advised self isolation with smell and taste training to improve and fasten smell and taste recovery along with the treatment protocol for COVID-19. In addition, patients were treated with low dose systemic corticosteroid ( Prednisolone 10 mg ) for 10 days. Intranasal corticosteroids and saline nasal wash were not prescribed as it may lower the immunity and saline wash may spread the aerosol more. The mean duration of anosmia was around 2 weeks ( 7 - 21 days ). Out of 37 patients having anosmia, 35 patients ( 94.6 % ) recovered from anosmia and two patients ( 5.4 % ) did not recover. Anosmia gradually improved to hyposmia where the patient was able to smell only strong smells. The mean duration of hyposmia was around 5 weeks ( 21 - 50 days ). Out of 35 patients having hyposmia, 33 patients ( 94.3 % ) recovered from hyposmia and 2 patients ( 5.7 % ) did not show any significant recovery. Table 1. Details of COVID-19 patients coming with olfactory or taste dysfunction.SERIAL NUMBERAGESEXKNOWN CONTACTINCUBATION PERIOD (DAYS)OLFACTORY PROBLEM PRESENT / ABSENTOLFACTION (DAYS)TASTE PROBLEM PRESENT / ABSENTTASTE PROBLEM (DAYS)ASSOCIATED SYMPTOMSONSET OF ANOSMIADURATIONOF ANOSMIAANOSMIA RECOVERED OR NOTDURATION OF HYPOSMIAHYPOSMIA RECOVERED OR NOTONSET OF REDUCED SENSE OF TASTEDURATION OF REDUCED SENSE OF TASTETASTE SENSATION RECOVERED OR NOT124MN_P 27Y21YP 228YFV, C, S, R, MS, H, D255MN_P 510Y28YP 538YFV, C, S, R, MS, H, D340MY3P 021Y47YP 068YFV, C, S, R, MS, H, D457MY4P 218Y49NP 267NFV, C, S, R, MS, H, D534MY5P 217Y50NP 267NFV, C, S, R, MS, H, D630FY5P 215Y21YP 236YFV, C, S, R, MS, H, D744MY8P 38Y48YP 357YFV, C, S, R, MS, H, D828MY0P 18Y48YP 155YFV, C, S, R, MS, H, D929MN_P 68Y48YP 756YFV, C, S, R, MS, H, D1055MN_P 58Y48YP 655YC, S, R, MS, H1166MY4P 88Y48YP 956YFV, C, S, R, MS, H, D1268MN_P 27Y48YP 054YFV, C, S, R, MS, H1334MN_P 1214Y32YP 1246YFV, C, S, R, MS, H1429MY3A_____P228Y_1548FY3A_____P538YC1627MY3P 021N_ P 021NFV, C, S, R, MS, H1726FY4P 07Y30YP 037YFV, C, S, R, MS, H1858MY6P 514Y21YP 635YC, S, R, MS, H1940MY2P 414Y30YP 444YFV, C, S, R, MS, H2028MN_P 315Y21YP 336YFV, C, S, R, MS, H2130MN_P114Y25YP 139YFV, C, S, R, MS, H, D2236FY3P 513Y21YP 634YFV, C, S, R, MS, H2333FN_P 414Y21YP 435YFV, C, S, R, MS, H2421FN_A_____P068Y_2547MY0P 17Y27YP 134YC, S, R, MS, H2638FY7P 014Y33YP 047YFV, C, S, MS, H2740FY4A_____P236YC2850MY3P 113Y21YP 134YC, S, R, MS, H2951FN_P 48Y21YP629YC, S, R, MS, H3028FN_P 111Y21YA____3132FY3P 510Y36YA____3231FN_P 921N_ P721NFV, C, S, MS, H3328MN_P 1121Y30YA____3438FY2P 221Y29YA____3540MN_P 021Y30YP051YC, S, MS, H3647MN_A_____P236Y_3760FY6P 321Y30YA____3855MY4P 37Y30YP337YC, S, MS, H3966MY6P 321Y26YA____4051FY3P 621Y30YP651YFV, C, MS, H4130MN_P 421Y27YA____4254FN_P 221Y30YP252YC, MS, H Abbreviations for Table 1:M = Male, F = Female, Y = Yes, N = No, P = Present, A = Absent, FV = Fever, C = Cough, S = Sore Throat, R = Rhinitis, MS = Muscle Ache, H = Headache, D = Diarrhea. Table 2. Calculation of data of COVID-19 with olfactory and or taste dysfunction.TABULATION OF DATA OF COVID- 19 POSITIVE PATIENT CAME WITH OLFACTORY AND/ TASTE PROBLEM TOTAL PATIENTS42 PATIENTS100% SEX MALE26 PATIENTS62%FEMALE16 PATIENTS38%AGE MALERANGE 24-68MEAN 42.65FEMALERANGE 21-60MEAN 38.56KNOWN CONTACT24 KNOWN CONTACTS57.14%INCUBATION PERIOD (DAYS)0-8MEAN 3.79 PROBLEM IN OLFACTION 37 PATIENTS88%ONSET OF ANOSMIA (DAYS)RANGE 0-12MEAN 3.43DURATION OF ANOSMIA (DAYS)RANGE 7-21MEAN 14.05ANOSMIA RECOVERED OR NOT 35 PATIENTS RECOVERED AND 2 NOT RECORVEDOUT OF 37 PATIENTS, 94.6 % RECOVERED AND 5.4 % NOT RECOVEREDDURATION OF HYPOSMIA (DAYS)RANGE 21-50MEAN 32.17HYPOSMIA RECOVERED OR NOT33 PATIENTS RECOVERED AND 2 NOT RECOVEREDOUT OF 35 PATIENTS, 94.3 % RECOVERED AND 5.7 % NOT RECOVERED PROBLEM IN TASTE35 PATIENTS83.33%ONSET OF REDUCED TASTE SENSATION (DAYS)RANGE 0-12MEAN 3.2DURATION OF REDUCED TASTE SENSATION (DAYS)RANGE 21-68MEAN 43.6TASTE SENSATION RECOVERED OR NOT31 PATIENTS RECOVERED AND 4 NOT RECOVERED88.6 % RECOVERED AND 11.4 % NOT RECOVERED PATIENT HAVING ONLY OLFACTORY DYSFUNCTION7 PATIENTS16.67%PATIENT HAVING ONLY TASTE DYSFUNCTION3 PATIENTS7.14%PATIENT HAVING BOTH OLFACTORY AND TASTE DYSFUNCTION30 PATIENTS71.43% ASSOCIATED SYMPTOMS FEVER22 PATIENTS52.38%COUGH32 PATIENTS76.19%SOAR THROAT28 PATIENTS66.67%RHINITIS24 PATIENTS57.14%MUSCLE ACHES30 PATIENTS71.43%HEADACHE30 PATIENTS71.43%DIARRHEA11 PATIENTS26.19% Ageusia collaborated with the duration of anosmia, and improved spontaneously with time. Initially patients were able to differentiate bitter taste, later taste sensation improved with time. The mean duration of reduced taste sensation was around six weeks ( 21 - 68 days ). Out of 35 patients having taste dysfunction, 31 patients ( 88.6 % ) recovered and four patients ( 11.4 % ) did not show any recovery. Incidentally it was noted that patients who did not recover from anosmia also showed poor recovery in taste. Patients who have not recovered are still under follow up.The most common associated symptoms included cough ( 76.19 % ), followed by headache and muscle ache ( 71.43 % ), sore throat ( 66.67 % ), rhinitis ( 57.14 % ), fever ( 52.38 % ), and diarrhea ( rare- 26.19 % ) . Discussion: Association of COVID-19 and Olfactory dysfunction Olfactory dysfunction is currently the most common clinical feature of COVID-19,15 especially in the early stages. Anosmia of sudden onset is the a classical early sign of COVID-19 disease.16 Klopfenstein et al study showed 54 ( 47 % ) out of 114 COVID-19 positive patients had clinical features of anosmia with patients principally developed anosmia 4.4 days after the outset of the SARS-CoV-2 infection and 98 % patients recovered of anosmia within 28 days.17 Olfactory dysfunction frequently accompanied by dysgeusia in COVID-19 patients.17,18 Incidence of Olfactory dysfunction in COVID-19 patients ranging from 33.9 to 68 with association of smell disorders was seen.19-23 Smell disorder incidence is seen higher in COVID-19 patients.19,20,23 Moein et al. executed olfactory function test ( OFT ) of 60 COVID-19 positive patients and 60 subjects as control group having similar age and gender of the patient's group and concluded that COVID-19 patients presented with marked olfactory dysfunction.24 Another investigation done using self-reported questionnaire which surveyed the prevalence of taste and / or smell disorders in COVID-19 and influenza patients.25 The study showed that incidence rate in COVID-19 cases ( 39.2 % ) was significantly higher than in influenza cases ( 12.5 % ).25 Mayo Clinic analyzed the symptoms and signs of COVID-19 infection by using artificial intelligence which revealed that the prevalence of anosmia or dysgeusia in COVID-19 positive patients was 28.6-fold more than that of COVID-19 negative patients and the study also disclosed that anosmia or dysgeusia was one of the earliest presentation of COVID-19 infection.26 COVID-19 infection has some association to host genotype with heritability for anosmia 47 %.27 Olfactory dysfunction has a high incidence rate in COVID-19 cases in some American and European countries, but it hardly occurs in Chinese patients.27,28 The cause of less cases of olfactory dysfunction in COVID-19 positive Chinese patient can be due to genotype mutation. Forster et al found change in amino acid in three central variants. The A and C genotype of SARS-Cov-2 presents remarkably in Americans and Europeans, with B type being most common genotype in East Asians. Type A and C genotype seem high pathogenicity for human nasal cavity, thus favoring increased prevalence of olfactory dysfunction in American and European countries.29 Nasal cavity and COVID-19 infection In humans it has been found that there are 7 types of coronaviruses namely SARS-CoV-2, Severe acute respiratory syndrome coronavirus ( SARS-CoV ), Middle East respiratory syndrome coronavirus ( MERS-CoV ), HCoV-NL63, HCoV-OC43, HCoV-229E and HCoV-HKU1.30 SARS-CoV-2 genome is a 29,903 bp single-stranded RNA coronavirus.31 SARS-CoV-2 virus bears a spiny protein named S1 which adheres to the ACE2 receptor present on host cell membrane.31 ACE2 receptors are distributed in the central nervous system.5 The olfactory system has olfactory bulb and nerve fibres. Viruses can invade this olfactory system via cribriform plate to involve the central nervous system.32,33,34 SARS-CoV-2 mainly reside in ciliated cells and goblet cells in the nasal mucosa, thus transmission occurs primarily through droplets.35 SARS-CoV-2 virus can pass from nasal cavity via nasolacrimal duct to eye, hence it can be detected in tears.36 Olfactory dysfunction following COVID-19 infection is believed to be caused by either damage to the olfactory epithelium or central olfactory system pathways.37 The exact catastrophic mechanism of SARS-CoV-2 virus on the olfactory system is still unresolved. It is ambiguous whether olfactory dysfunction is due to local inflammation of the nasal cavity or viral-induced olfactory nerve damage or both. Rhesus monkey can be used to study the physiological and pathological effect of the olfactory system by SARS-CoV-2 virus. Olfactory epithelium of COVID-19 positive patients can be biopsied for better delineation of the pathology of Olfactory dysfunction .38 Association of COVID-19 and Taste dysfunction Whether or not gustatory problems in COVID-19 patients really target the sense of taste is unclear. The fact that three of our patients experienced gustatory dysfunction alone with no smelling problems or any other associated symptoms, indicates that more than one pathophysiological pathway might exist. The gustatory system is transmitted via the Chorda tympani nerve supplying anterior two thirds of the tongue, Glossopharyngeal nerve supplying posterior one third of tongue and vagal nerve supplying vallecula. These recognize the basic tastes like sweet, sour, salty, bitter and umami. The key receptor for the entry of SARS-CoV-2 inside the host cells is Angiotensin Converting Enzyme-2 ( ACE2 ). ACE-2 receptor is expressed in multiple organs like lungs, heart, kidney, intestines, buccal cavity, brain etc. Hao Xu et al in his study showed that the ACE2 receptors are present and highly enriched in the epithelial cells of the oral cavity. Moreover, ACE2 was seen higher in tongue than in buccal and gingival tissues. These findings indicate that the oral cavity mucosa is a potentially high risk route of COVID-19 infection.39 Conclusion: From this study it is inferred that anosmia is an early and distinguished diagnostic sign seen in COVID-19 disease and many a times it is present even before diagnosis of the disease. Both olfactory and taste dysfunction are self recovering, with majority of the patient showed improvement. Factors leading to improvement could not be clearly defined but since it is a viral disease, improvement is directly related to viral progression. Patient need closed monitoring and follow up for any complication arising due to COVID-19 disease. Our study includes only stable patients without any comorbidities. All patients in our study were treated with oral medications and regular check up done by ENT surgeons and also by physician to keep a eye to any developing complication due to disease itself. Patients with additional comorbidities were excluded from the study, thus idea of anosmia and taste dysfunction and its recovery is not studied in comorbid patients, it may take longer time or different recovery phase in such patients, according to viral infection and it progression. In Indian subcontinent there is sudden high prevalence of this COVID-19 disease, thus it is very important to have a knowledge of the disease and its presenting symptoms. Patients may present with sudden onset anosmia as single clinical feature or it can be associated with taste dysfunction and / or dry cough, sore throat, headache, muscle ache, fever, rhinitis and diarrhea. Otolaryngologists should screen all patients coming with smell and taste dysfunction with real-time reverse transcription polymerase chain reaction ( rRT-PCR ) for COVID-19 to avoid delay in diagnosis of COVID-19 disease.