Discussion

Coronavirus disease 2019 is an active global pandemic; it has so far infected millions and it remains a global threat. As per the initial studies,^{Reference Guan, Ni, Hu, Liang, Ou and He1} the major symptoms associated with Covid-19 included fever, sore throat, cough, fatigue and shortness of breath. Over the past few months, other clinical manifestations have been associated with diagnosed or suspected Covid-19 positivity, such as the sudden appearance of olfactory and taste dysfunction, even in the absence of other symptoms.

The pathophysiology of olfactory and taste dysfunction in Covid-19 infection is still unknown. Chemosensory dysfunction may be seen in some viral infections, and coronavirus is already known to be associated with anosmia.^{Reference Suzuki, Saito, Min, Vladau, Toida and Itoh9} The SARS-CoV-2 infection most likely causes obstructive inflammation of olfactory clefts, or targets and damages olfactory epithelium support and stem cells, leading to olfactory disturbances.^{Reference Brann, Tsukahara, Weinreb, Lipovsek, Van den Berge and Gong10} Some types of coronavirus have been shown to propagate from the nasal epithelium, via the cribriform plate to the olfactory bulb, and the piriform cortex and brainstem.^{Reference Netland, Meyerholz, Moore, Cassell and Perlman11} Direct contact of the virus or its components with gustatory receptors can also lead to taste disturbances. This virus might target angiotensin-converting enzyme 2 (ACE2) expressing cells of the taste buds and/or olfactory epithelium via a cytopathic effect.^{Reference Finsterer and Stollberger12} Alternatively, an altered neurotransmission in the absence of neurosensory cell death might lead to olfactory and taste dysfunction. Severe acute respiratory syndrome coronavirus-2 may impact the synthesis of neurotransmitters (serotonin and dopamine) by ACE2-expressing cells.^{Reference Lechien, Chiesta-Estomba, De Siati, Horoi, Le Bon and Rodriguez7}

Mao et al.^{Reference Mao, Jin, Wang, Hu, Chen and He4} first reported olfactory and taste dysfunction in Covid-19 patients in China in February, 2020. In their retrospective study of 214 laboratory confirmed Covid-19 patients, 11 (5.1 per cent) reported hyposmia and 12 (5.6 per cent) reported hypogeusia. However, these data were derived from medical records, and minor symptoms such as olfactory and taste dysfunction might not have been adequately documented.

A cross-sectional survey was performed by Giacomelli et al.^{Reference Giacomelli, Pezzati, Conti, Bernacchia, Siano and Orelni8} in 59 Covid-19 positive hospitalised patients in Italy. They reported loss of smell or taste in 20 patients (33.9 per cent), and loss of both in 11 (18.6 per cent). Twelve patients (20.3 per cent) reported chemosensory symptoms before hospitalisation. This suggested that olfactory and taste dysfunction could be ancillary symptoms of Covid-19.

Hopkins et al.^{Reference Hopkins, Surda and Kumar13} reported that in 17 per cent of 2428 individuals, new onset anosmia was not associated with other symptoms of Covid-19. In a meta-analysis by Tong et al.,^{Reference Tong, Wong, Zhu, Fastenberg and Tham14} the prevalence of olfactory and gustatory dysfunction was 52.7 per cent and 43.9 per cent respectively.

Lechien et al.^{Reference Lechien, Chiesta-Estomba, De Siati, Horoi, Le Bon and Rodriguez7} studied olfactory and taste dysfunction in 417 mild to moderate laboratory confirmed Covid-19 patients who completed questionnaires, from 12 European hospitals. Olfactory dysfunction was reported by 85.6 per cent of patients, of which 79.6 per cent reported anosmia and 20.4 per cent reported hyposmia. In addition, 12.6 per cent and 32.4 per cent of patients reported phantosmia and parosmia, respectively. Olfactory dysfunction was reported before other symptoms in 11.8 per cent of patients, after other symptoms in 65.4 per cent and at the same time in 22.8 per cent. The olfactory dysfunction persisted after the resolution of other symptoms in 63 per cent of patients.

Kaye et al.^{Reference Kaye, Chang, Kazahaya, Brereton and Denneny15} used the Covid-19 Anosmia Reporting Tool for Clinicians, developed by the American Academy of Otolaryngology – Head and Neck Surgery, for reporting anosmia and dysgeusia related to Covid-19. On analysis of the first 237 entries, anosmia was noted in 73 per cent of patients prior to a Covid-19 diagnosis and was the initial symptom in 26.6 per cent of patients.

In our study, 22.4 per cent of patients reported olfactory dysfunction, 22.4 per cent reported taste dysfunction, and 24.1 per cent reported either olfactory or taste dysfunction. The differences in the frequency of olfactory and taste dysfunction in various studies may be a result of: possible selection bias, the lack of evaluation of olfactory and taste dysfunction in Covid-19 patients in China at the onset of the pandemic, and potential changes in the virulence and pathogenicity of the virus during the spread of the pandemic.

Lei et al.^{Reference Lei, Cao, Jie, Huang, Guo and Chen16} found differences in the epidemiology and clinical features of patients infected in and outside of Wuhan, and an ethnic pattern. Cao et al.^{Reference Cao, Li, Feng, Wan, Huang and Sun17} demonstrated a diversity in the expression pattern of ACE2 in Asian and European populations. This is the receptor of SARS-CoV-2, and may lead to differences in the susceptibility and response to this virus from different populations. According to literature, the prevalence of olfactory and taste dysfunction is substantially higher in European Covid-19 patients. However, there have only been a few studies on the occurrence of olfactory and taste dysfunction in Covid-19 patients in Asian patients. The current paper describes a large single-centre study, documenting the occurrence of olfactory and taste dysfunction in Covid-19 patients in India.

In our study, olfactory and taste dysfunction was proportionally more common in females than males. This finding was similar to that of studies by Lechien et al.^{Reference Lechien, Chiesta-Estomba, De Siati, Horoi, Le Bon and Rodriguez7} and Speth et al.^{Reference Speth, Singer-Cornelius, Oberle, Gengler, Brockmeier and Sedaghat18} The higher susceptibility of females to develop olfactory and taste dysfunction could be related to gender-related differences in the inflammatory reaction process. In a study by Meini et al.,^{Reference Meini, Suardi, Busoni, Roberts and Fortini19} chemosensory dysfunction in women was less frequent but lasted longer.

Our study showed a significant association between malaise, sore throat, cough, fever and the occurrence of olfactory and taste dysfunction. Lechien et al.^{Reference Lechien, Chiesta-Estomba, De Siati, Horoi, Le Bon and Rodriguez7} also identified a significant association between fever and the occurrence of olfactory and gustatory dysfunction.

In our study, the mean recovery time of olfactory and taste dysfunction was 4.9 days (range, 2–15 days). Meini et al.^{Reference Meini, Suardi, Busoni, Roberts and Fortini19} reported recovery from olfactory and taste dysfunction within four weeks in most patients. Lechien et al.^{Reference Lechien, Chiesta-Estomba, De Siati, Horoi, Le Bon and Rodriguez7} reported an early olfactory recovery rate of 44 per cent, with recovery occurring within the first 8 days following disease resolution in 73 per cent of patients with olfactory dysfunction. Klopfenstein et al.^{Reference Klopfenstein, Kadiane-Oussou, Toko, Royer, Lepiller and Gendrin20} reported a mean duration of anosmia of 9 days, with a complete recovery occurring in almost all patients within 4 weeks. Kaye et al.^{Reference Kaye, Chang, Kazahaya, Brereton and Denneny15} reported that 27 per cent of their patients experienced at least some improvement of olfactory dysfunction, with a mean time of 7.2 days. Yan et al.^{Reference Yan, Faraji, Prajapati, Boone and DeConde21} reported that 74 per cent of their patients experienced improved olfactory dysfunction with resolving Covid-19 infection.

Most Covid-19 patients with olfactory and taste dysfunction recover their sense of smell and taste within two to four weeks. This short recovery time supports the theory that non-neural olfactory epithelial cells are the potential target of SARS-CoV-2. However, it is possible that stem cells such as horizontal basal cells may be infected, which require more time to recover the olfactory function.^{Reference Brann, Tsukahara, Weinreb, Lipovsek, Van den Berge and Gong10} There may be long-lasting olfactory dysfunction if a large percentage of basal cells are damaged and the olfactory epithelium cannot effectively renew over time.^{Reference Schwob22}

The strength of our study is that it is a prospective study evaluating the occurrence of olfactory and taste dysfunction in Covid-19 patients. It also reports on the association between olfactory and taste dysfunction and other symptoms. This is the first study to report on the frequency of occurrence of olfactory and taste dysfunction in Covid-19 infected patients in India. The paper highlights differences in the frequency of olfactory and taste dysfunction between Asian and European populations.

The limitations of our study are that the patients did not undergo objective evaluation of chemosensory functions, such as psychophysical and/or electrophysiological tests, because of a high risk of Covid-19 exposure to healthcare workers. Secondly, our sample consisted of patients with mild to moderate disease, and they may not be representative of the infected population. The prevalence of olfactory and taste dysfunction in patients with severe disease is difficult to investigate and is unknown. Thirdly, in this study, all symptoms were self-reported by the patients. Therefore, the results of our study should be interpreted with caution. These limitations should be considered in future studies evaluating olfactory and taste dysfunction in Covid-19 patients.