key: cord-0999528-wxexl0qy authors: Lozada-Nur, Francina; N, Chainani-Wu; Fortuna, Giulio; Sroussi, Herve title: Dysgeusia in COVID-19: possible mechanisms and implications date: 2020-06-27 journal: Oral Surg Oral Med Oral Pathol Oral Radiol DOI: 10.1016/j.oooo.2020.06.016 sha: aa943c79abd10899424c60b8e3a0d289dbfc9eae doc_id: 999528 cord_uid: wxexl0qy nan For the purpose of this letter we will solely address our comments relating to new onset dysgeusia as a potential early marker of COVID-19 infection, as well as the implications of such association. [1] [2] [3] This is an interesting finding of practical significance, which may allow easier identification of pre-symptomatic or asymptomatic patients. This identification could play an important role in limiting transmission, particularly when testing is not widely available and/or reliable. Recent publications on this topic have included anecdotal reports 4, 5 and two epidemiological studies 6, 7 , with reported prevalence ranging from 68-85% for olfactory and 71-88.8% for taste disturbances in patients with COVID-19. These taste disturbances have included loss of taste (complete-ageusia or partial-hypogeusia) and altered taste (dysgeusia). For simplicity, we will use the term dysgeusia in this paper to include ageusia and hypogeusia. The distribution of these symptoms in subgroups of patients eg. those with specific underlying medical conditions which have not been reported yet. A European multi-center epidemiological study 6 analyzing the prevalence of olfactory and gustatory dysfunctions as a clinical presentation in a cohort of 417 laboratory-confirmed cases of COVID-19 with mild-to-moderate disease presentation reported that 88.8% of patients population had gustatory disorders. A number of patients also presented with several co-morbidities, the most common of which included allergic rhinitis, asthma, hypertension and hypothyroidism, but the percentage of patients with these conditions was low. Chemosensory dysfunction is a common occurrence. We know that dysgeusia can be associated with numerous medical conditions (e.g. upper respiratory viral infection, diabetes mellitus, malignancies, heart disease, candidiasis, Alzheimer's, asthma, liver and kidney disease, chronic Hepatitis C virus (HCV) infection, hypothyroidism, Parkinson's, or depression), and that various medications are known to interfere with taste function. [9] [10] [11] In a National Health and Nutrition Survey (NHANES) in 2012, 5% of over 142 million US respondents experienced taste disorders, most notably correlating with increasing age and with institutionalization or acute hospitalization of patients. 9 Also, a high prevalence of altered taste has been reported in a population of acute hospitalized German patients. 12 Furthermore, chemosensory data collected by NHANES between 2013-2014 identified a prevalence of smell disorders of 13.5% in persons aged 40+. In the same survey several risk factors were associated with a higher prevalence of smell dysfunction, including racial background (African-Americans, Latinos), lower income and educational level, older age, and a history of cancer or asthma, among other conditions. 13 Early in the Human Immunodeficiency Virus (HIV) epidemic, author FLN was among the first to report on the oral manifestations of opportunistic infections and tumors in the HIV/AIDS population. [14] [15] [16] The reporting on these markers were clearly a major contribution in alerting clinicians to the possibility of HIV carrier status in young people, otherwise healthy and without any known oral/dental and/or medical comorbidities. What is/are the likely mechanism by which patients develop taste dysfunction in While questions (1-3) will likely be answered from findings of future epidemiologic studies, we would like to share some hypotheses regarding potential mechanisms, which can be further investigated in research studies. ACE2 receptors have been found in the epithelium of taste buds, and salivary glands not only in rhesus macaques, but also in humans. 18 Salivary glands in rhesus macaques have been demonstrated to be an early target for SARS-CoV 19 and SARS-CoV RNA has been demonstrated to be present in saliva before pulmonary lesions. 20 It is therefore plausible that human salivary glands may be affected early on by SARS-Cov-2 thereby resulting in salivary gland dysfunction with subsequent salivary flow impairment in quality and quantity, and resultant dysgeusia as an early symptom in asymptomatic COVID-19 patients. A neurological nature has been suggested as a possible mechanism for dysgeusia. 21 Indeed, gustatory and olfactory functions are tightly linked 22 : an impairment of the olfactory system due to a direct damage of non-neuronal cells in the olfactory epithelium (OE)where ACE2 receptors are highly expressedvia replication and accumulation of SARS-Cov-2 23 can also result in taste disturbance. 22 The viral lytic pathway could also directly affect the peripheral neuronal trajectory of the gustatory tract in 2 ways: a direct damage of ACE2-expressing cells of the taste buds, peripheral taste neurosensory chemoreceptors 24 , or a direct damage of any of the cranial nerves (VII, IX, and X) responsible for gustation. Among these, the damage of chorda tympani (VII cranial nerve) might be the most plausible: once the nasopharynx is colonized, SARS-Cov-2 could use the Eustachian tube as port of entry and colonize the middle ear with a subsequent damage of the chorda tympani with subsequent dysgeusia. Less likely seems to be the involvement of the central nervous system (CNS), as usually CSN manifestations (e,g, meningitis/encephalitis) in COVID-19 patients last longer and are less frequent than dysgeusia. 24 We would also like to propose an inflammatory response pathway. The oral mucosa is lined with ACE2 receptors, used by SARS-Cov-2 to enter epithelial cells. 18, 19 It may be quite plausible that SARS-Cov-2 binds to ACE2 receptors present in oral mucosa, triggering an inflammatory response that leads to cellular and genetic changes which could alter taste. 11 This response may be mediated by the interaction of Toll-like receptors (TLRs) upon contact with the virus leading to tissue damage, a similar pathway to Acute Respiratory Distress (ARD). Wang H et al. 11 have shown in mammalian tissue that "taste bud cells express cytokines signaling pathways and that inflammation may affect taste functions via these pathways. Inflammatory cytokines such as IFN can trigger apoptosis and therefore may cause abnormal turnover in taste buds, which may result in net losses of taste bud cells and/or skewing the representation of different types of taste cells and ultimately lead to the development of taste dysfunction". This could be another plausible mechanism for taste alteration due to SARS-Cov-2 infection. It is also possible that the tissue hypoxia in patients with COVID-19 who are otherwise clinically conscious, and in a functional state may result in tissue injury which leads to the reported disturbance in taste. 25 Anemia and presumably the poor oxygen transport that ensues has been shown to result in dysgeusia. 26 The unusual feature of a mild clinical picture in some COVID-19 patients even with severe measured hypoxia may explain why in some patients, dysgeusia is reported in the early stages of COVID-19. Yet another possible mechanism may involve zinc, which is thought to play an important role in taste perception. It is possible that zinc chelation through immune mechanisms and molecules known to increase in concentration with inflammatory processes may result in acute hypozincemia 27 or a more localized change in cellular zinc homeostasis of oral gustatory cells due to infection with SARS-Cov-2. 27 This may result in taste disturbances similar to what has been observed in association with other processes leading to zinc insufficiency. 28 RCTs have demonstrated benefit of zinc supplementation in patients with taste disturbances. 29 In addition, zinc has been shown to inhibit Coronavirus RNA Polymerase Activity In Vitro 30 and is thought to play a role in antiviral immune responses. 31 Systematic reviews of RCTs have concluded that zinc lozenges at a dose >75 mg per day may decrease the duration of common cold symptoms in healthy children and adults. 32 Common cold-like illnesses are caused by other coronaviruses, rhinoviruses and adenoviruses, and there has therefore been interest in using zinc supplements for prevention during the current pandemic. It is of particular significance that dysgeusia (with or without olfactory symptoms) has been reported as an early or lone symptom of COVID-19, prior to development of lung or other organ involvement. We hypothesize that changes in localized cellular zinc homeostasis in oral gustatory cells due to immune responses to SARS-Cov-2 viral replication, may result in dysgeusia which may or may not be accompanied by hypozincemia. If this is the case, the time of onset of dysgeusia may correspond to the time when zinc supplementation in the form of lozenges or syrups may be most effective, as this localized delivery of zinc to oral and oropharyngeal mucosa may help control COVID-19 replication at early replication sites. Q&A on Coronaviruses (Covid-19). Publishes on 17 Coronavirus: loss of smell and taste reported as early symptoms of COVID-19 AAO-HNS: Anosmia, hyposmia, and dysgeusia symptoms of coronavirus disease Accessed 31 Reports increasingly suggest anosmia/hyposmia can signal early COVID-19 infection Sudden loss of Taste and Smell should be part of COVID-19 screen Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of coronavirus diseases (COVID-19): A multi-center European study Association of chemosensory dysfunction and Covid-19 in patients presenting with Influenza-like symptoms The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: A systematic review and meta-analysis The impact of aging and medical status on dysgeusia Disturbances of taste and smell induced by drugs Inflammation and taste disorders: mechanisms in taste buds Taste ability in hospitalized older people compared with healthy, age-matched controls Prevalence and risk factors of taste and smell impairment in a nationwide representative sample on the US population: A cross-sectional study New outbreak of oral tumors, malignancies and infectious diseases strikes young male homosexuals The diagnosis of AIDS and AIDS related complex in the dental office findings in 171 homosexual males Oral manifestations of tumor and opportunistic infections in the acquired immunodeficiency syndrome (AIDS): Findings in 53 homosexual men with Kapoki's sarcoma. 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Folic acid-responsive neurological diseases in Japan Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection Zinc deficiency in patients with idiopathic taste impairment with regard to angiotensin enzyme activity Zinc gluconate in the treatment of dysgeusia--a randomized clinical trial Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture The Role of Zinc in Antiviral Immunity Zinc lozenges may shorten the duration of colds: a systematic review