key: cord-0975669-97f906lw authors: Thomas, Davis C.; Chablani, Deepti; Parekh, Srishti; Pichammal, Reshmy Chellam; Shanmugasundaram, Karpagavalli; Pitchumani, Priyanka Kodaganallur title: Dysgeusia: A review in the context of COVID-19 date: 2021-11-17 journal: J Am Dent Assoc DOI: 10.1016/j.adaj.2021.08.009 sha: c42d8d4b869e914fb5758dada3c411a3c79ff9c4 doc_id: 975669 cord_uid: 97f906lw BACKGROUND: Taste disorders in general, and dysgeusia in particular, are relatively common disorders that may be a sign of a more complex acute or chronic medical condition. During the COVID-19 pandemic, taste disorders have found their way into the realm of general as well as specialty dentistry, with significance in screening for patients who potentially may have the virus. TYPES OF STUDIES REVIEWED: The authors searched electronic databases (PubMed, Embase, Web of Science, Google Scholar) for studies focused on dysgeusia, ageusia, and other taste disorders and their relationship to local and systemic causes. RESULTS: The authors found pertinent literature explaining the normal physiology of taste sensation, proposals for suggested new tastes, presence of gustatory receptors in remote tissues of the body, and etiology and pathophysiology of taste disorders, in addition to the valuable knowledge gained about gustatory disorders in the context of COVID-19. Along with olfactory disorders, taste disorders are one of the earliest suggestive symptoms of COVID-19 infection. CONCLUSIONS: Gustatory disorders are the result of local or systemic etiology or both. Newer taste sensations, such as calcium and fat tastes, have been discovered, as well as taste receptors that are remote from the oropharyngeal area. Literature published during the COVID-19 pandemic to date reinforces the significance of early detection of potential patients with COVID-19 by means of screening for recent-onset taste disorders. PRACTICAL IMPLICATIONS: Timely screening and identification of potential gustatory disorders are paramount for the dental care practitioner to aid in the early diagnosis of COVID-19 and other serious systemic disorders. various subtopics under which the sensation of gustation is discussed and the possible mechanisms of gustatory disorders. In the context of the COVID-19 pandemic, the topic of dysgeusia assumes paramount importance, especially because it is one of the first symptoms of COVID-19 to appear. The astute and educated dental care practitioner is one of the earliest to pick up symptoms of dysgeusia. The transmission of taste signals from various sites in the oral cavity to the brain stem is believed to occur through cranial nerves, namely, facial, glossopharyngeal, and vagus. 6 The location and course of the first-, second-, and third-order neurons, their corresponding ganglia and nuclei, and the cortical centers of taste have been well elucidated (Figure 1 ). 7 Third-order neurons carrying the taste sensations from the thalamus also project into the orbitofrontal cortex, termed the secondary taste cortex, which is responsible for the reward value of taste. [8] [9] [10] The difficulty in pinpointing a single cortical area as responsible for taste comes from the varied results that functional imaging studies have yielded in the past few decades. [11] [12] [13] The functional unit of taste is the taste bud, located on the various tongue papillae. The relative location of the taste buds on these papillae are shown in Figure 2 . Taste buds have receptors, which are the biological transducers that convert chemical energy from tastants into electrical energy, facilitating the transmission of these taste impulses. 7, 14, 15 Taste buds are present on the tongue, palate, pharynx, epiglottis, and esophagus. 7 Remote taste receptors have been reported in tissues from the gastrointestinal tract, bladder, brain, respiratory tract, heart, buccal mucosa, sinuses, white blood cells, bone marrow, thyroid, keratinocytes, and testicles. [16] [17] [18] [19] [20] [21] [22] [23] [24] The functional specificity of taste cells has prompted researchers to divide them into the following 5 types: type I (glialike), type II (bitter, sweet, umami), type III (sour), type IV (pluripotent), and type V (marginal cells). 25, 26 The older concept of "taste mapping"drepresenting the tongue diagrammatically and showing the relative concentrations of specific taste sensationsdhas been replaced largely with the newer concept that all areas of the tongue represent the different tastes almost equally ( Figure 3 ). 27 A similar topographic arrangement in the cerebral cortex has also been proposed. 28 Flavor is defined as a blend of taste, smell, and touch, acting as a premonition on the safety and quality of the food being consumed. [29] [30] [31] It is a perception with multiple inputs from additional sensations, including vision and hearing. 32, 33 The robust interaction between the gustatory and olfactory areas of the brain is well known. 34-37 There is a blend of olfaction, gustation, and texture in most of the taste perception ( Figure 4) . 38, 39 The orbitofrontal cortex, the basolateral amygdala, and the insular cortex have been reported to be associated with interactions among odor, taste, and flavor. 40,41 Odors conditioning and enhancing specific tastes, such as saltiness, have been reported in studies during the past few decades. 42,43 The analgesic effect of sweet sensation may have a role in activating the endogenous opioid system; in addition, endocannabinoids have been reported to change taste perception by means of modulating sweet receptors. 44 This might explain the preference for sweet foods in patients with chronic pain syndromes, such as burning mouth syndrome (BMS). The role of sweet sensation in regulating food intake, glucose homeostasis, and energy balance may be instrumental in the discovery of newer drugs for diseases such as diabetes and obesity. 45-47 Sour taste is generally considered to be an indicator of acid (hydrogen ions). The presence of salt-sensing cells in the taste buds in fungiform papillae and their absence in the circumvallate papillae, has been confirmed. 48-50 Salt sensation has a crucial role to play in the normal development of the gustatory circuits in the central nervous system. 51 The role of tongue cleaning and its positive effect on the identification of salt sensation has been well known. 52,53 Researchers have proposed that salt sensitivity in people with normal blood pressure could predict their susceptibility to hypertension. [54] [55] [56] Umami (glutamic acid) occurs naturally in a variety of foods, including tomatoes, seafood, and egg yolks. 57, 58 Multiple umami receptors have been identified in rodents in the past 2 decades, and the taste is mediated through glossopharyngeal nerve. 59 positive aspect of umami taste in terms of improvement of nutritional intake, enhancement of habitual choice of healthy foods, and improvement of food flavor. [65] [66] [67] [68] [69] The proposed negative effects of umami include hepatotoxicity, asthma, migraine headache, and central nervous system damage. [70] [71] [72] [73] Owing to the finding that a reduction in umami taste perception may trigger loss of appetite, subsequent health issues, and reduction in the quality of life, testing for this taste has been proposed to be one of the key tools for managing the treatment of patients with dysgeusia. 74 The bitter taste receptors that are present in the respiratory tract have been proposed to have crucial roles in the body's defense mechanism against possible invading microbes. 16 Their role in the possible detection of certain bacteria and in the process of bronchodilation has also been proposed and could become a novel target for therapy. Through the research of the previous 2 decades, we have come to know that approximately 30 taste receptor genes code for the bitter taste. 17, 75 Fat taste (oleogustus) is one of the newer described taste sensations and is proposed to be carried via the glossopharyngeal and chorda tympani nerves. [76] [77] [78] Calcium taste has been found to help modulate calcium metabolism, intake, and homeostasis in mammals and has specific receptors coded via multiple genes. [79] [80] [81] [82] [83] [84] EPIDEMIOLOGY OF GUSTATORY DISORDERS Prevalence rates for taste disorders have been reported as ranging from 0.6% through 20% in the literature. [85] [86] [87] Researchers have found that, in general, women perceive taste better. 88 Researchers from multiple studies have reported that there is a decline in taste perception with increasing age. 88, 89 There is a reported reduction in prevalence of taste dysfunctions with aging in women compared with men. 85 Researchers reported a strange association of taste disorders with educational attainment, in that the higher the level of education, the lower the incidence of taste disorders. 85 There was similar association reported with olfactory disorders; however, the researchers failed to provide a plausible explanation for this phenomena. Sour tasting ability was consistently found to be most affected with aging. 90 Liu and colleagues 85 found that Black participants in their study had a higher prevalence of taste disorders, suggesting an association between ethnicity and taste disorders. Taste disorders can range from dysgeusia (abnormal taste sensation) to ageusia (complete loss of taste sensation), depending on the degree of severity of the taste abnormality. The various terms used for the types of taste disorders are provided in Table 1 . The total experience of taste has olfaction as a major component. 91, 92 Most apparent gustatory dysfunctions (such as dysgeusia) are the result of impaired olfaction (for example, allergies) rather than gustation. [91] [92] [93] [94] Abnormalities in transport (inability of the tastant to reach the receptor), gustatory unit (abnormality of peripheral sensory organs), and neuronal unit (such as damage to the peripheral or central nervous system) are the mechanisms of such gustatory dysfunctions. 92, [95] [96] [97] In the oral cavity, the gustatory receptors can be exposed to pathologies (such as inflammation) or artificial restorative dental materials (such as acrylic) and can thereby affect gustation. 92, [98] [99] [100] Several genes and their associated receptors (for example, ENaC, T1R, T2R, TAS2R, and TRPV1) have been identified as coding for specific taste sensations. 25,45,108-114 Conceivably, any sequence variation in these receptors and genes can cause a taste disorder. Researchers have reported that more than 50% of the drugs prescribed routinely in the United States cause some level of a taste disorder. 115 The various medications that can cause dysgeusia are summarized in Table 2 . Aging is also a factor for reduction in taste sensation. 92 As alluded to earlier, multiple cranial nerves are involved in the sensation of taste, including trigeminal, facial, glossopharyngeal, and vagus. Mediators of chemosensation of taste include, but are not limited to, the tongue (factors are health of the tongue and papillae of the tongue), saliva (quality, quantity), oral mucous membrane, nerves, and neurotransmitters. 95 Consequently, any alterations in these factors can contribute to a change in taste perception. As would be expected, dentists are among the first clinicians that patients approach with taste disorders. The most common symptoms in these patients include dysgeusia, phantogeusia, or an accompanying burning sensation. 121 Many dental-related factors have been hypothesized to cause taste alterations, including local trauma, medications, infections, dental restorations, and salivary gland dysfunctions. 95 Radiation therapy of the head and neck area have also been found to result in dysgeusia. 122 Dysgeusia is also associated with several orofacial pain conditions, such as BMS and temporomandibular disorders. [123] [124] [125] [126] Researchers have also reported an association between dysgeusia and other conditions, such as Bell palsy and Guillain-Barré syndrome. [127] [128] [129] The relevance of dysgeusia in the context of the COVID-19 pandemic is explained below. Dysgeusia has been found to be associated with several systemic medical conditions, however, the mechanisms contributing to it are diverse. Systemic diseases commonly exhibiting taste dysfunction include, but are not limited to, Sjögren syndrome (SS), chronic renal failure, end-stage liver disease, endocrine disturbances (such as diabetes mellitus and thyroid disorders), genetic disorders (familial dysautonomia), neurologic disorders, and psychiatric conditions. Alterations in taste function have also been found in pregnant and postmenopausal women. 99 The conditions that are related to taste disorders etiopathologically and their proposed mechanisms are summarized in Table 3 . There are contradicting reports on the association between reduced salivary flow and taste disorders. [171] [172] [173] SS, an autoimmune disorder with associated xerostomia, has been reported to include taste disorders as well. 174 The mechanisms proposed to explain dysgeusia associated with SS include systemic inflammation, interaction with genetic pathways that influence gustation, an increase in the taste threshold, and small fiber neuropathy. 175, 176 Possibly due to the fact that sweet taste is independent of salivation, there was minimal alteration of the sweet taste in patients with SS. 177, 178 Other dysgeusia-associated disorders include autoimmune encephalitis, myasthenia gravis, systemic lupus erythematosus, multiple sclerosis, and Parkinson disease. 132, [179] [180] [181] [182] Dysgeusia associated with BMS Taste alterations accompany BMS. [183] [184] [185] These include phantogeusia (bitter, metallic, burning quality). [186] [187] [188] [189] The qualities of bitter and metallic that patients report as being associated with BMS are thought to be from cranial nerve IX being disinhibited subsequent to possible damage or hypofunction of the chorda tympani nerve. 185, 187, 189 Consequently, it has been reported in the literature that patients with BMS find relief from symptoms when consuming sugary or sweet foods, which possibly stimulate a hypofunctioning chorda tympani nerve. 188, 190, 191 There is a reported increase in taste threshold (that is, decreased taste sensitivity) of all tastes except umami. 187, [192] [193] [194] An increased fungiform papillae count has been proposed to be associated with "supertasters," who are apparently at a higher risk of having BMS. 195, 196 Psychological factors have also been implicated in dysgeusia related to BMS. 197, 198 Dysgeusia associated with infections Diseases such as upper respiratory infections, viral hepatitis, and oral cavity infections have been associated with an increase in the detection and identification of individual taste stimuli via taste buds, thereby causing dysgeusia. 132, [199] [200] [201] [202] [203] Inflammation has been found to disrupt normal cell turnover of taste buds, leading to dysgeusia. 132 HIV infections and subsequent therapies have been reported to be associated with dysgeusia. 155, 204, 205 Other infections reportedly associated with Although the COVID-19 pandemic began in early 2020, the data regarding anosmia and dysgeusia in the context of the association, pathogenesis, diagnosis, and prognosis of the disease are limited. 208 A change in taste sensation is one of the earliest symptoms of COVID-19 and many times precedes the actual respiratory manifestation of the disease. [209] [210] [211] [212] [213] Multiple hypotheses have been proposed in an attempt to explain the mechanistic pathway of how the COVID-19 organism affects gustatory senses. 209, 214 These include, but are not limited to, damage to the central nervous system, abnormal zinc homeostasis, angiotensin-converting enzyme 2 receptor manifestation, and increased proinflammatory cytokines. 14, [139] [140] [141] [142] [143] There is a high rate of sensation recovery rate in patients with COVID-19; however, whether more permanent loss of taste sensation occurs with COVID-19 infection is still unclear. 215, 216 The higher prevalence of taste alterations associated with the pandemic has prompted organizations, such as the European Centre for Disease Prevention and Ferric carboxymaltose [116] [117] [118] Antibacterial Ampicillin, ciprofloxacin, metronidazole [116] [117] [118] Anticholinergic Atropine [116] [117] [118] Antidepressant Amitriptyline, clomipramine, desipramine [116] [117] [118] Antiepileptic Carbamazepine, phenytoin [116] [117] [118] Antifungal Griseofulvin [116] [117] [118] Antihistamine and Decongestant Chlorphenamine, loratadine [116] [117] [118] Antihypertensive and Cardiac Medications Acetazolamide, amiodarone, propranolol, nitroglycerine [116] [117] [118] [119] [120] Anti-inflammatory Dexamethasone [116] [117] [118] Antimanic Lithium [116] [117] [118] Antimigraine Dihydroergotamine, sumatriptan [116] [117] [118] Antineoplastic Cisplatin, methotrexate, vincristine [116] [117] [118] Antiparkinsonian Levodopa [116] [117] [118] Antipsychotic Clozapine, trifluoperazine [116] [117] [118] Antiviral Aciclovir, interferon [116] [117] [118] Anxiolytic Alprazolam, buspirone [116] [117] [118] Bronchodilator Bitolterol [116] [117] [118] Central Nervous System Stimulant Amphetamine 116-118 Esomeprazole [116] [117] [118] Hypnotic Eszopiclone, zolpidem [116] [117] [118] Hypoglycemic Metformin [116] [117] [118] Intestinal Anti-infective Miconazole [116] [117] [118] Intestinal Anti-inflammatory Budesonide [116] [117] [118] Lipid-Lowering Atorvastatin 116-118 Baclofen, dantrolene [116] [117] [118] Pancreatic Enzyme Preparation Pancrelipase 116-118 Hydrogen peroxide [116] [117] [118] Smoking-Cessation Aids Nicotine [116] [117] [118] Thyroid Levothyroxine sodium, propylthiouracil [116] [117] [118] Control, the American Academy of OtolaryngologyeHead and Neck Surgery, and the World Health Organization, to recommend using taste alterations as a screening test and, when screening is positive, advise the clinician to test the patient for COVID-19. 215, 217, 218 Identification of gustatory disturbances in the absence of concomitant symptoms of COVID-19 is of paramount importance to alerting physicians about the possibility of COVID-19, thereby aiding in self-isolating and testing the people affected. 219 Various taste-testing measures have been used, ranging from simple chairside testing to objective and measured research-level testing for gustation. In a clinical setup, a clinician may use such tastants as a dilute aqueous solution of sugar, salt, sour, and bitter, although this method is subjective and lacks sufficient sensitivity and specificity. Objective testing can be done using electrogustometry, filter paper disk method, whole mouth method, taste strip method, and e-tongue method. The electrogustometry method tests the taste sensory nerves by means of measuring the electrical taste threshold in the soft-tissue areas supplied via the chorda tympani, greater petrosal, and glossopharyngeal nerves. 220, 221 In the filter paper disk method, test disks soaked in different taste solutions are placed on selected parts of the oral cavity. 220, 221 These tastes are applied in increasing concentration grades from the lowest to a point at which the participant identifies the correct taste. In the whole mouth method, participants rinse their mouths with multiple taste solutions with various molarities and identify the taste. This method also tests for taste threshold. 220 In the taste strip method, filter paper strips embedded with the 4 basic tastes are used and placed in successive graded concentrations at the center of the anterior one-third of the tongue when the tongue is protruded. 220, 222 The e-tongue method is used mostly in pharmaceutical research and uses an analytical instrument that helps interpret the data from a sensor that records electrical signals from the taste fibers. 223 Taste and smell sensations are closely interrelated when it comes to motivation to eat, enjoyment of food, and activation of the satiety centers of the brain. 224 Induction of abnormal eating habits by means of olfactory disorders has been documented in the literature. 29 Although taste disorders have been reported to affect body weight, evidence is lacking to link the former to an abnormal nutritional status. 224, 225 Patients with dysgeusia do not have a substantial change in their nutrition. 226, 227 Systemic diseases, such as diabetes and hypertension, have been reported to be associated with changes in the chemosensory function. 224 There have also been several researchers who have linked ageusia to weight loss and even to anorexia. [228] [229] [230] [231] [232] [233] [234] Substantial taste disturbances, such as reduction in taste acuity, abnormal salt taste, and metallic taste, have been proposed to cause noncompliance with recommended renal diets in patients with chronic kidney disease, thereby culminating in nutritional deficiencies. [235] [236] [237] The effect of dysgeusia on quality of life has been reported as varied in the literature, however, most researchers report considerable reductions in quality of life. 238, 239 CLINICAL PEARLS Taste alterations, as one of the earliest symptoms of COVID-19, can be used as a simple, early screening tool for detection of the infection. The simplest tool for testing olfaction is to have the patient respond to smelling small amounts of odorants that are easily identifiable, such as coffee, fragrant soap, or other nonpungent material. Care must be taken to ascertain that the patient is not experiences any nasal blockage, such as would occur with a common cold. In conjunction, the sense of taste can be checked easily by means of simply having the patient taste (sip and spit) dilute aqueous solutions of sugar, salt, sour, and bitter, as we mentioned above. The use of commercially available, more sophisticated kits is not usually warranted, as these techniques, such as electrogustometry, may be beyond the purview of a routine dental practice setup. Clinicians should understand that it is unlikely the patient will pick up minimal alterations of gustation unless prompted by the screening dentist. In the era of COVID-19, it may be prudent for dental clinicians to screen every patient routinely for olfactory and gustatory changes using a simple questionnaire with yes or no answers. The clinician should keep in mind that, in addition to COVID-19, several other conditions, including systemic diseases and medications, may be related etiologically to gustatory disorders. In the event that gustatory screening is positive for dysgeusia, the patient should be referred promptly for COVID-19 screening. If the patient is negative for COVID-19 and dysgeusia continues, the patient should be referred to a special senses clinic, possibly working together with the patient's primary care physician. Also, we should understand that taste disorders contribute considerably to reduced quality of life in patients. Screening for taste alterations can form the foundation for an early warning and detection system that a dentist can use to attempt to quell the spread and effects of COVID. 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