Post-COVID-19 persistent olfactory, gustatory, and trigeminal chemosensory disorders: Definitions, mechanisms, and potential treatments

Figure 1 Olfactory perception and its pathways. There are two routes for odor perception: The orthonasal and retronasal routes. The process of olfaction converts chemical information from odorants into electrical potentials extending from the olfactory epithelium to the bulb and then the brain. Brain areas for perception of olfaction sensation are divided into the primary and the secondary cortical olfactory areas. The primary areas include the uncus, anterior olfactory nucleus, olfactory tubercle, piriform cortex, lateral entorhinal cortex, and the cortical nucleus of the amygdala. The secondary areas include the hypothalamus, mediodorsal thalamic nucleus, nucleus basalis Meynert, hippocampus, the septal region, substantia innominata, mesencephalic reticular formation, and the orbitofrontal cortex.

Figure 2 Structure of the olfactory mucosa and topographical mapping of the olfactory sensory neurons and their connections. A: The olfactory mucosa is composed of the olfactory epithelium and the lamina propria. The epithelium is composed of olfactory sensory neurons and non-neuronal cells (the susentacular, microvillar, and Bowman’s gland and basal cells). A bipolar cell has dendrites at one end extending to the mucus and a single axon which projects to the glomerulus. Within a glomerulus, the axon of the bipolar neuron synapses with the mitral and tufted cells along with periglomerular cells; B: The olfactory neurons which express the same type of receptors converge onto the same glomerulus maintaining a topographical mapping of odorant receptors where they synapse with sensory neurons of the olfactory tract. The same topographical mapping is maintained in the glomeruli and bulb.

Figure 3 The process of olfaction. The signaling cascade which converts chemical information of the odorant into electrical information includes activation of cyclic nucleotide-gated ion channel followed by activated ADCY3 to convert ATP to cyclic adenine monophosphate (cAMP). cAMP unfolds Ca⁺⁺ activated Cl^- channels, causing influx of Na⁺ and Ca⁺⁺ from outside to inside the olfactory sensory neurons, and this activates the Cl^- channels, causing outflow of Cl^-, neuronal membrane depolarization, and the action potential. The latter extends from the epithelium to the bulb and then to the olfactory cortex.

Figure 4 Distributional mapping of the five basic taste sensations on the tongue, the gustatory pathways, and the taste bud and receptors. A: The five basic taste qualities are sweet, salty, sour, bitter, and umami; B: Tastants are detected by the taste buds on the tongue, soft palate, and epiglottis. Activation of taste receptors is transmitted to the sensory neurons in the facial, glossopharyngeal, and vagus cranial nerves from which their axons carry information to the nucleus solitaries in the medulla oblongata, to the ipsilateral ventral posteromedial nucleus of the thalamus, and then to the primary gustatory cortex. The nuclei in the medulla also send projections to the hypothalamus and amygdalae to activate brainstem reflexes. Secondary fibers project from the insula to the posterolateral portion of the orbitofrontal cortex; C: The taste bud has taste sensory and supporting cells. The taste receptors have long microvilli or hairs which project through the taste pore to connect with substances in the food or drink dissolved into the saliva. VPM: Ventral posteromedial.

Figure 5 Mechanism of dysosmia after severe acute respiratory syndrome coronavirus 2 infection. A: The disorganized olfactory neuroepithelium after severe acute respiratory syndrome coronavirus 2 infection and its associated immunological response would result in a disturbance of rewiring of the glomeruli; B: A glomerulus is no longer dominated by a single type of odor and the newly growing axon after injury would go to a different brain spot other than the one before injury, resulting in a distorted sense of smell.