Pathophysiology of olfactory dysfunction as a result of COVID-19.
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Loss or change of the ability to smell is a symptom in about 80% of COVID-19 patients. Approximately 25% of these people suffer from it for more than a month. Smell loss can cause problems such as insecurities about personal hygiene, loss of interest in food and drinks and risks such as not detecting fire or inedible food. These are factors that contribute to symptoms of depression and nutritional issues which often results in reduced quality of life. COVID-19 is still a novel disease and because it is so complex, the underlying mechanism is still unknown. In this review, the current hypotheses about the causes of smell loss and cellular mechanisms behind it will be discussed. We will discuss the possible swelling of the olfactory system, viral entry possibilities, which cells are infected, how the olfactory bulb is affected, inflammatory reactions, olfactory receptors, and alternative hypotheses. There are many possible mechanisms that can cause the smell loss in COVID-19 patients. As well as multiple hypotheses, there are multiple animal models possible to do research with, such as mice and hamsters, with the possibility of genetic modifications. Besides, there are numerous ways to measure infection, inflammation, expression of receptors and signs of cell death. Taken together, because of the differences between studies, it is difficult to draw reliable conclusions from the research done until now. Current studies show that it is most likely that the neurons in the nose mucosa and in the olfactory bulb are not infected themselves. Rather, it seems like their surrounding, supporting cells are infected with SARS-CoV-2. They are infected because of the entry molecules, such as ACE2, TMPRSS2, cathepsin L, furin and neuropilin-1, they possess. As the surrounding cells give support to the olfactory neurons in terms of ions, metabolism and nutrients, the neurons are not in balance when their supporting cells are infected. This leads to the loss or change of ability to smell. In turn, this can lead to changes further along in the nervous system. How long the smell dysfunction lasts, seems to depend on whether the stem cells of the nasal epithelium are infected as well. This means that the recovery of the olfactory mucosa would take longer. Besides this main hypothesis, there are other alternative hypotheses, concerning viral deposition, the serotonin/tryptophan pathway, and a possible self-defense mechanism. These do not get as much attention, but as they are not ruled out yet, these should be investigated as well. In conclusion, more and especially more structured research into these mechanisms is needed to draw reliable conclusions about the underlying mechanisms of olfactory dysfunction due to COVID-19.