OGD has become an important symptom in COVID-19. It is a frequent symptom, affecting about 40% of outpatients and also an important infection and infective marker (3,11, 12). Although in our series the prevalence of OGD was 8.5% (504 patients), this could be explained because inpatients use to be younger and have severe disease and it could be possible that anosmia is more frequent in mild disease (10). In fact, in our study this dysfunction was more frequent in younger patients (<52 years 15.80% vs 56-65 y. 15.48% vs 66-76 y. 7.05% vs >76 y. 3.47 p<0.000). Our results are in line with other inpatients studies (13). Female were significantly more affected by these dysfunctions (12.41% than male 8.67% p<0.0001). This finding is according to previous studies (4, 8, 9). The olfactory and gustative dysfunction was significantly more frequent in Afro-Americans and Latino-American than Caucasian or Asian people (p<0.0001). There were only 19 pregnant patients and we do not find any differences among them.
One interesting point is that anosmia was significantly more frequent in smokers (27.85% vs10.16% p<0.0001) and there was no relation with hypertension. These findings could be related to a previous lesion of nasal mucosa because the tobacco and predisposes to a higher olfactive epithelium lesion or the immune system has a higher reaction because of periodic toxic stimulation.
Patients reporting a loss of smell have fivefold decreased risk of death (OR 0.26 p>0.001) compare with those without this disorder, and it was not related to any other factor. These findings confirm previous studies, and it seems clear that the presence of anosmia would imply a more benign prognosis of the disease (9, 10). Indeed, the olfactory system is a unique neuroimmune interface where interaction between nervous and immune systems (14). It is well known that virus or environmental toxicants can induce inflammatory responses, including infiltration of immune cells and production of cytokines (15, 16). This inflammation can induce olfactive sensitive neurons degenerations and apoptosis as a protective mechanism (17). Because the health of the central nervous system (CNS) is likely to be heavily influence by the immune status of the olfactory system, the reactions should be harmonic, because new olfactory sensory neurons (OSN) may help in the repair of nasal damaged tissue (18). On the other hand, immune cells in the olfactory mucosa regulate the depletion of old OSN and generation of new OSN (19). This situation could explain our results that patients with an immune disfunction could have less OGD, because could be a lower immune reaction and therefore less epithelial and olfactive cells degeneration.
The pathophysiological point of view is quite interesting. Our group, like others, has already hypothesized about the possible relation between anosmia and CNS viral invasions (4, 20, 21). In fact, the olfactory nerve is a traditional way because is excused to the external world (22, 23). Other viruses like poliovirus or influenza use this route (24). And there is evidence that another coronavirus can reach the CNS direct through the olfactory bulb (25, 26). Nevertheless, it has not been demonstrated the neurotropism of SARS-CoV-2, and the neurological symptoms seems to be more related to the cytokine storm than to direct invasion. Most of the cerebrospinal fluid (CSF) analysis have been negative for SARS-CoV-2 RCP, and our study shows a better prognosis something clearly different from those seen in other viruses like influenza (27). For all those reasons we agree that the anosmia have to be related to the invasion of the olfactive epithelium and the possibility of neuroinvasion have to be relatively low and could be more related with Neuropilin-1 (28, 29). Furthermore, from the biological plausibility the olfactive sensitive neurons that do not express ACE-2 receptor which is fundamental in the SARS-CoV-2 cell invasion (28-30). Indeed, there is an elevated ACE2 expression in the olfactory neuroepithelium (230). Most of MRO studies shown normal olfactory bulb or an inflammation thar could be related to both, cytokine liberation or neuronal invasion (7, 31, 32)
We believe that a prior nasal epithelium invasion by SARS-CoV-2 should activate normal immunological reactions in patients and promoted type 1 IF activating anti-viral immunity and suppression of hyperinflammation (33, 34). This means that infected cells are rapidly cleared, viruses are inactivated by neutralizing antibodies and there is minimal inflammation (34). Avoiding in this way a dysfunctional immune response with excessive infiltration of monocytes, macrophages and T cells, the systemic cytokine storm and the secondary pulmonary and multi-organ damage (34).
The presence of anosmia is essential in the diagnosis of SARS-CoV-2 infection, but also could be important when in categorize patients and also in therapeutic decision-making. Even more, knowing that it is an early symptom of the disease. Knowing that other conditions as being Afro-American or Latino-American, Hypertension, renal insufficiency, or increase of RCP imply a worse prognosis we could develop a clinical score to estimate the vital prognosis for COVID-19 patients .
The exact pathogenesis of SARS-CoV-2 that causes olfactory and gustative disorders remains unknown but for sure is absolutely related to the prognosis. This point is relevant, insomuch as could be a plausible way to find a treatment. For this reason, study the anosmia and dysgeusia mechanism in COVID-19 seems to be fundamental. further prospective studies are needed to confirm our results.