Clinical Characteristics and Treatment of Anosmia and Ageusia Due to SARS-CoV2 Variants

The SARS-CoV-2 pandemic has consisted of multiple surges of infection because of continuous viral mutations. The WHO and CDC have defined the main SARS-CoV-2 variants based on international and national data for the circulation of SARS-CoV-2 into at least 4 waves. Studies from different parts of the world have demonstrated significant variations in the clinical manifestations of viral infection in relation to different SARS-CoV-2 variants. They also indicated that the current high levels of population immunity, due to prior infection and/or vaccination, have been associated with a vastly decreased overall risk of severe disease. Anosmia (with or without ageusia) was identified as a hallmark of COVID-19 early in the pandemic (ancestral Wuhan strain, alpha and delta variants), with a prevalence of \~60%. Prolonged olfactory disorders, lasting ≥6 months to years, has been reported in \~35-40% of infected individuals. However, studies reported that olfactory and gustatory disorders were less frequent with Omicron variants compared to pre-omicron variants. It has been indicated that SARS-CoV-2 can cause destruction, disorganization and molecular changes in the nasal olfactory neuroepithelium resulting in loss and distortion of the sense of smell. There are several trials to treat these persistent disorders but none has shown significant positive results except ours (Hamed et al., Expert Review of Clinical Pharmacology 2023;16(12):1261-1276 DOI: 10.1080/17512433.2023.2282715). Hamed et al. reported that cerebrolycin, a commercially available multimodal neurotropic factor, has the ability to cure at least 60% (100% complete and persistent recovery) of post-covid-19 persistent olfactory and gustatory dysfunctions. This drug is available in the market of at least 75 countries since 1996 and easily dispensed from local pharmacies after doctors prescriptions. It is used for treatment of many disorders of the central and peripheral nervous systems. This could be due to its ability to promote neurogenesis and remodeling of olfactory and gustatory neurons.

The diminished senses of smell (or hyposmia/anosmia) and taste (or hypogeusia/ageusia) have been commonly reported after infection by ancestral Wuhan, alpha and delta strains of the SARS-CoV-2 virus in ≥ 60% of patients. Persisted dysfunctions (deficits and distortions), lasting for months to years, were also reported in \~40%.

The SARS-CoV-2 pandemic has different waves of infection because of the dynamic viral mutations. The first wave (ancestral Wuhan strain) has been defined as the period from approximately the last week of February 2020 to the first Week of February 2021; the second wave (Alpha variant) started from approximately week 7 of February 2021 to July 2021; the third wave (Delta variant) was the period from approximately August 2021 to December 2021; and the fourth wave (Omicron and its subvariants) was the period from approximately January 2022 to December 2023 and after. These Viral strains were also categorized according to the main variants and their subvariants based on the viral pathogenicity and transmissibility, the clinical manifestations, immunity and response to vaccination. Studies from different parts of the world reported less severe viral manifestations in the periods of omicron strain and its subvariants compared to the pre-omicron years of the pandemic. They also reported less frequent involvement of olfactory and gustatory systems with omicron and its subvariants compared to previous viral variants (alpha and delta).

Experimental studies strongly indicated that post-covid olfactory and gustatory disorders are due to peripheral damage of the sensory neuroepithelia (olfactory and gustatory) and their disorganization by severe viral infection and its immune mediated pathology.

In general, the characterization of the prevalence and clinical manifestations and risk variables of olfactory and gustatory complications of different SARS-CoV-2 variants is unclear. furthermore, the treatment of these prolonged complications is still aworldwide challenge. Detailed search in clinical trials' websites, for example: WHO International Clinical Trials Registry Platform (ICTRP Search Portal-WHO; https://trialsearch.who.int/), Cochrane ENT Trials Register (https://ent.cochrane.org), Ovid Embase (https://tools.ovid.com), ClinicalTrials.gov, Medfind (https:// medfind.in), Web of Science, PubMed and Scopus, demonstrated that there is only a completed and published trial which showed promising positive and maintained results (Hamed et al., 2023). In this trial, the authors concluded that cerebrolysin, a commercially available multimodal neurotropic factor, had fast, promising, and constant effect, with cure rate of \>/+ 60%. This could be due to its ability to initiate and enhance neuronal regeneration, reorganization and remodeling of sensory neuroepithelia.

Eligibility Criteria:
Inclusion Criteria:

* Children and adults with sudden hyposmia/anosmia and/or hypoageusia/ageusia during COVID-19 pandemics (2020-2024).
* Persisting symptoms were defined as disorders lasting ≥6 months.
* Cooperation during objective evaluation
* compliance to drug treatment or olfactory and gustatory trainings for at least 8 weeks.

Exclusion Criteria:

* Prior neurological, medical or psychiatric disease which are known as a cause of progressive olfactory or gustatory dysfunction
* Nasal congestion
* Nasal polyps
* Surgery or head trauma or radiation for head and neck cancers as may result in injury to the nerves that control smell
* Exposure to toxic chemicals (such as pesticides and solvents) Cocaine or other drug abuse
* Lack of compliance to drug treatment or olfactory and gustatory trainings for at least 8 weeks.
* Lack of cooperation to complete the objective testings.