Reviewing the Effect of Doxycycline in COVID-19 Associated Anosmia
The global healthcare emergency - Coronavirus Disease 19 (COVID-19) caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) usually manifests with respiratory symptoms. (1) However, similar to other human respiratory Coronaviruses, it also seems to have neuroinvasive and neurotropic activity. Three categories of neurological symptoms are associated with COVID-19 including central nervous system (CNS) manifestations, peripheral nervous system (PNS) symptoms, and musculoskeletal disorders. Hyposmia or anosmia has been reported as a possible PNS symptom caused by COVID-19. (2) It has been documented that alteration in smell seems to be one of the first clinical presentations of COVID-19 disease, often associated with or without the loss of taste (dysgeusia). We review the correlation of anosmia in viral infections, COVID-19, and the potential scope of Doxycycline for its treatment
Anosmia – Immunological Response to Viral Infections
The three leading causes of loss of smell include head trauma, chronic sino-nasal inflammation, and upper respiratory tract viral infections. (3) Post viral transient chemosensory dysfunction after a common cold is widely ascertained. (4) The swelling of mucosa in the olfactory cleft seems to be a cause of temporary olfactory and taste loss, typically reported during a common cold. (3)
The olfactory neuroepithelium represents a critical immunological barrier within the nasal cavity which is exposed to the external environment and thus subject to exogenous insults as well as endogenous host defense responses. Interferon (IFN) gamma signaling pathways have been implicated as pivotal in regulating such immune reciprocation, through modulation of inflammatory responses and pattern-recognition receptors expressed during infection (5)
Anosmia in COVID-19 Infections – Role of Sustentacular Cells
Several hypotheses regarding the development of anosmia have been proposed since the outset of the pandemic. The olfactory cleft inflammation and obstruction cause a localized conductive loss, resulting from injury to sustentacular supporting cells in the olfactory epithelium or, invasion and subsequent damage to the olfactory bulb. Olfactory cleft obstruction may contribute to olfactory dysfunction in patients, perhaps most likely in those who eventually will show early resolution. A central mechanism seems consistent among patients with more prolonged olfactory deficits. Sustentacular cells showing Angiotensin-converting enzyme-2 (ACE-2) immunohistochemical expression 200 to 700 times greater than nasal or tracheal epithelia seem to be the main gateway for SARS-CoV-2 (6)
Potential Action of Doxycycline in COVID-19 associated Anosmia & Parosmia
Doxycycline is a broad-spectrum antimicrobial agent; it exhibits anti-inflammatory effects along with in vitro antiviral activity against several RNA viruses. Doxycycline is a highly lipophilic antimicrobial agent that chelates zinc compounds on matrix metalloproteinases (MMPs) of mammalian cells (7) . An in vitro study showed that murine coronaviruses rely on MMPs for cell fusion and viral replication. Other mechanisms of viral fusion and replication by coronaviruses utilize host proteases (8) , which could be a possible target to doxycycline.
Besides ACE2, it has been reported that a cell-surface receptor, CD147, could play a role in mediating SARS-CoV-2 cell entry (9) . The expression of CD147 is detected in ciliated and goblet cells in the human nasal mucosa (10) . Reports have indicated that Doxycycline has a significant inhibitory effect on CD147 expression (11) . While more studies are yet to better define whether Doxycycline can inhibit viral entry by reduced CD147 expression levels; due to its more established immunomodulatory and anti-inflammatory properties, Doxycycline could limit the pro-inflammatory state induced by the glial cells, activated by the neurotropic SAR-CoV-2 virus, thus facilitating optimal epithelial reconstitution in the olfactory epithelium (OE) (12)
Doxycycline in COVID-19 related Anosmia – Preliminary Clinical Experience
Based on preliminary case observations cited by Bonzano et al, the administration of Doxycycline 200 mg once daily seems to improve respiratory symptoms and anosmia in a modest subset of COVID-19 patients who completely recovered from it within only 2 days of treatment. Doxycycline treatment was continued for about 8 days. The average time of recovery of COVID-19-linked anosmia in doxycycline-treated patients was about 2.5 days. A sudden improvement in all symptoms was reported in the doxycycline group, however, the most exciting finding was the rapid recovery of smell. (13)
Final Comments and Future Directions
Doxycycline has emerged to be a potential partner in COVID-19 therapies (14) since early months of the pandemic due to its broad-spectrum antibacterial efficacy, antiviral activity, and diverse pleiotropic and anti-inflammatory potential. The plausible benefit of doxycycline in improving smell alterations in COVID-19 patients seems to be attributed to its anti-inflammatory effects. While more durable quantitative and qualitative evidence is yet to established in this direction, there seems to be yet another rationale emerging to support the consideration for use of Doxycycline in the treatment of COVID-19 infections. (13)
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Doxycycline, click HERE
References:
Adapted from:
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