The Oral Health Implications of COVID-19 Pharmacotherapy

INTRODUCTION
As the COVID-19 pandemic moves across the world, research shows confirmed human to human transmission of SARS-CoV-2 with its symptoms ranging from mild flu-like to severe life-threatening pneumonia.¹ At this point, there is no specific treatment available in combating COVID-19. Healthcare professionals use multidisciplinary approaches, including multi-drug treatment and intensified therapeutic measures, that can potentially affect oral health and mucosal tissue. This article aims to provide a brief overview of the potential oral health-related implications of pharmacotherapy, especially for COVID-19.

PHARMACOTHERAPY FOR COVID-19
With no specific pharmacological treatment available for COVID-19 and prognosis still undefined, the WHO recently commenced a SOLIDARITY trial, an international clinical trial to validate various medications for the potential treatment of severe COVID-19 complications, and to find an effective treatment.² The pharmacotherapy under investigation is a combination of antimalarial (chloroquine/ hydroxychloroquine) and antiviral (remdesivir, lopinavir, ritonavir) medications.² Many scientists advocate specific antivirals such as remdesivir, ribavirin, favipiravir, oseltamivir, and umifenovir to treat COVID-19 patients.^3,4 The most widely known treatment that seems to work by reducing viral load in COVID-19 patients is lopinavir and ritonavir, combinations of protease inhibitors which are typically used in treating HIV cases.³ Chloroquine was initially believed to show some level of efficiency and safety against COVID-19 pneumonia due to its potential broad-spectrum antiviral activity against SARS-CoV-2 infection; however, recent studies suggest otherwise.^4,5 Another group of antivirals like Interferons (interferon α2b and interferon ß) has proved to be beneficial at an early phase of infection.⁶ However, if given at a later stage, it worsens the cytokine storm and exacerbates the inflammatory process.⁶ Studies have shown that as COVID-19 progresses, cytokine storms are known to develop in patients, leading to secondary acute respiratory distress syndrome, followed by shock, tissue perfusion disorders, and eventually multi-organ failure.^6,7

Despite the inconclusive evidence in the potential use of corticosteroid therapy in the treatment of COVID-19, frontline physicians in mainland-China preferred the use of corticosteroids to manage COVID-19 pneumonia in critically ill patients.⁷ Recently, the National Institute of Health (NIH) recommended dexamethasone for COVID-19 patients with or without mechanical ventilation support. However, one should not neglect potential risks associated with the use of corticosteroids, including secondary bacterial or fungal infections, prolonged virus shedding, and increased risk for nosocomial (originating in a hospital/healthcare associated) transmission.⁸ Therefore, it is urgent to find new and specific drug treatment methods. The timely update by the National Institute of Health (NIH) on treatment guidelines for Coronavirus Disease 2019 (Table 1), shows a summary of potential drugs under evaluation for treatment of COVID-19, and their oral health related impact.⁹

Table 1

Summary of potential drugs under evaluation for treatment of COVID-19 and its oral health related impact.

Meanwhile scientists are in a dilemma for using broad spectrum antibiotics in the treatment of COVID-19. Chinese physicians seem to be widely prescribing broad-spectrum antibiotics for COVID-19. Azithromycin has been studied for the treatment of COVID-19, only in combination with hydroxychloroquine.¹⁰ One should consider that inappropriate use of the antibiotic can lead to its resistance and Clostridium difficile infection.¹¹ The increased use of antibiotics in therapeutic and prophylactic procedures should encourage dentists to question and reflect upon antibiotic prescription practices. With antibiotics being widely prescribed in cases of oral infection, increasing emergence of antibiotic resistance will make the use of antibiotics even less effective in the future.

EFFECT OF PHARMACOTHERAPY ON ORAL HEALTH
The effect of pharmacological management for COVID-19 on oral health requires special attention. Widely used antiviral drugs have oral health implications such as the development of erythema multiforme, mouth ulcers, and xerostomia.¹² While parotid lipomatosis, taste disturbances, and perioral paraesthesia are oral health-related adverse effects of protease inhibitor therapy,¹³ Interferon therapy can lead to decreased salivary flow rate and ultimately to dental problems.¹⁴ The oral side effects of antiviral drugs may include dry mouth, and this dryness based on reduced saliva can lead to oral candidiasis, dental caries, alterations in the taste sensation (dysgeusia), or loss of taste sense (ageusia).¹³ It is worth noting that oral candidiasis is a prominent infection of the oral cavity found in elderly or immunocompromised patients,¹⁵ resulting from corticosteroids or antibiotics therapy, and invasive surgical procedures performed during the treatment of COVID-19. Please refer to Table 1 for the summary of COVID-19 drugs and their oral health-related effects.

Hospitalized older populations with existing comorbidities (hypertension, cardiac diseases, diabetes) can be more vulnerable to oropharyngeal infections.¹⁹ Moreover, the prevalence of nosocomial infections in critically ill COVID-19 patients is drastically increased due to the use of endotracheal tubes and continuous ventilatory support. These interventions, combined with systemic therapies, can contribute to tube-related discomfort, thirst, oral lesions, and the accumulation of saliva, sputum, plaque, and oral bacteria.²⁰ Therefore, critically ill patients in intensive care units (ICU) require meticulous oral health maintenance. Also, there is a need to promote standard oral health protocols for COVID-19 patients admitted into the ICU, to improve oral healthcare service delivery.

The inflammatory cytokine response may influence and exacerbate the overall impact of COVID-19 on oral health. Inflammatory mediators (IL-1, IL-8, and TNF-α) are not only produced by the immune cells, but also by the gingival epithelium that releases these cytokines.²¹ Both homeostasis and inflammatory processes are modulated by cytokines that act in the first wave of responses against pathogens and stimuli at barrier sites, while contributing to chronic disease progression. This changes the oral ecology in the subgingival region.²² The cytokine storm of COVID-19 can further lead to rapid worsening of periodontal health. Changes in the subgingival communities of pathogens due to dysbiotic processes (rather than colonization of specific bacteria), determine the development and progression of periodontal disease.²² There seems to be a strong need to implement appropriate measures to monitor the oral health of recovering COVID-19 patients and those being treated for COVID-19.

The overall impact of COVID-19 on oral health may be multi-directional, partly due to being immune-related, exacerbated by the inflammatory response to the virus’s pathological nature through direct and indirect mechanistic features. There is a need for further data that reveals the effect of COVID-19 infection on the oral mucosa, salivary glands, orofacial functioning, and taste sensation. Further studies are required to examine the association between the combination of antiviral therapy and oral health outcomes (dental and periodontal diseases) among COVID-19 patients.

Oral Health welcomes this original article.

Conflict of Interest: The authors declare that there is no conflict of interest to disclose that could be perceived as affecting the opinions and impartiality of the information reported.

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About the Authors

Dr. Radhika Chhibber has a Bachelor of Dental Surgery (BDS) degree, with a year of clinical practice from India. She is currently at McGill University doing her MSc in Dental Science with a research focus on pediatric periodontal health.

Dr Madhura Tandale has a Bachelor of Dental Surgery (BDS) degree with two years of clinical practice from Mumbai, India. She has recently graduated from McGill University with a MSc in Dental Science.

Dr. Zeeshan Sheikh has trained as a dental clinician and a biomaterial scientist with degrees of BDS, MSc and PhD in dentistry from Baqai Dental College, Queen Mary, University of London and McGill University. He has also completed two Post-Doctoral Fellowships at the Faculty of Dentistry, University of Toronto and at Mt. Sinai Hospital. He is currently a Periodontics & Implant Surgery Resident in year two of training at Dalhousie University. His research expertise lies in developing novel biomaterial options for bone grafting and maxillofacial regenerative applications.

Dr. Haider Al-Waeli has BDS, and M.Sc. degrees and certification from the Jordanian board in Periodontics. He finished his PhD at McGill University and his interest is in chronotherapy and bone healing after surgery. He is in the second year of Periodontics residency at Dalhousie University.