Viral Pandemics and Oral Health: Lessons Learned From HIV to SARS-CoV-2

Abstract

Not since the human immunodeficiency virus (HIV) and the acquired immune deficiency syndrome (AIDS) pandemic began, have we had a transformative experience in dentistry that has made us deeply reexamine our practices and come to terms with a new reality of how dentists care for their patient's health. What is different now than in 1985 is the more rapid pace of research and broad global public emphasis on conquering the severe acute respiratory coronavirus 2 (SARS-CoV-2) that causes Corona Virus Disease of 19 (COVID-19), and limiting its spread that results in damage to both our health and finances. Both are pandemics to be reckoned with. HIV introduced the enduring era of blood-borne pathogens and now SARS-CoV-2 has brought us into the era of respiratory pathogens. While HIV targets lymphocytes and immune function and SARS-CoV-2 targets the angiotensin-converting enzyme 2 (ACE-2) widely expressed receptor cells and the renin-angiotensin system, lessons from our experience with HIV can inform aspects of our response to the highly infectious SARS-CoV-2. Enhanced infection control Dentists, who at the start of the AIDS pandemic were described as working in a confined dark contaminated space with sharp instruments, have of necessity established themselves as experts in infection control practices, which have continued to evolve over time. I began dental school training the University of North Carolina at Chapel Hill in 1982 at the nascence of the AIDS pandemic, when the hepatitis B virus (HBV) was the main infectious disease of concern at the time. My infection control training was from James J. Crawford, PhD and I was memorably impacted by his “What if Saliva Were Red” video. Originally developed in the 1970s, this video graphically illustrated the widespread dissemination of the otherwise invisible saliva around the dental operatory during routine practice. From this dramatic demonstration, it became clear there was a need for improved cross-infection control practices to prevent infection with blood-borne pathogens. Until around the discovery of HIV in 1985, dentists typically wore gloves only for surgical and some endodontic procedures, long sleeve gowns were nonexistent in restorative dental practice, handpieces were not routinely autoclave sterilized, and masks and protective eyewear was rarely used in general dental settings. And yes, as we somewhat painfully adapt today to the extra gear, particularly the N95 respirator and full-face shields, in the 1980’s we mourned the loss of fine tactile sensations with routine use of gloves. In the early AIDS pandemic, enhanced sterilization and engineering designs helped keep us safer from sharps injuries, dental unit waterline contamination and suction equipment backflow, and handpiece cross-contamination, as today enhanced air handling systems, face shields, and new office designs help to keep us safer in our aerosol generating environment. We have now added plexiglass barriers as social distancing/sneeze-guard shields to protect our main office staff, as lessons from our early use of disposable plastic cover barriers on operatory light handles, dental chairs and operatory trays/handpiece setups taught us how to simplify maintaining clean surfaces prone to contamination with potentially infectious agents. We now are challenged with quickly introducing more safety measures for our work in an environment of droplets and aerosols from the mouth in this age of a respiratory pandemic. An early survey in May and June 2020 of practicing dentists in private practice and public health settings in the United States (U.S.), a short 2 months after the first COVID-19 wave and national shortages of personal protective equipment caused offices to move to emergency only dental care, showed that 99.7% of offices had implemented enhanced infection control procedures. 1 These were most often more frequent disinfection, COVID-19 screening procedures including temperature checks, social distancing, and providing face masks to staff and patients. 1 Meeting the challenges of producing a safer office practice environment and educating the public and our dental team members on our risk mitigation strategies are helping overcome public fear of COVID-19 spread in the dental office. The early days of the AIDS pandemic were filled with fear of spread of AIDS in the dental office. A common practice in the early days of the AIDS pandemic among practices that would accept AIDS patients was providing care only at the end of the day so the invisible virus would dry and die on surfaces overnight. Uncertainty over many aspects of the new air-borne COVID-19 disease and the dramatically increased demand on a limited supply of personal protective equipment caused a shut-down of dental practices to only emergency dental services and limitations on use of aerosol-generating dental equipment. Today with practices reopened, a main concern is SARS-CoV-2 viral particles lingering in the air in the operatories, suggesting the need to allow time between patients for the room air to settle and/or implementation of high-efficiency particulate air filtration systems. Fortunately, with today's wide-spread influence of the internet, transition to electronic health records and patient engagement in health, many patients have the capacity for audio/video visits with their healthcare providers. These technological advances helped to transform the nascent telehealth system into one that is a robust alternative for triage and dental visits not requiring hands-on examination and procedural-based care, helping to solve healthcare access challenges. A race for vaccines for prevention As soon as vaccines became available against HBV, healthcare workers were immunized, and over a short time period vaccine technology moved from plasma-derived to recombinant DNA technology. 2 Despite globally wide-spread infant HBV vaccination programs implemented in the ensuing years, HBV has not been eradicated. While HIV has eluded the efforts to develop a preventive vaccine largely due to its global genetic diversity, 3 SARS-CoV-2 has appeared to be relatively genetically stable, thus creating hope for success in efforts toward creation of a SARS-CoV-2 vaccine. What would be most useful for prevention of future pandemics would be development of a vaccine that was widely effective against many alpha and beta human coronavirus strains. While hope for a COVID-19 vaccine to quell transmission is widespread, we must not lose sight of the fact that diverse vaccine development technologies and novel drug discovery efforts made today will benefit our response to the next pandemic. Given the length of time for drug and vaccine development and approval, we now need to commit to getting ahead of the curve with well-organized and funded collaborative efforts to add to the pipeline. Salivary diagnostics Molecular evidence of both viruses can be found in whole saliva fluids, although in lower concentration than in blood. Evidence supports SARS-CoV-2 to be community spread via saliva droplets and aerosols through coughing, sneezing, speaking, singing and breathing. 4 One of the key reasons for HIV testing advocacy was the observation that HIV-infected individuals unaware of their infection were the most likely to spread HIV; this is also true for SARS-CoV-2 where 80% of transmission may be due to undocumented asymptomatic infection. 5 Saliva based SARS-CoV-2 diagnosis of this enveloped, positive-sense, single-strand RNA virus by RT-PCR or immunoglobulin/antigen detection has emerged as a promising testing option to the traditional nasopharyngeal swab test. 4 It is likely that the work that went into developing the more recent generation antibody/antigen tests for HIV helped accelerate the pace of development of testing modes for SARS-CoV-2. OraSure Technologies Inc. (Bethlehem, PA, USA) delved into saliva or oral-fluid based HIV antibody testing. Their efforts that moved from lab to rapid point-of-care to at-home testing over the course of several years have likely paved the way for more rapid progress and acceptance of saliva-based rapid SARS-CoV-2 testing. To date, one study analyzing multiple immunoglobulin response to SARS-CoV-2 in various biological fluids, including self-collected saliva for rapid SARS-CoV-2 diagnosis, has been published as a protocol without results, 6 so additional results of this study and others are needed to support antibody testing for SARS-CoV-2 in saliva. The real hope is for saliva-based point-of-care rapid tests, as was created in OraQuick Advance® HIV-1/2 (Orasure Technologies, Inc.) for diagnosis of HIV infection. Therapeutics There has been limited progress in developing a specific treatment for COVID-19 at present despite advances in repurposing the nucleotide analog antiviral Remdesivir® and exploiting passive immunity approaches with production of convalescent plasma from recovered patient therapies or multiple neutralizing monoclonal antibody cocktails (Regeneron and Eli Lilly). It took considerable research investments and six years for approval of azidothymidine, the first antiretroviral drug in the fight against HIV, originally synthetized for use as a cancer treatment agent, and even longer until highly effective antiretroviral therapies were available. 7 We are just at the beginning of our human interaction with corona virus diseases and since cross-species transmission of viral pathogens has emerged as a threat to humans, 8 a sustained investment in antiviral research can better prepare us for the future. Our repurposing of today's antiviral drug discoveries fuels hope of more rapid solutions to future viral pandemics that are inevitable. Head and neck findings Dysgeusia and anosmia have resulted from this new viral infection's destruction of target nerves in the gustatory and olfactory sensory systems. Evidence now supports glial and neuronal stem cell invasion of ACE2, which is the main host cell receptor of the SARS-CoV-2 virus, and a secondary receptor, transmembrane protease serine-2 (TMPRSS2), explaining the development of dysgeusia and anosmia. 9 Head and neck involvement of COVID-19 extends beyond the changes in taste and smell. ACE2 and TMPRSS2 receptor expression, enabling viral entry into the host and clinical expression of disease, has been found in human major and minor salivary glands and oral epithelium, including epithelial cells, fibroblasts, T cells and B cells. 9 A recent living systematic review of literature published through June 6, 2020 of the prevalence of oral signs and symptoms in COVID-19 patients, involving 10,228 patients in 19 countries, demonstrated the most common finding was gustatory impairments in 45%, suggesting this condition should be considered important in the clinical picture of COVID-19’s initial presentation and disease progression. 10 Of the different taste disorders, the most common was dysgeusia (38%), followed by 35% hypogeusia and 24% ageusia. 10 Authors of this review report that the diversity of oral mucosal lesion presentations including irregular and aphthous-like ulcers, white and erythematous plaques, blisters, petechiae, and desquamative gingivitis, found on the lips, tongue, palate, buccal mucosa and gingiva, suggest coinfections and secondary manifestations of COVID-19. Nearly every month, new reports are revealing oral lesions possibly or probably associated with COVID-19 infection, with a predominance of attention increasingly placed on hemorrhagic and aphthous-like ulcerations with necrosis 11 and vesiculobullous and macular lesions. 12 Cruz Tapia and colleagues 11 suggest their four cases of angina bullosa hemorrhagica-like lesions, vascular disorder and nonspecific stomatitis, support thrombi formation and vasculitis in the oral mucosa of COVID-19 patients. Interestingly, the dermatology literature is also demonstrating that vesicular rashes appear early and may help diagnosis, while vascular rashes may be useful in predicting severe disease. 13 To determine co-occurrence of skin lesions (exanthems) and oral cavity lesions (enanthem) in patients with COVID-19, oral cavities were examined in 21 patients with skin rashes and 6 (29%) had oral lesions, all on the palate, and described as macular and/or petechial, with no association with drug intake and laboratory studies suggested they were a stronger indicator of viral etiology than a drug reaction. 14 When the diversity of oral mucosal and salivary gland disorders were observed in HIV/AIDS patients, international collaborative groups such as the European Community (EC)-Clearinghouse on Oral Problems Related to HIV Infection and World Health Organization (WHO) Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus gathered to reach consensus on presumptive and definitive diagnostic criteria of multiple lesions and to classify them according to levels of association with HIV from strongly associated, less commonly associated, to those seen in HIV infection. 15 As more becomes known about oral manifestations of SARS-CoV-2, vaccination efforts continue slowly, and future coronavirus infections/pandemics are likely, the need may arise for an international collaborative consensus to be reached for defining and classifying oral lesions and the dysgeusia/anosmia that is becoming more characteristic of COVID-19. Will global teleconferencing be used to gather this expert data-driven consensus? Similar to patients who have HIV infection, the host immune response to SARS-CoV-2 likely impacts COVID-19 disease expression and clinical course of disease in the oral cavity. COVID-19 disease sequelae are not fully understood SARS-CoV-2 is not known to result in chronic infection, yet many post-COVID-19 symptoms including myocardial and neurological consequences are suggested. Medium and long-term consequences of infection, particularly if severe disease manifestations, are yet unexplored. Are there persistent autoimmune sequelae? What is the trajectory of recovery of smell and taste? Are relapses or reinfections possible? Will there be other neurological or neurovascular delayed diseases? Is there potential for SARS-CoV-2 virus to hone to cranial nerves such as in the case of varicella-zoster virus contracted as varicella (chicken pox) and lying dormant in the dorsal root ganglia of the trigeminal nerve that reactivates a life-time later as shingles (herpes zoster)? Will there be common or rare long-term sequelae? Can we determine who is at greatest risk? Are underlying mechanisms of SARS-CoV-2 infection expressed as immunologic disease manifestations that may become more apparent with aging of recovered patients? Are there preventive approaches that can be developed to alleviate subsequent clinical disease expression? We learned from HIV disease management that the antiretroviral drugs can have acute and long-term toxicities including ulcers, xerostomia/parotid lipomatosis, taste disturbances, perioral paresthesia, erythema multiforme and facial fat wasting. 16 Will there be oral toxicities or benefits of COVID-19 treatments particularly as treatments target the cytokine storm, a procoagulant state, and local and systemic activation of inflammation? We are better together In this new global pandemic, we need to learn from early disease hotspots, and continually reassess successes and failures of varied prevention, diagnosis and treatment approaches. In the U.S., both HIV and SARS-CoV-2 infection rates and deaths tend to be higher among people of color, those living in poverty, and other vulnerable populations. As with HIV, many more SARS-CoV-2 infected individuals are asymptomatic in disease expression. Fortunately, we believe SARS-CoV-2 is cleared from the body with time and an antibody response to the virus may provide protection in most people from further infection and disease progression. To give a global perspective of relative disease burden, the WHO reports an estimated 38 million (31.6-44.5) globally were living with HIV at the end of 2019; 1.7 million (1.2-2.2) were newly infected with HIV in 2019 and there were 690,000 (500,000-970,000) HIV-related deaths in 2019. 17 Although likely underestimates, the WHO similarly reports COVID-19 cases for the year of 2020 to already exceed 2019 HIV cases at 42.5 million, as we enter the second Fall 2020 wave, with confirmed COVID-19 deaths at 1,147,301 (for 2020 with the first case reported on January 4, 2020 through October 25, 2020). 18 This means deaths from COVID-19 this year are approaching double the number of annual deaths last year from HIV. This will happen again. Who will take the lead? With viruses constantly mutating and evolving and people living in closer proximity to animals, our future likely holds the possibility of new strains of coronavirus or other viruses that come to infect animals making the transition to humans and resulting in human to human spread, like SARS-CoV-2 did. Systems need to be developed for early recognition and containment. A broader understanding and mitigation of underlying conditions that support animal to human disease transmission are critical for prevention. To understand our current enemy, the SARS-CoV-2 virus, manage COVID-19 disease consequences and prepare for and hopefully prevent future zoonotic viral pandemics, we need international multidisciplinary teams leading research to determine which characteristics of COVID-19 are universal versus mediated by local conditions of health, medical resource access, cultural customs, and other social determinants of health. We have seen this with our fight against HIV/AIDS through the collaborative efforts of the International AIDS Society, established in 1988 and representing 180 countries, activities of the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS), and many international nonprofit and non-governmental organizations. We have witnessed great strides in the early months of this pandemic when our U.S. National Institutes of Health created supplemental funding for existing extramural grants to add components related to the clinical impact of SARS-CoV-2 on patients’ health outcomes. Internationally, as was the case at my home academic institution, many researchers engaged in and supported for their HIV/AIDS work pivoted to work on COVID-19. While many COVID-19 studies could be conducted in laboratory biosafety level 2 (BSL-2) laboratories using standard precautions, those studies involving virus isolation needed BSL-3 laboratories and procedures. 19 As this is similar to the biosafety categorization for work with HIV, 20 many already established BSL-3 laboratories engaged in HIV research became rapidly repurposed as COVID-19 research facilities. Almost overnight, our HIV clinical researchers became COVID-19 researchers, as critical new studies were designed. Without HIV/AIDS, this research infrastructure needed for COVID-19 work would likely not have existed. We now need better mobilization of scientific collaboration globally and continued support of federal and international agencies to sustain our work in prevention and treatment for COVID-19 to prepare us for future outbreaks and sustain our global population. This is a global health crisis, needing a global response. Where do we go from here? The COVID-19 pandemic has further revealed the fundamental place of dentistry in the health system as an essential health care service whose role is to assure eradication of disease and management of pain in the maxillofacial structures to preserve quantity and quality of life and to prevent decline in a person's systemic health. We have been effective at keeping patients with dental complaints out of our nation's hospital emergency departments during the early COVID-19 shut-downs. We have adapted and will continue to adapt to the challenges ahead. The question arises as to whether we can now mobilize our oral health team to participate in viral disease testing and vaccination efforts in the days ahead. Here's hoping we have many “wins” in 2021 for our further integration into the health system.