Ocular Manifestations in Epstein Barr Virus Infection

*Andi Arus Victor*

## **Abstract**

The Epstein-Barr Virus (EBV), a member of the Herpesvirus family, occurs commonly and infects more than 90% of people worldwide. Most of systemic EBV infections throughout childhood and adulthood are typically asymptomatic or paucisymptomatic. Even though ocular involvements in EBV infections are infrequently reported, an increasing number of ocular manifestations have been previously reported . Ocular manifestation caused by EBV infection involved all segments of the eye, including oculoglandular syndrome, dry eye syndrome, dacryoadenitis, conjunctivitis, episcleritis, keratitis, uveitis, choroiditis, retinitis, retinal vasculitis, and papillitis. Previous reports found neurologic complications such as papilledema, optic neuritis, ophthalmoplegia, impaired accommodation, and facial nerve palsy. Any atypical ocular inflammatory process should be considered EBV infection in the differential diagnosis. The ocular manifestations of systemic EBV infection are varied and have not been emphasized. And the role of EBV infection in ocular manifestations should be fully described.

**Keywords:** Epstein-Barr virus, oculoglandular syndrome, dry eye syndrome, dacryoadenitis, conjunctivitis, episcleritis, keratitis, uveitis, choroiditis, retinitis, retinal vasculitis, papillitis, papilledema, optic neuritis, ophthalmoplegia, impaired accommodation, facial nerve palsy

### **1. Introduction**

The Epstein-Barr Virus (EBV) was first introduced in 1964 by Epstein, Anchong, and Barr [1–3], from a tissue sample of Burkitt's lymphoma and was observed with an electron microscope. EBV has the same characteristic as herpes viruses in tissue cultures from specimens of Burkitt's lymphoma. EBV is included in the family of *Herpesviridae*, which has a characteristic of the viral genome covered inside a nucleocapsid bounded by the viral envelope. In 1968, 4 years right after its first discovery, EBV was found to be the causal agent of the infectious mononucleosis (also called glandular fever). On other studies that conducted after, EBV was also found on tissue samples of nasopharyngeal carcinoma [3, 4], non-Hodgkin's lymphoma, T-cell lymphoma, as well as oral hairy leukoplakia that associated with Acquired Immunodeficiency Syndrome (AIDS) [4, 5].

EBV DNA has a nature of double-strand and consists of guanosine and cytosine as much as 58%. Due to the nature of the receptors on B-cell surfaces, EBV shows a great permissivity toward B lymphocytes. When B lymphocytes are infected by EBV, they will be "transformed" into lymphoblasts in vitro, this process known as immortalization. EBV occurs commonly and infects approximately 90% of human [1–3].

EBV-specific antibodies are found in about 95% of adults and 50–85% of the children [4, 5]. EBV infections are typically asymptomatic or have a subclinical infection, but once infected, it can lead to a viral carrier state for a lifetime. In some cases, primary EBV infection occurring during early adulthood could show clinical significance that is known as glandular fever or infectious mononucleosis [2, 5, 6]. Fortunately, most patients with infectious mononucleosis show a short recovery period since both cellular and humoral immune responses play a prominent role during the infection.

Ocular manifestations caused by EBV infection have been previously described. Previous studies showed that specific antibodies were detectable in 65% of tear and 87.5% of serum samples from 40 normal subjects [4]. EBV infection manifested in the eye may involves all segments of the eye, including oculoglandular syndrome, dry eye syndrome, dacryoadenitis, conjunctivitis, episcleritis, keratitis, uveitis, choroiditis, retinitis, retinal vasculitis, and papillitis [3]. Follicular conjunctivitis is the most common ocular disease during acute EBV infection. It is observed in 1–38% of cases and is usually unilateral. Bilateral stromal keratitis with coin-shaped lesions noted on tapering of systemic steroid therapy has been reported [6]. Uveitis occurred in 0.5% of patients with EBV infection [6].

The ocular manifestations of systemic EBV infection are numerous and have not been emphasized. Therefore, the role of EBV infection in ocular manifestation should be fully understood.

## **2. Pathophysiology infection of EBV**

Usually, the first introduction to EBV in the period of childhood will cause subclinical infection, however if this primary event happens during adolescence, most of the time would trigger infectious mononucleosis. This syndrome consists in an acute and self-limiting lymphoproliferation of infected B cells and, at the same time, the development of virus-specific T cells that are triggered in order to tackle viral dissemination.

EBV transmission occurs by the sharing of saliva and then cause infection of mucosal surfaces and lymphoid tissues [3]. Almost most of seropositive individuals shed virus in their saliva. It was proposed earlier that initial replication of the virus happened also in the epithelial cells of the oropharynx, which causes the B cell infection by the previously infected epithelial cells. However, newer studies suggest that B cells located in the oropharynx could be infected first and act as the primary site.

During the latent stage of the infection, the site in which EBV persists within the body is the resting memory B cells. The viral replication in the oropharynx is partially suppressed in patients taking acyclovir, in the other hand, the amount of B cell EBV infected in the circulation remains the same.

Typical symptoms and signs are fever, pharyngitis, lymphadenopathy, and splenomegaly. The basic lesion is a perivascular infiltration of both normal and abnormal lymphocytes in all the tissues except bone marrow [7].

These cells are metaplastic noninvasive and to be formed *in situ* from other cells of the reticuloendothelial system. This lesion distributed throughout the body, and in any individual patient may be most marked in the central nervous system, liver, lungs, and other organs or systems.

Before the entry process into B cell, gp350, a major envelope glycoprotein, fixes to the receptor of the virus, CD21 molecule, which is located on the surface of the B cell. There are other factors besides CD21 that play a significant role, such as major histocompatibility complex (MHC) class II molecules that acts as a cofactor during B cells infection. EBV genome linear DNA molecules encode 100 viral proteins.

#### *Ocular Manifestations in Epstein Barr Virus Infection DOI: http://dx.doi.org/10.5772/intechopen.93721*

These proteins are significant in the process of construction of virion as well as carrying forward immune responses of the host.

EBV infection in vivo of the epithelial cells consequences in active replication while simultaneously with lysis of the cells as well as production of virus. Meanwhile, EBV infected B cells in vitro will become immortalized and causes latent infection. Only a small portion of cases that viral replication is triggered immediately after the infection of B cells.

Both cellular and humoral immunity plays an important role in the infection of EBV in humans. Even though the presentation of antibodies designed against viral structural proteins is critical, cellular immunity plays a higher role on the controller of EBV infection. The control of proliferation of EBV infected B cells in the primary infection is carried forward by CD4+, CD8+, and natural killer cells. During the period of infectious mononucleosis, a proportion of 40% of CD8+ T cells are focused on single replicative EBV protein sequence, meanwhile only 2% are focused to single latent EBV protein sequence.

During acute infection, first IgM and then IgG antibodies to viral capsid antigens (VCA) appear. Anti-VCA IgG may lead to virus carrier state and persist for a lifetime [3, 7]. Antibodies to early antigens rise during the acute phases of the disease and subsequently decrease to low or undetectable.

EBV can exist regardless of competent responses from the healthy immune system that are targeted toward it. It would most probably suggest that EBV has developed some tactics to evade the response from the immune system. EBV encrypts a cytokine as well as cytokine receptors that have a crucial role in moderating capable immune system therefore this allows tenacious infection. The 70% of amino acid sequence of EBV BCRF1 has the same characteristics as interleukin-10.

The protein of BCRF1 imitates the behavior of interleukin-10 of inhibits interferon-γ synthesis by in vitro human peripheral-blood mononuclear. In addition to that, EBV BARF1 protein acts as a soluble receptor for colony-stimulating factor 1. It is known that colony- stimulating factor 1 usually upregulates the expression of interferon-α of monocytes, therefore BARF1 protein able to operate as a decoy receptor to halt the action of cytokine. Since inhibition of the outgrowth of EBV infected cells in vitro is done by interferon-γ and interferon-α, BARF1 and BCRF1 proteins could aid the EBV to avoid the immune system of the host in the period of both acute as well as latent infection. EBV also codes more than two proteins that cause apoptosis inhibition. Protein of the EBV BHFR1 is similar to the protein of human bcl-2 protein, this protein has the same function on blocking apoptosis. In addition, EBV LMP-1 increases several cellular protein expressions that hinders the process of apoptosis, i.e. bcl-2.

Antibodies to EBV nuclear antigens appear weeks to months later, providing serologic evidence of past infection. Lesions of the special sense organs are somewhat rare, but there are few reports of eye lesions or manifestations [7].

Ocular manifestations have been reported to affect all segments of the eye and most commonly associated with acute mononucleosis [3]. Manifestations in the ocular may be the cause of direct involvement of the eye and its adnexa through inflammatory syndrome similar to that of infectious mononucleosis, and those affecting vision and the neuro-ophthalmologic apparatus owing to a more remote occurrence of the lesion, most commonly involving the central nervous system [7].

## **3. Clinical manifestation**

Ocular manifestations of acute EBV infection may affect the central nervous system to the extent of disturbance in the visual or oculomotor pathways, in

addition it could as well cause a disorder in the eye and adnexa of the eye [4, 8]. Further manifestations were observed due to the advancement of diagnostic tools that could give much more sensitive and specific results [8].

Neurologic abnormalities caused by EBV could disturb the host vision. Disorders that have been reported previously consisted of papilledema, convergence deficiency, nerve palsies, retinal necrosis, central nervous system vasculitis, retinochoroiditis, necrotizing retinitis with extensive hemorrhage that were co-infected with human immunodeficiency virus and cytomegalovirus and optic neuritis [9].

The appearance of yellowish, coalescing lesion in the macula as well as edematous optic disk were seen in a patient with EBV infection by Kim et al. [10]. From our previous case-report, it was examined from funduscopy a peculiar finding of prominent presentation of white sheathing retinal phlebitis covering all four retinal quadrants (**Figure 1**). Other reports had described this finding as frosted branch angiitis. It was also well known that frosted branch angiitis has been seen regularly in numerous disorders such as Crohn disease, Behcet disease, and systemic lupus erythematosus. However, from our previous case, the patient did not show any typical symptoms of Crohn disease, Behcet disease, and systemic lupus erythematosus, also, PCR was done on the patient's serum and was positive for EBV.

EBV infects lymphoid tissues and also mucosal surfaces. In the cellular level, EBV infects B cell and conforming virus-specific T cells, which will lead to symptoms such as lymphadenopathy and pharyngitis. Based on seroepidemiologic data, it was reported that EBV infects all parts of the eye, though the most common abnormality includes follicular conjunctivitis. After the availability of serologic virus-specific tests, other disorders of the anterior segment that is associated with EBV were detected more frequently, which includes keratitis, iritis, episcleritis, as well as dacryoadenitis.

It was found by Plugfelder et al., [11], that some cases of primary Sjogren's syndrome developed right after infectious mononucleosis. These authors [11] gathered patients that have aqueous tear deficiency and evaluated them for a serologic finding of EBV infection. A significant correlation was found between elevated early antigen EBV titers and severe aqueous tear deficiency once the results were placed in multivariate analysis. This suggests that EBV infection could be a risk factor in developing aqueous tear deficiency [11, 12].

Inflammation of the conjunctiva has been seen and linked with keratitis, that variate from mild hyperemia to mild follicular reaction in the inferior and superior

#### **Figure 1.**

*Bilateral fundus photographs showing white sheathing of retinal veins in four retinal quadrants (frosted branch-like appearance) with macular edema. Reprinted from [1]. Copyright 2016 by Retinal Cases & Brief Reports.*

*Ocular Manifestations in Epstein Barr Virus Infection DOI: http://dx.doi.org/10.5772/intechopen.93721*

**Figure 2.**

*Subepithelial infiltrates resembling adenoviral infection-associated keratitis in a patient with recent primary EBV infection. Reprinted from [2]. Copyright 1990 by Surv Ophthalmol.*

tarsal conjunctiva. A study by Matoba [4] has found stromal keratitis related to EBV infection to infect all layers of stroma. Matoba [4] has also reported there were two forms of EBV-related keratitis, the first type was a granular, multiple, well-defined, ring, or circular-shaped opacities which was distributed all over the anterior as well as mid-stroma. Another form is nonsuppurative, multifocal keratitis including deep layers or full thickness of peripheral cornea and also related to various grades of vascularization [4]. In another study by Chodosh J, stromal keratitis associated with EBV infection presented three principal forms (**Figure 2**) [7].

Type I: multifocal subepithelial infiltrates that resemble adenoviral keratitis.

Type II: multifocal, blotchy, pleomorphic infiltrates with active inflammation or granular ring-shaped opacities (inactive form) in anterior to midstroma.

Type III: multifocal deep or full thickness peripheral infiltrates, with or without vascularization.

Matoba et al. [4] proposed a hypothesis about the pathophysiology of EBV related keratitis onset being carried forward by infectious and immunologic processes. Due to the quick response to the introduction of topical corticosteroid and seeming resolution of the inflammation without involving the use of antiviral therapy, it is more likely that immunologic processes were involved rather than viral replication. If this is true, the cornea was affected could be due to native keratocyte share a similar antigen with EBV, or it might be caused by EBV antigen develops located within the tissue [4].

Other common symptoms affecting the ocular include periorbital edema, pain when rotating the eyes, deep orbital pain, photophobia, as well as headache. It was spotted by Tanner [8] that episcleritis, as well as uveitis as part of the ocular manifestation of EBV infection. Tanner [8] reported nongranulomatous uveitis taking place at the end stage of clinical manifestation of infectious mononucleosis had been noted in four cases. One specific exhibition is the disorder of the oculomotor apparatus. Fledelius et al. [8] observed an exclusive inferior rectus paresis. Motto and Ashworth [8] were the first to notice a bilateral papilledema case of infectious mononucleosis with the nonappearance clinical manifestation of encephalitis nor meningitis. Other studies observed ptosis, nystagmus, as well as diplopia in their patients [8].

#### **4. A diagnostic approach for detecting ocular disease by EBV infection**

Most of the ocular manifestations linked to the EBV infection have been based mostly on seroepidemiologic data. This claimed is supported by the fact that

numerous patients with EBV infection that showed ocular manifestations have been confirmed from in-situ hybridization of EBV genome from the biopsy of suspected tissue specimens.

The diagnosis of EBV infection by serologically for quite sometimes has been hinge on heterophile antibodies detection [4]. Heterophile antibodies are classified in the IgM group and would typically reach its highest levels around the second to third week since the first onset of the sickness and would exist and visible till 1 year [4]. They are detectable in up to 90% of adults who suffered from primary EBV infection [4].

Monospot test is a test that could be used in detecting EBV infection. This test is a quick slide agglutination test for specific heterophile antibodies produced by the human immune system in response to EBV infection. The sample will clump when it exposes to equine erythrocytes if these specific antibodies present in the patient's blood specimen. The Monospot test is considered to be a very specific test. However, its sensitivity falls in the range of 70–90% [13]. Patients with atypical clinical features and patients and with suspected of chronic infection are better evaluated with EBV specific serologic test that measure antibody levels against VCA, EBNA, and EA [4].

### **5. Management**

The overall goal of EBV treatment is mainly supportive since the disease is usually self- limited [4]. Antiviral drugs have been used to inhibit the replication cycle of the virus. The action of antiviral agents can be divided into: (1) disrupting with cellular process which the virus uses for its replication; (2) inhibits the function of the virus by bind to the nucleic acid; (3) modifies the viral envelope which is resulting in preventing the virus infecting new cells; (4) inhibits the formation of new progeny by interfering with viral assembly; (5) interferes with the viral enzyme and inhibits their function; (6) prevents the processing of viral precursor polypeptide. The effect of some of the antiviral agents used in EBV infection is uncertain, but some studies have reported good results of treating EBV infection with systemic antiviral [4, 12].

Several antiviral drugs have been used to treat EBV infection and can be grouped into three as nucleoside analogs such as ganciclovir, valganciclovir, acyclovir, valaciclovir, acyclic nucleotide analog such as cidofovir and adefovir, and pyrophosphate analog such as foscarnet [12]. Acyclovir is recommended as the first-line drug for treating EBV infection. Therefore, it has become the most commonly prescribed antiviral regimen [14–16]. Anderson et al. [14] have found a significant reduction of EBV-infected B-lymphocytes after acyclovir treatment. Accordingly, systemic acyclovir therapy showed a good result of treating EBV-associated ocular involvement and Acute retinal necrosis [15].

Acyclovir triphosphate inhibits viral replication by acting as a competitive substrate for viral DNA polymerase, and its subsequent incorporation into the viral DNA chain results in obligate chain termination. The recommended regime is intravenous acyclovir 10 mg/kg every 8 hours (or 1500 mg/m2 ) per day for 5–10 days, followed by oral acyclovir 400–800 mg 5 times daily for an additional 6–12 weeks. Second eye involvement may occur within the first 6 weeks after EBV infection; thus, the minimum duration of subsequent oral therapy was 6 weeks. Even though some ophthalmic centers are switching to oral therapy alone, few studies found a higher level of intravitreal acyclovir when given intravenously [15–17]. From the limited data available, one may conclude that acyclovir given intravenously and orally is the recommended regime [16, 17].

*Ocular Manifestations in Epstein Barr Virus Infection DOI: http://dx.doi.org/10.5772/intechopen.93721*

The effectiveness of steroid along with antiviral drug in treating ocular manifestations of EBV infection remains unclear. Some studies described that ophthalmic steroids relieve the symptoms of ocular inflammation in the anterior segment of the eye, including keratitis, anterior uveitis, and ocular allergies or injuries, yet its effect on the posterior part is still not clear [2, 4, 17].

## **6. Conclusion**

It can be concluded that distinctive characteristic pathologic clinical manifestation, as well as lesions of infectious mononucleosis, exists in the ocular area. The ocular manifestations of systemic EBV infection are wide-ranging and have not been highlighted. EBV infection is best diagnosed using heterophile antibody tests to detect primary EBV infections and serology tests for asymptomatic patients. Despite of the self-limiting nature of the disease, acyclovir still becomes the first line of treatment with its attribute to reduce the viral replication. EBV infection should be included in the differential diagnosis of most unusual inflammatory course of the eye.

## **Conflict of interest**

There are no conflicts of interest in this chapter.

## **Author details**

Andi Arus Victor Department of Ophthalmology, Faculty of Medicine, Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Cohen JI. Epstein-Barr virus infection. The New England Journal of Medicine. 2000;**343**:481-492

[2] Victor AA, Sukmana N. Retinal vasculitis associated with Epstein-Barr virus infection, a case report. Retinal Cases & Bried Reports. 2016:1-4

[3] Slobod KS. Molecular evidence of ocular Epstein-Barr virus infection. Clinical Infectious Diseases. 2000;**31**:184-188

[4] Matoba AY. Ocular disease associated with Epstein-Barr virus infection. Survey of Ophthalmology. 1990;**35**:145-150

[5] Kramer S, Brumer C, Zierhut M. Epstein-Barr virus associated acute retinal necrosis. The British Journal of Ophthalmology. 2001;**85**:110-120

[6] Wong KW, D'Amico DJ, Hedges TR III, et al. Ocular involvement associated with chronic Epstein-Barr virus disease. Archives of Ophthalmology. 1987;**105**:788-792

[7] Chodosh J. Epstein-Barr virus stromal keratitis. Ophthalmology Clinics of North America. 1994;**7**(4):549-556

[8] Tanner OR. Ocular manifestations of infectious mononucleosis. In: Presented at the 36th Annual Meeting of the Pacific Coast Oto-Ophthalmological Society, 1st May 1952, Salt Lake City; 1952

[9] Andi AV. Ocular Manifestations in Epstein Barr Virus Infection [Online First]. IntechOpen; October 5th 2020.

[10] Kim SJ, Baranano DE, Grossniklaus HE, Martin DF. Epstein-Barr infection of the retina: Case report and review of the literature. Retinal Cases and Brief Reports. 2011;**5**:1-5

[11] Pfugfelder SC, Tseng SCG, Pepose JS, et al. Epstein-Barr virus infection and immunologic dysfunction in patients with aqueous tear deficiency. Ophthalmology. 1990;**97**:313-323

[12] Yaro A. Epstein-Barr infection: Current treatment options. Annals of Tropical Medicine and Public Health. 2013;**6**(1):10-13

[13] Stuempfig ND, Seroy J. Monospot test. [Updated 2019 Mar 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. p. 1

[14] Keorochana N. A case report of Epstein-Barr virus associated retinal vasculitis: Successful treatment using only acyclovir therapy. International Medical Case Reports Journal. 2016;**9**:213-218

[15] Rafailidis PI, Mavros MN, Kapaskelis A, Falagas ME. Antiviral treatment for severe EBV infections in apparently immunocompetent patients. Journal of Clinical Virology. 2010;**49**(3):151-157

[16] Patrick MK, Claire YH, Susan L. Antiviral selection in the management of acute retinal necrosis. Clinical Ophthalmology. 2010;**4**:11-20

[17] Lee FF, Foster CS. Pharmacotherapy of uveitis. Expert Opinion on Pharmacotherapy. 2010;**11**:1135-1146

## **Chapter 5**


Foreword

It is with great honor that I have had the privilege of traveling and lecturing with many of the editors of this novel Volume 1 of Contemporary Developments and Perspectives in International Health Security. As I have traveled the world and visited every continent, it is striking to see the lives of ordinary citizens around the world and how different basic health and living standards (security) are based on where one lives.

I do remember one time in New Delhi, India, where a cab driver lamented at the conditions of the roads in India and told me of his dream of visiting America. He showed me a video of his relative in the United States, driving down a highway with clearly marked lanes, much more orderly than we were experiencing in our drive through this massive and beautiful Indian city. The paving of a dirt road not only expands the possibilities to travel more efficiently but also extends to health, culture, and community. The international experience highlights the interwoven aspects of everyday life that can impact a person's ability to live and survive based on the culture and components of a secure civilized society.

A threat to one can be a threat to all. Death, disease, famine, and pestilence. The reality of the coronavirus disease 2019 (COVID-19) created a ripple in our world that will impact humans for years, if not decades, to come. The broadened definition of International Health Security (IHS) is the right idea at the right time. The focus on HIS as that is based on individuals who participate in their community, as well as the security of physical, emotional and spiritual needs, is the link to foster dialogue and discovery well into the future.

In 2020 we find ourselves in the midst of one of the most information-dense times in human history. As medical knowledge doubles every few months, keeping up makes the organization of this information and best evidence a necessity across the world. The manifestation of Moore's Law, the metronome of digital advancements as a function of silica chips doubling the capacity and shrinking in size by half every 18–24 months, is our next generation smartphone universe and access to massive sets of information, right in the palm of one's hand. With the thought of Elon Musk's Starlink, the satellite connectivity of every continent and possibly every person will be the realization of a truly global human network. Gordon Moore, the founder of Intel Corporation, described the phenomenon that has seen computer processing progress to artificial intelligence and machine learning. The mathematics behind these amazing advancements and more in some economically resourced zip codes of the world is astonishing. As the world transitions from analog to the digital transformation of knowledge, power, and truth amidst societies, communities, and health systems, the next step is to codify the language used to describe our new world with the new challenges we encounter every day.

Each person is the first line in an onslaught of massive information and even more disinformation. What is the truth? What is logic? What is the spin? What does the evidence say? What would the scientist do? Now, what would the politicians do? The world and information availability is not the problem; it is the critical analysis of this information and separating the wheat from the chaff. When should I evacuate with this incoming storm? Am I at risk for this new infectious disease? Signal-to-noise ratios depend on the individual and cohort goals of you and your "family" social group to interpret information and balance it with one's experience and insight. In some cultures the fight is for equal opportunities. The future challenge is equalizing outcomes.

It is our health. Do we control our health information? Is it in a form that is portable, secure, and able to be updated as new information emerges? Can information help us meet and achieve our own hierarchy of needs? The future of HIS will be determined by how communities try to implement best practices for all. The equality of all with freedom, liberty, and justice in America is much different than that of the 194 other countries and sovereign nations.

IHS is the thread to this earthen security blanket. The idea of IHS is innovation. This book is a testament to the importance of seeing how the global security of the individual is transformed into IHS. We are more interconnected than we have ever been. The future is the understanding of this reality through further innovation and creativity. This is why this book is so important. The topics to focus on will be much different post COVID. Telemedicine was a great leap forward, while lockdowns were a significant step back. The future is the innovation of ideas such as IHS, and the path forward is feasible for the destiny of an evolved humanity.

The infrastructure of culture and access to health care, emergency care, and other necessary services is much different depending on where one lives. According to 2008 data from the World Bank, 80 percent of the world's population lives on less than \$10 dollars a day. There are billions of living in poverty. The wealthiest 20 percent are creating 75 percent of the world's income, while the less fortunate 40 percent are able to contribute only 5 percent of the world's income. Economic disparity, food "deserts," and energy insecurity stagnate the standards of living in some areas across generations, even in high-income nations. Health disparities exist in every country, yet in many nations, these are closely related to socioeconomic status, ethnicity, immigration status, and being a refugee.

A global pandemic resulted in the need to have thoughtful, evidence-based strategies in response to the many threats to human health. Living a healthy life that is productive and full should be an option for every human, but that is sadly not the case. Growing up in America is a much different experience than growing up in Delhi. Yet for whatever class, caste, or socioeconomic condition one finds themselves in, injuries and infections persist in everyday life, without exceptions. The coronavirus is the most recent threat to IHS. Secure patient data, artificial intelligence, and genetically modified organisms are just some of the many modern challenges faced by individuals worldwide. How does the global network of humanity respond to twenty-first century threats to IHS? How should we prioritize education and knowledge, scientific curiosity and skepticism, thoughtful deliberation and teamwork? IHS recognizes that each individual exists with humanity and free will, yet many persons do not have the socioeconomic environment conducive to learning, growing, and securing a humane life with basic elements of health security.

The world is more interconnected than ever before and when supply chains, essential minerals, and medical supplies were transported seamlessly pre COVID and distributed in an efficient way; with COVID, the world is a much different place. This is why the topic of IHS is more important than ever. The health of every

**V**

person has a connectedness of purpose and happenstance related to each other in multiple ways. Moving forward, the prioritization of IHS will be important for generations to come as modern humans survive and thrive in a world of social media, information overload, and cyber- and in-person threats to health. This volume and subsequent textbooks on IHS are resources to help solve the many challenges that confront humanity in our modern times. The old adage of Pandora's Box had the ills of the world being released onto humanity, yet at the bottom of that "box" was hope. This book stands out as a hope of collaboration between

Global participation in this knowledge economy will need entrepreneurs and innovators from across the world. To solve modern problems, we need modern solutions from a wide array of scientists and persons with experience and desire to help affect change. The authors of this book are dedicated to contributing to that change with much-needed attention to the importance of the current moment and the language needed to solve these problems around IHS. Historians will mark 2020 as a turning point, and this book is the first to conceptualize humanity as the

Respectfully,

Professor,

**David P. Bahner MD** Ultrasound Division Chief,

The Ohio State University, Columbus, Ohio, United States

Department of Emergency Medicine,

multiple experts to confront threats to health.

common denominator in IHS.

person has a connectedness of purpose and happenstance related to each other in multiple ways. Moving forward, the prioritization of IHS will be important for generations to come as modern humans survive and thrive in a world of social media, information overload, and cyber- and in-person threats to health. This volume and subsequent textbooks on IHS are resources to help solve the many challenges that confront humanity in our modern times. The old adage of Pandora's Box had the ills of the world being released onto humanity, yet at the bottom of that "box" was hope. This book stands out as a hope of collaboration between multiple experts to confront threats to health.

Global participation in this knowledge economy will need entrepreneurs and innovators from across the world. To solve modern problems, we need modern solutions from a wide array of scientists and persons with experience and desire to help affect change. The authors of this book are dedicated to contributing to that change with much-needed attention to the importance of the current moment and the language needed to solve these problems around IHS. Historians will mark 2020 as a turning point, and this book is the first to conceptualize humanity as the common denominator in IHS.

Respectfully,

**David P. Bahner MD** Ultrasound Division Chief, Professor, Department of Emergency Medicine, The Ohio State University, Columbus, Ohio, United States

Preface

International health security (IHS) is a broad and highly heterogeneous area. Within this general context, IHS encompasses subdomains that potentially

definition of health security stems from the realization that topics such as EID; food, water, and pharmaceutical supply chain safety; medical and health information cybersecurity; and bioterrorism, although important within the overall realm of health security, are not only able to actively modulate the wellness and health of human populations, but also are likely do so in a synergistic fashion.

influence (and more specifically endanger) the well-being and wellness of humans. The general umbrella of IHS includes, but is not limited to, natural disasters, emerging infectious diseases (EID) and pandemics, social determinants of health, systemic racism and discrimination, rapid urbanization, population growth, environmental matters, civilian violence, warfare and terrorism, inappropriate use of antibiotics, and the abuse of social media (SM). The need for this expanded

The editors of this book believe that the broadly defined IHS inherently encompasses the plurality of concepts that include "public health," "global health security," and "planetary health." At the same time, it is important to ensure that the overall context of IHS implementation maintains compatibility with the modern concept of the world constituting a collection of independent countries and states that operate within a well-defined set of international conventions, organizations, and frameworks. This is the foundation and the starting point of our approach, upon which we expand and build our multi-pronged argument for the more broadly defined and understood IHS.

This inaugural tome of our multi-volume collection, Contemporary Developments and Perspectives in International Health Security, introduces many of the topics directly relevant to modern IHS theory and practice. Starting with a summative assessment by the IHS Working Group of the American College of Academic

International Medicine, the book then moves on to discuss a variety of contemporary topics such as refugee crises, cybersecurity, SM, big data analytics, scientist training, and point-of-care diagnostics. Unique contributions to Volume 1 include a compendium by Reis and Cipolla on the impact of organized systems of care on IHS, focusing on the tremendous value of such systems to our overall healthcare security landscape.

Of importance, a new set of insidious threats to health security emerged with the widespread adoption of the Internet and various SM platforms. These important topics are covered in two excellent chapters by Miller, et al., and Conti, et al. The first of the two chapters discusses an all-too-common phenomenon of ransomware that increasingly plagues our healthcare systems and contributes to significant risk of critical data loss. The second chapter discusses both the benefits and the dangers of modern SM technology, including some of the proposed approaches to mitigate the negative aspects. Of special concern is the emerging evidence regarding the very design of SM platforms, with the key element of the business model being the

ability to fractionate people into self-reinforcing, opinion-based camps.

The book then shifts focus to very important and emerging topics of the refugee crisis and refugee healthcare. Attributable to a confluence of multiple factors,


**1. Introduction**

The phenomenon and ethics of "voting" will be explored in the context of "human enhancements", which, for purposes of this analysis, are broadly defined as intentional modifications of a person who is accepted prior to the enhancement as genetically human, of any possible type of modification or combination of types.1 Enhancements may be made with or without the consent of the enhanced human. For example, an enhancement could be made prior to birth (or prior to the age at which consent is recognized as valid) or could be forced on the human. Or an enhancement could be made with consent by, or at the request of, the enhanced human. In most cases, the enhancement is perceived as a way to "improve" the human, such as by improving their physical, mental or emotional abilities, but the analysis herein does not require that the enhancement actually be an improvement under any ranking theory or particular perspective. Enhancements can also be permanent or temporary.

In Section 2, "voting" will be examined for enhanced humans who fall into two broad categories—those with moderate enhancements, where the "humanity" of the enhanced

**Citation:** Blodgett-Ford, S.J. Human Enhancements and Voting: Towards a Declaration of Rights and Responsibilities of Beings. *Philosophies* **2021**, *6*, 5. https://doi.org/10.3390/ philosophies6010005

Received: 12 November 2020 Accepted: 23 December 2020 Published: 14 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

1 For purposes of this analysis, a descendant of a "human" (*Homo sapiens*) who was genetically or otherwise altered to such an extreme that they would no longer commonly be perceived to be "human" (or who no longer even had an organic embodiment) is still defined as an "enhanced human". However, in Section 3, we will propose to eliminate the requirement of "humanity" in voting rather than using such a "Grandfather Clause" approach and instead broadly extend voting rights to all living beings and all conscious beings.

person is not seriously in question, and those with extreme enhancements, where humans who lacked similar enhancements would likely question the "humanity" of the enhanced human. The question of who has the right to vote and how they can vote will be explored primarily in the context of voting in the United States at the federal level. Existing patterns of discrimination around the globe would likely continue substantially "as is" for humans with physical and mental enhancements who are viewed as "still human." For the "beyond human" category of enhancements, the established rules and practice of voting are likely to be directly challenged. For both moderate and extreme enhancements, humans who are not enhanced (or are less enhanced) may be disenfranchised if certain enhancements become prevalent among the voting population.

In Section 3, voting by enhanced and non-enhanced humans will be examined using an extension of a theory of engagement articulated by Professor Sophie Loidolt that emphasizes the importance of legitimization and justification and "facing the appeal of the other" to determine what is "right" "from a phenomenological first-person perspective [1]. Seeking inspiration from the Universal Declaration of Human Rights (UDHR) of 1948 [2], voting rights and responsibilities will be re-framed from a foundational working hypothesis that all conscious and all living "beings" (including enhanced and non-enhanced humans) should have a right to vote directly. Representative voting should be considered as an admittedly imperfect alternative where direct voting is not possible, such as due to communication limitations, or as an additional option to direct voting, in the case of a group that suffers from historic systematic discrimination. Finally, the framework in which voting occurs, as well as the processes, temporal cadence of voting, and role of voting in the overall architecture and functioning of government, should be seen as provisional pending a "to be determined" approach (or approaches) designed, modified, refined, abolished and rebuilt from scratch as needed, with the participation from as diverse a group of beings as possible. Voting in a particular structure of governance has not been legitimized if it is delivered by fiat "as is" to those beings who were excluded from participation in the design and ratification of such structure—whether because they were enhanced to an extreme level or because they were not enhanced/less enhanced. Applying an extension of Loidolt's framework, we must recognize the urgency that demands the impossible with openness to that universality in progress (or universality to come) that keeps being constituted from the outside.

### **2. Discussion—Human Enhancements and Voting—Moderate and Extreme**

Common assumptions about who has the right to vote and what "voting" involves warrant careful examination to see what they reveal, what they hide, and what they can tell us about biases that might exist against enhanced humans (or non-enhanced humans) who are perceived as "other" or "lesser" than those who hold political power. For purposes of this analysis, the meaning of "enhanced" shall be any intentional modification of a human being, whether done prior to birth (e.g., through genetic engineering of human embryos), or after birth, such as through implants, chemical enhancements, or other modifications. While such enhancements are often intended to be efforts to "improve" the human being who is enhanced, either with or without the consent of the enhanced person, for purposes of this analysis there will be no effort to assess whether such enhancements are actually an "improvement" or "benefit" to the enhanced human, to their family, to any broader group, or to society generally. One person might view an increase of intelligence as an "improvement" while another might view it as a negative change if the enhancement was only to computational abilities or analytical intelligence without any corresponding increase in capacity for empathy, compassion or "emotional intelligence." Similarly, a person who was born as a female biologically and then underwent surgery to become male might view it as an improvement for themselves as they felt their body reflected their true identity more accurately, but another person might view the loss of child-bearing capacity as a negative. As a final example, someone who values an idealized "normative" "able" human body might view an enhancement to a human body that brings that body closer

to their ideal norm as an enhancement, while a person who embraces diverse forms of embodiment and living might consider such a modification as a negative.2

The present analysis of voting and human enhancements is agnostic as to the benefits of enhancements. We assume that enhancements (for better or for worse) are already occurring and are likely to occur in the future, potentially with greater variations, increasing numbers and extremity, and may be permanent, semi-permanent or reversible at will. In this context, we explore the effects of biases in the history of voting in the United States, using the examples of ancestry and gender, and consider how they might continue for both moderate and extreme human enhancements.

Restrictions on voting in the United States have been used to systematically discriminate against humans viewed as "other" or "lesser", in large part to preserve the established distribution of wealth and power. Similar patterns of discrimination can be seen in many other countries—currently and historically, including, just as a few examples, systematic and intentional disenfranchisement of indigenous peoples in Australia, Canada and Japan [7–9]. There is a risk that such discrimination would continue substantially "as is" for humans with physical and mental enhancements who are viewed as "still human." In addition, humans who are not enhanced or who are less-enhanced may be disenfranchised if certain enhancements become so prevalent that they are the "new normal."

For "beyond human" or "no longer human" types of enhancements, the established phenomenon of voting is likely to be directly challenged by extreme physical and/or mental enhancements, including hybrid organic/inorganic humans and mental enhancements such as a "networked consciousness" or an "extended mind." For example, it has been hypothesized that "consciousness does not originate from a single brain section" and instead "originates globally" [10]. If so, it is possible that there could be an enhanced human in the future whose "consciousness" arose from a network of organic and inorganic elements that were distributed (physically) in various locations, potentially even among different human embodiments. Such enhancements would put serious pressure on the United States model that being human is a necessary condition for voting,3 both for elected human representatives as well as on votes for particular laws or amendments. Finally, in the case that either moderate or extreme enhancements, such as those contemplated in the DARPA (United States Defense Advanced Research Agency) program, became common among the voting population, non-enhanced or less-enhanced humans may be viewed as disabled or less-abled humans, and they may (legally and in practice) be denied the right to vote [12,13].

For purposes of this discussion, human enhancements may include any intentional physical and/or mental modifications of a human being, made either before birth, such as through gene editing or embryo selection, or after birth, whether by the human being or by another person, with or without the consent of the enhanced human. The term "cyborg" will also, at times, be used to refer to an enhanced human who has a physical or mental enhancement that includes an inorganic component, such as a prosthetic or

2 See [3] (quoting dancer, artist and poet Neil Marcus "Disability is not a 'brave struggle' or 'courage in the face of adversity', disability is an art. It's an ingenious way to live."). Consider also the esteemed composer Molly Joyce, who has to compose without using her left hand, and "has carved a unique sound as a composer by treating disability differently: not as an impediment but as a wellspring of creative potential [4]." An additional example of an "ideal" body relates to skin color. In many countries, due to a legacy of racism, a lighter skin color is viewed as an "improvement" and may objectively benefit the person having such skin color, including in employment opportunities and advancement. Consider the practice of skin bleaching in Jamaica. In his analysis of the practice, Professor Christopher Charles concluded that "self-hate" was not the primary driver for skin lightening in Jamaica and noted that reasons for skin lightening were more nuanced: "Some Black Jamaicans recognize the color and racial distinctions in society. This should not be viewed as self-contempt. It is borne out by their experience that the Blacker one is, the less status and privilege one has in the society. They recognize the reality of contemporary Jamaica. They do not necessarily accept it [5]." In the United States, caste-based discrimination allegedly is occurring in the technology industry [6] ("The lawsuit notes that the employee is Dalit Indian and that he has a darker complexion than non-Dalit Indians.").

3 Non-human corporations and other legal entities that are "persons" under the law can still have influence one election results even though they cannot vote. See the United States Supreme Court decision in the *Citizens United* case against the Federal Election Commission [11], in which the Court held that limitations on spending for political campaigns by groups, including corporations and labor unions, violate the Constitutional First Amendment right to free speech.

wearable enhancement or a neural implant. We will consider moderate enhancements first, then turn to extreme enhancements.

### *2.1. Moderate Human Enhancements—"Still Human"*

In this section, we will consider voting by people who have been physically or mentally enhanced through moderate enhancements and are still recognized as "human". Such enhanced humans could have a wide variety of physical and/or mental enhancements, or combinations thereof, which could also in theory be malleable throughout their lifetime. For example, physical enhancements could result in an enhanced human being, or appearing to be, of a different ethnicity or ancestry, gender (or genders) or age. Enhancements could also lead to heightened or modified sensory perceptions, such as being able to touch, taste, smell, see, or hear in a different manner than a non-enhanced human. Enhancements could also allow the human to communicate via wifi and or access the Internet directly, such as via neural implants.

In all such cases, in this category of moderate enhancements, the enhancements cannot be so extreme that the person with the enhancements is perceived in their society as being no longer human or inhuman. What would "voting" mean for such enhanced humans? The answer is not clear, and could depend on whether the enhancements were made prior to birth or after birth and whether they were such that the person was characterized as "lesser" or "other" than those humans who were entitled to vote—or who were more able to vote due to enhancements.

The right to representation in government (and the lack of such representation in the English Parliament) was one of the core reasons the American colonists revolted against England. Taxation without representation was viewed as tyranny.4 Based solely on this aspect of United States history, it would be easy to conclude that any person who was required to pay taxes to the United States federal government, enhanced or not, would be entitled to vote in United States elections. This simple rule could mean that a human who was physically enhanced and "still human" would have the right to vote if they paid taxes in the United States, regardless of whether they were citizens of the United States or even physically located in the United States.

However, the historical and current phenomenon of voting in the United States greatly deviates from such a simplistic model. Instead, it reflects systematic efforts over hundreds of years—and continuing to the present—to deny the right to vote to those viewed as "other" or "lesser" than the group(s) controlling the wealth and power of the United States—initially wealthy white men from England and later wealthy white women as well5 [15].


**Author details**

Murat Eyvaz\* and Ahmed Albahnasawi Department of Environmental Engineering, Gebze Technical University, Kocaeli, Turkey

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Introductory Chapter: Arid Environment DOI: http://dx.doi.org/10.5772/intechopen.108683*