Updates on Etiology

## **Chapter 2** Etiology of Dry Eye

*Pushpa D. Rao*

#### **Abstract**

The scope of this chapter is to provide insights into the classification based on the significant factors causing dry eye. The etiological causes of dry eye have been classified broadly into two primary arms. The first arm, aqueous deficient dry eye (ADDE), illustrates malfunction of normal lacrimal secretion causing tear hyposecretion. ADDE is subdivided into Sjogren's and the non-Sjogren's syndrome. The former exclusively includes systemic autoimmune characteristics, while the latter comprises age-related disorders, genetic disorders, denervation in the lacrimal gland, and obstruction in tear secretion. The second arm, evaporative dry eye (EDE), explains the excessive loss of aqueous from the tear film despite the normal lacrimal secretion. Extrinsic EDE is with ocular surface pathology caused by vitamin A deficiency, contact lens wear, use of topical drugs with preservatives, and ocular surface diseases (allergic eye disease). The intrinsic EDE encompasses abnormalities in the meibomian lipid deficiency, low blink rate, and poor lid congruity. In brief, clinical tests to investigate the corneal epithelium integrity and the tear film have been discussed. This chapter aims to highlight the main etiologies of dry eye disease (DED) and current updates on techniques involved in diagnosing DED to help clinical practice.

**Keywords:** dry eye, etiology, tear film, tear hyperosmolarity, ocular surface

#### **1. Introduction**

Dry eye disease (DED) is associated with a chronic inflammatory condition of the ocular surface comprising tear hyperosmolarity and disorder of the lacrimal functional unit (LFU) [1]. LFU contains the lacrimal glands, ocular surface (cornea, conjunctiva, and meibomian glands), and the sensory and motor nerves that connect them to form an integrated system known as a "Reflex arc" [2]. LFU plays a significant role in maintaining the tear film in a regulated manner. Environmental, endocrinological, and cortical influence the functionality of LFU. Its function is to preserve the integrity of the tear film and the corneal transparency [2, 3]. There are two compartments of tears at the surface of the open eye. The first lies in the fornices and the spaces behind the lids, and the second is called the pre-ocular tears that comprise the tear menisci and the tear film. The tear film is about 3 μm thick layer [4]. The lipid layer hinders the evaporation of tear film surfaced on the top of the tear film, derived from the meibomian glands. The lacrimal gland mainly contributes to the aqueous component of the tear film lying below the surface lipid layer. The conjunctival goblet cells contribute to the mucin layer that lies over the corneal surface [5]. The mucin forms like a gel layer over the corneal surface and protects to keep up the moisture of

the normal ocular surface. These three layers of the tear film help protect the exposed ocular surface from desiccation. Lacrimal secretion is at its minimum during sleep [6]. When the eyes are open in the waking state, the lacrimal secretion is determined by the sensory stimuli to increase the tear flow rate. A functional Reflex arc is the key to controlling the tear flow and maintaining the homeostasis of tear osmolarity. The Reflex arc comprises the afferent and the efferent limb, while the former is contributed from the trigeminal innervation of the ocular surface (cornea) [7]. The trigeminal neurons synapse in the superior salivatory nucleus in the brainstem. This is the nervus intermedius of the VIIth cranial nerve, carrying the region where the efferent limb of the reflex arc arises. These parasympathetic nerve fibers synapses with the other neuronal connections, help supply to the glandular tissues, and aid in their secretion function. The reflex arc functions as a "feedback loop" [2, 3] and can be influenced by humidity, airflow, temperature, and blink rate. Damage to the afferent sensory nerves or the efferent autonomic and motor nerves will lead to dysfunction in the tear-secreting glands. This causes an alteration in the function of LFU, leading to tear film instability and ocular surface disease, mainly dry eye. Inflammation in the ocular surface accompanying chronic alteration in tear secretion due to reduced corneal sensation results in tear film instability [8]. Therefore, dysfunction of LFU has been identified to be prominent in the development of various forms of dry eye. There are two major divisions of dry eye (discussed later in this chapter): 1. Aqueousdeficient dry eye and 2. Evaporative dry eye. Both lead to tear hyperosmolarity.

#### **1.1 Ocular surface homeostasis and hyperosmolarity**

Homeostasis in the ocular surface is correlated with the tear hyperosmolarity influenced by the sensory stimulation to the lacrimal gland via the LFU. In evaporative dry eye, the lacrimal gland is healthy to stimulate secretory response and compensate for the tear volume with a rise in tear osmolarity. However, this is accountable for a high-volume dry eye with increased tear secretion in patients suffering from meibomian gland dysfunction, which causes a deficiency of the tear film lipid layer [9]. On the contrary, the aqueous-deficient dry eye with dysfunction in the lacrimal gland is characterized by tear hyperosmolarity associated with low tear volume [10]. Of note, excessive reflex stimulation of the lacrimal gland may induce cytokine responses in the gland, initiating a cascade of autoantigen expression and T-cell activation with the release of inflammatory mediators into the tears [3]. "Lacrimal exhaustion" may also be induced due to intense reflex stimulation of the lacrimal gland [11].

Hyperosmolarity is regarded as the central mechanism for various forms of dry eye as a response to reduced tear flow or increased tear evaporation. Tear film instability and thinning of the tear film with excessive aqueous evaporation are the events that influence tear hyperosmolarity. Tear hyperosmolarity stimulates a sequence of inflammatory events in the ocular surface epithelium, involving NF-kB signaling and MAP kinases pathways [12] with the secretion of inflammatory cytokines (IL-1α, IL-1β, and TNF-α) and matrix metalloproteinases (e.g., MMP9) [13]. The cytokines activate inflammatory cells at the ocular surface [14], cause apoptosis of the surface epithelium, and reduced expression of glycocalyx mucins, eventually leading to the loss of goblet cells [15]. Damage to the epithelium or apoptosis is fundamental for ocular surface staining in a dry eye. Additionally, a loss of protective barrier (glycocalyx mucins) will aid in the dye (fluorescein) entry in comparison to the normal lubricated ocular surface with an intact ocular surface barrier [10]. Goblet cell loss is a phenomenon investigated in dry eye [16, 17], demonstrated by conjunctival

#### *Etiology of Dry Eye DOI: http://dx.doi.org/10.5772/intechopen.110142*

biopsy and impression cytology that show reduced levels of the gel mucin MUC5AC [18]. Tear hyperosmolarity and inflammatory mediators in tear causes discomfort, especially during blinking, due to the loss of goblet cell mucin that helps maintain the ocular surface's lubrication. Ocular surface damage, mainly with the loss or damage to the epithelial glycocalyx, leads to insufficient lubrication, tear film instability, and progressive shortening of the tear film break-up time [19]. In the presence of a shorter break-up time, an increase in the level of hyperosmolarity is expected. Ocular surface damage, caused by osmotic stress and inflammatory events, will result in the reflex stimulation of the lacrimal gland. This is responsible for increasing the blink rate and increasing lacrimal tear secretion. Patients with meibomian gland dysfunction were diagnosed with the high-volume dry eye with increased tear secretion [9]. Experimental models suggest that intense reflex stimulation of the lacrimal gland may induce an inflammatory response in the gland. This will lead to a cascade of events, such as autoantigen expression in the gland, T-cell activation, and the release of inflammatory mediators into the tears [3, 20]. Reports have indicated to induce a state of "lacrimal exhaustion," which may need further evidence to test this hypothesis [21]. Tear Hyperosmolarity attained at the eye surface gives rise to a vicious cycle of events that results not only in symptoms and compensatory responses but also in ocular surface damage and mediating inflammatory responses. Eventually, it drives into a self-perpetuated disease.

#### **1.2 The role of the environment in dry eye**

Dry eye is susceptible to environmental conditions that can increase tear evaporation and osmolarity. These conditions may aggravate various forms of dry eye or trigger its onset in predisposed patients. The term environment can be broadly divided into (a) physiological variation between the individuals that include low natural blink rate [22], variations in the palpebral aperture [23], and sex hormones [24, 25]. (b) ambient conditions an individual encounters include environmental factors that increase tear evaporation, such as lower relative humidity, high wind velocity, air conditioning, air travel, or exposure to another artificial environment [26]. This influences tear hyperosmolarity induced by prolonged blink interval or with widened palpebral aperture, which is common during extended usage of a video display terminal, microscopy, reading, and the performance of challenging visual tasks, which reduce the blink rate or more extended periods with the eyes held up in gaze [27]. The other factors include the use of systemic drugs, which reduce lacrimal secretion, causing tear hyperosmolarity and may be listed as a risk factor for dry eye [28]. A correlation between activities of daily living the dry eye disease symptoms has been explored [29]. Awareness of such influences may allow preventative measures to be implemented.

#### **1.3 The role of corneal sensitivity**

A phenomenon of increased corneal sensory excitability was reported in dry patients [30]. This is expected to increase pain and compensatory lacrimal response in dry eye patients. Interestingly, in dry eye, morphological changes have been recorded via confocal microscopy that showed a reduction in the subbasal nerve plexus bundles in the cornea [31]. These results relate to observations made in several reports suggesting impaired corneal sensitivity in chronic dry eye disease [32]. With advancing dry eye disease, sensory loss at the ocular surface is evident, which reduces the sensory drive and stimulation to the lacrimal gland. Therefore, tear hyperosmolarity would increase

with reduced lacrimal secretion, eventually leading to a fall in tear volume and tear film thickness. Furthermore, a slowing of tear film lipid layer spreading [33], with an increase in tear evaporation, is observed. Overall, ocular surface changes during dry eye are negatively affected by a reduction in corneal sensitivity and a loss of sensory drive.

#### **2. Major etiological causes of dry eye**

The leading etiological causes of dry eye have been portrayed as etiopathogenic classification developed by the subcommittee presented in the National Eye Institute (NEI) industry workshop report with a current understanding of DED (**Figure 1**).

As stated earlier in the 1995 report, the term keratoconjunctivitis sicca (KCS) is regarded as synonymous with the term dry eye. As illustrated in **Figure 1**, there are two major classes of dry eye: (1) aqueous tear-deficient dry eye (ADDE) and (2) evaporative dry eye (EDE). ADDE refers to mainly the failure of lacrimal secretion, while EDE has been subdivided to differentiate the causes that are dependent on intrinsic conditions of the eyelids and ocular surface and those that arise from extrinsic influences. It is recognized that disease initiated in one significant division may coexist with or even progress to dry eye by another considerable mechanism. This is part of a vicious cycle of interactions that can enhance the severity of dry eye. Overall, consequences of dry eye include goblet cell loss, which will contribute to loss of tear film stability, ocular surface damage and evaporative water loss, and symptoms resulting from a failure of ocular surface lubrication and inflammation.

The major groups and subgroups of dry eye are described below.

#### **2.1 Aqueous tear-deficient dry eye (tear deficient dry eye)**

Dysfunction in the lacrimal gland leads to the aqueous-deficient dry eye that reduces lacrimal tear secretion and volume [34]. Tear-deficient dry eye causes tear hyperosmolarity. Reduced lacrimal secretion may be due to 1 Sjogren syndrome, 2

**Figure 1.** *Etiological classification of dry eye.*

#### *Etiology of Dry Eye DOI: http://dx.doi.org/10.5772/intechopen.110142*

obstruction to its outflow, and 3 an intervention with the homeostatic mechanism. A reflex sensory blockade may be caused due to topical anesthesia, and efferent blockade may be due to damage in the pterygopalatine ganglion and third-order neurons [35]. Additionally, lacrimal secretion may be pharmacologically inhibited by certain systemic drugs [36]. Tear film hyperosmolarity causes an increase in osmolarity of the ocular surface epithelium and stimulates a cascade of inflammatory events involving MAP kinases and NFkB signaling pathways [12, 37] and the secretion of inflammatory cytokines (interleukin (IL)-1A; -1B; tumor necrosis factor (TNF)-A); and matrix metalloproteinases (MMP-9) [13]. During lacrimal dysfunction due to lacrimal gland infiltration and inflammation, inflammatory mediators generated in the gland may find their way into the tears and be delivered to the ocular surface. The inflammatory mediators are detected in tears and can be derived from the lacrimal gland or the ocular surface (conjunctiva and cornea). Studies have reported that the tear film lipid layer in ADDE has a delayed spreading of the lipid layer in the interblink [38, 39]. In severe ADDE, spreading may be undetectable by interferometry, suggesting significant damage to the tear film lipid layer. Delayed improper spreading of the tear film may increase an aqueous loss from the tear film. ADDE can be divided into two major subgroups, Sjogren syndrome dry eye (SSDE) and non-Sjorgen syndrome dry eye.

#### *2.1.1 Sjogren syndrome dry eye (SSDE)*

Sjogren syndrome is an exocrinopathy that involves the lacrimal and salivary glands targeted by an autoimmune process. Immune cell infiltration, mainly the activated T cells, occurs in the lacrimal and salivary glands, which causes acinar and ductular cell death. This leads to the hyposecretion of tears or saliva. The inflammatory process in the glands leads to the expression of autoantigens in the epithelium of the ocular surface [40] with the homing of tissue-specific CD4 and CD8 T-cells [41]. Th1 cells and cytokines as INF-ϒ were considered to be the main components of tissue damage, with new evidence of the major role played by Th-17 cells (T follicular (Tf), Th22, and Treg cells—the IL-17 axis) and the cytokines, especially IL-17, in the salivary and lacrimal glands [42, 43]. A neurosecretory block influences the hyposecretion of the tears due to the effects of immune cell influx and secretion of inflammatory cytokines or the presence of circulating antibodies (e.g., anti-M3 antibody) directed against muscarinic receptors within the glands [44, 45].

There are two forms of SSDE:


It is essential to note the risk factors of SSDE, which include genetic profile [48], androgen status [49], and exposure to environmental agents. For instance, a study investigated from a mouse model of ocular HSV-1 infection showed that the lacrimal gland was affected by the immune cell influx (CD4 and CD8 T cells), causing reduced tear volume [50]. Additionally, nutritional deficiency in omega-3, Vit C, and other unsaturated fatty acids has also been reported in patients with SSDE [51]. Environmental factors causing increased evaporative water loss from the eye may trigger inflammatory events at the ocular surface via a hyperosmolar mechanism. A defective tear film lipid layer is identified to contribute to dry eye leading to evaporation [52]. This can be correlated to high rates of meibomian gland dysfunction in SSDE patients when compared to the average population [52]. Overall, the ocular dryness in SSDE is due to hyposecretion in the lacrimal glands associated with the characteristic inflammatory changes within the gland in the presence of inflammatory mediators in tears [53].

#### *2.1.2 Non-Sjogren syndrome dry eye*

Non-Sjogren syndrome dry eye is a type of ADDE caused due to lacrimal dysfunction but not with the characteristics of systemic autoimmunity; age-related dry eye is the most common. The different types of NSSDE are briefly discussed below.

#### *2.1.2.1 Primary lacrimal gland deficiencies*


#### *2.1.2.2 Secondary lacrimal gland deficiencies*

Inflammatory infiltration of the lacrimal gland is known to cause dysfunction in tear secretion.


#### *2.1.2.3 Obstruction of the lacrimal gland ducts*

Obstructing the principal, palpebral, and accessory lacrimal gland ducts lead to aqueous-deficient dry eye. Additionally, deformity in the eyelid influences uneven tear film spreading. Specific conditions are discussed below.


#### *2.1.2.4 Reflex hyposecretion*

#### *2.1.2.4.1 Reflex sensory block*

Tear secretion in the waking state is induced by trigeminal sensory input arising from the nasolacrimal passages and the eye. When the eyes are open, an increased reflex sensory drive is stimulated from the exposed ocular surface. A depletion in the sensory movement from the ocular surface may play a role in the cause of dry eye in two routes, first, by reducing reflex-induced lacrimal tear secretion and, second, by lowering the blink rate and, thereby, increasing evaporative loss [47]. It is evident from the reports that experiment conducted on the rabbit models has shown that trigeminal denervation alters the regulation of lacrimal protein secretion [77].


#### *2.1.2.4.2 Reflex motor block*

The VII cranial nerve nervus intermedius carries postganglionic, parasympathetic nerve fibers (of pterygopalatine ganglion origin) to the lacrimal gland. Significant damage to the VII cranial nerve leads to dry eye due to loss of lacrimal secretomotor function and lacrimal hyposecretion. Additionally, incomplete lid closure with multiple neuromatosis has also been reported as a characteristic of dry eye [93]. Several studies have reported a correlation between dry eye and reduced lacrimal tear secretion with systemic drug agents such as beta-blockers, antispasmodics, diuretics, and antihistamines [84]. On the contrary, no relationship was found with calcium channel blockers or cholesterol-lowering drugs [84].

#### **2.2 Evaporative dry eye**

Evaporative dry eye is caused due to increased water loss (evaporation) from the tear film in the presence of normal lacrimal secretory function. The tear film lipid layer is the main barrier to evaporation from the ocular surface. The loss of the tear film lipid layer due to meibomian gland dysfunction (MGD) is the leading cause of evaporative dry eye. Nevertheless, evaporation may also be increased by a prolonged blink interval or a widened palpebral aperture [9]. Of note, tear hyperosmolarity is also observed as an elevated characteristic feature due to evaporative water loss from the tear film. Evaporative dry eye can be distinguished further concerning the intrinsic disease affecting lid structures or dynamics or extrinsic, where the ocular surface disease occurs due to various irrelevant exposure such as topical drugs, contact lenses, and others (discussed in Section 2.2.2).

#### *2.2.1 Intrinsic causes*

#### *2.2.1.1 Meibomian gland dysfunction (MGD)*

MGD is a condition with meibomian gland dysfunction and posterior blepharitis, the leading and common cause of evaporative dry eye [94]. MGD is associated with the obstruction in the gland hindering lipid secretion. Other observations are noted in experimental models, including glandular cyst formation and meibomian duct keratinization [95, 96]. MGD can be distinguished as simple or cicatricial, primary or secondary. In simple MGD, the orifices of the gland remain located within the eyelid skin (anterior to the mucocutaneous junction). In cicatricial MGD, the orifices of the duct are drawn posteriorly onto the tarsal mucosa and the lid. This makes it incapable of delivering lipids to the tear film. Criteria for diagnosis are based on morphologic features of the gland acini and duct orifices. Methods are developed to grade the degree of MGD [97], measure the degree of gland dropout (meibography) [98, 99], and measure the levels of lipid in the lid margin reservoir (meibometry) [100]. MGD is correlated with the deficiency in the tear film lipid layer leading to an increase in tear evaporation with a higher risk of the occurrence of evaporative dry eye. An exciting finding showed the importance of meibomian lipid composition and its effect on tear film lipid layer stability. Variations in meibomian lipid composition were investigated in different individuals; for instance, one group of subjects had low levels of cholesterol esters and esters of unsaturated fatty acids, while the other group had high levels of these fractions [101]. Intriguingly, it was studied that the eyelid commensals (coagulase-negative staphylococci [CoNS], Propionibacterium acnes, and S aureus) play a role in releasing

esterases, lipases fatty acids, mono- and diglycerides into the tear film [102]. The study also showed that the subjects who had a high commensal load on the eyelid margin had meibomian lipid composition rich in cholesterol when compared to the issues with low levels of cholesterol in the meibomian lipid [103]. Therefore, microbial load on the lid margin may influence the development of blepharitis.

#### *2.2.1.2 Disorders of lid aperture and lid/globe congruity or dynamics*

An increase in palpebral fissure width exposes the tear film to greater evaporation with a risk of desiccation in the ocular surface and tear hyperosmolarity [19, 104]. Desiccation of the ocular surface occurs due to poor lid apposition or lid deformity, leading to improper tear film resurfacing [19]. In Graves' disease, the effect of proptosis on exposure is compounded by lid retraction, incomplete blinking, or lid closure, by restriction of eye movements, which plays a part in tear spreading [105]. Increased ocular surface exposure and evaporation also occur in up gaze [106]. Desiccating stress in the ocular surface may also occur in the workplace through activities such as snooker, where, while aiming, the head is inclined downward, and the eyes are in the extreme up gaze [107].

#### *2.2.1.3 Low blink rate*

A complete blinking is essential to replenish the tear film by evenly distributing the aqueous tears (lacrimal glands) and lipids (from meibomian glands) over the ocular surface. Aqueous tears evaporate from the tear film during the interval between each blink. Hence, reduced or low blinking will result in dryness of the ocular surface, leading to increased evaporative loss and dry eye.

Ocular surface desiccation may be due to a reduced blink rate, which increases the blink interval time and extends the period for tear evaporation before the next blink [108, 109]. Reduced blink rate may occur during tasks involving increased concentration, especially while working at video terminals [27], with video games, at microscopes, and when the eyes are in a downgaze, as in reading. This phenomenon may also occur in the extrapyramidal disorder Parkinson's disease (PD) due to a reduction in the dopaminergic neurons of the substantia nigra [110]. Additionally, reduced reflex tearing in PD has been associated with autonomic dysfunction, considering the presence of sympathetic and peripheral parasympathetic ganglia and Lewy bodies in the substantia nigra [111]. Other contributing factors in PD include impaired meibomian oil delivery, decreased reflex tearing due to autonomic dysfunction, and the effects of androgen deficiency on the lacrimal and meibomian glands [112]. Overall, it can be summarized from these studies that there are multiple causes of dry eye in PD.

Of note, a common extrinsic risk factor for dry eye in today's world is increased digital screen time, for example, smartphone, tablet, laptop, and computer use. Studies have reported a relationship between digital screen use and dry eye, affecting the blinking dynamics and leading to ocular dryness [113]. Furthermore, a relationship between increased digital screen use and ocular surface metrics involving tear volume and tear-break-up time status has been studied, affecting the aqueous component of the tear film [114]. Blink rates during reading tasks on digital screens have been found to reduce compared to rest conditions [27, 115]. Intriguingly, reading hard-copy material also decreases the blink rate like reading on a digital screen [116, 117]. A resurgence in digital screen use during the COVID-19 pandemic led to an increased risk factor for DED in the individuals staying home with an incentive to learn, work, and socialize remotely [118].

#### *Etiology of Dry Eye DOI: http://dx.doi.org/10.5772/intechopen.110142*

Digital screen use is part of everyday life and is a risk factor for DED. A valid explanation to relate digital screen use and DED is the reduced blink rate and increased percentage of incomplete blinks during the digital screen. This may lead to ocular surface dryness, eventually leading to the development of DED with chronic use of the digital screen for extended periods. Hence, the prevention of DED may involve the following:


#### *2.2.2 Extrinsic causes*

A disease of the ocular surface disorder may lead to poor surface wetting, early tear film break-up, tear hyperosmolarity, and eventually dry eye conditions. Extrinsic causes include mainly vitamin A deficiency and the effects of extensively applied topical anesthetics and preservatives. Additionally, contact lenses may be responsible for an increased risk of dry eye.

#### *2.2.2.1 Vitamin A deficiency*

Deficiency in vitamin A may cause dry eye (xerophthalmia) through a decrease in several functional conjunctival goblet cells with reduced expression of glycocalyx mucins [119]. Vitamin A is reported to be essential for both the development of goblet cells in mucous membranes and the presentation of glycocalyx mucins [119, 120]. In patients with xerophthalmia, lacrimal acinar damage is diagnosed that may have a lacrimal, aqueous tear-deficient dry eye featured with unstable tear film [121]. Vitamin A is found to be crucial for inducing mucin gene expression, mucin production, and the maintenance of mucin [122, 123]. Retinoids have been shown to play a role in regulating mucin gene expression *In-vivo*. The reports have indicated the importance of vitamin A via studies conducted in vitamin A-deficient humans and rat models. The study reported reduced conjunctival goblet cells with keratinization in the conjunctival epithelium [124]. Therefore, vitamin A deficiency is known to cause alteration in mucin production by the ocular epithelium leading to dry eye conditions.

#### *2.2.2.2 Topical drugs and preservatives*

Topical drug components can induce a toxic and inflammatory response from the ocular surface. Topical drug (eye drop) formulations with preservatives are the most common offenders, such as benzalkonium chloride (BAC). Preservative components in the eye drop cause ocular surface epithelial cell damage leading to punctate epithelial keratitis, which interferes with the tear film stability and ocular surface lubrication (surface wettability). The effects of preservative, especially BAC, in the eye drops is a significant cause of dry eye symptoms in glaucoma patients [125]. This condition was rescued by using preservative-free eye drops [125]. Using eye drops with preservatives on a long-term basis must be avoided. The use of topical anesthesia causes ocular surface drying. It reduces lacrimal secretion by lowering the sensory

drive to the lacrimal gland [126] and also reduces the blink rate. Chronic use of topical anesthetics may cause neurotrophic keratitis-inducing corneal perforation [127, 128].

#### *2.2.2.3 Contact lens wear*

Contact lens wear is prominent in the developed world. There were 35 million wearers cited in the USA in the year 2000 [129]. Therefore, it is essential to study the causes of contact lens-related symptoms and intolerance experienced in the wearers. The main reason for contact lens intolerance is dryness and discomfort in the eye [130, 131]. Long-term use of contact lens wear may induce corneal epithelial changes [132] and the expression of inflammatory surface markers (HLA-DR and ICAM-1) [133]. Several studies have indicated its effect on conjunctival goblet cell density [134] and mucin expression [133, 135]. Women report dry eye symptoms more frequently than men [80]. Dry eye symptoms in contact lens wearers are associated with a higher tear osmolarity [80]. Poor lens wettability may also play a role in the increased evaporation rate.

#### *2.2.2.4 Ocular surface disease*

Reports have indicated that chronic ocular surface disease causes tear film instability with dry eye symptoms. Allergic eye disease will provide an excellent example to discuss the phenomenon of dry eye [136].

Several forms of allergic conjunctivitis can be listed as follows: (a) seasonal allergic conjunctivitis, (b) vernal keratoconjunctivitis, and (c) atopic keratoconjunctivitis. A common mechanism that occurs during allergic conjunctivitis is the exposure to antigens inducing the release of inflammatory cytokines via degranulation of IgE-primed mast cells. A Th2 response is activated first in the conjunctiva and later in the corneal epithelium. During this process, a loss of surface membrane mucins is observed with damage to the conjunctival and corneal epithelium [137]. Damage to the ocular surface with the release of inflammatory mediators will lead to allergic symptoms and reflex stimulation of the lacrimal gland. Inflammatory changes are observed in the case of vernal keratoconjunctivitis and atopic keratoconjunctivitis. Corneal surface irregularities (punctate epithelial keratitis) and conjunctival goblet cell defects can lead to tear film instability and, eventually, to dry eye symptoms in allergic eye disease. This condition may be augmented during meibomian gland dysfunction, intensifying the ocular surface drying [138]. In atopic keratoconjunctivitis, lid apposition and tear film spreading are interfered with, thus, exacerbating the dry eye.

#### **3. Brief overview of novel diagnostic technologies for dry eye**

There are several newer diagnostic techniques for dry eye. There will be a few commonly used techniques that will be highlighted in this chapter.

i.Tear osmolarity: tear hyperosmolarity is one of the major hallmarks of dry eye. A device named "Tearlab" is commercially available to measure the osmolarity of tears. A tear collection strip is designed by the Tearlab so that the capillary action can collect along the Tearlab strip. The Tearlab strip can then be inserted into the instrument to measure tear osmolarity. This test's sensitivity was better compared to traditional techniques to test dry eye, especially in mild to moderate cases. Nevertheless, it is recommended to test the tear film break-up time in severe dry eye cases.


### **4. Conclusion**

This chapter has provided insights into factors associated with dry eye disease. They have been distinguished into their primary forms, aqueous deficient and evaporative dry eye. Ocular surface abnormalities and tear hyperosmolarity are both equally essential in the mechanism of dry eye. However, water loss is the common etiological factor in both forms of dry eye disease. Etiological triggers and causes outlined in this chapter form the basis for framing diagnostic and therapeutic approaches. It is essential to consider a standardized approach for diagnosing dry eye. A standard testing regimen will be good to practice that includes tests for tear film break-up time (TBUT), Schirmer test, and corneal staining status with fluorescein. More advanced testing can lead to successful treatment strategies.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

Pushpa D. Rao1,2

1 Department of Pharmacology and Biomarkers, PTC Therapeutics, New Jersey, USA

2 Department of Ophthalmology, Wayne State University School of Medicine, Michigan, USA

\*Address all correspondence to: pdrao@med.wayne.edu; rao.pushpa@gmail.com

© 2023 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.

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#### **Chapter 3**

## Computer Vision Syndrome

*Hossein Aghaei and Parya Abdolalizadeh*

#### **Abstract**

Using of computers and other video display terminals (VDTs), such as laptops, smart phones, tablets, e-readers, and even watches, are part of our everyday life and more and more users are experiencing a variety of ocular and non-ocular symptoms related to computer use. These complaints include eyestrain, tired eyes, headaches, eye irritation, eye redness, itching, blurred vision, double vision, dry eye, and neck, back, and shoulder pain as extra-ocular issues, which have been termed computer vision syndrome (CVS). Based on pieces of evidence, between 64% and 90% of computer users experience visual symptoms. Children are also affected as they spend many hours each day using digital devices with visual displays for doing schoolwork, especially after starting the COVID-19 era, playing video games, and sending and receiving text messages on cell phones. With the increased use of these electronic devices, CVS is becoming a major public health issue. Proper identification of symptoms and causative factors is necessary for the accurate diagnosis and management. There are some strategies for reducing the complaints related to prolonged use of digital screen devices.

**Keywords:** computer vision syndrome, video display terminal, digital eye strain, digital device, electronic device, accommodation, vergence, asthenopia, ocular surface, dry eye

#### **1. Introduction**

The use of computers and other digital electronic devices such as tablets and smartphones for both vocational and nonvocational activities including e-mail, internet search, and entertainment such as playing games is almost universal in either developed or developing societies. Computers have made life easier in terms of unlimited access to information, improved work efficiency, and ease of communication that could not have been imagined about a few decades ago.

Despite the improvement in the quality of life, more and more people have become susceptible to the worse effects of working at a computer terminal for long time.

At first, using of computer was restricted to desktop computers located in the workplace (personal computer, PC). Today's visual requirements may include viewing laptop and tablet computers, electronic book readers, smartphones, and other digital devices either in the workplace, at home, or also as a leisure activity in any location at any time. Moreover, using of digital devices is not restricted to adults. A study of over 2000 American children between 8 and 18 years of age showed that in an average

day, they spend approximately 7.5 h using entertainment media, 4.5 h watching TV, 1.5 h on a computer, and over an hour playing video games [1]. Furthermore, these digital devices have now shifted into the pockets of millions of smartphone users [2]. Most smartphone owners have been reported to be adults aged from 18 to 34 years. However, next studies reported that the majority of teenagers between 14 to 18 years in the USA (87%) own smartphones [3].

The American Optometric Association defines CVS as the combination of eye and vision problems associated with the use of computers [4]. With apparently increased use of computers and its related input devices, this well-known clinical object gains significant importance. Asthenopia and symptoms related to dry eye disease are the ocular part of the syndrome. There are also musculoskeletal, dermatological, neurological, and psychological detrimental effects that are experienced in relation to the use of different types of digital devices [5].

The complaints associated with the use of computers and other electronic devices have not yet been known to cause permanent damage. However, it may result in a reduction of work accuracy and quality, which can reduce productivity. The extensive use of different types of electronic devices for various reasons desires consideration into the extent of the detrimental effect on the population.

#### **2. Definition**

The advent of computers changed human life. Today, digital display devices are required in houses, offices, and even pockets as smartphones. In 2017, about 95% of individuals aged 18–34 used handheld electronic devices such as smartphones and tablets [6]. Most of the business-related activities are also computer-based. According to the 6th European Working Conditions Survey, more than half of European workers utilize digital devices in their working [7]. The exposure to digital screen devices is not restricted to young adults, especially, after COVID-19 pandemic due to the implementation of the new public health measures such as social distancing. As the elderly people live alone in isolated circumstances during COVID-19 outbreak, these devices help them to communicate with others and stay active socially. Similarly, the children and students have used distance education or virtual leisure after COVID-19 pandemic, which led to an increase in all symptoms associated with the abuse of these devices [8].

The term computer vision syndrome (CVS), or digital eye strain, is applied collectively to a complex of visual and ocular symptoms in users of digital display devices such as computers, tablets, and smartphones. These devices have additive effects in the long term. Moreover, any activities that require extra effort for near vision in users of digital devices can enhance CVS symptoms [9]. CVS has been recognized for more than 20 years [10]. The American Optometric Association states CVS as a collection of eye and vision disorders caused by activities that strain near vision and that occur in conjunction with or during the use of computers for long hours [4]. The symptoms of CVS are classified into internal and external categories: [4, 11] Blurred vision, eye strain/fatigue, light/glare sensitivity, delay to change focal point, diplopia, and headache are internal symptoms caused by refractive, accommodative, or vergence anomalies. External symptoms include burning, itching, and tearing, which are rooted from dry eye disease. Some musculoskeletal symptoms, such as pain in the shoulders or neck, are also considered as CVS complexes [4, 12].

The CVS is usually diagnosed subjectively using self-reported questionnaires. However, subjective complaints may not be parallel with objective clinical findings, which cause over- or under-estimation of this condition [13]. Additionally, imprecise definition of CVS and considering various symptoms have led to heterogeneous results that have made it difficult to compare this health problem between populations with different characteristics. There are some validated questionnaires being developed to diagnose this syndrome, including the 17-item computer-vision symptom scale questionnaire, a six-item visual fatigue scale*,* and the computer vision syndrome questionnaire (CVS-Q ) [14, 15].

#### **3. Epidemiology**

The CVS is the most common occupational hazard of the twenty-first century with an increasing trend [16]. It is considered a public health crisis that reduces physical and physiological well-being, employees' quality of life, occupational efficiencies, workplace productivity, and job satisfaction [4, 17, 18]. As little as 2 hours of sustained digital device usage a day is likely to develop a range of vision-related problems [9, 13, 18]. Universally, approximately 60 to 70 million individuals suffer from CVS, with 1 million new cases annually [19]. Its prevalence varies from 50% to 90% in different populations, professionals and age groups depending on demographic, environmental, and contextual factors [19–22]. The problem of CVS is extremely high in underdeveloped nations because of the inadequate accessibility and utilization of personal protective equipment, the high workload, and the restricted break time when using a computer [5, 23].

Since 2020, the COVID-19 pandemic has changed the lifestyle of the population by forcing them to follow social distancing protocols, which makes individuals more dependent on digital devices for their communication, education, daily activities, and even entertainment. Based on the strong correlation of overuse of digital devices with the prevalence and severity of CVS, it is expected that COVID-19 pandemic plays a devastative factor for this public health problem. All age groups are affected including children [21, 24], preadolescents [8], adults [25], and elderly [26]. The prevalence of CVS even rose to 80% among students due to virtual education during the lockdown period [8, 27]. Beside students, women were at higher risk for CVS during pandemic because they helped their children in virtual learning platforms [26]. Although the prevalence of CVS has shown an increasing pattern during COVID-19 pandemic, general population suffers from lack of knowledge about CVS, as well as its protective measures [28]. During pandemic, less than 10% of people are familiar with protective devices, protective guidelines for digital device use such as 20-20-20 rule, and even regular ophthalmological visits for optical correction [28]. Meanwhile, COVID-19 infection has ocular manifestations such as conjunctivitis whose additive impact on CVS remains unknown.

#### **4. Causes and pathophysiology**

Different variables have contributed to CVS. Generally, three distinct mechanisms have been identified including (1) inappropriate oculomotor responses, (2) ocular surface disease, and, (3) poor environmental conditions [29, 30]. These mechanisms

can interact with each other. Moreover, there are personal factors such as age, which affect CVS through two or three mechanisms.

#### **4.1 Inappropriate oculomotor responses**

Two eyes should have efficient vergence and accommodative responses to focus on a target. If the brightness of the target is nonuniform, sustained focus needs more ocular effort. As the components of digital targets (pixels) are brighter at the center, eyes will have repeated struggles to maintain a focus on the digital screens. It makes ciliary body fatigue and the accommodative problems associated with CVS [31].

#### *4.1.1 Vergence*

*Vergence* is a binocular coordination to provide a single image of a visual target by merging the retinal images of two eyes. Prolonged use of digital screen devices and overexertion of the extraocular muscles can alter the ranges of vergence amplitude, horizontally, for both convergence and divergence movements [8, 32]. Therefore, the prevalence of vergence abnormalities such as convergence insufficiency increases among computer users [33]. This non-strabismic binocular dysfunction presents as an exodeviation, which causes the CVS symptoms such as asthenopia, inefficient performance of near activities, and musculoskeletal discomfort due to abnormal head posture [8, 34, 35]. On the other hand, some have proposed that exophoria at neardistance is a compensatory action for over-convergence during long-term computer use [36]. Therefore, the subjects with small amounts of exophoria may have less CVS symptoms compared to those subjects who converged accurately on the monitor for a long time.

#### *4.1.2 Accommodation*

Inappropriate accommodative responses, whether under or over-accommodation, result in eyestrain during computer using [37]. More accommodative demand leads to more accommodative fatigue. Therefore, the closer eye-screen distance in devices such as smartphones induces more accommodative fatigue and eye strain. Some subjects with symptomatic CVS also have an increased lag of accommodative response. The delay becomes more after extended viewing due to accommodative fatigue [29]. On the other hand, transient decrease in accommodative function can occur after using digital screen devices, which returns to baseline values by the end of the workday or week [33]. In other words, computer use may produce a decline in the ability to make dynamic oculomotor changes, possibly due to fatigue. Especially, patients with CVS have poor accommodative response that produces blurred vision, diplopia, myopia, and delay in the change of focus.

#### *4.1.3 Uncorrected refractive errors*

From the perspective of refractive errors, close work can induce transient myopic shifts due to accommodative effort [30, 38, 39]. This transient refractive error remains uncorrected during near-working with computer. Therefore, computer users with myopic change can complain of asthenopia [39]. Luberto et al. [39] have suggested that the temporary myopic shift can be an objective assessment parameter for evaluation of CVS fatigue. Beside transient refractive change, having baseline

#### *Computer Vision Syndrome DOI: http://dx.doi.org/10.5772/intechopen.111740*

refractive error, particularly myopia, adds to the risk of developing CVS [24, 38, 40]. To achieve and maintain clear and single vision of targets on digital screens, the retinal image should be focused appropriately. Thus, spherical hyperopia and high myopia should be corrected [24, 29, 30]. Astigmatic errors, as low as 0.5 to 1 diopter, are also important to increase symptoms of CVS [29]. In presbyopia, an insufficient addition in near correction makes the patient to tilt the neck backward (extension) to see the screen clearly [41]. This inappropriate posture can increase CVS symptoms. Progressive additive lenses, especially occupational types, provide good vision at near and intermediate distances for computer workers with presbyopia, which can influence both ocular symptomatology and the neck posture [42, 43].

#### *4.1.4 Eyeglasses*

Those who wear eyeglasses have a higher prevalence of CVS [9, 27, 44]. Incorrect prescriptions may cause under-correction of refractive errors, especially in individuals with presbyopia who require close proximity to the device to keep the images in focus. Indeed, computer screens are formed by pixels instead of solid images, which make focusing harder [44].

#### *4.1.5 Contact lens*

Wearing contact lenses increases the severity of ocular discomfort in patients with CVS [45, 46]. Contact lenses irritate the ocular surface, make unstable tear film, and alter the blink rate. Therefore, contact lens comfort of computer users is highly dependent on lubrication of the eye. Moreover, lens type is a key factor in the development of these symptoms. Silicone hydrogel lenses are more preferred than conventional hydrogel lenses by computer users [47]. Residual refractive errors, especially astigmatism, may also contribute to CVS among contact lens users. It is a routine practice pattern that spherical contact lenses are prescribed for subjects with astigmatism <1.0 D. Therefore, increased CVS symptoms occur, not as a result of the contact lens inducing dry eye, but rather as a result of the uncorrected refractive error.

#### **4.2 Ocular surface disease**

Decompensation and desiccation of ocular surfaces are common in computer users, which are related to corneal dryness, reduced blink rate, and increased corneal exposure.

#### *4.2.1 Ocular and systemic disease*

The likelihood of CVS is higher among computer users with a previous ocular disease either chronic or acute with long-term side effects [5, 9]. Underlying dry eye is the most important ocular disease in developing CVS among computer users. Any several systemic disease or medications contributing to ocular drying can also enhance CVS.

#### *4.2.2 Blink rate and pattern*

Normal blinking rate is 22 blinks per minute while relaxed. Using a computer over a long period alters the pattern and rate of blinking [48]. The blink rate is

significantly decreased during using digital screen devices. It decreased to 10 and 7 blinks per minute during reading a book and computer texts, respectively [48]. This reduction is more as font size and contrast decrease or the cognitive demand of the task increases [49]. Additionally, the downward movement of upper eyelid is not complete during computer use. Therefore, the upper eyelid does not touch lower eyelid and does not cover exposed cornea, which causes an incomplete blinking pattern. Infrequent and incomplete blinking contributes to a poor tear film quality, insufficient wetting of the ocular surface, and temporary stresses the cornea, resulting in symptoms of dry eye.

#### *4.2.3 Line of sight (angle of gaze)*

People usually have small angle of gaze and look downwards when they read texts on the paper. In small angle of gaze, the upper eyelid covers a substantial portion of the cornea, thus preventing tear evaporation and ocular discomfort symptoms [48, 50]. On the contrary, computer users usually view the digital screens in a horizontal gaze with a wider palpebral fissure. More corneal exposure accelerates tear film instability and CVS. Angle of gaze can also alter the accommodative and vergence response, and therefore the level of CVS symptoms [51].

#### **4.3 Poor environmental conditions**

Poor ergonomic conditions and worse posture in front of digital screen devices can cause musculoskeletal symptoms. Poor lighting, imbalance of light between the computer screen and working room, and poor contrast can exacerbate CVS severity [52, 53].

#### *4.3.1 Lighting condition*

The appropriate lighting levels vary according to the tasks. Writing and reading need higher lightening levels because they are tasks with greater visual demands [54, 55]. Improper environmental lighting levels, whether low or high intensities, adversely affect ocular comfort during using computers [29, 30, 41, 56]. The weak lighting condition can cause the eyes to tire gradually [29, 41, 56]. In dark environment, blink rate is decreased that accelerates desiccation of cornea. On the other hand, bright light sources (overhead fluorescent, large windows, and desk lamps) appear to significantly reduce the accommodation amplitude, wash out screen character images, and create reflection and glare [29, 56, 57]. Nowadays, the brightness of digital screens can be adjusted according to environmental lightning levels, which provides better performance for users.

#### *4.3.2 Workplace air conditions*

The office air conditioning can influence ocular surface of computer users. A low ambient humidity, a high temperature, and ventilation fans increase the evaporation of tear film, which accelerates ocular dryness [58]. The humidity of 45% has been recommended as a lower limit for workplaces [59]. Air pollution, such as airborne paper dust, laser and photocopy toner, and building contaminants, can also affect the comfort of computer users in office, negatively [58, 60].

#### *4.3.3 Seating position*

The inappropriate seating position of computer users is associated with CVS [9, 41]. Unfortunately, the ergonomic practices are not usually applied by most of the computer users [40]. The incorrect posture causes ocular discomfort, glare, and muscular spasm. Moreover, short eye-digital screen distance exposes users to more electromagnetic radiation emitting from the computer. On the other hand, the visual demands due to poor ocular accommodation and/or under-corrected refractive errors can also result in inappropriate posture leading to musculoskeletal difficulties. Oculomotor fatigue may change the innervation to the postural muscles in the neck, shoulder, and upper back, resulting in discomfort in these areas.

#### *4.3.4 Distance*

Each type of digital screen device has its own recommended viewing distance. Eye-screen distance is 50–70 cm for computers and 20–30 cm for mobile phones and tablets with smaller screens [48, 61]. Maintaining a proper viewing distance from digital screens decreases the symptoms of CVS [20, 40]. Closer eyes to digital screens require more accommodative effort and ocular muscle stress [5, 20]. In addition, more ocular surface decompensation and exacerbation of dry eye occur in proximity of eyes to digital screens [62].

#### *4.3.5 Time*

The symptoms of CVS appear to increase as the duration of exposure increases [5, 8, 9, 20, 21, 24, 44]. This may be because a computer generates electromagnetic radiation or high-energy blue light, which stresses the ciliary muscle in the eye, resulting in eye strain after continued exposure to the computer screen. Beside the amount of daily hours, the years of computer use also affect CVS development [5]. The CVS appears to have a cumulative nature rather than to be an acute condition. Therefore, long years of using a device equal more accumulated stress on the eyes, which might intensify the risk of developing CVS.

#### *4.3.6 Rest break*

Taking rest break is a protective factor for CVS [44, 63]. Dividing the work hours by short rest times during continuous computer work results in relaxing intraocular muscles, which can then decrease eye strain and headache [18]. Additionally, tear film is refreshed during rest break.

#### *4.3.7 Personal factors*

#### *4.3.7.1 Sex*

Females display a significantly greater number of CVS symptoms [5, 11, 40–42]. This association with sex could be related to dry eye [64]. Nevertheless, some symptoms may be more frequent in males such as burning sensation, dry eyes, red eyes, and blurred vision [44].

#### *4.3.7.2 Aging*

By aging, the quality of retinal image has been decreasing due to the decrease of lens transparency, which increases the ocular aberrations and light scattering. Additionally, presbyopia is an important factor associated with asthenopia. Presbyopic digital device users experience more accommodative stress during focusing at near distance [10]. The prevalence of dry eye and ocular surface disease, as contributor factors of dry eye, are also higher among older people. However, some protective mechanisms, such as senile miosis counteract with this process, improve the depth of focus and reduce accommodative strain in elderly.

#### *4.3.7.3 Socioeconomic level*

Occupational factors such as monthly income, employment status, and job stress or exhaustion affect the prevalence of CVS [65, 66]. High-paid workers are able to afford the protective facilities such as antiglare devices, eyeglasses as well as ocular medications and lubricants. These subjects may also have better workplace conditions and good awareness on computer ergonomics [65]. In general, there is a reverse relationship between knowledge on safety measures of computer use and the severity of CVS among computer workers [65].

#### *4.3.7.4 Multiple digital device usage*

The use of digital screen devices outside work is an important factor of CVS [20, 24]. Some possible reasons may be smaller screens of smartphones and tablets, closer eye-screen distance, and longer exposure times, which aggravate the risk of experiencing CVS.

#### **5. Ocular signs and symptoms of CVS**

The most common ocular and non-ocular complaints associated with CVS or digital eyestrain are:



#### **Table 1.**

*Major categories of symptoms in computer vision syndrome.*


We can put these complaints in four categories (**Table 1**).

In most occasions, symptoms of CVS occur because the visual demands of the task are more than the visual abilities of the individual to comfortably perform them. In a review of asthenopia, Sheedy et al. detected that symptoms commonly associated with this syndrome incorporated eyestrain, eye fatigue, discomfort, burning, irritation, pain, ache, sore eyes, diplopia, photophobia, blur, itching, tearing, dryness, and foreign body sensation. While investigating the effect of several symptominducing conditions on asthenopia, the authors determined that two vast categories of symptoms existed. The first group, termed external symptoms, included burning, irritation, ocular dryness, and tearing and was related to dry eye. The second group, termed internal symptoms, included eyestrain, headache, eye ache, diplopia, and blur and is generally caused by refractive, accommodative, or vergence anomalies. Consequently, the authors proposed that the underlying problem could be detected by the location and/or description of symptoms [67].

There are some investigations that compared visual problems in using digital devices and hard copy, and it is very interesting that even when using a modern flat panel monitor; subjects reported significantly greater blur during the computer task (increasing the demands placed upon ocular accommodation and vergence), when compared with a hard-copy printout of the same material and environmental conditions [68, 69]. Many of the visual symptoms experienced by users are only transient and will decline after stopping computer work or use of the digital device and in rare occasions it persists.

CVS, or digital eyestrain, can be diagnosed through a comprehensive eye examination. We should pay attention to patient history, visual acuity measurements, refraction, accommodation, and binocular vision status. Prolonged VDTs usage has been shown to cause reduced power of accommodation, removal of the near point of convergence, and deviation of phoria for near vision [70].

#### **6. Treatment**

Certainly, the management of CVS requires a multidirectional approach because of the variety of complaints between users. When treating a patient, it is essential to consider both ocular therapies, as well as adjustment of the user's workstation, environment, and habits in an ergo-ophthalmologic approach.

Potential therapeutic interventions for patients with symptoms of CVS can be divided into three main parts namely:

1.Refractive and accommodative disorders.

2.Vergence anomalies.

3.Ocular surface problems.

In examining patients with CVS, the following clinical parameters should be evaluated [with all near testing being performed at the distance(s) at which the electronic screen(s) are positioned]:

1.Best corrected visual acuity.

2.Refractive error (including binocular balancing)

3.Accommodative error (lag) at the appropriate working distance.

4.Monocular and binocular amplitude of accommodation.

5.Monocular and binocular accommodative facility.

6.Negative and positive relative accommodation.

When examining patients with CVS, the following clinical vergence parameters should be measured [with all near testing being performed at the distance(s) at which the electronic screen(s) are positioned]:


3.Horizontal and vertical fixation disparity and/or associated phoria.

4.Vergence facility.

5.Vergence ranges (negative and positive relative vergence)

6.Stereopsis.

7.AC/A and CA/C ratios.

#### *Computer Vision Syndrome DOI: http://dx.doi.org/10.5772/intechopen.111740*

Computer use has been associated with both a reduced rate of blinking and a high number of incomplete blinks when compared with viewing hard-copy materials. Dry eye therapies, which have been proposed to minimize symptoms of CVS, include the use of lubricating drops, ointments, and topical medications for blepharitis or allergic conditions. Additionally, blink training to increase the blink rate during computer use [71], as well as changes in ambient humidity (around 45%), hydration (drinking more water) and redirection of heating and air conditioning vents have all been proposed.

Some important points in preventing or reducing the complaints of CVS have to do with the computer and how it is used. This includes lighting conditions, chair comfort, location of reference materials, the position of the monitor, and the use of rest breaks. American optometric association has given some recommendations for proper body position during using computer, which emphasize on proper height of the chair, table, and monitor for straight position of the neck and back, as well as 90-degree angle of elbow. Moreover, a support for the feet can prevent hanging of the legs (**Figure 1**) [72].

#### **6.1 Location of the computer screen**

Most people find it more comfortable to view a computer when their eyes are looking downward. Ideally, the computer screen should be 15 to 20 degrees below eye level (about 4 or 5 inches) as measured from the center of the screen and 20 to 28 inches from the eyes. This position reduces the width of palpebral fissure and consequently decreases the evaporation of tear.

#### **6.2 Reference materials**

These materials should be located above the keyboard and below the monitor. If this is not possible, a document holder can be used beside the monitor. The aim is to position the documents, so the head does not need to be repositioned from the document to the screen.

#### **6.3 Lighting**

Position the computer screen to avoid glare, particularly from overhead lighting or windows. Use blinds or drapes on windows and replace the light bulbs in desk lamps with bulbs of lower wattage.

#### **6.4 Anti-glare screens**

If there is no way to minimize glare from light sources, consider using a screen glare filter. These filters lessened the amount of light reflected from the screen.

#### **6.5 Seating position**

Chairs should be comfortably padded and conform to the body. Chair height should be adjusted so the feet rest flat on the floor. Arms should be adjusted to provide support, while typing and wrists should not rest on the keyboard when typing.

#### **6.6 Rest breaks**

To prevent eyestrain, try to rest eyes when using the computer for extended period of time. Resting the eyes for 15 minutes after 2 hours of continuous computer use. Also, for every 20 minutes of computer viewing, look into the distance 20 feet away for 20 seconds to allow the eyes a chance to refocus (20:20:20 rule).

#### **6.7 Blinking**

To minimize the chances of developing dry eye when using a computer, try to blink frequently and completely. Surface of the eye is moistened by regular and effective blinking.

#### **7. Prevention**

In providing an appropriate form of spectacle correction, practitioners must consider both the viewing distance and gaze angle (both horizontal and vertical). A mild glasses prescription may be needed to reduce vision stress on the job. It has a good

*Computer Vision Syndrome DOI: http://dx.doi.org/10.5772/intechopen.111740*

idea for computer users to get a complete eye exam every year. If glasses are worn for distant vision, reading or both, they may not provide the most efficient vision for viewing a computer screen, which is about 20 to 30 inches from the eyes. Tell the doctor about job tasks and measure on-the-job sight distances. Accurate information will help get the best vision improvement. Patients may benefit from one of the new lens designs made, specifically for computer work.

Blue light from LED and fluorescent lighting, as well as monitors, tablets, and mobile devices, can negatively affect vision over the long term. Special lens tints and coatings can diminish the harmful effect of blue light. Minimize glare on the computer screen by using a glare reduction filter, repositioning the screen, or using drapes, shades, or blinds. Also, keeping screens clean, dirt-free and removing fingerprints can decrease glare and improve clarity.

#### **7.1 Adjust work area and computer for comfort**

In terms of viewing distance, the United States Occupational Safety and Health Administration state that the preferred viewing distance for a desktop monitor is between 50 and 100 cm (representing an accommodative stimulus in a corrected individual of between 1 and 2D). Additionally, they recommend that the center of the computer monitor should normally be located 15–20° below the horizontal eye level, and the entire visual area of the display screen should be located so the downward viewing angle is never >60° [73]. When using computers, most people prefer a work surface height of about 26 inches. Desks and tables are usually 29 inches high.

#### **7.2 Use an adjustable copyholder**

Place reference material at the same distance from eyes as the computer screen and as near to the screen as possible. That way the eyes will not have to change focus when looking from one to the other.

#### **7.3 Take alternative task breaks throughout the day**

Make phone calls or photocopies. Consult with coworkers. After working on the computer for an extended period, do anything in which the eyes do not have to focus on something up close.

#### **7.4 Limit screen time for using electronic devices in children**

Recommended amount of screen time for children (the Canadian Pediatric Society and the American Academy of Pediatrics):


**Using of special apps.** Such as Microsoft's "Night light," Apple's "Night shift," and Samsung-blue Light Filter.

**Adequate work environments.** Appropriate room temperature (20–22°C), ambient humidity (around 45%), and no direct horizontal or upper air from ventilation fans.

**Regular breaks during digital display.** Take a break from the screen every 30–60 minutes is mandatory. The use of screens should be avoided 1 hour before bedtime.

Encourage outdoor activity over screen time.

### **8. Conclusion**

Although the use of computer and other electronic devices are an inevitable part of modern life, every user should have sufficient knowledge about causes, prevention, and treatment of the visual and nonvisual side effects of long-term use of these devices. Otherwise, we have to wait for a big epidemic of visual problems, especially in children and young people, in the not-so-distant future.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Acronyms and Abbreviations**

CVS Computer vision syndrome VDT video display terminals

#### **Author details**

Hossein Aghaei\* and Parya Abdolalizadeh Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran

\*Address all correspondence to: draghaei.h@gmail.com

© 2023 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.

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**Chapter 4**

## Dry Eye and Allergic Conjunctivitis

*Rachel Dandar and John Sheppard*

#### **Abstract**

The primary goal of this chapter is to discuss the nuanced but prevalent clinical presentation of the patient with concurrent diagnoses of dry eye and allergic conjunctivitis. First, we discuss the epidemiology of dry eye disease and allergic conjunctivitis. We briefly discuss allergic blepharoconjunctivitis, a closely related entity with a different treatment focus. We thereafter discuss novel therapies, including loteprednol, varenicline nasal spray, reproxalap, and drug-eluting daily disposable soft contact lens. Lastly, we discuss a few biologic agents that hold promise for vernal and atopic keratoconjunctivitis, two forms of allergic eye disease that are more aggressive and can result in severe vision loss.

**Keywords:** tear film instability, ocular toxicity, allergic conjunctivitis, dry eye, allergic blepharoconjunctivitis

#### **1. Introduction**

Dry eye disease is a ubiquitous and often chronic condition, encountered frequently in ophthalmic practice. In 2017, more than 16 million Americans were afflicted by dry eye, approximately 6.8% of Americans [1]. Twice as common in women as in men, dry eye has also been demonstrated to increase in frequency with advancing age. With an aging population, the prevalence of dry eye will only increase. Typical symptoms of dry eye often include eye pain, grittiness, photophobia and blurred vision. The definition of dry eye disease was recently refined by the Tear Film & Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) as "a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles" [2]. It should come as no surprise that additional ocular pathology, including meibomian gland dysfunction, allergic eye disease and iatrogenic factors, such as cataract surgery, can exacerbate dry eye by disrupting homeostasis of the tear film.

A variety of inflammatory ocular surface conditions can result in increased tear film osmolality and disruption of tear film homeostasis. Allergic conjunctivitis is classically associated with IgE-hypersensitivity to allergens. Within this cascade involves activation of mast cells, which results in an early response and a late phase response. The early response is associated with elevated levels of prostaglandins and histamine within the tear film [3]. The late response involves upregulation of interleukin-8 (IL-8) and macrophage inflammatory protein (MIP) [3]. Frequently, this presents

clinically as tear film instability with inflamed conjunctival mucosa. In this chapter, we will focus on allergic eye disease as a concomitant diagnosis complicating the management of dry eye, in addition to highlighting novel treatments that are promising for the management of both conditions.

Allergy is a widespread condition, but ocular manifestations of allergic disease may be under-recognized within our current population. The first attempt at providing epidemiology on the incidence of specifically allergic eye disease was through data obtained between 1988 and 1994 [4]. While allergic rhinitis had previously been evaluated on prior censuses, allergic ocular symptoms had been overlooked. In this first evaluation, almost 30% of people had both nasal and ocular symptoms, with far fewer reporting ocular symptoms alone (6.4%). This study also revealed that isolated ocular symptoms are more common in patients as they age, typically over 50 years old, compared to combined nasal and ocular symptoms in younger age groups [4]. This should come as no surprise as it has already been thoroughly documented that the prevalence of atopy decreases with age whereas the prevalence of dry eye increases with age.

Like many diseases, allergic eye disease exists on a spectrum, with milder forms of allergy including seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC), ranging to the more severe atopic (AKC) or vernal keratoconjunctivitis (VKC). Whereas SAC and PAC classically impact the conjunctiva, VKC more frequently impacts the cornea and can severely reduce visual acuity through shield ulcers, vernal plaques and neovascularized scars [5]. As such, the treatments for allergic eye disease can vary widely in intensity depending on the severity of the presentation. VKC is more common among patients with concomitant atopic disease; as such, the more severe forms of ocular allergy are more likely to affect younger patients. Particularly for younger patients who may still be within the amblyogenic age range, aggressive management is indicated to combat corneal manifestations of VKC, in some cases requiring systemic therapies. For SAC and PAC, management is more often through topical therapies, but can become difficult when faced with coexistent dry eye.

In most studies related to ocular allergens, the predominant focus is most often on SAC and PAC as these are conditions more prevalent in older age groups, and thus within the work force. There are several well-documented allergens that are more likely to present with ocular symptoms as opposed to nasal symptoms: pet dander, dust, pollen, mold, and certain cosmetics. An additional interesting feature of this study was that the allergic disease was more prevalent in the southern United States, presumably secondary to higher humidity and relatively more pollen production [6]. With ongoing climate change and global warming, pollen production will continue to increase, suggesting that the prevalence of ocular allergy will only increase with time. Another consideration regarding ocular allergy prevalence includes the impact on vision, quality of life and economic productivity. While only 3% of adults have symptoms severe enough to prevent working outside of the home, the AIRS Survey revealed that the average self-reported decrease in productivity from allergic eye disease was 26 points, falling from a self-reported productivity of 91/100 with no allergic symptoms to 65/100 with the worst allergic symptoms [7]. As such, there is a need for effective therapies to mitigate the symptoms of allergic eye disease, to improve quality of life for those suffering from allergies and to enable these patients to continue to engage fully in their professions, instead of being limited by their symptoms.

Classic symptoms of allergic eye disease often overlap with those of dry eye, including redness, itching/pruritis, grittiness, burning, epiphora/tearing and blurred

#### *Dry Eye and Allergic Conjunctivitis DOI: http://dx.doi.org/10.5772/intechopen.110662*

vision. However, allergic eye disease complicates the management of dry eye, as some treatments for stand-alone dry eye may not be as effective or as tolerable for the patient with concomitant allergic disease. Artificial tears may be considered as an initial therapy for patients with either dry eye or allergic conjunctivitis, but further treatment choices may become more difficult. It is not uncommon for muscarinic topical anti-histamines to dry the ocular surface, while topical therapies for dry eye and meibomitis frequently create hypersensitivity or irritative effects on the allergic ocular surface. Similarly, punctal plugs obviously would be a less desirable choice in a patient with allergic conjunctivitis, as this would result in prolonged exposure of the allergen to the ocular surface. Mast-cell stabilizers may be of utility in these patients, but can take days to weeks to reach peak efficacy, and as such, will not provide patients with immediate relief. As such, there is a need for more nuanced medications that can adequately address both allergic conjunctivitis and dry eye.

#### **2. Allergic contact blepharoconjunctivitis**

First, we will briefly discuss allergic contact blepharoconjunctivitis, a disease similar to SAC and PAC, but with slightly different management. The most common cause of an allergic contact blepharoconjunctivitis is the use of cosmetics. The inciting agent in these cases can include a variety of metal allergies, such as nickel, cobalt and chrome, as well as allergies to the fragrances added to these cosmetics [8]. While the solution for blepharoconjunctivitis in the setting of cosmetic use may be simple, allergen avoidance, it can often be difficult to pinpoint a cosmetic as the underlying cause of symptoms. Often, the history may be challenging. Women, who are twice as likely as men to experience symptoms of dry eye, are more likely to wear cosmetics, specifically mascara, on a daily basis. As such, their constellations of symptoms could easily be confused with an environmental allergen (akin to dust or dander). Furthermore, this allergic blepharoconjunctivitis may be exacerbated by the mechanical impact of cosmetic products. For example, application of mascara or eyeliner may obstruct meibomian gland orifices, which can lead to further team film instability and aggravation of dry eye and allergic symptoms [8]. As previously mentioned, dry eye is twice as common in women as in men, so providers must be aware of the impact of cosmetic use. For patients in whom allergen avoidance is less practical, such as those suffering from pollen allergies, there are a variety of novel therapies being released to attempt to better control the nuanced symptoms of concomitant dry eye and allergic eye disease.

#### **3. Novel treatments for seasonal and perennial allergic conjunctivitis**

One of the first efforts to address the inflammatory component of dry eye was the application of topical steroid therapy. In late 2020, KPI-121 0.25% (EYSUVIS, Kala Pharmaceuticals, Inc.) became the first commercially available mucus-penetrating particle (MPP) formulation of loteprednol etabonate ophthalmic emulsion approved for episodic dry eye. Investigated through the STRIDE trials, loteprednol etabonate was approved for four times daily (QID) use up to 2 weeks at a time [9, 10]. The mucus-penetrating particle vehicle enables the medication to avoid entrapment by conjunctival mucins and achieve better ocular penetration [9, 10]. For patients with a component of allergic disease, a low-dose topical steroid may be of particular use,

as an intermittent topical steroid therapy may address underlying inflammation present in both dry eye and allergic disease. There are however some patients for whom a topical steroid may not be the best treatment option. For example, while there were no differences in intraocular pressure between the two STRIDE trial arms, loteprednol still has a higher rate of elevated intraocular pressure (IOP) than other topical medications such as olopatadine. As such, practitioners may still be hesitant to prescribe loteprednol for the patient with glaucoma, who may have a higher proclivity of IOP elevations [10]. Furthermore, as the medication is approved for only 2 weeks at a time, loteprednol would not be the best first choice for a patient with perennial symptoms.

Another medication that may be of particular interest for patients with both dry eye and allergy is Tyrvaya™ (varenicline solution) Nasal Spray. This novel dry eye treatment, initially approved in late 2021, enables a patient to avoid eye drops entirely. For some patients with either dry eye and/or allergic disease, application site reaction (i.e. burning pain on instillation of drops) may prohibit use of topical therapy. Tyrvaya™ could be considered in such patients, as the nasal spray circumvents this specific problem. Investigated by Ocean Point through the MYSTIC phase II randomized trial and the ONSET-2 Phase III Randomized Trial, Tyrvaya™ has repeatedly been shown to significantly improve signs and symptoms of dry eye [11, 12]. The primary endpoint in these studies was improvement in Schirmer's test by 10 mm or more by 4 out of 12 weeks of therapy; however, tear production was shown to increase as quickly as 5 minutes after administration [11]. While the exact mechanism of action is not completely understood, Tyrvaya™ is thought to be a neuro-stimulating agent, activating the parasympathetic pathway of the nasociliary branch of the trigeminal nerve in the nose, thereby increasing baseline tear production. Varenicline, the active ingredient in Tryvaya™, has previously been used as a smoking cessation aid. There is longstanding safety data for this medication, considering Chantix is used systemically in much higher doses with excellent tolerance. The side effect profile of Tyrvaya™ is relatively benign. The most common adverse reaction is sneezing, which occurs in 82% of patients. Cough, throat irritation and instillation-site (i.e. nose) irritation are among other common adverse reactions [11, 12].

While the use of Tryvaya™ in the setting of stand-alone allergic eye disease has not yet been investigated, for patients that suffer from both allergic eye disease and dry eye, Tryvaya™ may be of utility. Patients with a diagnosis of allergic rhinitis often use other medications administered via nasal spray to control their nasal symptoms, such as fluticasone, or FLONASE. For these patients, a nasal route of administration may be more-readily accepted, as they are familiar with/accustomed to this route of therapy. Given twice daily in each nostril, Tyrvaya™ can not only reduce topical treatment burden for patients, but is also an excellent option for patients who have difficulty with drops. Tyrvaya™ has advantages for patients with reduced neck mobility or reduced upper limb mobility, tremors, digital arthritis, patients who live alone and those who struggle self-administering eye drops. Another patient population that may benefit from Tyrvaya™ includes be the complex glaucoma patient who has developed allergic disease and toxicity in the form of medicamentosa. Of note, Tyrvaya™ has not been tested on patients with obstructive sleep apnea (OSA) who use continuous positive airway pressure (CPAP), with prior sinus surgeries, with a history of PKP, or those with recurrent nosebleeds [11]. As such, conclusions are unable to be drawn about its effectiveness in these specific demographics. Nevertheless, a single

pharmaceutical with both a new delivery route and a novel mechanism of action holds great potential for patients afflicted by dry eye and allergic eye disease.

Another novel therapeutic, Reproxalap, is currently being investigated and developed by Aldyera to address both allergic conjunctivitis and dry eye disease. This topical medication is a novel, small-molecule immune-modulating covalent inhibitor of reactive aldehyde species (RASP) [13, 14]. While the exact mechanism of action of Reproxalap is not completely understood at this time, it is hypothesized to address the inflammatory component of both dry eye and allergic disease. RASP potentiate inflammation through a variety of inflammatory mediators and pathways, and as such, inhibition of RASP may inhibit the propagation of the inflammatory cascades.

Reproxalap was first evaluated in the treatment of dry eye alone in the Phase III TRANQUILITY trial. Participants were randomized to 0.1% reproxalap, 0.25% reproxalap and placebo groups. They were then exposed to a controlled adverse environment, consisting of low humidity for 90 minutes, after a 12-week course of QID treatment. Symptomatic relief was appreciated as early as 2 weeks into the treatment course, at the first follow up visit [13]. Patients experienced symptomatic improvement in a dose dependent response, particularly in relation to symptoms of grittiness and dryness [13]. Researchers also appreciated improvements in nasal fluorescein staining in the 0.25% group, so 0.25% Reproxalap QID was advanced to additional clinical trials. For patients with allergic conjunctivitis, Reproxalap was evaluated in a randomized, double-blind Phase IIb Trial and in the Phase III ALLEVIATE Trial [14, 15]. In each of these studies, participants were randomized to various treatment groups, including 0.25% Reproxalap, 0.5% Reproxalap and placebo. For both doses, participants who had been administered Reproxalap noted improvement in symptoms, notably tearing, itching and redness [14, 15]. However, participants taking the higher dose, 0.5% Reproxalap, experienced a higher rate of instillation site reaction, with higher rates of redness and irritation after the first dose, so the 0.25% regimen is being advanced [14]. Reproxalap is a promising medication for those suffering from both dry eye and allergic conjunctivitis.

Another novel therapeutic strategy currently under development are contact lenses impregnated and eluting a variety of different pharmaceutical agents. For patients who wear soft contact lenses, the current options for treatment of allergic conjunctivitis are limited. Topical drugs currently available, including ketotifen and olopatadine, are not recommended for use while soft contact lenses are in place due to the preservative benzalkonium chloride (BAK). For many patients, this translates to spectacle use during high allergy seasons in order to be able to instill anti-allergy drops and achieve symptomatic relief. There have been a variety of clinical trials in the past several years directed towards creation of drug-eluting daily disposable soft contact lens (DDSCL) [16]. The first DDSCL, Acuvue® Theravision™ with Ketotifen (ATK) (Johnson & Johnson Vision Care, Inc., Jacksonville, Florida, USA), was approved by the FDA in April of 2022. Prior to approval, multiple case studies were performed demonstrating subjective and objective improvement with use of ATK during high allergy seasons, with symptomatic relief of itch, and improvement in clinical features, including episcleral, ciliary and scleral injection, as well as extent of papillary reaction [17, 18]. It is thought that the ketotifen within the DDSCL is gradually released into lacrimal fluid below CL, to maintain therapeutic levels for longer, in contrast to topical drops, which have a more temporary effect as they are washed from the tear film.

A further consideration of a DDSCL as a therapeutic strategy is that a contact lens serves as a physical barrier, much like a bandage contact lens (BCL), in addition to the potential for a slow, sustained release of medication. As such, a DDSCL may be a parsimonious solution for a patient with both dry eye and ocular allergy. One current limitation of this specific therapy is that the toric options for DDSCL are currently limited to astigmatic errors of less than 1 diopter [16]. There have been additional studies regarding the creation of DDSCL with olopatadine and DDSCL with epinastine hydrochloride, but these have not yet entered human trials [19, 20]. Nonetheless, FDA approval of ATK as the first DDSCL is promising for the ophthalmic community, as ATK may enable patients to achieve better symptomatic control during highallergy seasons, and DDSCL technology may expand to other ophthalmic conditions and enable patients to achieve better compliance with and tolerance of mediation regimens.

#### **4. Novel treatments for atopic and vernal keratoconjunctivitis**

Thus far we have focused primarily on novel therapies with a target audience of primarily patients who suffer from SAC and PAC. For patients afflicted by VKC, there have also been promising novel therapeutics developed over the last several years. While milder cases of VKC may be managed through topical and systemic anti-histamines, topical mast cell inhibitors, and tacrolimus ointment (0.03–0.1%), topical steroid dependence in these children is common and can result in a series of untoward side effects, including ocular hypertension, steroid-induced glaucoma and cataract. For children who are dependent on topical steroids, topical cyclosporine A (CsA, 0.5–2%) has been of great utility in partial or total reduction of topical steroid therapy. Unfortunately, topical CsA is ineffective for approximately 1/3 of children, and another 1/6 of children are still dependent on topical steroids despite topical CsA [21]. Omalizumab, a monoclonal, chimeric anti-IgE antibody has been used for allergic asthma since 1999 [22] and has recently garnered interest in the treatment of VKC. The underlying pathophysiology for the atopic triad, asthma, eczema and allergy, overlaps, with both IgE mediated and cell-mediated pathways provoking symptoms of the triad.

For patients with AKC and VKC, omalizumab has been used with some success. Delivered via subcutaneous injection, the dose and frequency of omalizumab therapy varied nearly fourfold among children, which may in part be related to the severity of the presentation and the extent of inflammatory levels in these patients [23]. Not all children had symptomatic improvement of ocular symptoms with omalizumab, which should come as no surprise, given approximately 50% of patients who suffer from VKC and/or AKC do not have an IgE-dependent immune response [24, 25]. For those children who experienced a response to omalizumab, often their symptoms of asthma and eczema improved as well [23].

Another consideration is that for some children, omalizumab alone was adequate to control symptoms, whereas for others, omalizumab alone did not adequately control symptoms. As such, there is a need for additional therapeutic targets for those with VKC and/or AKC arising through different mediators. Furthermore, omalizumab is not approved for the treatment of ocular allergy alone. Patients with severe symptoms would be best treated through multispecialty collaboration, with input from such specialties as Allergy, Immunology, Rheumatology, and/or Pulmonology for the prescription, dosing and management of these medications, as well as

#### *Dry Eye and Allergic Conjunctivitis DOI: http://dx.doi.org/10.5772/intechopen.110662*

monitoring of the concomitant diseases. As such, omalizumab is a promising therapy for patients with severe VKC, and may help some, but not all, reduce their treatment burden.

For patients with AKC or VKC who have an incomplete or no response to omalizumab, another promising therapeutic target interleukin-5 (IL-5). IL-5 is a powerful, proinflammatory cytokine within the cell-mediated pathway of inflammation, affecting primarily eosinophils. Mepolizumab and reslizumab are humanized monoclonal antibodies that bind directly to IL-5, while benralizumab is anti-eosinophil monoclonal antibody that binds to the alpha subunit of the IL-5 receptor [26, 27]. Although none of these drugs have been studied in regards to allergic conjunctivitis, initial reports the treatment of patients with allergic and eosinophilic predominant asthma have been promising [28]. Given the common inflammatory cascades that result in the classic atopic triad, they may be considered potential future biologic therapies for patients with AKC and VKC.

#### **5. Conclusions**

Allergic eye disease, affecting around 1 in 3 Americans, is a ubiquitous condition and will likely only increase in prevalence as global warming and climate change result in higher temperatures and humidity. Existing on a wide spectrum, from milder forms like SAC and PAC, to more severe, vision-threatening forms in AKC and VKC, treatment of allergic eye disease can be complex, as it often coexists with dry eye disease. As novel medications with vastly different mechanisms of action and routes of administration are developed to address nuanced forms of dry eye and allergic disease, physicians will have more tools to address clinical signs and symptoms of dry eye and allergic eye disease in their patients.

#### **Author details**

Rachel Dandar1 \* and John Sheppard1,2

1 Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, VA, USA

2 Virginia Eye Consultants/CVP Physicians, Norfolk, VA, USA

\*Address all correspondence to: dandarr@evms.edu

© 2023 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.

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Section 3
