2.1 Introduction

Viral conjunctivitis (“pink eye”) is the most common form of conjunctival infection [1]. In the medical literature, viral conjunctivitis is widely regarded as a trivial disease, causing transient eye irritation, injection, chemosis, and increased lacrimation. However, viral conjunctival infections are now understood to be caused by a rich and diverse consortium of viruses, many of which have distinct and variable patterns of disease presentation, unique epidemiologic features, and natural histories. While most cases will resolve spontaneously with no long-term complications, several viral infections have chronic manifestations that may result in visual impairment and disability. The viruses responsible for ocular infection also have wide-ranging tissue tropisms, and a significant proportion of affected patients will develop conjunctivitis as just one of the many clinical features associated with systemic disease. The social and economic burdens of viral conjunctivitis are compounded by the ease of transmission among its causative agents, which continue to be implicated in global and nosocomial outbreaks. In this chapter, we offer an overview of the etiologies and clinical syndromes associated with these infections, which remain an important but underappreciated cause of ocular morbidity.

2.2 The History of Viral Conjunctivitis

Historically, our understanding of viral conjunctivitis has been driven by clinical studies conducted in the wake of international and regional outbreaks. These research efforts led to the isolation of numerous pathogens and their conjunctivitis-associated types, including human adenovirus [2, 3] and human enteroviruses [4, 5]. However, references to epidemic conjunctivitis can be found in medical historiography dating back to at least the seventeenth and eighteenth centuries, and possibly earlier. In this early modern period, viral conjunctivitis was likely included among the many etiologies of “ophthalmia”, a general term used to describe the red, inflamed, and/or blind eye [6, 7]. References to “ophthalmia” were dominated by descriptions of chronic, cicatrizing disease most consistent with Chlamydia trachomatis infection [8], which was itself erroneously believed to be caused by a viral pathogen originating from the Middle East [9]. However, other important outbreaks were described as having preferentially affected those in itinerant professions, including sailors, tradespeople, and the military [10]. The rapid and explosive nature of disease spread suggest that at least some outbreaks were viral or bacterial in nature [11]. Importantly, the physicians and historians who documented the spread of these epidemics were among the first to speculate that disease could be transmitted directly from individual to individual [12,13,14]. The circulation of this idea contributed to the gradual erosion of the prevailing miasmal theory of disease, which identified “bad air” as the source of all maladies. Therefore, early accounts of epidemic viral conjunctivitis likely had some role in the paradigm shift towards the germ-theory of disease, which would rise to prominence by the late nineteenth century [15].

2.3 Etiologies of Viral Conjunctivitis

Human adenoviruses, picornaviruses, and herpesviruses are the most common causes of viral conjunctivitis, accounting for up to 82% [16,17,18,19], 45% [20, 21], and 5% [16,17,18,19,20] of all cases, respectively. However, these figures should be treated as approximations because viral conjunctivitis remains a clinical diagnosis for the vast majority of patients, and laboratory confirmation is typically sought only in cases of diagnostic uncertainty and in particularly severe cases. Furthermore, it is intuitively obvious that the relative preponderance of these viral etiologies may differ in outbreak settings and/or with seasonal variation [22]. Nonetheless, the conjunctiva is a fertile tissue for many viral infections, which can be remembered with the mnemonic PHARAOH (Tables 2.1 and 2.2):

  • Picornaviruses, e.g., enterovirus, and poxviruses, e.g., variola, vaccinia, molluscum contagiosum, and orf viruses

  • Herpesviruses

  • Adenoviruses

  • Rubella and rubeola (measles)

  • Arboviruses (e.g., dengue, zika, and chikungunya)

  • Other (e.g., coronavirus, influenza virus, and Newcastle disease virus)

  • Human immunodeficiency virus (HIV)

Table 2.1 Etiologies of conjunctivitis (human DNA viruses)
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Table 2.2 Etiologies of conjunctivitis (human RNA viruses)
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The clinical presentations of viral conjunctivitis are mostly nonspecific, producing symptoms such as eye irritation, pain, pruritus, and foreign body sensation, and signs including conjunctival injection, discharge, edema, formation of follicles, papillae and/or membranes, and regional lymphadenopathy. Despite these common clinical findings, likely the result of convergent inflammatory pathways which are activated following viral infection, a weighted differential diagnosis can nonetheless be generated with an appreciation of certain patterns of ocular disease and their associated nonocular features. These may be pathognomonic or highly suggestive of certain viruses.

2.4 Adenoviral Conjunctivitis

2.4.1 The Human Adenoviruses

The human adenoviruses (HAdVs), belonging to the family Adenoviridae and genus Mastadenovirus, are a collection of nonenveloped, medium-sized (~70–90 nm), double-stranded DNA (dsDNA) viruses with a strong historical association with ocular infection [23, 24]. The first known clinical descriptions of adenoviral conjunctivitis were made by Austrian ophthalmologists Ernst Fuchs [25] and Karl Stellwag von Carion [26] during a large central European outbreak in the late nineteenth century. This disease was of a particularly severe form of adenoviral conjunctivitis subsequently termed as “epidemic keratoconjunctivitis” (EKC) [27], the only form of adenoviral conjunctivitis known to be accompanied by significant corneal infection. Particularly notable epidemics of EKC affecting thousands of patients were later reported in Madras in 1930 [28], and in the naval yards of Pearl Harbor in Hawaii and San Francisco in the early 1940s [29]. These latter outbreaks led to the popular designation of this mysterious affliction as “shipyard eye” [3, 30]. The causative agent of EKC would not come to light until the first adenovirus was serendipitously isolated in human adenoid tissue, by Rowe and colleagues in 1953 [31], amid efforts to identify the virus responsible for the common cold. The subsequent identification of HAdV type 8 (HAdV-D8) in conjunctival scrapings from an EKC patient [2] established the viral etiology of this disease. HAdVs are extremely contagious and resistant to environmental desiccation, and can be transmitted easily through contact with infected persons and their surroundings [32]. Currently, there are 103 HAdV types, across seven species (A to G), which have been formally recognized with whole genome sequencing (WGS) [23, 33]. In virology, WGS has succeeded serum neutralization and hemagglutination inhibition as the more accurate method of taxonomic classification. HAdV types are determined on the basis of unique nucleotide sequencing of major capsid proteins (penton, hexon, and/or fiber knob), or by unique patterns of genome recombination.

2.4.1.1 Clinical Syndromes Associated with Human Adenovirus

HAdV conjunctivitis is caused by species B (HAdV-B), D (HAdV-D), and E (HAdV-E) adenoviruses, which are classically associated with three distinct syndromes: simple follicular conjunctivitis (types B3, E4, and B7), pharyngoconjunctival fever or PCF (types C2, B3, E4, B7, and B14), and EKC (types D8, D37, D53, D54, D56, D64, and D85). The incubation time for adenovirus ranges from 5 to 14 days. Simple follicular conjunctivitis, perhaps the most common form, is characterized by conjunctival injection, chemosis, edema, conjunctival follicle formation, and serous discharge. Bilateral disease is common. PCF, as its name suggests, is a clinical syndrome characterized by febrile pharyngitis and follicular conjunctivitis. Although its name was coined following a nosocomial outbreak at the National Institutes of Health, Maryland, USA in 1954 [34], the first clinical descriptions of PCF were made by the French physician Beal during a Parisian epidemic in 1904 [35]. PCF is therefore also eponymously known as Beal’s conjunctivitis [36]. These forms of HAdV conjunctivitis typically resolve spontaneously within 2 weeks of symptom onset, and usually do not require specific therapeutic intervention beyond symptomatic measures.

The most severe form of HAdV conjunctivitis is the aforementioned EKC, which may lead to chronic visual complications [32]. EKC is characterized by a classic constellation of signs including preauricular lymphadenopathy, hyperacute and sometimes membranous conjunctivitis, corneal epithelial keratitis, and the hallmark formation of delayed-onset subepithelial infiltrates (SEIs) (Fig. 2.1) [37]. Conjunctivitis seen in EKC is associated with the formation of exudative membranes which, if left untreated, may fibrose and lead to restriction of ocular motility [38]. The corneal manifestations of EKC distinguish this entity from other forms of HAdV conjunctivitis. In addition to a diffuse epithelial keratitis with punctate epithelial and/or macroepithelial erosions, SEIs develop in an estimated 20–30% of patients, leading to chronic, relapsing and remitting disease [39]. These SEIs, shown in animal models to involve aggregations of neutrophil-predominant leukocytes, are mediated by a complex inflammatory response within the corneal epithelium and stroma [40,41,42]. Their presence may result in reduced vision, photophobia, and glare. Despite decades of research in therapeutics, ranging from topical antiseptics [43,44,45,46,47,48], antivirals [49,50,51], and immunomodulators such as tacrolimus and cyclosporin [52,53,54,55,56], topical corticosteroids remain the only treatment known to reliably alter the course of EKC. When expertly applied, topical corticosteroids may be administered to the eye following the removal of conjunctival membranes, and/or to achieve remission in patients with chronic SEIs. However, tapering must be pursued slowly owing to the risk of rebound SEI formation.

Fig. 2.1
figure 1

Clinical Manifestations of Epidemic Keratoconjunctivitis (EKC): (a) geographic epithelial keratitis with a large epithelial defect; (b) severe, fulminant membranous conjunctivitis with symblepharon formation, which may lead to restriction of ocular motility; and (c) corneal subepithelial infiltrates (SEIs) as shown by slit lamp examination. Note the relatively uniform size of these SEIs, which tend to be <0.5 mm. SEIs seen in keratitis caused by other viruses (e.g. HSV and VZV) are often larger in diameter. [Reproduced with permission from “Jonas RA, Ung L, Rajaiya J, Chodosh J. Mystery eye: Human adenovirus and the enigma of epidemic keratoconjunctivitis. Prog Retin Eye Res 2019: 100826” published by Elsevier]

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2.5 Herpes Conjunctivitis

2.5.1 The Human Herpesviruses

The herpesviruses, belonging to order Herpesvirales and family Herpesviridae, are a collection of large (120–260 nm), spherical, dsDNA viruses composed of an icosahedral capsid, a protein-rich tegument, and an external lipid envelope [57,58,59]. Nine herpesvirus species are known to infect humans, and collectively they are known as the human herpesviruses 1 through 8 (HHV 1–8, with HHV-6 further subdivided into HHV-6A and HHV-6B). The viruses most strongly associated with conjunctivitis are the first five HHVs: HHV-1, otherwise known as herpes simplex virus type 1 (HSV-1); HHV-2 or herpes simplex virus type 2 (HSV-2); HHV-3 or varicella zoster virus (VZV); HHV-4 or Epstein-Barr virus (EBV); and HHV-5 or human cytomegalovirus (HCMV). Of the remaining HHVs, HHV-6 and HHV-8 (Kaposi sarcoma-associated herpesvirus, KSHV) also demonstrate ocular surface tropism [60,61,62] but have been more closely studied in other settings, including their potential role in oncogenesis [63,64,65]. All HHVs establish lifelong latent infections in a variety of cell types [66,67,68,69]. For example, the most common cause of ocular infection, HSV, remains nestled in sensory neurons within the trigeminal and dorsal root ganglia [70,71,72,73,74]. Persistence in extraneuronal tissues such as the cornea [75, 76] and ocular surface epithelium [77, 78] have also been reported. In general, the manifestations of herpetic eye disease occur as the result of primary infection, or the reactivation of latent virions within infected nerve ganglia.

2.5.2 Herpes Simplex Virus Conjunctivitis

HSV-1 and HSV-2, of the subfamily Alphaherpesvirinae and genus Simplexvirus, are indistinguishably associated with conjunctivitis. Conjunctival HSV infection typically manifests as an acute, unilateral, and diffuse follicular conjunctivitis resulting in increased lacrimation, foreign body sensation, and preauricular lymphadenopathy [79]. The application of fluorescein or rose bengal staining to the ocular surface may reveal characteristic bulbar geographic or dendritic ulcer(s) on slit lamp examination [80, 81]. The presence of blistering herpetic vesicles and/or ulcers found along the eyelid margin, periocular skin, lips, and oral cavity, in a nondermatomal distribution, is particularly suggestive of HSV. In these patients, it is critically important to carefully examine the cornea for evidence of epithelial, stromal, and/or endothelial keratitis. The presence of corneal disease mandates specific therapeutic interventions, including antiviral and/or topical corticosteroid therapy [82,83,84], along with considerations of oral antiviral prophylaxis. The involvement of any of these corneal layers, which may be the result of contiguous spread from adnexal lesions [85], represents a more severe form of infection which may lead to vision loss if not treated in a timely and appropriate manner. In the absence of corneal disease, HSV conjunctivitis typically follows a benign clinical course without specific intervention, and most cases will resolve within 2 weeks of onset [16], although rarely chronic blepharoconjunctivitis may last for months [79, 86]. An important caveat, however, is that viral reactivation may result in disease beyond the site of primary infection [84]. Patients with HSV conjunctivitis should therefore be counseled on the possibility of viral reactivation in both the ocular adnexa and cornea, which require prompt ophthalmological review.

2.5.3 Herpes Simplex Virus Conjunctivitis in Neonates

HSV is the most common viral cause of ophthalmia neonatorum, a form of neonatal conjunctivitis which develops in the first month after birth [87]. Although HSV may infect neonates in utero through transplacental transmission, most infections are caused by neonatal HSV exposure during delivery. This may occur either through contact with active genital lesions or silent shedding through the birth passage mucosa [88, 89]. Neonatal HSV affects up to 12 in 100,000 live births in the USA [90, 91], with over 60% of cases caused by HSV-2 [92]. Postpartum newborn checks are an opportune time to screen neonates for HSV infection, as lesions on the skin, eye, and mouth may arise between the first and third weeks of life [93]. Herpetic vesicles involving the periocular skin and lids are common, and may be associated with conjunctivitis [94]. The presence of findings consistent with HSV infection should prompt comprehensive examination of the anterior and posterior segments of the eye to assess for the presence of keratitis and/or chorioretinitis which, although rare, are sight-threatening and may result in cortical blindness in the developing infant. Also, and importantly, the presence of any indication for ocular HSV warrants immediate referral to a neonatologist or pediatrician, owing to the possibility of systemic HSV viremia. Suspicion for systemic HSV should prompt admission of the child for lumbar puncture, cultures and testing by polymerase chain reaction, and intravenous acyclovir. Neural and/or visceral HSV invasion may result in lifelong complications even with the timely administration of systemic antiviral therapy [95]. Unfortunately, despite advances in treatment, disseminated disease carries greater than 50% mortality rate [96].

2.5.4 Varicella Zoster Virus (VZV) Conjunctivitis

The varicella zoster virus (VZV) belongs to the Alphaherpesvirinae subfamily and genus Varicellovirus [59, 97]. Like its close relatives HSV-1 and HSV-2, VZV is a neurotrophic virus which establishes lifelong latency in neuronal ganglionic tissue, and is therefore capable of causing both primary and recurrent disease [98]. VZV is associated with two main clinical syndromes: primary varicella infection (“chickenpox”) manifests as an intensely pruritic, vesicobullous rash during childhood; and herpes zoster, which is the result of viral reactivation, and estimated to affect 20–30% of the population over their lifetime [99, 100]. Primary VZV infection is occasionally associated with ocular manifestations [101, 102], most commonly bulbar conjunctival ulcers. Ocular VZV infection may also occur as the result of viral reactivation within the ophthalmic (V1), and less commonly, the maxillary (V2) divisions of the fifth cranial nerve [103], leading to a clinical syndrome known as herpes zoster ophthalmicus (HZO). HZO accounts for roughly one-fifth of all herpes zoster cases, and is characterized by the unilateral eruption of painful, crusty, maculopapular lesions in a classic dermatomal distribution. This clinical picture may be preceded by the formation of the same lesions at the nasal tip (Hutchinson’s sign), representing involvement of the nasociliary branch of the ophthalmic nerve [104, 105]. The lesions associated with HZO are most apparent on the periorbital skin, eyelids, forehead, and nose, and may extend onto the conjunctiva and corneal limbus. Importantly, an insidious variant of HZO known as ophthalmic zoster sine herpete involves the absence of these characteristic skin lesions [106,107,108]. Conjunctivitis is the most common ocular manifestation of HZO [109, 110], is typically self-limiting, and does not require specific treatment. Very rarely, it may be associated with the formation of membranes and cicatricial disease [111]. As with HSV, it is critically important to carefully examine the cornea in HZO. Vision-threatening corneal involvement occurs in up to two-thirds of HZO patients [112], and may manifest as an epithelial, stromal, and/or endothelial keratitis. The presence of keratitis may warrant antiviral and/or corticosteroid therapy to salvage vision [113, 114]. Comprehensive reviews of HZO-associated corneal disease can be found elsewhere [112, 115].

2.5.5 Other Herpetic Etiologies of Conjunctivitis

HHV-4 (EBV) and HHV-5 (HCMV), both lymphotropic viruses, are now increasingly recognized as ocular surface pathogens. EBV, of the subfamily Gammaherpesvirinae and genus Lymphocryptovirus, has been mostly studied in the context of heterophile antibody-positive infectious mononucleosis (IM) [116], autoimmune conditions such as primary Sjogren’s syndrome [117], and is now known to be an oncogenic virus owing to its close association with Burkitt’s lymphoma [118] and epithelial cell neoplasia [119]. It has also been identified as an etiologic agent in ocular surface infections. CD21, the canonical EBV receptor, is found on B-lymphocytes as well as ocular surface epithelium [120,121,122]. EBV infection of B-lymphocytes, its site of viral latency, may encourage “transfer infection” to the basolateral surface of neighboring epithelial cells through the activation of B-lymphocyte-specific adhesion molecules [122]. This unique signaling biology may explain why conjunctivitis is seen in up to 40% [123] of patients with EBV-associated IM. EBV may manifest as a unilateral follicular conjunctivitis associated with lid edema, conjunctival hemorrhage, and palpable preauricular and/or cervical lymphadenopathy [124,125,126,127]. EBV is also a rare cause of Parinaud’s oculoglandular syndrome, comprised of chronic granulomatous tarsal conjunctivitis and regional lymphadenopathy [125, 128]. Although less common, HCMV, belonging to the subfamily Betaherpesvirinae and genus Cytomegalovirus, has also been associated with viral conjunctivitis, specifically in the context of HIV infection [129,130,131,132,133,134]. Both EBV and HCMV conjunctivitis may be associated with potentially sight-threatening keratitis [135,136,137,138,139,140], uveitis [141,142,143,144,145], and retinitis [146,147,148], once again emphasizing the importance of thorough ophthalmic examination in conjunctivitis patients.

2.6 Picornavirus Conjunctivitis

The picornaviruses, belonging to the family Picornaviridae, are a collection of small (~30 nm), nonenveloped, icosahedral, positive-sense single-stranded RNA viruses [149]. Several members of the genus Enterovirus are associated with conjunctivitis, including four human enterovirus species (A–D) and three rhinovirus species (A–C). The most well-known clinical syndrome associated with the picornaviruses is acute hemorrhagic conjunctivitis (AHC), caused principally by human enterovirus species C (including coxsackievirus A24 variant, CA24v) and enterovirus species D (enterovirus type 70, EV70) [150, 151]. With an exceptionally short incubation time (≤24 h), AHC manifests as a rapid onset, painful, follicular conjunctivitis associated with eyelid swelling, epiphora, and serous or seromucoid discharge, initially arising in one eye but often quickly evolving into bilateral disease. The hallmark feature of AHC is the development of subconjunctival hemorrhages of varying severity, ranging from small petechial lesions to confluent areas of frank bleeding that are easily provoked by eye rubbing. Corneal punctate erosions and epithelial keratitis may occur in some patients, but subepithelial infiltrates are thought to be rare in enteroviral infection [152]. There is no specific therapy for AHC, and despite its striking clinical features, infection usually resolves within 1–2 weeks following symptom onset.

The emergence of AHC in the late 1960s, coinciding with the first successful lunar landing, led to this infection being named “Apollo 11 Disease” [153]. The first global pandemic of AHC occurred in 1969, with two main epicenters: Accra, Ghana [154, 155], and the Indonesian island of Java [153]. The disease spread rapidly throughout Africa, Asia, and continental Europe [4, 156], with 1.5 million people affected in the Indian cities of Mumbai and Calcutta alone [153, 157]. This emergent pathogen—later identified as EV70 from conjunctival scrapings of affected individuals [156]—was of significant global concern because of its neural tropism [158,159,160]. The neuroinvasive manifestations of EV70 include meningoencephalitis, myelitis, and cranial neuritis, and are clinically indistinguishable from infection caused by the feared poliovirus, which is also a member of the human enterovirus species C. Fortunately, the incidence of neurological disease caused by EV70 is not as high as that caused by polio. A large concurrent AHC outbreak arose in Singapore and Malaysia in 1971, leading to 60,000 cases [5]. Initially thought to be caused by the same virus that initiated the 1969 pandemic, the causative agent was later identified as CA24v [161]. EV70 and CA24v, both temperature-sensitive viruses [162, 163], continue to be implicated in periodic outbreaks [164,165,166,167,168], mostly affecting densely populated coastal cities in tropical climates. The largest outbreak since the 1970s occurred in South Korea in 2002, with CA24v-AHC affecting over one million individuals [169]. For reasons that are unclear, while EV70 has caused global pandemics, CA24v has remained mostly confined to Asia.

2.7 Poxvirus Conjunctivitis

2.7.1 Variola (Smallpox) Conjunctivitis

The Poxviridae family of viruses consists of large, ovoid, dsDNA viruses [170, 171]. Four are associated with ocular infection: variola, vaccinia, molluscum contagiosum, and orf viruses [172]. These viruses cause conjunctivitis principally through shedding of virions from adjacent infections on the periorbital skin and lid margins. The most lethal of all poxviruses is the variola or smallpox virus, belonging to the subfamily Chordopoxvirinae and genus Orthopoxvirus. Although smallpox was eradicated in 1977 [173], and no known natural reservoirs exist, smallpox and its close relatives remain of significant public health interest owing to their potential misuse as agents of bioterrorism and biological warfare [174, 175]. Smallpox, which has an incubation period of up to 19 days, is transmitted via respiratory droplets, direct contact, and fomites [176]. The clinical manifestations of smallpox include the generalized eruption of a disfiguring and painful pustular rash, often preceding overwhelming viremia and eventual death in 10–20% of all those infected [177]. The virus was also responsible for severe visual complications, occurring in up to 10% of all cases, and capable of affecting all structures in the eye [174]. The most common of these manifestations was the development of smallpox conjunctivitis of varying severity. While most cases were benign and characterized by subclinical conjunctivitis with mild watery discharge, more severe forms involved the formation of painful, weeping pustules on the eyelid, bulbar conjunctiva, and corneal limbus. These caused severe photophobia, profound injection, and chemosis. Active viral shedding in tears and from ocular surface pustules frequently led to corneal ulceration, the most common cause of smallpox-related blindness [178].

2.7.2 Vaccinia Conjunctivitis

The primary immunogenic ingredient in smallpox vaccines is a replication-competent vaccinia virus, a close relative of variola and also a member of the subfamily Chordopoxvirinae and genus Orthopoxvirus. Historically, vaccinia infections emerged as one of the unintended consequences of worldwide smallpox immunization programs [172, 179], with an estimated incidence of 1 in 40,000 primary vaccinations [180, 181]. Although the smallpox vaccine is no longer provided in most countries, it is still administered in selected populations. For example, the United States Department of Defense Smallpox Vaccination Program immunized nearly 500,000 military personnel in 2002 [182]. Smallpox immunization produces a distinct papule (up to 1 cm) at the site of injection, which harbors replicating vaccinia virus [183]. Vaccinia ocular infection is precipitated by accidental autoinoculation, from vaccination site to hand to eye [184]. The local papule left after vaccination is thought to shed virions for up to 3 weeks until the scab has fallen off [185]. Following an incubation period of 5–7 days, vaccinia infection of the eye typically results in the formation of white umbilicated pustules on the periorbital skin and eyelids [186, 187]. The same lesions may also arise on the conjunctiva, leading to an acute and diffuse papillary reaction, and serous or mucopurulent discharge [172]. Curiously, conjunctival follicles are not prominent. Vaccinia lesions on the conjunctiva may ulcerate [172], and in severe cases may be associated with the production of a thick, symblepharon-forming membrane. Corneal involvement is rare, occurring in ~1 of 1.2 million primary vaccination recipients [188]. Clinical signs can range from a mild epithelial keratitis to active stromal and endothelial disease, complicated by corneal ulceration. The Centers of Disease Control and Prevention recommends off-label application of topical antivirals (e.g., trifluridine) and consideration of vaccinia immune globulin in severe cases of vaccinia keratoconjunctivitis [183]. Importantly, acyclovir is reported to be ineffective in treating the ocular manifestations of vaccinia [172].

2.7.3 Other Poxvirus-Related Conjunctivitis

Infection with molluscum contagiosum virus, a member of the subfamily Chordopoxvirinae and genus Molluscipoxvirus [171], is characterized by the pathognomonic formation of multiple painless, discrete, dome-shaped papules with umbilicated centers on the skin. On occasion, molluscum contagiosum can also infect mucous membranes, including the conjunctiva [189]. Following an incubation period of 6–7 weeks, molluscum contagiosum may manifest as unilateral periocular and bulbar conjunctival papules associated with a secondary follicular conjunctivitis [190]. Although benign and not sight-threatening, chronic conjunctivitis has been reported in immunosuppressed patients and has been occasionally associated with cicatricial punctal occlusion [191]. Corneal signs, if present, may include corneal micropannus formation and punctate epithelial keratitis [192]. Anecdotal evidence suggests that oral acyclovir might be effective in treating this disease [193], but elimination of the molluscum lesion on the eyelid margin by incision, excision, or curettage eliminates the source of viral replication and is generally curative in immune competent individuals [191]. The last of the poxviruses capable of infecting humans is the orf virus, belonging to the subfamily Chordopoxvirinae and genus Parapoxvirus. Orf virus is trophic to sheep and goats, causing pustular dermatitis of the mouth, nose, and teats [194]. However, zoonotic transmission of orf virus has been reported in humans following close contact with livestock, with case reports of maculopapular lesions arising along the canthal folds and conjunctiva, associated with a self-limited mild to moderate conjunctivitis [194].

2.8 Other Important Causes of Viral Conjunctivitis

2.8.1 Arbovirus Conjunctivitis

The arboviruses, an informal acronym for “arthropod-borne” viruses, are transmitted through arthropod vectors including mosquitoes and ticks [195]. The arboviruses, which are single-stranded RNA viruses, have gained international notoriety in recent years owing to their rapid global dissemination. In the last decade alone, outbreaks have swept through the Americas, Africa, and Asia, driven primarily by the tropical and subtropical spread of the mosquito species Aedes aegypti and Aedes albopictus. The most prominent of these include dengue and zika viruses, both of the family Flaviviridae and genus Flavivirus; and chikungunya virus, of the family Togaviridae and genus Alphavirus. Others include Rift Valley fever [196] and yellow fever viruses [197]. The presenting features of arboviral infection vary widely, ranging from asymptomatic disease to an acute febrile illness characterized by constitutional malaise, myalgia, polyarticular arthralgia, headache, and a generalized morbilliform exanthem [198]. Ocular infection may occur as a self-limiting, nonpurulent conjunctivitis with retro-orbital pain [199,200,201], seen most commonly as the presenting features of zika and chikungunya infection, to potentially sight-threatening uveitis [202, 203], chorioretinitis [204, 205], and optic neuritis [206, 207]. Arboviral infections should be considered part of a weighted differential diagnosis for patients seen in endemic countries and returned travellers, particularly important in resource-constrained settings with limited access to laboratory testing [208]. No specific treatments exist for arbovirus-associated conjunctivitis.

2.8.2 Measles, Mumps, and Rubella Conjunctivitis

The worldwide availability of vaccines against measles, mumps, and rubella (MMR) viruses has led to significant decreases in their overall incidence. However, recent worldwide measles epidemics in 2019 reflect alarming declines in vaccination rates owing to vaccine skepticism and/or hesitancy, as well as waning immunity from childhood immunization [209,210,211]. The MMR viruses are transmitted through respiratory droplets, direct contact, and fomites. Affected individuals typically develop a prodrome of fever, generalized malaise, and arthralgia, followed by the eruption of a generalized morbilliform exanthem. Conjunctivitis features in 60–70% of all acute presentations of rubella [212] and measles [213], but is less common in mumps [214]. The follicular conjunctivitis caused by these viruses is clinically indistinguishable from other viral causes, although a range of associated ocular and extraocular signs may provide diagnostic clues to etiology. For example, acute mumps infection is traditionally associated with parotitis and dacryoadenitis, while measles is associated with pathognomonic Koplik spots— small, raised lesions on an erythematous base—along mucosal surfaces, most commonly on the buccal mucosa but also occasionally found on the conjunctiva [215, 216]. The conjunctivitis seen in measles can be accompanied by corneal ulceration, which occurs within 2 weeks of the viral exanthem [217]. The combination of conjunctivitis, rash, and respiratory symptoms in unvaccinated patients, particularly young children, should always prompt suspicion of MMR infection and referral for urgent medical evaluation.

2.8.3 Conjunctivitis Associated with Human Immunodeficiency Virus

The human immunodeficiency virus (HIV) is associated with either primary or secondary infections of nearly all ocular structures [218]. HIV-associated conjunctivitis may arise through several mechanisms. In acute seroconversion illness, which usually occurs in the first few weeks following HIV infection as the immune system generates detectable levels of HIV antibody, a mild and self-limiting conjunctivitis may develop as part of a flu-like syndrome characterized by malaise, coryza, sore throat, and generalized lymphadenopathy [219, 220]. Progressive immune destruction in HIV-infected patients is associated with an increased risk of reactivation of HSV [221, 222] and HZO [223]. The association between HIV infection and risk of recurrent HZO is particularly strong [224]. HZO occurs in up to 15% of all HIV-infected persons [225], and the relative incident risk of recurrent disease is estimated to be approximately six times that of HIV-negative individuals [226]. HZO in HIV-infected patients is more likely to involve the cornea [227], and more likely to result in chronic pseudodendritiform keratitis, with lesions that lack the characteristic terminal bulbs and central staining seen in HSV epithelial keratitis [228]. HZO in young patients should warrant consideration of HIV testing, particularly in those who may disclose a history of high-risk sexual activity and/or intravenous drug use.

HIV is also associated with increased severity of other ocular infections. In immunocompromised persons, lesions caused by molluscum contagiosum are usually of greater size and number, and secondary chronic conjunctivitis is common [229]. Additionally, opportunistic pathogens which are not usually associated with conjunctival disease may more commonly manifest on the ocular surface of HIV-infected persons, including Mycobacterium tuberculosis [230], Pneumocystis carinii [231], and microsporidia [232, 233]. A third mechanism by which HIV may result in conjunctivitis is through immune reconstitution inflammatory syndrome (IRIS), which occurs in the months immediately following the initiation of highly active antiretroviral therapy. This condition is characterized by the paradoxical worsening of the inflammatory manifestations of preexisting infections, some of which may have escaped detection at a prior stage [234]. IRIS may unmask previously subclinical HZO [235], microsporidial keratoconjunctivitis [236], and molluscum contagiosum [237]. Finally, HIV is associated with conjunctival microangiopathic changes in up to 80% of patients, mirroring those also found in the retina [238, 239]. Considered to be benign, vascular changes including microaneurysm formation and segmental vessel tortuosity are usually best appreciated at the corneal limbus. However, the pathogenesis of these changes, and their possible relation to HIV infection, remain unclear.

2.8.4 Other Causes of Conjunctivitis

The viruses described above are not an exhaustive list of those capable of causing ocular surface infection. The human papilloma virus (HPV), belonging to the family Papillomaviridae, subfamily Firstpapillomavirinae, and genus Alphapapillomavirus [240], is a ubiquitous epitheliotrophic virus which is acquired through close contact with infected body surfaces. Neonatal peripartum transmission occurs through the birth passage, while adult transmission occurs through intimate contact with infected persons [241]. Importantly, several HPV subtypes have oncogenic properties and are now considered causative agents of squamous cell neoplasia [242, 243]. Although these causal associations are strongest in the setting of cervical cancer, HPV has also been implicated in the pathogenesis of conjunctival tumors. HPV subtypes 6 and 11 are classically associated with the formation of benign conjunctival papillomas, which are composed of pinkish-red fibrous bands of tissue and pathognomonic frond-like vascular loops [244,245,246]. In contrast, HPV subtypes 16 and 18 are associated with ocular surface squamous neoplasia (OSSN), which encompasses premalignant conjunctival intraepithelial neoplasia (CIN) [247, 248] and malignant squamous cell carcinoma [249, 250]. Chronic immune suppression is a strong risk factor for the development of HPV-associated OSSN, the incidence of which increased dramatically with the emergence of HIV/AIDS in the 1980s [251].

A range of respiratory viruses, including coronavirus [252], influenza virus [253], parainfluenza virus [254], are also known to cause conjunctivitis. Early studies of the 2019–2020 coronavirus disease (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2), have now analyzed a cumulative volume of over 55,000 laboratory-confirmed cases [255, 256]. “Conjunctival congestion”, most likely representing viral conjunctivitis, has been reported to be a presenting feature in approximately 0.8% of all infected patients. It is likely, therefore, that conjunctivitis will continue to feature as part of case-finding matrices used in further epidemiologic studies as the global outbreak unfolds. Another family of viruses which have caused multiple pandemics in the last century, the influenza viruses, are also important causes of conjunctivitis. It is known that certain types (e.g., human and avian influenza A, H7 subtype [257, 258]) have an unusual affinity for the ocular surface, possibly through preferential binding to terminal sialic acids on the surface of conjunctival epithelium [259]. The eye is not often thought of as a portal of entry for respiratory viral infections, or a site of viral replication, but recent findings suggest that the ocular surface may serve as an important conduit to subsequent nasopharyngeal and respiratory infection by these viruses.

Newcastle disease is caused by avian avulavirus 1 of the family Paramyxoviridae and genus Avulavirus, which occasionally causes outbreaks in poultry workers and veterinarians who may come into contact with poultry secretions and droppings [260,261,262]. The first known case was described in a poultry worker inadvertently exposed to fluid from a fertilized chicken egg [263]. The patient later developed generalized malaise, fever, headache, and mucopurulent conjunctivitis, with a clinical course lasting a week before an uneventful recovery. This form of conjunctivitis produces a follicular or papillary reaction associated with hyperemic and edematous changes. The future emergence of novel viruses, particularly those capable of zoonotic transmission, will continue to expand the list of pathogens capable of causing ocular surface infection.

2.9 Diagnostic Evaluation of Viral Conjunctivitis

2.9.1 Traditional Methods of Diagnosis

In most cases of viral conjunctivitis, the diagnosis is made on the basis of clinical findings, and identification of the precise causative agent is unnecessary. However, all patients with viral conjunctivitis should undergo a thorough anterior and posterior segment examination at the slit lamp, as there may be signs which can significantly alter the differential diagnosis. Conjunctivitis associated with corneal findings, anterior chamber inflammation or posterior pole changes, and/or relevant extraocular features, should warrant consideration of alternative and possibly more severe diagnoses. It is vitally important, for instance, to establish whether HSV or VZV infection is confined to the conjunctiva, or if there is corneal involvement. As emphasized earlier, the presence of keratitis can alter how the patient should be treated. Unusual or atypical findings may also warrant laboratory testing. Viral culture has long been considered the gold standard of virus detection, but is limited by its relatively poor sensitivity [264] and protracted turnaround time. Tzanck smears, which are prepared by using hematoxylin-eosin, Giemsa, or Papanicolaou stains on material collected from deroofed vesicular lesions, may be used to identify multinucleated giant (Tzanck) cells and acidophilic nuclear inclusion bodies that are strongly suggestive of herpetic infection. However, these smears alone are poorly sensitive and cannot distinguish between HSV and VZV [114]. Paired acute and convalescent serology is rarely helpful because several weeks must elapse before a demonstrable rise in antibody titers, after which the therapeutic window may have closed.

2.9.2 Molecular Diagnosis of Viral Infections

It is now possible to diagnose a variety of viral infections with diagnostic molecular assays. For instance, polymerase chain reaction (PCR) assays have been used to diagnose HSV from conjunctival swabs and/or tears, with reported sensitivities of up to 92% [265]. However, because viral shedding may occur in otherwise asymptomatic individuals [266], PCR is prone to false-positive results and unable to differentiate active from latent infection. Molecular assays have also been used for adenoviral conjunctivitis. Point-of-care tools such as the RPS Adeno Detector and its later model, the AdenoPlus (Rapid Pathogen Screening, Fl) are both US Food and Drug Administration-approved devices which detect adenovirus in tear samples based on an enzyme-linked immunosorbent assay (ELISA) specific to the highly conserved HAdV hexon protein, with results available within 10 min. While company-sponsored trials have reported sensitivities and specificities of over 85% for the RPS Adeno Detector [267] and AdenoPlus [268], their application in real clinical scenarios has yielded less encouraging results, with sensitivities and specificities ranging from 39.5–50% and 92–95.5%, respectively [269, 270]. PCR is regarded as a more accurate molecular test for HAdV conjunctivitis, and its use continues to shed new light on pathogens that may cause ocular disease that is indistinguishable from that caused by HAdV. For instance, an international, multicenter randomized clinical trial investigating the use of auricloscene in participants clinically diagnosed with EKC showed that 22% of those recruited were PCR-negative for HAdV [271]. A substantial proportion of these patients developed SEIs, suggesting that there are other viruses—yet to be identified—which are capable of causing EKC or EKC-like syndromes.

2.9.3 Whole Genome Sequencing

The advent of whole genome sequencing (WGS) has changed how epidemiologic investigations are conducted in emerging outbreaks. The procurement of data in real time as an epidemic evolves is particularly helpful in identifying the causative agent, its origins, and modes of transmission. In one recent example, WGS was used to guide infection control procedures during a nosocomial outbreak of systemic and ocular HAdV-B3 in a neonatal intensive care unit, which led to a total of 23 infections and four newborn deaths [272]. During this event, WGS was performed on nasopharyngeal aspirates of affected patients and their surrounding environment, quickly identifying HAdV-B3 as the culprit pathogen. These data showed that the outbreak had been driven primarily through the repeated use of ophthalmic instruments used to screen newborns for retinopathy of prematurity [272, 273], and this knowledge allowed for immediate modifications to be made to isolation procedures and clinical workflows. WGS may also provide unprecedented insights into the molecular epidemiology of implicated pathogens, allowing for spatial and/or geographic mapping in a variety of community and healthcare settings [22]. With a deeper understanding of viral transmission dynamics, it is possible to implement interventions that may mitigate risk of exposure in large populations. As costs decline and sequencing efficiency improves, WGS may also one day be optimized as a diagnostic tool for individualized clinical care.

2.10 Management of Viral Conjunctivitis

Despite years of research in potential therapies, few, if any, agents have been found to fundamentally alter the course of viral conjunctivitis. Where pertinent, specific treatments have been described in the text above. For the most common etiologies, supportive therapies including cool compresses, artificial tears, and topical nonsteroidal anti-inflammatory drugs [274] may offer symptomatic relief to some patients. Conjunctival membranes, which occur most frequently in EKC, can be gently removed and treated with a topical corticosteroid. In the absence of effective medications, prevention of disease transmission is even more critical. Patients with pink eye should be counseled regarding the importance of hand hygiene and self-quarantine, minimizing close contact with others and their personal articles. As a general rule, patients should be advised that viral shedding should be expected to occur for at least 10 days following symptom onset [32, 275]. This may warrant a brief furlough from work or school until symptoms have subsided, which is particularly important for healthcare workers who may come into contact with immunocompromised patients, the elderly, and neonates. For eye care providers, it is important to ensure ophthalmic instruments are cleaned thoroughly with hospital-grade disinfectants (e.g., chlorine-based agents [276]) after every patient encounter, and to avoid repeated use of common bottled ophthalmic medications (e.g., topical cycloplegic and anesthetic eye drops) across different patients. Follow-up should be initiated on an as-needed basis, and patients should be informed that any changes to their vision should prompt urgent ophthalmology review.

2.11 Conclusions and Future Directions

Despite its burden of disease and costs to society, viral conjunctivitis remains an underappreciated cause of ocular morbidity. Although many of the etiologies of viral conjunctivitis produce stereotypical symptoms and clinical findings, these infections should not be considered a homogenous disorder. Rather, the virosphere is replete with agents that infect the eye, either as a localized process or as a part of systemic infection. Eliciting a thorough patient history and comprehensive physical examination is important for all patients, and the presence of other ocular and/or systemic findings should prompt consideration of less common etiologies and definitive diagnostic testing. The history of viral conjunctivitis outbreaks in the last century strongly suggests that new and emerging viruses will cause wide-scale disease outbreaks in the future. Indeed, the viruses discussed in this chapter do not form an exhaustive list of all viral agents capable of infecting the ocular surface. Further research in molecular diagnostics may bring us closer to a more complete understanding of the pathogenesis, epidemiology, and disease associations of viruses, in ways that may inform future inquiries into urgently needed novel therapeutics for this age-old disease.