Viral eye: Emerging insights into corneal and ocular surface viral infections

Abstract

Viral infections of the ocular surface significantly contribute to morbidity and visual impairment globally. The herpes simplex virus (HSV), adenovirus, cytomegalovirus (CMV), and human papillomavirus (HPV) are predominant pathogens impacting the cornea and conjunctiva, resulting in recurrent illness, epidemic outbreaks, and virus-associated neoplasia. Progress in virology, immunology, and molecular diagnostics has enhanced comprehension of host–virus interactions and introduced novel therapeutic opportunities. A narrative literature review was performed utilizing PubMed, Scopus, and Web of Science, encompassing papers published from 2000 to 2025, with a specific focus on research from 2020 onwards. Eligible publications were peer-reviewed clinical and experimental investigations, together with reviews that focused on epidemiology, etiology, diagnostic methodologies, and therapeutic alternatives. Research indicates that HSV keratitis is the predominant infectious cause of corneal blindness in high-income nations, although adenovirus persists in instigating epidemics of keratoconjunctivitis in the absence of licensed antiviral treatments. CMV keratitis, previously confined to immunocompromised persons, is now acknowledged in immunocompetent patients as a causative agent of corneal endotheliitis. HPV is associated with ocular surface squamous neoplasia, especially in areas with elevated ultraviolet exposure and high human immunodeficiency virus prevalence. Innovative molecular diagnostics, innovative antiviral agents, immunomodulatory approaches, and immunization initiatives signify significant progress that could enhance preventative and therapeutic results.

Key Words: Herpes simplex keratitis; Cytomegalovirus keratitis; Adenoviral conjunctivitis; Viral eye infections; Ocular surface squamous neoplasia

Core Tip: Viral infections of the ocular surface are prevalent and significant contributors to corneal and conjunctival disorders globally. The herpes simplex virus is a primary cause of infectious corneal blindness, adenoviruses are responsible for epidemic conjunctivitis outbreaks, cytomegalovirus is increasingly acknowledged as a cause of keratitis in immunocompetent individuals, and human papillomavirus plays a role in ocular surface squamous neoplasia. Progress in molecular virology, immunology, and diagnostics is transforming comprehension and management, while novel antivirals, immunotherapies, and vaccines present new avenues for prevention and treatment.

INTRODUCTION

Ocular viral infections are a major global health issue, significantly contributing to morbidity, visual impairment, and socioeconomic hardship. The predominant viral ocular illnesses are conjunctivitis and keratitis, with adenoviruses responsible for 65%-90% of viral conjunctivitis in adults, and herpes simplex virus (HSV) causing roughly 1.7 million new cases of keratitis globally each year[1-4]. These infections exhibit high contagion rates, resulting in recurrent outbreaks in both community and healthcare environments, hence causing significant job absenteeism, inappropriate use of antibiotics, and increased healthcare costs[3,5]. In addition to their immediate effects, viral ocular infections may lead to irreversible corneal scarring, neurotrophic keratopathy, or ocular surface neoplasia, highlighting their enduring implications for vision and quality of life.

The range of viruses associated with ocular surface and corneal diseases is continually broadening. Adenoviruses are the predominant etiological agents of acute viral conjunctivitis in adults, with epidemic keratoconjunctivitis (EKC) attributed to serotypes including HAdV-8, -37, and -64. These highly transmissible strains can persist on fomites for weeks, precipitating epidemic outbreaks that necessitate stringent infection control measures[3,4]. Corneal involvement can lead to subepithelial infiltrates, chronic keratitis, and enduring vision impairments. Topical corticosteroids offer temporary symptomatic relief during the late inflammatory stages; however, their extended usage has hazards such as increased intraocular pressure and delayed virus clearance. Despite ongoing research into novel antivirals aimed at viral entry and replication, no drug has received regulatory approval for adenoviral keratoconjunctivitis.

HSV and varicella-zoster virus (VZV) are primary contributors to infectious corneal blindness in affluent nations[1,4]. HSV keratitis exhibits a recurring pattern, impacting the epithelial, stromal, and endothelial layers, with successive recurrences heightening the likelihood of irreversible visual impairment. Oral prophylaxis with acyclovir markedly lowers recurrence rates, with treatment customized according to disease phenotype: Topical ganciclovir or oral antivirals for epithelial keratitis, and corticosteroids in conjunction with antivirals for stromal keratitis and endotheliitis. VZV, especially as herpes zoster ophthalmicus, can induce both acute and chronic ocular problems. The recombinant zoster vaccination has proven to be an effective preventive strategy, diminishing both the incidence and severity of ocular zoster disease[6].

Cytomegalovirus (CMV), formerly linked to retinitis in immunocompromised patients, has emerged as a notable etiological factor for corneal endotheliitis and anterior segment pathology. CMV keratitis is now observed in immunocompetent individuals, generally presenting as recurrent endotheliitis or keratouveitis. Diagnosis necessitates PCR confirmation from aqueous humor, and therapy typically entails systemic or topical ganciclovir. Antiviral resistance continues to pose a significant barrier in situations necessitating long-term prophylaxis[7].

Alongside these established infections, some developing and re-emerging viruses have been associated with ocular surface illness. Severe acute respiratory syndrome coronavirus 2, monkeypox virus, Zika virus, and dengue virus have all been linked to conjunctivitis, keratitis, and, in certain instances, posterior segment complications, including retinitis and optic neuritis[8,9]. Their acknowledgment highlights the eye's susceptibility as both a locus of infection and a possible reservoir for viral dissemination. CMV retinitis continues to be a significant cause of blindness in areas with elevated human immunodeficiency virus (HIV) incidence, particularly where access to antiretroviral medication is restricted[10]. The prevalence of herpetic ocular illness is probably underestimated in low- and middle-income countries because of elevated HSV seroprevalence and limited access to specialized medical treatment[2].

The extensive repercussions of these infections are seen in the epidemiology of corneal blindness, which is one of the primary contributors to global vision impairment. An estimated 5.5 million individuals are bilaterally blind or experience moderate-to-severe vision impairment due to corneal opacity, while an additional 6.2 million are unilaterally blind. The greatest impact is noted in low-resource environments, when infectious keratitis, ocular damage, and postoperative sequelae are common[11]. Preventive measures, such as infection control, vaccination, and early detection, are essential for mitigating the long-term effects of these disorders.

Recent advancements in molecular biology and immunology are revolutionizing the comprehension of host–virus interactions at the ocular surface. High-throughput systems biology methodologies, single-cell transcriptomics, and computational modeling have elucidated the intricacies of antiviral immune responses, emphasizing the interaction between innate immunity, adaptive mechanisms, and viral evasion tactics[12-14]. These discoveries enhance comprehension of viral persistence and latency while also facilitating the advancement of targeted therapeutics and precision medicine approaches in ophthalmology. Innovative diagnostic instruments, including multiplex PCR and next-generation sequencing, provide the swift and precise identification of many eye infections concurrently, enhancing diagnostic efficacy and informing personalized treatment[15].

This study aims to consolidate existing knowledge on four principal viral and virus-associated ocular surface diseases: HSV keratitis, adenoviral conjunctivitis, CMV keratitis, and human papillomavirus (HPV)-related ocular surface squamous neoplasia (OSSN). Each of these diseases illustrates a distinct facet of viral pathology-recurrent infection, epidemic transmission, immune evasion, and oncogenesis. This study emphasizes the problems and potential in tackling viral eye illness by integrating epidemiology, etiology, clinical characteristics, diagnostic innovations, and therapeutic approaches. Advancements in virology, immunology, and clinical care will be essential in alleviating the global impact of corneal and ocular surface viral infections.

This review serves as a narrative minireview aimed at synthesizing contemporary evidence regarding corneal and ocular surface viral infections, specifically emphasizing HSV keratitis, adenoviral conjunctivitis, CMV keratitis, and HPV-associated ocular OSSN. A thorough literature search was conducted utilizing PubMed/MEDLINE, Scopus, and Web of Science to identify articles published from January 2000 to June 2025, with particular focus on studies from 2020 onward to capture the latest advancements in molecular virology, immunology, diagnostics, and therapeutics.

The search strategy utilized a blend of Medical Subject Headings and free-text keywords, encompassing terms such as “herpes simplex keratitis”, “HSV keratitis”, “adenoviral conjunctivitis”, “epidemic keratoconjunctivitis”, “cytomegalovirus keratitis”, “CMV endotheliitis”, “human papillomavirus”, “HPV ocular surface squamous neoplasia”, and “viral keratitis”. Boolean operators were employed to expand or narrow searches as necessary. Further research were obtained by manually examining the reference lists of significant review articles and original publications.

Eligible studies were deemed acceptable if they were peer-reviewed and included original data, clinical observations, or thorough reviews pertinent to viral infections of the ocular surface. Publications were considered if they pertained to epidemiology, etiology, clinical characteristics, diagnostic methods, or therapeutic approaches. Only articles published in English were included. Studies concentrating solely on posterior segment symptoms of viral infections or unrelated to corneal and ocular surface disorders were omitted.

The titles and abstracts were screened for relevance, and full texts were examined in instances of ambiguity. This review, being narrative in style, did not undergo a formal risk-of-bias evaluation; still, priority was accorded to well conducted clinical studies, randomized trials, systematic reviews, and experimental research published in indexed journals. The literature was meticulously examined and compiled to emphasize existing knowledge, developing trends, and prospective directions in ocular surface virology.

HSV KERATITIS

HSV keratitis is a predominant cause of infectious corneal blindness in affluent nations, with HSV-1 responsible for the majority of cases, while HSV-2 is infrequently involved unless in neonatal or immunocompromised situations[16]. The global prevalence is significant, with around 1.7 million new cases each year and hundreds of thousands affected by recurring or chronic disease. The repetitive occurrence of HSV keratitis significantly impacts visual impairment, healthcare expenses, and the quality of life for patients[2,17]. The implementation of novel therapeutic strategies has progressed at a sluggish pace, and despite extensive study over several decades, the disease continues to pose a significant public health concern[18].

Subsequent to the first ocular infection, HSV develops latency within the trigeminal ganglion. Reactivation may be induced by stress, ultraviolet radiation, fever, or immunosuppression, leading to anterograde transfer of the virus via sensory nerves to the corneal surface, resulting in recurrent epithelial or stromal pathology[16,19]. Latency and reactivation are pivotal to HSV pathogenesis, with immunological dysregulation and viral evasion mechanisms sustaining chronic illness. Corneal pathology is influenced by both viral replication and an increased host immune response, leading to tissue damage and scarring[20].

The clinical spectrum of HSV keratitis is extensive, including epithelial keratitis, stromal keratitis, endotheliitis, and neurotrophic keratopathy[16-21]. Epithelial keratitis generally manifests as dendritic or geographic ulcers, directly resulting from viral replication in corneal epithelial cells. Stromal keratitis is primarily immune-mediated, characterized by recurring inflammation that leads to opacification, thinning, and neovascularization, ultimately impairing vision. Endotheliitis arises from inflammation of the corneal endothelium produced by viral antigens, frequently linked to uveitis and corneal edema. Recurring incidents may result in corneal hypoesthesia and neurotrophic keratopathy, characterized by compromised corneal innervation that causes inadequate healing and an increased susceptibility to ulceration and perforation. Each recurrence elevates the probability of permanent visual impairment and necessitates corneal transplantation[21].

Diagnosis is predominantly clinical, augmented by slit-lamp examination; nevertheless, laboratory confirmation is becoming increasingly vital in unusual or treatment-resistant patients. PCR is the most sensitive and specific diagnostic technique, facilitating quick viral detection from corneal scrapings or aqueous humor samples. Recently, metagenomic sequencing techniques have been investigated, especially for atypical or co-infected individuals; however, these methods are primarily limited to research environments and are not yet broadly accessible in clinical practice[22].

Therapeutic techniques are customized according to the clinical subtype of HSV keratitis. Epithelial keratitis is treated with topical antivirals such as ganciclovir gel or acyclovir ointment, or with oral medications such as acyclovir, valacyclovir, and famciclovir[23]. Stromal and endothelial variants necessitate the use of combination oral antivirals and topical corticosteroids to manage immune-mediated injury while inhibiting viral replication[24]. Prolonged oral prophylaxis with acyclovir has been shown to diminish the likelihood of recurrence, serving as a fundamental aspect of preventive therapy[25]. Novel antivirals with enhanced safety profiles are being studied; nonetheless, resistance continues to pose a therapeutic challenge, particularly in immunocompromised individuals[26]. Despite extensive efforts over several decades, no HSV vaccine has achieved clinical application, although numerous vaccine candidates have demonstrated immunogenicity in preclinical or early clinical trials[27]. Recombinant human nerve growth factor (cenegermin) has been effective in facilitating epithelial repair and vision restoration in patients with neurotrophic keratopathy[28].

Recent studies emphasize the intricate relationship among viral infection, immunological dysfunction, and corneal nerve degeneration. Recent immunobiological research has highlighted the contributions of innate and adaptive immune responses, encompassing dendritic cells, T cells, and pro-inflammatory cytokines, in sustaining stromal keratitis[16,29]. The degenerative impact of HSV on corneal nerves intensifies disease chronicity, since structural and functional changes lead to hypoesthesia and compromised wound healing[30]. Comprehending these pathways is essential for creating tailored therapeutics that can disrupt the cycle of recurrence, immune-mediated fibrosis, and neurotrophic injury. Despite advancements in diagnosis and management, HSV keratitis continues to be a significant cause of visual impairment, necessitating more research to develop innovative antivirals, and immunomodulatory approaches that can modify the progression of this complex illness.

ADENOVIRAL CONJUNCTIVITIS

Adenoviral conjunctivitis is the predominant etiology of viral conjunctivitis in adults, representing 65%-90% of global occurrences, with an estimated annual prevalence of up to 20 million cases in the United States alone. Outbreaks frequently occur in healthcare facilities, educational institutions, military settings, and various community environments, demonstrating the significant transmissibility of adenoviruses. Transmission occurs through direct contact with contaminated hands, fomites, or medical devices, as well as by respiratory droplets and, infrequently, contaminated water[1,3,31]. The virus can remain on environmental surfaces for weeks, with transmission rates in close-contact settings reported between 10% and 50%, highlighting the difficulty of controlling outbreaks[31-33].

The clinical manifestations of adenoviral ocular illness differ based on the viral serotype. EKC is predominantly linked to human adenovirus serotypes 8, 19, and 37 whereas pharyngoconjunctival fever (PCF) is generally induced by serotypes 3, 5, 7 and 11[33]. EKC outbreaks are notably common in Asia, typically peaking around winter and spring, while PCF exhibits a seasonal preponderance in the summer months in areas such China, Australia, and the United States. Epidemiological data over several decades corroborate the worldwide prevalence of pathogenic serotypes and demonstrate changing trends in epidemic dynamics[34].

Adenoviral conjunctivitis clinically manifests with an abrupt onset of erythema, irritation, serous discharge, and conjunctival hyperemia. EKC is generally characterized by chemosis, conjunctival pseudomembranes, and ipsilateral preauricular lymphadenopathy. Corneal involvement occurs in up to 50% of EKC patients, presenting as subepithelial infiltrates that induce discomfort, photophobia, diminished vision, and enduring corneal opacities that may continue for months[31-34]. Adenoviral keratoconjunctivitis, although typically self-limiting, may lead to persistent keratitis and prolonged morbidity from corneal scarring.

The pathogenesis of adenoviral conjunctivitis is associated with the virus's affinity for the ocular surface. The entry of viruses into corneal epithelial cells is facilitated by the interaction between the adenoviral fiber knob and host cell receptors, particularly sialic acid-containing glycans and integrins like αVβ1 and α3β1[35,36]. These molecular interactions enable viral binding, internalization, and infection of the corneal epithelium, explaining the pronounced affinity of specific adenovirus serotypes for ocular tissue. This tropism elucidates the clinical severity of EKC and signifies a potential target for innovative antiviral treatments.

The diagnosis of adenoviral conjunctivitis is typically clinical, although point-of-care immunoassays like the AdenoPlus test offer rapid confirmation with high sensitivity and specificity[37]. Molecular diagnostic techniques, like as PCR, are accessible in reference laboratories but are not commonly employed in clinical practice except in severe cases or outbreak scenarios[15].

Management of adenoviral conjunctivitis is primarily supportive, focusing on symptomatic relief with artificial tears, cold compresses, and strict hygiene measures, as no antiviral therapy has yet been proven effective[38]. Topical antibiotics are not warranted unless bacterial superinfection is anticipated. Corticosteroids can mitigate severe inflammation or chronic subepithelial infiltrates; nevertheless, they carry dangers such as viral persistence and steroid-induced glaucoma, thus should be utilized selectively. Emerging evidence indicates that povidone-iodine (1%-5%) may expedite symptom resolution and diminish viral load, especially when used in conjunction with topical corticosteroids like dexamethasone; however, the evidence is of low certainty, and this strategy is not yet regarded as standard practice[39]. Clinical trials of topical antivirals, such as ganciclovir, trifluridine, and cidofovir, have produced inconsistent outcomes, exhibiting limited efficacy and tolerability concerns[40,41]. As of now, no antiviral treatment has received approval from the United States Food and Drug Administration (FDA) or other regulatory bodies especially for adenoviral keratoconjunctivitis.

Prevention is paramount, particularly in outbreak scenarios. Stringent hand hygiene, disinfection of surrounding surfaces, sterilization of ophthalmic tools, and isolation of infected patients are crucial to mitigate transmission. These measures are especially critical in high-risk environments, like hospitals, long-term care institutions, and ophthalmology clinics, where nosocomial transmission has been extensively recorded.

Future research in adenoviral conjunctivitis is exploring next-generation antiviral strategies and preventive approaches. Tailored antivirals, such as multivalent sialic acid conjugates and glycosaminoglycan (GAG) mimetics, have shown promise in in vitro models by blocking viral attachment to cell-surface receptors[42,43]. Broader-spectrum antiviral agents like cidofovir, ganciclovir, and ribavirin are under investigation, though none are yet approved[44]. Research is also being conducted on gene-editing methods that inhibit viral entrance pathways. Innovative approaches, including CRISPR–Cas9 gene editing targeting viral DNA entry or replication, are being studied as potential therapeutics[45]. These advancements offer potential for alleviating the substantial burden of adenoviral ocular illness worldwide.

CMV KERATITIS

CMV is acknowledged as an opportunistic infection in immunocompromised persons, typically linked to retinitis in patients with severe HIV/AIDS or those receiving immunosuppressive treatment. In the last twenty years, CMV has been recognized as a specific etiological agent of keratitis and corneal endotheliitis in immunocompetent individuals[46]. This paradigm shift has significant therapeutic ramifications, especially in areas where corneal transplantation is prevalent and where anterior segment pathology may resemble other etiologies of keratitis or graft rejection[47]. Rising findings from Asia and Europe have underscored CMV as an undervalued yet substantial contributor to corneal endothelial dysfunction and anterior uveitis[48].

The viral pathogenesis in CMV keratitis entails the reactivation of latent virus within the anterior chamber, resulting in direct infection of corneal endothelial cells[49]. Viral replication results in endothelial cell depletion, persistent inflammation, and compromise of the blood-aqueous barrier, frequently associated with increased intraocular pressure due to trabecular meshwork involvement. CMV can endure latency in myeloid lineage cells while influencing local immune responses. A crucial aspect of immune evasion is the inhibition of cytotoxic T lymphocyte (CTL) activity; research indicates that pp65-specific CTL responses confer protection and correlate with improved long-term results, while IE1-specific CTLs may inadvertently induce harmful inflammation[50,51]. These data indicate that the host immune response has a dual role in influencing disease severity and prognosis.

Clinically, CMV keratitis typically manifests as corneal endotheliitis, distinguished by coin-shaped or linear keratic precipitates, corneal edema, and varying degrees of anterior chamber inflammation[49]. Increased intraocular pressure is prevalent, resulting in secondary glaucoma if unrecognized and untreated. Patients who have undergone keratoplasty may experience CMV endotheliitis, frequently misidentified as graft rejection, complicating therapy and jeopardizing graft survival[47].

Precise diagnosis necessitates a heightened level of suspicion in instances of unexplained corneal edema and keratic precipitates, especially when associated with intraocular hypertension. PCR analysis of aqueous humor is the diagnostic gold standard, offering great sensitivity and specificity for the identification of CMV DNA. Quantitative PCR facilitates the evaluation of viral load, which may be associated with disease activity and prognosis. Metagenomic next-generation sequencing (mNGS) has recently emerged as a promising diagnostic instrument in unusual or ambiguous cases, providing the capability to detect CMV with other ocular viruses with enhanced sensitivity[52,53]. Serologic testing is of restricted value in this context, as systemic CMV seropositivity is prevalent and does not indicate localized ocular infection. Imaging methods, such as specular microscopy, can offer supplementary information by assessing endothelial cell density and tracking disease development[54].

Treatment approaches for CMV keratitis emphasize antiviral inhibition of viral replication. Topical ganciclovir gel, generally available in doses between 0.15% and 2%, is frequently utilized as the primary treatment for anterior segment illness in immunocompetent individuals[46-49]. Oral valganciclovir is utilized for more severe cases or those with inadequate response to topical treatment, whilst intravenous ganciclovir is often designated for immunocompromised individuals or refractory conditions. Induction therapy succeeded by maintenance dose is essential for attaining viral suppression and averting relapse[54]. In cases of resistance or intolerance, other antivirals such as foscarnet have been tested; nevertheless, their ocular application is restricted and linked to toxicity issues[55].

The long-term prognosis for CMV keratitis is typically positive if the infection is detected and treated immediately. Nonetheless, recurrent illness continues to pose a significant issue, frequently requiring extended or repeated antiviral treatment regimens. In patients experiencing repeated relapses, long-term preventive antivirals may be contemplated, however the danger of resistance must be balanced against the advantages of viral suppression.

Future therapies may encompass immunomodulation aimed at reinstating protective CTL responses. Early clinical experience with adoptive virus-specific T-cells (VSTs) shows feasibility and safety for refractory CMV and could be adapted to anterior-segment disease[56]. Furthermore, next-generation antivirals with improved safety/resistance profiles-letermovir (terminase inhibitor) and maribavir (UL97 kinase inhibitor) are effective systemically and may help address recurrence and resistance[57,58]. Among emerging antiviral candidates, filociclovir represents a promising novel drug currently in early-phase clinical evaluation, although clinical trial data remain limited[59].

HPV AND OSSN

OSSN includes a range of dysplastic and malignant lesions affecting the conjunctiva and cornea, from conjunctival intraepithelial neoplasia (CIN) to invasive squamous cell carcinoma[59]. The epidemiology exhibits significant geographic diversity, with the highest incidence observed in equatorial Africa, where ultraviolet exposure and HIV prevalence are key cofactors and the correlation between HPV and OSSN seems to differ by geographic area[60]. Recent investigations from South Africa demonstrate that HIV-positive individuals have an elevated likelihood of harboring HPV-positive OSSN, and that co-infection leads to more aggressive disease presentations[61].

The carcinogenic processes of HPV in ocular surface disease resemble those identified in cervical and oropharyngeal carcinogenesis. High-risk HPV genotypes, particularly HPV16, HPV18, and HPV33, integrate into host epithelial cells, where the viral oncoproteins E6 and E7 inactivate the tumor suppressors p53 and retinoblastoma, respectively. This disturbance results in unregulated cell cycle progression, genetic instability, and defective apoptosis, facilitating the malignant transformation of conjunctival epithelial cells[62,63]. HPV-induced OSSN typically exhibits a non-keratinizing phenotype, heightened p16 expression as an indicator of viral oncogenic activity, and active transcription of E6/E7 oncogenes[64,65]. Studies have substantiated the involvement of HPV in conjunctival neoplasia by establishing the presence of high-risk HPV DNA in OSSN lesions and detecting viral transcripts indicative of active viral oncogenesis[66].

Clinically, HPV-associated OSSN encompasses a broad range, from moderate dysplasia to aggressive squamous cancer. HPV positive is more commonly observed in CIN and non-keratinizing invasive lesions than in keratinizing malignancies[59-64]. Patients affected are typically younger, especially in HPV-positive instances, and may have more aggressive lesions along with an increased probability of recurrence[64,65].

The diagnosis of HPV-associated OSSN depends on a mix of clinical and analytical methods. In vivo confocal imaging facilitates non-invasive lesion assessment, demonstrating aberrant epithelial architecture and elevated nuclear-to-cytoplasmic ratios[67]. Conclusive verification of HPV necessitates molecular tests. PCR is extensively employed for the detection of HPV DNA, whereas immunohistochemistry staining for p16 functions as a surrogate marker for viral carcinogenic activity[68]. Advanced techniques, such as RNA in situ hybridization for E6/E7 transcripts, demonstrate transcriptionally active infection and more precisely identify HPV-driven malignancies[64]. These diagnostic strategies resemble methods used in cervical and oropharyngeal cancer, highlighting the molecular parallels of HPV oncogenesis across mucosal epithelia.

The management of OSSN has significantly advanced, offering many surgical and medical alternatives. Surgical excision with extensive margins is fundamental, typically accompanied by cryotherapy to minimize recurrence risk[62]. Topical pharmacological therapy are increasingly preferred for diffuse, multifocal, or recurring conditions. Interferon alpha-2b, delivered topically or through subconjunctival injection, demonstrates great efficacy and tolerability, rendering it a compelling choice for long-term therapy[62,64]. Other frequently utilized topical treatments comprise mitomycin-C and 5-fluorouracil, which are efficacious but linked to ocular surface toxicity, hence reserved for more severe or refractory lesions[64]. Systemic therapy, including immune checkpoint inhibitors, has been investigated for advanced or metastatic cases, especially in individuals with concurrent HIV-related immunosuppression[69,70].

The significance of HPV vaccination in the prevention of OSSN is an increasingly pertinent topic. The prevalence of high-risk HPV genotypes 16, 18, and 33 in HPV-positive OSSN indicates that existing preventive vaccinations aimed at these genotypes may provide indirect ocular protection. Although direct clinical evidence of decreased OSSN incidence post-HPV immunization is currently lacking, preliminary genetic results offer a compelling basis for additional research. Enhancing immunization initiatives, especially in areas with elevated HIV prevalence and OSSN burden, may serve as an effective long-term approach to diminish the incidence of HPV-related ocular neoplasia.

A concise overview of the major viral ocular surface infections, including their clinical features, diagnostic approaches, management strategies, and prognostic considerations, is summarized in Table 1.

Table 1 Summary of major viral ocular surface infections.

Virus	Main clinical features	Key diagnostic tools	Typical management	Prognostic considerations	Key emerging developments/future directions
HSV	Recurrent epithelial and stromal keratitis; risk of corneal scarring and neurotrophic keratopathy	Slit-lamp exam; PCR for HSV DNA; in vivo confocal microscopy	Topical or oral antivirals (acyclovir, valacyclovir); corticosteroids for stromal disease	High recurrence rate; vision loss from scarring and thinning	rhNGF for neurotrophic keratopathy[28]; sustained-release/nanocarrier antivirals[70]
Adenovirus	Epidemic keratoconjunctivitis; subepithelial infiltrates; highly contagious outbreaks	Clinical exam; rapid antigen tests; multiplex PCR	Supportive care; off-label antivirals under investigation; topical steroids for infiltrates	Usually self-limited; infiltrates may persist and cause visual disturbance	Receptor-blocking agents (multivalent sialic-acid conjugates, GAG mimetics)[42,43]; CRISPR–Cas9 strategies[45]; adjunct 5% povidone-iodine (select settings)[39]
CMV	Corneal endotheliitis, keratic precipitates, ocular hypertension; common post-keratoplasty	PCR of aqueous humor; specular microscopy; mNGS in refractory/atypical cases	Topical ganciclovir; oral valganciclovir for refractory disease	Recurrent disease leads to endothelial loss and graft failure	mNGS to clarify atypical presentations[53]; next-generation antivirals (letermovir, maribavir) for resistant cases[57,58]; adoptive virus-specific T-cells in refractory disease[56]
HPV	OSSN, from CIN to invasive carcinoma	PCR for HPV DNA; p16 IHC; E6/E7 mRNA in situ hybridization	Surgical excision ± cryotherapy; topical IFN-α2b, MMC, 5-FU	Recurrence risk higher in immunosuppressed patients	Potential indirect prevention via HPV vaccination (genotypes 16/18/33 prevalent in HPV-positive OSSN)[59,60]; immune checkpoint inhibitors in advanced cases[69]; RNA-ISH for E6/E7 to identify HPV-driven disease[64]

HSV: Herpes simplex virus; NGF: Nerve growth factor; rhNGF: Recombinant human nerve growth factor; CMV: Cytomegalovirus; mNGS: Metagenomic next-generation sequencing; HPV: Human papillomavirus; OSSN: Ocular surface squamous neoplasia; CIN: Conjunctival intraepithelial neoplasia; IFN: Interferon; MMC: Mitomycin-C; 5-FU: 5-fluorouracil; IHC: Immunohistochemistry; RNA-ISH: RNA in situ hybridization; GAG: Glycosaminoglycan.

FUTURE PROSPECTIVE

The future care of viral keratitis and conjunctivitis is increasingly influenced by advancements in precision medicine, encompassing medication research, immunization, artificial intelligence (AI), and global collaboration. The primary objective is to amalgamate molecular insights with clinical practice to enhance personalized therapy, mitigate vision-threatening consequences, and bolster public health readiness against viral ocular infections.

A particularly promising area pertains to the advancement of tailored antiviral treatments and immunotherapies. Conventional antivirals like acyclovir and ganciclovir, although efficacious, are constrained by inadequate ocular bioavailability, difficulties in corneal penetration, and the development of resistance. Investigations into sustained-release delivery technologies, such as nanocarriers, liposomes, and in situ gelling formulations, have demonstrated considerable promise to extend corneal residence duration and attain therapeutic drug concentrations while minimizing systemic exposure[70]. In the case of adenoviral keratoconjunctivitis, for which no FDA-approved antiviral is available, innovative candidates including sialic acid analogs, cold atmospheric plasma, GAG mimetics and broader-spectrum antiviral agents are undergoing active preclinical and early clinical evaluation[32,40,42,44]. Immunomodulatory treatments, such as topical cyclosporine and tacrolimus, are being investigated as adjuncts to alleviate the inflammatory damage linked to viral keratitis; nevertheless, the data remains uncertain, and long-term outcomes necessitate more confirmation[38].

Vaccination techniques have significant potential in alleviating the global impact of viral ocular diseases. The recombinant zoster vaccination has shown exceptional effectiveness in preventing herpes zoster ophthalmicus, substantially reducing the risk of keratitis and related sequelae[6]. Currently, there is no licensed vaccination for HSV; nevertheless, recent preclinical studies indicate promising outcomes, with several options targeting viral glycoproteins and latency-associated genes in development[27]. Ocular-specific vaccinations for adenovirus and HPV are currently nonexistent, however systemic HPV immunization offers indirect protection against high-risk oncogenic genotypes associated with OSSN. The prevalence of vaccine-targeted genotypes (HPV16 and HPV18) in OSSN reinforces the justification for possible ocular advantages[59]. Research on adenovirus vaccines is advancing, especially for respiratory and systemic diseases, with ongoing exploration for potential eye protective adaptations.

AI is becoming a vital instrument for diagnosis and outbreak monitoring. The clinical distinction between viral and bacterial conjunctivitis is notoriously difficult, resulting in numerous misdiagnoses and unwarranted antibiotic prescriptions. Deep learning algorithms utilizing multimodal ocular imaging and slit-lamp pictures demonstrate potential for enhancing diagnostic accuracy, while AI-augmented clinical decision-support systems may aid in patient triage and diminish unnecessary antibiotic prescriptions[71,72]. In addition to individual health care, AI is being incorporated into worldwide monitoring systems. Large-scale programs like the SCORPIO study integrate RNA deep sequencing with AI-driven analytics to monitor pathogen diversity, track viral outbreaks, and uncover new ocular pathogens in real time[73]. Such methodologies aim to bridge the divide between laboratory diagnosis and public health interventions.

Global collaboration networks constitute a significant frontier. Multicenter consortia provide swift data dissemination, standardization of diagnostic procedures, and synchronized therapy trials among varied patient demographics. The coronavirus disease 2019 pandemic highlighted the significance of these networks in real-time pathogen surveillance and clinical trial coordination, with analogous systems being applied for viral ocular illnesses. Collaborative registries and clinical trial networks will be crucial in validating innovative antivirals, standardizing treatment protocols, and improving readiness against re-emerging viral threats.

The future of managing viral ocular surface diseases is progressing towards precision medicine. Progress in sustained-release antivirals and innovative immunotherapies, along with the enhancement of immunization methods, offers potential for diminishing acute morbidity and long-term consequences. AI-driven diagnostics and outbreak surveillance are poised to transform the precision and promptness of diagnoses, while global networks will facilitate coordinated international responses. These advancements collectively present a vision for the therapy of viral keratitis and conjunctivitis that is increasingly customized, preventative, and internationally integrated.

Viral infections of the ocular surface continue to be a predominant cause of visual impairment globally, presenting significant clinical and public health challenges. Although herpesviruses, adenoviruses, CMV, and HPV have been acknowledged as significant infections for an extended period, emerging knowledge regarding their biology and clinical implications is continually transforming diagnostic and therapeutic strategies. Progress in molecular diagnostics has significantly enhanced the capacity to accurately and swiftly identify viral infections, minimizing wasteful treatments and facilitating targeted therapies. These advancements underscore the manner in which the incorporation of laboratory innovation into clinical practice can directly improve patient outcomes.

A consistent characteristic in all viral ocular infections is the interaction between viral persistence and the host immune response. Although immune activation is crucial for pathogen elimination, dysregulated inflammation frequently leads to corneal scarring, neovascularization, and chronic conditions. This fragile equilibrium highlights the necessity for medicines that both inhibit virus replication and regulate detrimental immune responses. The acknowledgment of immunopathology as a key factor influencing therapeutic outcomes has created new opportunities for the application of immunomodulatory medicines and preventive methods to avert recurrence. Future management will rely on novel drug delivery systems and next-generation antiviral agents. Conventional topical and systemic treatments are constrained by inadequate ocular absorption and the potential for resistance development. Sustained-release formulations, nanomedicine strategies, and innovative medicines aimed at viral entrance or replication are poised to revolutionize therapy paradigms. Vaccines offer potential for prophylaxis, having shown efficacy in herpes zoster and presenting increasing prospects in herpes simplex and HPV-related diseases. Immunization's capacity to diminish incidence and long-term consequences is among the most effective interventions for global eye health.

The wider context of viral ocular illness underscores the necessity of interdisciplinary collaboration and public health involvement. Emerging viral threats indicate that ocular indications may serve as early indicators of systemic outbreaks, highlighting the necessity for worldwide surveillance and prompt response mechanisms. AI and global networks will increasingly connect epidemiology, diagnostics, and medicinal research. Ultimately, continuous advancement will depend on the integration of virology, immunology, pharmacology, and clinical ophthalmology within a cohesive precision medicine framework.

CONCLUSION

In summary, viral ocular surface diseases provide persistent difficulties while simultaneously offering unique potential. The integration of modern diagnostics, novel medicines, preventive immunization, and international collaboration provides a means to diminish blindness and enhance global quality of life. By adopting these tactics, the forthcoming phase of treatment for patients with viral keratitis and conjunctivitis will be more focused, preventative, and efficacious than ever before.