Management of Subepithelial Infiltrates Following Viral Keratoconjunctivitis: A Narrative Review

Introduction

Viral conjunctivitis is deemed to be one of the most common contagious disorders encountered in general and ophthalmic primary care practice. Adenovirus is the most common causative agent accounting for 15% to 70% of all cases worldwide, far less frequent causes are herpes simplex virus, varicella-zoster virus, influenza virus, picornavirus, and Epstein Barr virus. Inflammation (conjunctival hyperemia, chemosis, engorgement of the blood vessels, ocular discharge), and pain are spectacular features of this self-limiting condition. [1–4]. the estimated percentage of transmission has been reported to range from 10% to 50%. Due to the highly augmented proportion of transmission, it is essential to take into consideration recommended preventative measures such as isolation of the infected individuals, hand washing, and strict sterilization [5–7]. Viral conjunctivitis prevalence might be variable and generally impacted by many factors such as the patient’s age as well as the seasons of the year. Usually, in order to diagnose viral conjunctivitis, it exclusively depends upon the clinical features [8–13].

As such, viral conjunctivitis has shown to be associated with a number of complications including the development of sheets of fibrin-rich exudate adhering to the upper and lower tarsal conjunctiva which is known as pseudomembranes [14]. Although bacterial superinfections are uncommon, they emerge along with viral conjunctivitis. Yet, multifocal subepithelial infiltrates (SEIs) are the most frequently observed complication in clinics [15]. That is what we intend to focus on in this review article. Thus, we are aiming to widen, strengthen, and enhance our comprehension towards SEIs in order to direct all these facets to enhance patient’s management.

Figure 1. Ocular signs of inflammation in the left eye. The eye shows clear signs of inflammation, including conjunctival hyperemia with dilated and engorged blood vessels. Ocular discharge is also visible.

Figure 2: PRISMA flowchart illustrating the study selection process. The diagram outlines the number of studies identified, screened, assessed for eligibility, and included in the review, along with the reasons for exclusion at each stage.

Corneal Subepithelial Infiltrates

Corneal SEIs are strongly associated with adenoviral conjunctivitis, they are in fact considered pathognomonic for adenoviral conjunctivitis and frequently seen within the second or third week after the onset of the infection [16]. The incidence of SEIs is estimated to be in a range of 49.1 to 80% [17,18]. The hypotheses behind SEIs pathogenesis believed to be cellular immunological reactions that have been triggered by viral replication in the corneal stroma under the Bowman’s Membrane (BM) [16]. To correlate this hypothesis, there was a study that followed the clinical course of adenoviral conjunctivitis which basically suggests that the innate immune system has a role early on of the disease which is represented by dendritic cells that are located mainly at the level of the Bowman’s layer [19]. Histopathological features revealed accumulation of lymphocytes, macrophages/monocytes, and activated fibroblasts [20].

These SEIs are not specific for adenovirus conjunctivitis only, although they are considered as pathognomic but there are many other causes which have been addressed in previous studies such as Brimonidine Tartrate, which is medication used to treat glaucoma, and acanthamoeba keratitis [21,22] These infiltrates may persist for years which subsequently leads to uncomfortable sensation of glare, reduction in vision when these infiltrates obscure the optical axis, and eventually lead to progressive corneal scarring [10,23]. Other studies have reported some patients feeling foreign body sensation in both eyes and the tendency to have dry eye syndrome is higher in those patients [21]. This explains the diffuse punctate epithelial findings which are usually seen in dry eye disease patients. some other findings have been seen in slit lamp examination include diffuse multifocal round-oval shape, greyish-white, and pinhead sized over the cornea [16,24,25]. SEIs are usually located in the center of the cornea, but this does not exclude the involvement of the entire corneal surface [23].

Figure 3. Slit lamp examination of corneal sub-epithelial infiltrates (SEls). Both the right and left eyes exhibit multiple greyish-white, pinhead-sized lesions distributed across the cornea.

The infiltrates typically resolve over time with no impact on the cornea or visual pathway, however occasionally they tend to progress to permanent condition and cause scars on the cornea. Reversible versus irreversible scars can be differentiated by Optical coherence tomography (OCT), and the leading point is BM which tells wither it is irreversible scars or not [ 26,27]. In order to reverse this condition, some studies reported that steroids can prevent the development of SEIs, however discontinuation may lead to the recurrence of this entity [16,23]. There are many other management approaches that have been used to treat or/and prevent subepithelial infiltrates [24]. Preventing and treating epidemic properly is the key to avoid the development of these infiltrates, as we mentioned previously some precautionary measures must be established in the clinics such as rigorous decontamination of hands, surfaces and objects, using a disposable tonometer heads and eye drop dispensers, and using povidone iodine (PVP-I) 2% is reported to decrease the incidence of corneal subepithelial infiltrates. It must be applied as soon as adenoviral is suspected, as it will decrease the viral load, therefore reduces the severity and as a result decrease the risk of complications [28,29]. An equally significant aspect of the treatment of adenoviral keratoconjunctivitis, a combination of PVP-I 1.0% and dexamethasone 0.1% might prevent the development of subepithelial infiltrates [30]. This article is aimed to overview the different approaches mentioned in previous to treat subepithelial infiltrates associated with viral conjunctivitis.

Medical Management

For SEIs, medical and surgical treatment options are the two types of management available.

1.1 Corticosteroide

Topical steroids are only advised for severe cases of acute adenoviral keratoconjunctivitis (AAK) with chemosis, lid swelling, or membranous conjunctivitis to prevent scarring. Short-term topical steroids, on the other hand, have been frequently applied to relieve pain. When compared to supportive care management, investigators found that topical corticosteroids and Cyclosporine ( caused fewer serious symptoms and decreased the duration of the symptoms. When taken in the acute phase of infection, steroids inhibit the formation of corneal subepithelial infiltrates [31].

The effectiveness of corticosteroids in treating and preventing keratoconjunctivitis complications has been studied in multiple reports. The first report identified 53 people who had adenovirus type 8 infection confirmed by culture. A 6-week course of steroids neomycin combination drops rather than lubricants had no impact on the course of conjunctivitis or the amount of SEIs [32].

Correspondingly, in the second report, the clinical course of epidemic keratowas studied in 74 patients during an outbreak of about 3,000 cases in late 1988 at a U.S. military base in the Philippines. Patients were randomly assigned to treatment with dexamethasone or artificial tears in a double-masked fashion. There had been no significant difference in manifestations or time spent in quarters between the three groups [33].

In the third report, however, twenty patients in a double-blind study with epidemic keratoconjunctivitis who did not have characteristic subepithelial corneal infiltrates at the beginning of the course of infection were given either topical corticosteroid or non-steroid eye drops for 4 weeks, 4 times daily. When compared to placebo drops, corneal infiltrates did not appear in a notable percentage of individuals on corticosteroid. Moreover, subepithelial corneal infiltrates were observed when corticosteroid drops were stopped, but it was cleared when the steroids were resumed up to a year later [34].

It is debatable whethertopical steroids should be used to treat SEIs. In the acute phase, they are routinely administered but this may only have a temporary relieving impact. As established in experimental animals, corticosteroids have been reported to enhance adenovirus replication rates, also, longer viral shedding might prolong illness and infection durations. On the other hand, steroids have a high risk of major adverse effects, including cataracts, glaucoma, opportunistic infections of the eye and delayed corneal healing [25]. It is recommended that corticosteroids be avoided until patients have a pseudomembrane or bothersome subepithelial infiltrates, although it is uncertain whether they have a prophylactic impact on the development of corneal SEIs when given early in the infection. One study suggested a stepladder approach starting with immunosuppressant such as tacrolimus and steroid is added only in recalcitrant cases [63].

1.2 Antiviral

There is currently no FDA-approved effective therapeutic specific antiviral known to reduce the duration of the infection, relieve the distressing clinical symptoms, limit viral replication or inhibit the formation of corneal opacities.

Earlier studies have been focused on the treatment of adenoviral keratoconjunctivitis using antiviral drugs. In clinical trials, ribavirin was found to have limited in vitro effectiveness and to be inadequate against the three most common adenovirus serotypes linked to EKC (Ad8, Ad19, and Ad37) [35,36]

Huang et al. used polymerase chain reaction (PCR) to evaluate the antiviral activity of ganciclovir against HAdV types 3, 4, 8, 19, and 37, and found that it had a significant, dose-dependent inhibitory impact on the serotypes that cause EKC [37]. Similarly, Tabbara et al. investigated the effects of ganciclovir 0.15 % ophthalmic ointment with preservative-free artificial tears in 18 patients with adenovirus keratoconjunctivitis in Saudi Arabia. The conjunctivitis in the ganciclovir group cleared up in 7.7 days, compared to 18.5 days in the artificial tears group [38].

Topical cidofovir 0.2% was considered acceptable and did not cause any discomfort but it had no statistically significant influence on the course of adenoviral keratoconjunctivitis in the acute or chronic phases [39]. A randomized, controlled, double-blind study was conducted to examine the efficacy of cidofovir eye drops with and without cyclosporine eye drops, as well as their potential to prevent further sequelae such as SEIs. The topical 0.2 % cidofovir identified by investigators is a well-tolerated agent with no evidence of local or systemic adverse side effects. However, this study reported no significant impact of the investigated therapeutic interventions on the normal course of KC's acute phase. Additionally, the frequency of corneal infiltrates at the end of the 21-day treatment period was not altered by cidofovir 0.2% [39].

1.3 Corticosteroid Sparing Agents:

1.3.1 Cyclosporine (CsA)

CsA belongs to the immunomodulator class of drugs. Many studies have shown that treating SEIs is both successful and safe. Muftuglu et al. included in his study eighteen eyes from 13 people who received topical steroid eye drops for SEIs following epidemic keratoconjunctivitis and were symptomatic after steroid eye drop tapering or withdrawal [40]. Topical steroids were not given to any of the patients in the acute phase of conjunctivitis; they were only given to those who had symptomatic SEIs in the chronic phase of the condition. Topical 0.05 percent CsA eye drops were used four times a day in addition to loteprednol etabonate (LE) three times a day for three weeks, after which LE was reduced to weekly and topical 0.05 percent CsA therapy was continued for six months. In this study, individuals with SEIs saw a substantial reduction in symptoms such as pain, halo/glare, and photophobia after receiving topical 0.05 percent CsA treatment. Following therapy, 76.9%, 100%, and 100% of patients, respectively, rated these symptoms as minor, none, and none. Another trial on patients with SEIs was conducted, in which CsA was administered as four drops of CsA daily to 70 eyes (48 patients) with SEIs following AAK. After the acute period of AAK, treatment began 18.5 months (3–72) later. The dose decrease was based on the clearance of infiltrates in each patient. Investigators discovered that 40 of the 70 eyes reacted favorably to therapy, 16 did not, 4 had therapy halted due to ocular pain (burning), and 10 had follow-up of less than 3 months [41]. Research showed that during the acute infection, 1% CsA was given four times a day for 21 days, resulting in early subjective relief of local symptoms and a tendency toward a decreased incidence of corneal opacities [39]. In a study comparable to topical steroids, the authors discovered a considerable reduction in the number of drugs that patients were using after shifting to topical CsA [42]. This was mostly due to the fact that some of the patients were steroid responders who needed glaucoma drugs to keep their IOP under control. Furthermore, they reported that CsA therapy reduced IOP, but this difference was not statistically significant [42]. Other study evaluated the efficacy of low potency corticosteroid and 0.5% CsA, however complete resolution of SEIs was reported in 70% of the cases after 6 months in those who mediated with steroid. This study recommended using low potency corticosteroid as shown in their study the recurrence rate was lower than the previous literatures and with fewer side effects [64]. CsA’s showed low rate of recurrence compared to corticosteroid, as one study showed recurrence rated was 88% with corticosteroid and 5% with CsA, another study reported 9% (3 out of 51 eyes) of recurrence rate with CsA [64, 34, 65

1.3.2 Tacrolimus

Tacrolimus has significant immunosuppressive and anti-inflammatory effects by reducing T-cell activation; it inhibits the immune system and inflammation by suppressing an enzyme (calcineurin) that is required for T-cell proliferation [42]. Currently, there are two FDA-approved concentrations of tacrolimus—0.1% and 0.03%. For ophthalmic use, topical tacrolimus (0.03%) has been reported to be beneficial in treating giant papillary conjunctivitis and vernal keratoconjunctivitis [43,44].

Bhargava et al., compared the safety and efficacy of tacrolimus 0.03 percent ointment versus dexamethasone 0.05 percent ointment for subepithelial infiltrates (SEIs) following adenoviral keratoconjunctivitis (AK), finding that tacrolimus 0.03 percent ointment is more effective than dexamethasone 0.05 percent ointment with a low recurrence rate and no substantial increase in IOP, although some patients may experience burning and a foreign-body sensation [25].

Patients with SEIs who had previously been treated with topical corticosteroids with either no improvement or the drug being stopped owing to a related intraocular pressure (IOP) increase were included in a prospective non-controlled interventional case series. For 22 weeks, the patients were given 0.03 % tacrolimus ointment twice daily. At the end of the treatment, all of the patients showed considerable objective clinical improvement, and none of them had a severe degree of SEIs. According to the patients, the intensity of the patients' symptoms was significantly reduced. However, during the management of SEIs, unusual adverse effects of this medication, including extreme dizziness, have been documented [45].

A further report on 7 patients who had been unresponsive to topical steroids found that topical 0.03 % tacrolimus appeared helpful for the management of SEIs following AK, as all participants exhibited relief from ophthalmologic complaints such as tearing, impaired vision, burning, and foreign body sensation. Treatment was judged successful in 6 of 7 patients (85.7%), with satisfactory control of the SEIs during the study follow-up [46]. Recent study showed efficacy against persistent SEIs when using tacrolimus in resistant cases [66].

Surgical Management

The subepithelial infiltrates after EKC may persist for months to years, and the medical management with corticosteroids or antiviral drugs may fail to restore the corneal transparency as the symptoms often recur after discontinuing these medications [24]. In addition, the long-term use of corticosteroid is associated with several side effects such as the formation of cataract or development of glaucoma (23), as well as thinning of the corneal stroma (24). Phototherapeutic keratectomy (PTK) and photorefractive keratectomy (PRK) are safe and effective methods for managing anterior corneal disorders using an argon fluoride (193-nm) laser to ablate corneal tissue (47,48). In the setting of EKC, the subepithelial infiltrates are triggered by immunogenic factors in the corneal stroma, so, removing this subepithelial and stromal tissue can reduce the risk of recurrence (49).

Mitomycin C (MMC) is an antitumor antibiotic. Itis an alkylating agent that acts similar to radiation by decreasing the rate of cell proliferation (50). It is commonly used in many ophthalmological procedures, including PTK and PRK, to prevent subepithelial fibrosis in order to avoid corneal haze and to enhance the corneal wound healing process (50,51).

Many studies have confirmed the efficacy of using PTK to treat subepithelial infiltrates (SEIs), which yields significant improvements in visual function. (24,52,53) Subepithelial opacity causes an irregular corneal surface, and PTK is also used to smoothens this irregular surface and results in better vision (54). Yamazaki et al. reported successful removal of the subepithelial infiltrates with significant decrease in all symptoms in all of the patients after the treatment with PTK using low-dose MMC, as well as significant improvement in contrast sensitivity postoperatively. The level of patient’s satisfaction after surgery was assessed and all the patients reported satisfactory improvement in visual acuity and quality [24].

Elhamaky conducted a comparative study between transepithelial phototherapeutic keratectomy with MMC and topical tacrolimus in patients with adenoviral corneal SEIs, comparing them with a third control group. The study found a significant improvement of the best corrected visual acuity, Ocular Surface Disease Index (OSDI) score, corneal densitometry, and corneal higher-order aberrations in both the transepithelial PTK and topical tacrolimus groups without significant changes in the control group. [52].

In another retrospective comparative study, Oliveira et al. have shown that the visual acuity has significantly improved in the PTK group in comparison with the control group [55]. PTK has some difficulties like the prediction of preoperative depth of pathology to determine the amount of tissue to be removed. This difficulty can be overcomed by some devices like pentacam or optical coherence tomography (OCT), using these technologies to analyze the anterior segment of the eye without contact [24,52].

There are various reports about the efficacy and safety of PRK in removing the subepithelial infiltrates [23,49,56]. PRK without the use of MMC has successfully corrected myopia, removed the subepithelial infiltrates and prevented the recurrence within the laser-treated central cornea in a previous report, with recurrence of asymptomatic infiltrates only at the periphery [22,48]. The topical use of MMC with PRK may provide a better outcome with satisfactory clinical and refractive results without any postoperative complications [23,56]. PRK is preferred over PTK in patients with preexisting myopia because it offers better refractive accuracy [23,57].

Complications:

A well-documented complication in the literature of the use of PTK or PRK is the hyperopic change that is induced by the ablation and flattening of the central areas of the cornea [58,59]. The degree of hyperopic shift is unpredictable but mostly directly related to the depth of ablation. [58,60]. Minimum ablation of the cornea produces less hyperopic shiftand consequently a better quality of vision (61). Another way to minimize the hyperopic shift is by moving the eye in a circular fashion under the laser, modifying the edge of the ablation zone by treating it with a 2.0-mm-diameter beam to keep the corneal surface in a convex shape [24]. A two-step PTK procedure can also be used as it may results in a shallower ablation and minimize the hyperopic risk [52,58,62].

Other complications of both procedures are haze formation, postoperative pain and recurrence of the initial corneal pathology [23,56]. All of these risks along with the hyperopic shift can be reduced significantly with the use of intraoperative MMC, shallow ablation and enlarging the treatment zone to 8 to 9 mm [50,52,62].

Recurrence:

The recurrence of SEIs has been reported by many studies in the literature with different rates depending on the type of management. Bhargava et al showed that the medical treatment of SEIs with tacrolimus and corticosteroids have shown a recurrence rate of 7.5% and 17.5%, respectively. [24] The use of PTK or PRK have shown better outcomes in terms of the recurrence. Yamazaki reported a recurrence rate of 9.6% after the management with PTK, which occurred simultaneously with the discontinuation of steroids drops. [16,24,25] Oliveira et al studied the outcomes and recurrence rates of SEIs after treatment with PRK and MMC in comparison to a control group. The study showed a recurrence rate of 11.7% in the treatment group and 77.7% in the control group. [16,24,25] In the same way in another comparative study, the persistence of SEIs at 1-year follow-up was significantly lower in transepithelial PTK (9%) and tacrolimus (23.8%) groups than in the control group (85%) [52]. PRK treatment without the use of MMC has been reported in the literature to prevent the recurrence of the SEIs centrally but not at the periphery, while the recurrence in the central area has been observed in other reports. [22,48] The use of MMC with PRK may be beneficial in preventing the recurrence of SEIs as no recurrence was seen in any patient for more than 1 year follow-up in two previous studies. [23,56]

Conclusion:

In summary, corticosteroid sparing agents showed more efficacy against the SEIs compared to corticosteroid. They exhibited fewer side effect and less recurrence rate. Side effect that was reported with tacrolimus was burning and a foreign-body sensation. In regard to surgical management, PTK and PRK have a better long-term outcome and less recurrence rate compared to the medical management The use of MMC in conjunction with PTK or PRK has less recurrence risk along with significant decrease in the postoperative side effects like haze formation. Additional long-term follow-up studies are needed to assess the persistence of these improvements and the long-term risk of recurrence, as most of the studies carried out were assessing the patients in follow-up intervals of less than 2 years. Controlled comparative studies are also needed to assess the outcomes and recurrence risks of PTK and PRK, as well as a larger comparative studies to compare them with the medical management.

Funding: Nil

Conflicts of Interest: All authors declare that they have no potential conflicts of interest and report no disclosures.

Ethics approval and consent to participate: Not applicable

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