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INTRODUCTION
The prevalence of infections caused by the herpes simplex virus (HSV) types 1 and 2 increases with age. It is estimated that these infections may affect up to 90% of the adult population in Africa, North and South America, and up to 40% in Europe [1]. However, only 20−30% of patients infected with HSV develop clinical symptoms, most commonly in the form of labial herpes (cold sores) [2].
Herpetic eye infection can occur during the first exposure to HSV (primary infection) or as a result of the virus affecting the eye as another anatomical location in a person with latent HSV infection (secondary infection) [3]. Due to the fact that primary infections require direct contact of the virus with the mucous membrane of the eye, primary infections do not occur frequently. In most cases, the infection is secondary and caused by ganglionic reactivation, resulting in axoplasmic flow that carries the HSV to the ocular surface [4]. The literature indicates that the ratio of primary to secondary infections in ophthalmology is 1 : 5 to 1 : 14 [5]. Additionally, the incidence of HSV eye infections is estimated at 20.7-31.5 cases per 100,000 population, with an annual incidence of 8.4-13.2 new infections per 100,000 individuals [6, 7]. The highest reported incidence of ocular HSV (herpes simplex virus) is 149 infections per 100,000 population [6], which would translate to approximately 50,000 infected individuals in Poland and around 500,000 patients in the United States. Additionally, studies have shown that ocular HSV recurs in approximately up to 24.5% of cases within 12 months, 32.9% within 24 months, and 50.0% over a 10-year period [8, 9]. Based on current knowledge, herpes simplex keratitis (HSK) is considered the most common cause of corneal clouding [10].
Among patients with a history of herpetic eye infection, any ophthalmic procedure within the eye carries a risk of recurrence. Reactivation of the HSV can result from both surgical manipulation and reduced immune system activity caused by perioperative steroid therapy [11]. It is also assumed that age and a primary infection lasting more than seven months are risk factors for an unfavorable prognosis [12]. The aim of the study was to examine the risk factors for HSV infection recurrence in ophthalmic surgery and to explore potential methods for preventing such recurrences.
FACTORS CONTRIBUTING TO HERPES SIMPLEX KERATITIS RECURRENCE
Postoperative use of steroid eye drops
Postoperative HSV keratitis has been described as a late complication of various ophthalmic procedures, including cataract surgery [11], vitrectomy [13], LASIK [14], excimer laser photokeratectomy [15] and corneal transplantation [16]. Every surgical intervention may be associated with the occurrence of a postoperative inflammatory response. If it progresses in an uncontrolled manner, it may lead to dangerous complications such as posterior synechiae, uveitis, or secondary glaucoma [17]. Consequently, postoperative steroid therapy is frequently administered after ophthalmic procedures, such as refractive surgery, cataract surgery, vitreoretinal surgery, and keratoplasty [18]. The mechanism of action of steroid medications is based on their immunosuppressive properties. By inhibiting the synthesis of arachidonic acid, steroids decrease the production of prostaglandins and leukotrienes, which are key inflammatory mediators [19]. Moreover, through their effects on gene expression, corticosteroids reduce the activity of inflammatory cells and affect specific cascades, including cytokine production and the arachidonic acid pathway [20]. Steroids also reduce the activity of other processes linked to the immune response, such as chemotaxis, phagocytosis, or epithelial adhesion, thereby regulating the severity of inflammation [21].
Although steroid eye drops are commonly employed in the management of interstitial keratitis [22], studies have shown a significant association between steroid therapy and an increased risk of HSV infection recurrence. A key role in this process is attributed to prostaglandins, which are capable of inhibiting the proliferative immune response induced by HSV [21]. Steroid therapy significantly suppresses the inflammatory response, which can promote viral infections. In an animal model study, an elevated risk of recurrence of corneal HSV infection was observed after topical application of prostaglandin analogs [23]. Qui et al. observed that 1.8% of patients undergoing keratoplasty developed postoperative interstitial keratitis, which was partially associated with prolonged steroid treatment [24].
The risk of HSV reactivation is strongly linked to the dose of steroid medications used. The immunomodulatory effects of steroids lead to a reduction in leukocyte levels [25], while high-dose steroid therapy weakens macrophage function, a key component of the body’s primary defense against pathogens [26]. Scientific findings suggest that macrophages play a crucial role in suppressing HSV replication following corneal infection [27]. Studies conducted in both animal models and cell lines have demonstrated the significant role of corticosteroids (dexamethasone) in inducing HSV reactivation [25, 28].
Irritation of the corneal neural plexus
The cornea is one of the most densely innervated structures in the human body, with a nerve density 300–600 times greater than that of the skin, ensuring structural and functional integrity of the ocular surface. Damage to corneal nerves due to disease, trauma, surgical intervention, or even corneal epithelial injury can contribute to epithelial defects and reduced corneal sensitivity [29]. This impairment also creates a strong trigger for HSV reactivation [30]. It may occur following surgical procedures such as deep anterior lamellar keratoplasty, cross-linking, cataract surgery, and phototherapeutic or photorefractive procedures [31]. In a study conducted by Bayer et al. using an animal model, it was observed that HSV reactivation occurred both after corneal cryotherapy and radial keratotomy [32]. An additional factor contributing to viral reactivation may be the increased expression of transcriptional factors such as c-fos, c-jun, c-myc, and interferon regulatory factor-1 (IRF-1), induced by damage to the corneal nerve plexus [33]. Therefore, it can be hypothesized that HSV is capable of reactivation through stress-induced cellular activation pathways [34]. Corneal nerve plexus irritation may also occur following excimer laser procedures. Animal model studies have demonstrated that both superficial photorefractive keratectomy (PRK) and LASIK procedures can trigger HSV reactivation in the eye [35]. A potent stimulus for HSV reactivation is the suppression of nerve growth factor (NGF) secretion, which is essential for proper neuronal function. In vitro studies have further demonstrated that procedures damaging the corneal nerve plexus are associated with reduced NGF expression [36]. The article by Kanclerz and Alió pointed out that damage to the nerve endings of the cornea and the administration of steroids during the perioperative period are the two most significant factors leading to the recurrence of HSV and HZO infections [37].
Other potential mechanisms responsible for HSV reactivation, especially in refractive surgery, include ultraviolet (UV) radiation and hyperthermia. It has been found that local hyperthermia can reactivate latent virus from both trigeminal and lumbosacral ganglia [38]. In another animal model experiment conducted by Laycock et al., it was observed that recurrent herpes keratitis occurred in 80% of animals exposed to UV irradiation, in a wavelength-dependent manner [39]. However, the likelihood of thermal damage contributing to the onset of herpes simplex keratitis seems minimal, as modern laser systems induce less than a 5°C temperature increase during myopic ablation procedures [40]. It is important to highlight that the safety threshold temperature of 40°C was never exceeded during the 750 Hz excimer laser refractive procedure [41].
Other factors contributing to herpetic keratitis recurrence
Other potential triggers for HSV reactivation include stress, both systemic and localized [42]. The interaction between social stress and HSV activation has been reported, involving neuroendocrine mechanisms and the activation of the hypothalamic-pituitary-adrenal axis [43]. The primary molecular mechanism integrating physiological signals to regulate the lytic cycle is local mTOR kinase signaling in axons – where both physical and metabolic stress can autonomously influence HSV development at the neuronal level [44]. The induction of viral activity can also be triggered by local cellular stressors, such as hypoxia or disruption of protein synthesis [44].
It is worth noting that a higher rate of viral reactivation is observed among patients with identified immunodeficiencies [45], as well as in older individuals, in whom the increased risk of infection may result from impaired cellular immunity [46]. An increased risk of HSV recurrence is also observed in patients with a history of interstitial keratitis. Moreover, the risk of recurrence has been positively correlated with the number of previous keratitis episodes [47]. Interestingly, a history of epithelial herpes simplex keratitis does not constitute a risk factor for recurrent ocular HSV infection [45]. Additional factors that may contribute to the onset of HSV infection include immunosuppression and environmental influences, such as psychological stress [48]. Interstitial keratitis has been reported in a case series of patients following uncomplicated blepharoplasty [48]. Due to reduced immunity, the occurrence of interstitial keratitis is possible following infection with the SARS-CoV-2 (COVID-19) virus [49], and even after receiving the COVID-19 vaccine [50].
RISK OF HERPES SIMPLEX KERATITIS RECURRENCE AFTER OCULAR SURGERIES
The recurrence of herpes simplex keratitis after ophthalmic procedures is well-documented in the literature, with a significantly higher risk of recurrence seen in cases involving penetrating keratoplasty (PK) [51]. HSV reactivation is positively associated with the frequency of graft rejection episodes, the presence of corneal epithelial defects, and corneal neovascularization after PK procedures, in contrast to patients undergoing PK without observed HSV reactivation [52, 53]. Therefore, an appropriate preventive approach appears particularly crucial to ensure proper treatment progression and the success of the medical procedure. Available scientific evidence indicates a significant reduction in the risk of graft rejection among patients undergoing PK who received antiviral treatment. In a study by Ghosh et al., graft rejection rates were 52% among patients treated with topical antiviral therapy and 19% in those receiving oral antiviral therapy. A significantly higher number of HSV recurrence episodes was also observed in patients treated topically compared to those who received systemic treatment (55% and 12%, respectively) [51]. Similar evidence was provided by Barney et al., who reported a significantly higher risk of graft rejection in patients who did not receive prophylactic treatment (54%) compared to those who received antiviral therapy (14%). The applied prophylaxis also led to a marked decrease in HSV recurrences [54].
Similar effects were observed in patients undergoing deep anterior lamellar keratoplasty (DALK) for corneal scarring secondary to prior HSV infection. HSV recurrence was observed in 33% of patients, showing a positive correlation with graft rejection rates [55]. Postoperative visual acuity was comparable between both methods (DALK and PK); however, DALK demonstrated a superior graft survival rate due to the elimination of the risk of endothelial graft rejection [56, 57]. Shuang-Quin et al. observed a threefold lower incidence of herpes simplex keratitis recurrences in patients after DALK compared to PK. The graft rejection rate following PK was 42.3%, whereas no rejection episodes were observed in patients undergoing DALK procedures [58]. Additional evidence was provided by Lyall et al., who reported HSV recurrence in 33% of patients and graft rejection in 50% of patients after DALK [59]. The study results suggested that DALK for HSV-related corneal scarring was associated with a high rate of postoperative complications.
The risk of HSV recurrence has been observed as a potential complication following cataract surgery. In a study conducted by Lu et al., 40.4% of patients experienced a recurrence of keratitis caused by the varicella-zoster virus (VZV), a member of the herpesvirus family, after cataract surgery [60]. Moreover, any ocular surface inflammation – including post-HSV keratitis – may impair visual acuity improvement following cataract surgery [61].
The precise risk of HSV reactivation after corneal refractive procedures is yet to be determined. Silva et al. demonstrated that recurrence of ocular HSV can be prevented in patients undergoing photokeratorefractive surgery when concurrent antiviral prophylaxis is administered [62]. Similar evidence was provided by Jarade et al., who reported no cases of HSV reactivation following laser vision correction [63]. However, the study was limited due to the small number of included patients.
The key scientific studies that outline methods for preventing HED following ophthalmic surgeries are listed in Table I.
Table I
Available scientific evidence for prevention strategies for post-surgical herpes simplex keratitis
| Study | Procedure | Study type | Intervention (group size) | Type of treatment | Result |
|---|---|---|---|---|---|
| Altay et al. 2017 [64] | PK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg 5 times a day for 3 months, reduced to twice a day for the subsequent 12 months (n = 55) | Administered 6 times daily; dosage reduced over 12 months | Different recurrence and graft rejection rates were observed between patients with stable corneal scars versus those with descemetocele/perforation, though 3-year graft survival rates remained comparable |
| Ren et al. 2016 [67] | DALK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg every 4 hours for 1 month, followed by 400 mg twice a day for the next 12 months (n = 89) | Dexamethasone 0.1% + tobramycin 0.3%; dosage reduced over 3 months | DALK proved effective for treating deep corneal stromal opacities. In some cases, postoperative stromal folds were observed. Recurrence of HED was noted in 8 eyes |
| Liu et al. 2016 [66] | DALK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg 5 times daily + 0.15% ganciclovir 4 times daily for 3 weeks before surgery; postoperative administration of 400 mg 5 times daily for 1 month, then twice daily for 12-18 months; 0.15% ganciclovir 4 times daily for 6-12 months (n = 27) | Dexamethasone + tobramycin 4 times daily for a month, followed by 0.02% fluorometholone | DALK using cryopreserved glycerol-preserved corneal tissue resulted in good visual acuity and a low HED recurrence rate (7.41%) |
| Li et al. 2014 [27] | DALK for HED | Retrospective analysis | Oral administration of acyclovir 200 mg every 4 hours for 3 months, followed by 400 mg twice daily for the next 12 months (n = 48) | Dexamethasone 0.1% + tobramycin 0.3%; dosage reduced over 3 months | No episodes of HED recurrence were observed during the 36-month follow-up period |
| Lyall et al. 2012 [59] | DALK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg twice daily (n = 18) | Dexamethasone 0.1% 4 times daily, with dosage reduced over the following 6-9 months | DALK in the treatment of HED was associated with a high rate of complications, including recurrence of HED (33%) and graft rejection (50%) |
| Wu et al. 2012 [58] | DALK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg 3 times daily combined with topical administration of acyclovir 0.1% 4 times daily for 3 months (n = 43) | Dexamethasone 0.1% 4 times daily for 3 weeks, followed by fluormetholone 0.02% for up to 6 months | DALK can not only remove corneal lesions caused by HED but also reduce transient and persistent viral latency in the cornea |
| Goodfellow et al. 2011 [53] | PK for primary HED | Retrospective analysis | Oral administration of acyclovir vs. topical administration of acyclovir vs. no treatment (no specified dose; n = 403) | No specified treatment | Oral antiviral therapy reduced the risk of graft rejection in patients undergoing primary PK for herpetic keratitis; no effect was observed for topical treatment |
| Sarnicola and Toro 2010 [69] | DALK for HED | Case study | Oral administration of acyclovir 800 mg 3 times daily for the first month, twice a day in the second month, and once a day until the 12th month (n = 52) | Dexamethasone 0.1% 4 times a day for the first month, twice a day in the second month, once a day until the 12th month (n = 52) | No episodes of graft rejection or HED recurrence during the 31-month follow-up period; comparable visual effect and better survival rate than with PK |
| Awan et al. 2010 [55] | DALK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg twice daily (n = 18) | Dexamethasone 0.1% 4 times daily for the first 4 weeks; dose reduction over the following 6-9 months | |
| Leccisotti 2009 [70] | DALK for HED | Retrospective analysis | Oral administration of acyclovir initiated 1 month before surgery, continued for the following 5 months, then reduced to 400 mg twice daily for an additional 6 months (n = 12) | Dexamethasone 0.1% | DALK in HED demonstrated a safe intraoperative profile and significantly improved visual acuity in cases of myopia (–2D) |
| Jansen et al. 2009 [71] | PK for HED | Randomized controlled clinical trial | Oral administration of acyclovir 400 mg twice daily (n = 35) vs. Placebo (n = 33) For 6 months | No specified treatment | Oral administration of acyclovir protected against HED recurrence during the 5-year follow-up period (lower monthly recurrence rate; p = 0.037) |
| Ghosh et al. 2008 [51] | PK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg twice daily (n = 26) vs. topical acyclovir 3% 5 times daily (n = 29) For 12–24 months | Prednisolone sodium phosphate 1% every 4 hours, dosage reduced over 1 year | A higher rate of recurrence of herpetic keratitis was observed in the topical treatment group (55% vs. 19%; p < 0.001) and graft rejection (52% vs. 19%; p < 0.001) after 24 months |
| Goldblum et al. 2008 [65] | PK for HED | Retrospective analysis | Oral administration of acyclovir 800 mg 3-5 times daily for 4 months, reduced to 400 mg twice a day until 36 months (n = 19) vs. Oral administration of valacyclovir 1000 mg three times daily for 4 months, reduced to 250 mg twice daily for up to 30 months (n = 20) | Postoperative use of topical steroids | Similar effect in preventing recurrences (3 patients taking acyclovir and 2 patients taking valacyclovir; p = 0.66) and graft rejection (2 patients from each group; p = 1.0); valacyclovir doses may be more comfortable for the patient |
| Garcia et al. 2007 [72] | PK for HED | Retrospective analysis | Oral administration of acyclovir 200 mg 4 times daily or 400 mg twice daily (n = 56) vs. No treatment (n = 14) | Postoperative administration of steroids four times daily | Fewer recurrences (p = 0.006) and better graft acceptance (p = 0.04) among patients taking oral acyclovir |
| de Rojas Silva et al. 2007 [73] | LASIK | Retrospective analysis | 500 mg of valacyclovir twice daily for 1 week before surgery and 2 weeks after surgery (n=48) | Dexamethasone 0.1% in combination with tobramycin 3 mg/ml, administered 4 times daily for 1 week postoperatively*** | During the follow-up period, no reactivation of herpetic keratitis was observed in any patient |
| van Rooij et al. 2003 [74] | PK for HED | Randomized controlled clinical trial | Oral administration of acyclovir 400 mg twice daily (n = 35) vs. Placebo (n = 33) For 6 months | Dexamethasone 0.1% every 4 hours, dosage reduced after 8 months | The graft survival analysis regarding the probability of no recurrence showed a lower risk of HED recurrence in the acyclovir-treated group (p = 0.026) |
| Tambasco et al. 1999 [75] | PK for HED | Retrospective analysis | Oral administration of acyclovir 400 mg twice daily (n = 20) vs. No treatment (n = 24) For a minimum of 12 months | No specified treatment | In the group receiving oral treatment, no corneal keratitis recurrence episodes were observed, compared to a 21% recurrence rate in the placebo group (p = 0.03). The graft rejection rate was higher in the placebo group (17% compared to 0%; p = 0.06) |
| Akova et al. 1999 [76] | PK for HED | Case study | Oral administration of 400 mg of acyclovir once daily (n = 19) vs. No treatment (n = 16) For 1 year | Prednisolone acetate 1% every 4 hours, dosage reduced over 1 year | Low-dose oral acyclovir prevents recurrences of HSV infection (8.3–28.6% vs. 33.3-50% in untreated patients. Recurrence in 2 cases after discontinuation of steroids |
| Barney and Foster 1994 [54] | PK for HED | Randomized controlled clinical trial | Oral administration of 800-1000 mg acyclovir in 4–5 divided doses (n = 14) vs. No treatment (n = 9) | Sodium phosphate1% 4 times daily, with dosage reduced over 1 year | No recurrences in the oral acyclovir group vs. 44% recurrences in patients without acyclovir. Graft failure in 14% of eyes treated with acyclovir compared to 56% without acyclovir |
| Fagerholm et al. 1994 [77] | PTK for HED | Retrospective analysis | Acyclovir 0.1% ointment twice daily for 1 month, followed by 4 times daily for 2 months (n = 20) | Dexamethasone 0.1% twice daily for 1 month, followed by 4 times daily for 2 months | PTK enhanced vision quality in specific cases, with no evidence suggesting an increase in recurrence rates |
RECOMMENDED PROPHYLACTIC MEASURES DURING THE POSTOPERATIVE PERIOD
Ocular surgical procedures may carry a risk of HSV reactivation, which can be mitigated through appropriate preventive strategies. Barney et al. demonstrated that oral acyclovir treatment following keratoplasty completely prevented herpes simplex keratitis recurrence, in contrast to the control group, where HSV reactivation was reported in 44% of patients. Moreover, patients undergoing this therapy showed lower rates of corneal regrafting [54]. Similar observations were made in subsequent randomized clinical trials, which confirmed a significant reduction in both the risk of herpes simplex keratitis recurrence and corneal graft rejection following implementation of postoperative acyclovir therapy after keratoplasty [71, 74, 78]. Literature review indicates that the greatest benefits are achieved by initiating oral acyclovir treatment one day before surgery. Hung et al. demonstrated that administration of acyclovir at a dose of 400 mg five times daily resulted in a significant increase in its concentration in the aqueous humor, with an average level of 3.26 µM. This value was significantly higher than the normal ED50 range for HSV and showed a strong correlation with the plasma concentration of acyclovir, which averaged 8.74 µM [79]. A review of the literature by Gessa-Sorroche et al. suggests that starting oral acyclovir therapy before the procedure and then continuing it for several weeks after the surgery significantly reduces the frequency of HSV and HZO recurrences as well as the risk of transplant rejection. The authors recommend a therapy dose of at least 400 mg twice daily for at least 12 months in high-risk patients [80].
Topical acyclovir treatment is less effective due to its relatively poor corneal penetration [68, 81]. Schulman et al., in animal model studies, demonstrated that the bioavailability of the drug can be improved by administering it subconjunctivally [82]. However, retrospective studies indicate greater efficacy of oral acyclovir therapy in preventing HSV recurrence compared to topical treatment (with corresponding rates of viral keratitis recurrence at 12% and 55%, respectively) [51]. While doses of 200 mg taken twice daily can provide a prophylactic effect, a dosage of 400 mg appears to deliver superior benefits [83]. Prophylactic therapy typically continues for 5-7 days post-surgery or until the complete healing of the scar [84]. A comparable effect can be achieved using valacyclovir, as demonstrated in the study by Goldblum et al. The study found no significant differences in the number of HSV recurrences or graft failures between the groups treated with acyclovir or valacyclovir during the 5-year follow-up period [65].
The implementation of appropriate perioperative prophylaxis appears to be particularly important, as the absence of such measures can result in a 55% risk of virus reactivation. Additionally, the risk of graft rejection has been reported at 52% [51]. Although cases of acyclovir-resistant HSV have been reported [85], scientific evidence suggests that oral acyclovir therapy remains the most effective perioperative prophylaxis. HSV treatment also incorporates ganciclovir and trifluridine, which effectively inhibit viral replication and improve patient outcomes [86]. However, the efficacy of ganciclovir was only confirmed in the study by Liu et al., where the drug was used as prophylaxis against reactivation in anterior lamellar corneal transplantation procedures [66].
CONCLUSIONS
Reactivation of the HSV can result from both local surgical manipulations and reduced immune system activity caused by perioperative steroid therapy. Irritation of the corneal nerve plexus is a common occurrence in various ophthalmic procedures, such as penetrating keratoplasty, lamellar keratoplasty, cross-linking, photorefractive and phototherapeutic surgeries, as well as cataract surgery. Among patients with a history of herpetic eye infection, any ophthalmic procedure within the eye carries a risk of recurrence. Strong scientific evidence supports recommending oral prophylaxis during the perioperative period for patients undergoing penetrating keratoplasty due to HSV-related corneal scarring, and for individuals with a positive history of ocular HSV infection. For other surgical procedures, the evidence remains less conclusive. Appropriate prophylactic measures can significantly reduce the risk of HSV reactivation as well as the likelihood of graft rejection. Current clinical evidence supports oral acyclovir prophylaxis (400 mg twice daily) as the optimal postoperative regimen following ophthalmic surgery. Treatment should begin immediately before surgery and continue until the discontinuation of steroids or for 5-7 days after surgery if steroid medications are not used. At present, the scientific literature does not offer a definitive answer on the actual risk of HSK recurrence following other eye surgeries (such as cataract and photorefractive procedures), underscoring the need for further research in this field.
