Herpetic Keratitis Research Articles

Predisposing factors, microbiological features and outcomes of patients with clinical presumed concomitant microbial and herpes simplex keratitis.

To describe the predisposing factors, pathogens and outcomes in patients with clinical presumed concomitant microbial and herpes simplex keratitis (HSK) at Sydney Eye Hospital, Australia over a 5-year period. A retrospective case review was conducted. Patients with clinical presumed concomitant microbial and HSK from 2012 to 2016 were identified from pathology and hospital coding databases. Data were extracted from the medical records. VA was converted to the logarithm of the minimum angle of resolution (logMAR). 'Poor' outcome was defined as final VA worse than 6/60, or decrease in VA during treatment, or presence of complication, or needed surgical intervention. 126 episodes in 121 patients were included; median age 70 years (range 18-96); 56% male. Predisposing factors included blepharitis 20/126 (16%) cases, and corneal transplantation 19 (15%). Forty-six (37%) cases had prior HSK. Coagulase-negative staphylococci 51/116 (44%), Staphylococcus aureus 11 (9%), and Pseudomonas aeruginosa 11 (9%) were the most common isolates. The median VA at initial visit was 1.7 logMAR (range 0.04-2.7) and at final visit, 0.98 logMAR (range 0-2.7) (P < 0.05). Complications occurred in 70 episodes: persistent epithelial defect in 38 (30%); intraocular pressure elevation in 15 (12%), and corneal perforation in 12 (10%). 'Poor' outcome was recorded in 46/75 (61%) episodes. Patients with clinical presumed concomitant microbial and HSK face significant ocular morbidity and poor visual outcome. In our setting, previous HSK, corneal and ocular surface disease, were common predisposing factors and Gram-positive bacteria were the most commonly associated organisms.

Herpes Simplex Virus Keratitis in a University Tertiary Referral Centre - Clinical Features and Surgical Approaches.

To assess prevalence, clinical manifestations, required keratoplasties, follow-up, and outcome in patients with Herpes Simplex Virus Keratitis (HSK) attending a University Tertiary Referral Center. Retrospective (12 years), descriptive, observational study. A total of 817 eyes with clinical diagnosis of HSK from 779 patients were classified by the type of presentation. We gathered data on the visual acuity, refraction, IOP, and required surgical procedures. Stromal involvement including scars represented the most common diagnosis in our department and the main indication of penetrating keratoplasty (PKP). Epithelial keratitis (16%) presented with the best visual acuity at the first visit. Necrotizing keratitis represented 17% of the patients, 78% of whom required PKP; this group also had the worst visual acuity at first examination and was the main indication for emergency PKP. Among all eyes, 288 (35%) required PKP. Atotal of 230 (28%) PKPs were elective procedures and 58(7%) PKPs were performed as emergency procedures. Two patients with quiet endothelial decompensations after recurrent HSV endotheliitis were treated with DMEK and had good visual outcomes without HSV recurrence at last follow-up. HSK is a prevalent disease with severe consequences when not treated appropriately and on time. Even when making an accurate diagnosis, the disease can be extremely aggressive, with all the implications it brings to the patients and health system. Elective PKP had better outcomes in terms of visual acuity and clear graft percentage compared to emergency PKP.

Delayed diagnoses of Acanthamoeba keratitis at a tertiary care medical centre.

To determine the prevalence and reasons for delays in diagnosis in patients with Acanthamoeba keratitis (AK) presenting to Wilmer Eye Institute, Baltimore, Maryland. This retrospective study analysed all patients with culture-positive AK seen between 2012 and 2019 at a tertiary referral centre. Patient demographic information, clinical history, risk factors, symptom duration, referral patterns, slit lamp examination findings, visual acuity and need for surgery were collected. The study included 45 eyes of 43 patients. On average, patients were symptomatic for 52.6 days before culture collection. Thirty-one percent of patients were diagnosed within 28 days of symptom onset while 69% were diagnosed after 28 days. Before presentation to a tertiary care centre, 69% of patients were evaluated by an ophthalmologist outside of this institution and 27% were evaluated by a provider other than an ophthalmologist. AK was most commonly misdiagnosed as herpetic keratitis, occurring in 38% of patients. The strongest risk factor for AK was contact lens use. Only 11% of patients presented with the classic ring infiltrate and 82% had pain. Patients with an early versus late diagnosis had a mean Snellen visual acuity (VA) of 20/224 versus 20/296 at presentation (p = 0.33) and a mean Snellen VA of 20/91 versus 20/240 at final visit (p = 0.07). 11% of patients required a therapeutic penetrating keratoplasty. Delayed diagnosis of AK in our cohort occurred due to a misdiagnosis as herpetic keratitis, non-specific clinical signs including the lack of pain in a number of patients, and a delay in referral to a tertiary care centre. Any contact lens wearer with an atypical keratitis should be referred promptly for Acanthamoeba cultures.

Efficient establishment of reactivatable latency by an acyclovir-resistant herpes simplex virus 1 thymidine kinase substitution mutant with reduced neuronal replication

Herpes simplex virus 1 causes recurrent diseases by reactivating from latency, which requires the viral thymidine kinase (TK) gene. An acyclovir-resistant mutation in TK, V204G, was previously repeatedly identified in a patient with recurrent herpetic keratitis. We found that compared with its parental strain KOS, a laboratory-derived V204G mutant virus was impaired in replication in cultured neurons despite little defect in non-neuronal cells. After corneal inoculation of mice, V204G exhibited defects in ocular replication that were modest over the first three days but severe afterward. Acute replication of V204G in trigeminal ganglia was significantly impaired. However, V204G established latency with viral loads as high as KOS and reactivated with high frequency albeit reduced kinetics. Acyclovir treatment that drastically decreased ocular and ganglionic replication of KOS had little effect on V204G. Thus, despite reduced neuronal replication due to impaired TK activity, this clinically relevant drug-resistant mutant can efficiently establish reactivatable latency.

Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.

PurposeIn clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.Patients and MethodsThe medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.ResultsOut of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.ConclusionApplication of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.

Bilateral Herpes Simplex Keratitis Presenting as Bilateral Ulcerative Blepharo-Keratoconjunctivitis: A Rarity or Pattern

Bilateral Herpes Simplex Keratitis Presenting as Bilateral Ulcerative Blepharo-Keratoconjunctivitis: A Rarity or Pattern

Marginal epithelial herpes simplex virus keratitis–There is more than meets the “eye”

Marginal epithelial herpes simplex virus keratitis–There is more than meets the “eye”

Targeting herpes simplex virus with CRISPR-Cas9 cures herpetic stromal keratitis in mice.

Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious blindness. Current treatments for HSV-1 do not eliminate the virus from the site of infection or latent reservoirs in the trigeminal ganglia. Here, we target HSV-1 genomes directly using mRNA-carrying lentiviral particles that simultaneously deliver SpCas9 mRNA and viral-gene-targeting guide RNAs (designated HSV-1-erasing lentiviral particles, termed HELP). We show that HELP efficiently blocks HSV-1 replication and the occurrence of herpetic stromal keratitis (HSK) in three different infection models. HELP was capable of eliminating the viral reservoir via retrograde transport from corneas to trigeminal ganglia. Additionally, HELP inhibited viral replication in human-derived corneas without causing off-target effects, as determined by whole-genome sequencing. These results support the potential clinical utility of HELP for treating refractory HSK.

Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series

BackgroundBurkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.MethodsWe retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.ResultsThe most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.ConclusionsB. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.

Dot1l Aggravates Keratitis Induced by Herpes Simplex Virus Type 1 in Mice via p38 MAPK-Mediated Oxidative Stress.

Background Disruptor of telomeric silencing 1-like (Dot1l) plays a vital role in biological processes as a well-known methyltransferase. However, its role in herpes simplex virus type 1- (HSV-1-) infected keratitis remains unclear. Methods In vitro and in vivo models were assessed to investigate the role of Dot1l in HSV-1 induced keratitis. C57BL/6 mice corneas were infected with HSV-1 for different days, with or without Dot1l inhibitor, to demonstrate the regulation of Dot1l in herpes simplex keratitis (HSK). Human corneal epithelial (HCE) cells were cultured and infected with HSV-1 to identify the molecular mechanisms involved. Results In this study, we found that Dot1l was positively related to HSK. Inhibition of Dot1l with EPZ004777 (EPZ) alleviated corneal injury, including oxidative stress and inflammation in vivo. Similarly, the inhibition of Dot1l with either EPZ or small interfering RNA (siRNA) showed an inhibitory effect on HSV-1-induced oxidative stress and inflammation in HCE cells. Moreover, our study revealed that the expression of p38 MAPK was elevated after HSV-1 infection in HCE cells, and the inhibition of Dot1l could reduce the increased expression of p38 MAPK induced by HSV-1 infection in vivo and in vitro. Conclusion Our results demonstrated that the inhibition of Dot1l alleviated corneal oxidative stress and inflammation by inhibiting ROS production through the p38 MAPK pathway in HSK. These findings indicated that Dot1l might be a valuable therapeutic target for HSK.

Commentary: Diagnostic markers for suspected herpes simplex virus keratitis - A bridge too far.

Commentary: Diagnostic markers for suspected herpes simplex virus keratitis - A bridge too far.

Confocal microscopy in the diagnosis of acanthamoeba keratitis

To evaluate the capabilities of corneal confocal microscopy (CCM) in the diagnosis of acanthamoeba keratitis. We examined 33 patients (35 eyes) with suspected acanthamoeba keratitis using light and laser confocal microscopy of the cornea (ConfoScan and HRT devices, respectively). CCM was technically feasible in 23 of 35 cases (65.7%). Acanthamoeba cysts were detected in 16 cases (69.6%); trophozoites were visualized in 17.4% of cases; signs of keratoneuritis were detected in 12 eyes (52.2%); in 7 cases (30.4%), hyporeflective honeycomb-like cavities were observed in the stroma; deep stromal striae were observed in 9 cases (39.1%); activated keratocytes were detected in 11 patients (47.8%), and Langerhans cells were detected in 19 cases (82.6%). The main diagnostic value of confocal microscopy is the detection of direct markers of AK - cysts and trophozoites of Acanthamoeba. Both light and laser CCM techniques are suitable for the diagnosis of AK, but the resolution of laser confocal microscopy is higher. The non-invasive nature of this method and the possibility of multiple subsequent examinations make it possible to verify the diagnosis of acanthamoeba keratitis and monitor the treatment.

Innovative ex vivo model of human herpetic keratitis to evaluate antiviral drugs: proof of concept with 0.15% ganciclovir ophthalmic gel

AbstractPurposeWe have recently developed and characterized a unique model of herpetic keratitis reproducing dendritic or geographic ulceration on human corneas stored in our corneal Bioreactor (BR). The BR is a multi‐application experimentation platform developed to keep the cornea alive for prolonged periods of time in a physiological environment of intraocular pressure and environmental renewal.AimTo evaluate whether this model can be used to test the efficacy of antiviral eye drops.MethodsHSV‐1 keratitis was obtained as previously described: paired corneas discarded from our eye bank were stored in the BR for 14 days (D) at 21 mmHg and 2.6 µl/min of medium renewal (CorneaMax, Eurobio, France) to allow epithelial regeneration. A superficial linear epithelial lesion was then made in the centre, followed incubation of the epithelial surface for 1 hr in a solution of 106 Plaque‐Forming Unit/mL HSV‐1. Three days post‐infection, 0.15% ganciclovir ophthalmic gel used with active molecule at 3.75 µg/ml was instilled on the cornea inside the BR, 3 times/day during 14D and 2 times/day during 5D. The gel was rinsed after 10 min with BSS. The paired cornea was treated similarly with the vehicle (carbomer 974P). Changes in epithelial ulceration size were monitored daily by non‐invasive imaging through the transparent BR windows. Histology and immunolabeling (HSV‐1 gpB, epithelial markers) were done at D40.ResultsFor the control corneas, the entire epithelium desquamated at D10. At D40 all keratocytes expressed gpB and endothelial cells partly disappeared. For ganciclovir‐treated corneas, only half of the epithelium desquamated at D14, then it began to regenerate during the third week to reach 1 to 3 epithelial layers at D40. Epithelial and endothelial cells were not infected (gpB‐). Some keratocytes were infected only in the periphery.ConclusionsModel of herpetic keratitis in the BR has a high potential to evaluate antiviral eye drops efficacy.

Potential effect of decreased levels of folic acid and vitamin B12 on herpes simplex virus keratitis reactivation

Background/Aim. Most cases of herpetic keratitis present a recurrent disease as a result of herpes simplex virus type 1 reactivation from latency in the nearest sensory ganglia. Therefore, understanding the mechanisms of latency and reactivation of the latent virus is an important link in comprehending the onset of the recurrent eye disease itself. Epigenetic regulation of virus reactivation, as a result of the presence of transcriptionally active Latency-Associated Transcript (LAT) region in the latent viral genome, has already been demonstrated in several studies. The activity of the LAT region is directed to the chromatin arrangement. Epigenetic modulation of DNA methylation is associated with folate and vitamin B12 intake or their serum concentrations. To our knowledge, there is no report on the potential role of vitamin B12 and folic acid in herpes simplex virus keratitis reactivation. The aim of this study was to analyze the potential role of folic acid and vitamin B12 in the control of ocular herpes simplex keratitis reactivation. Methods. The study included 50 patients older than 18 years of age with recurrent herpes simplex virus eye disease. Levels of vitamin B12 and folic acid were measured in the acute phase of the disease. All patients were followed up for at least one year and episodes of recurrent herpetic eye diseases were recorded. Results. The recurrence rate of herpetic keratitis was statisticall significantly lower in patients with a higher blood level of vitamin B12. In addition, the recurrence rate of herpetic keratitis was lower in patients with a higher blood level of folic acid. However, statistical significance was lower in comparison with that for vitamin B12. Conclusion. The decreased levels of vitamin B12 and folic acid might have a vital role in herpes simplex keratitis reactivation.

Herpes simplex keratitis revisited.

The degree to which viral infection and the host's immune reaction to viral particles participate in the inflammatory process across various forms of herpetic keratitis has remained controversial. This fact has created conflicts regarding the classification of and therapeutic planning for such morbidities. This review aims to stimulate reflection on the classifications' adequacy, nomenclatures, and therapeutic approaches related to these entities.

Recent Updates on the Role of Nanoparticles in the Treatment of Viral Diseases.

Viral infections such as AIDS, hepatitis, herpes keratitis, and herpes labialis became resistant to drugs and it is difficult to design vaccine. In current era drug-resistant viruses are now treated by nanoparticles (NPs) and this field is known as nanobiotechnology that relates nanoscience with the biological system. NPs due to their antiviral activity are used in the treatment of viral diseases. The advantages of using the NP is its specific target action and increase the efficiency of treatment with minimum side effects. Liposomes, quantum dots, polymeric NPs, solid lipid NPs, silver NPs, gold NPs, and magnetic NPs are used to treat viral infections. NP-based therapeutics have completely replaced the usage of drugs and vaccines for viral diseases treatment. Nano vaccines have been investigated for the delivery of drugs; biomaterials-based NPs are in development to be formulated into nano vaccines. But there are limitations in the manufacturing and stabilization of NPs in the body. This review focuses on the antiviral activity of several NPs, its uptake by different viruses for viral disease treatment, nano vaccines, and the limitation of the NPs as nanotherapeutics.

Successful Treatment of Cryptococcus albidus Keratitis with Voriconazole 1% Drops and Oral Itraconazole

The Cryptococcus genus, include a wide group of yeast, which species are usually found in water and plants. C neoformans and C gatti are considered pathogens for humans and animals, whoever Cryptococcus laurentii, C albidus and C curvatus are considered as potential environmental pathogen for both. We describe one fungal keratitis caused by Cryptococcus albidus, in a male 41 years old, diagnosed previously with diabetes type 2, and ocular surgery for cataract extraction 7 years before, actually he presented a corneal ulcer in right eye diagnosed before as herpetic keratitis unresponsive to Aciclovir, after de first ocular observation in our hospital in Cornea Service, and samples for culture taken, the final diagnosis was Cryptococcus albidus keratitis, the treatment with antimycotic drugs, topic voriconazole 1% and oral itraconazole 100mgs each 12 hs was administered. The corneal ulcer was healed in 3 weeks and the FBCVA was 20/30.

Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction

Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target.

Herpes simplex virus stromal keratitis and endotheliitis after femtosecond laser–assisted cataract surgery and astigmatic keratotomy

Two weeks after uneventful femtosecond laser–assisted cataract surgery (FLACS) with laser astigmatic keratotomy (AK) in the right eye, a 72-year-old woman developed a corneal ulcer and infiltrate in the superonasal AK incision, with severe anterior chamber reaction. She was initially treated for bacterial followed by fungal keratitis, without resolution. She was referred to our university corneal service for consultation. Based on clinical presentation and slitlamp examination, the patient was diagnosed with herpes simplex virus keratitis (HSK). The patient was administered topical steroid eyedrops and systemic antiviral therapy, with full resolution of the keratitis. To the authors’ knowledge, this is the first reported case of herpes simplex virus stromal keratitis and endotheliitis after FLACS combined with AK. This report postulates about possible etiologic factors for activation of HSK after femtosecond laser treatment and proposes preventative actions.

The analysis of the evidence base of the clinical efficiency and safety of acyclovir for topical application

Herpes viruses are a family of DNA viruses, among them herpes simplex virus is the most common (HSV). An important task of modern medicine is effective and safe pharmacotherapy of viral diseases caused by HSV.Aim. To analyze the range of drugs for the topical application in the pharmacotherapy of HSV at the pharmaceutical market of Ukraine, as well as search the evidence base of acyclovir, the leader of the pharmaceutical market.Materials and methods. The analysis of the range of antiherpetic drugs for the topical application was performed according to the analytical system of the study of the pharmaceutical market of Ukraine “Pharmstandard” by the company “Morion”. To analyze the clinical efficiency and safety of the antiherpetic drug “Acyclovir”, the following well-known evidence-based databases were used: Cochrane Library, Trip Database, PubMed, Nice.Results. Antiherpetic drugs for the topical application at the pharmaceutical market of Ukraine for 2016-2018 were quantitatively represented from 17 to 20 TN based on 7 INNs, mainly by foreign manufacturers. Drugs of acyclovir were the most accessible and widely presented at the market. The search for the evidence base of acyclovir for the topical application made it possible to find 7 systematic reviews devoted to the treatment of herpes diseases in the evidence-based medicine databases. Numerous studies have shown that the topical treatment with the acyclovir HSV cream on the lips and in genital herpes is less effective than its systemic application. And the use of acyclovir ointments in the treatment of herpetic keratitis is not inferior in effectiveness to the reference drugs. Conclusions. The analysis of systematic reviews and meta-analyses has shown that the topical treatment with the acyclovir HSV cream is less effective than its systemic application. The effectiveness of the use of acyclovir ointments in the treatment of herpetic keratitis has also been proven.