Sensitivity of Human Mastadenovirus, the Causal Agent of Pharyngoconjunctival Fever, Epidemic Keratoconjunctivitis, and Hemorrhagic Cystitis in Immunocompromised Individuals, to Brincidofovir.

Human mastadenovirus (HAdV), a linear double-stranded DNA (dsDNA) virus, is the causal agent of several diseases, including pharyngoconjunctival fever, epidemic keratoconjunctivitis, and hemorrhagic cystitis, in immunocompromised individuals. There are more than 100 reported types of adenoviruses, but the pathogenicity of many HAdVs remains unknown. Brincidofovir (BCV) is a hexadecyloxypropyl lipid conjugate of cidofovir (CDV) that is active against dsDNA viruses. Clinical effectiveness of BCV against certain HAdV species has been reported; however, its activity against novel HAdV types remains unknown. We investigated the half-maximal inhibitory concentration (IC50) values of BCV for novel HAdV types and found that the epidemic keratoconjunctivitis-associated HAdV-D54 prevalent in the Asian region was the most susceptible. The mean overall IC50 value of BCV was lower than that of CDV, indicating that BCV is effective against HAdVs, including the novel types. IMPORTANCE We investigated the IC50 values of BCV for novel HAdV types and found that the epidemic keratoconjunctivitis-associated HAdV-D54 prevalent in the Asian region was the most susceptible. In addition, the mean overall IC50 value of BCV was lower than that of CDV, indicating that BCV is effective against HAdVs.

Recurrent keratoconjunctivitis as the sole manifestation of COVID-19 infection: A case report.

INTRODUCTION: Ocular symptoms are uncommon manifestations of coronavirus disease 2019 (COVID-19) infection. Earlier study reported that dry eye, blurred vision, foreign body sensation, tearing, itching, conjunctival secretion, conjunctival congestion, ocular pain, and photophobia are among the ocular symptoms that could be found in COVID-19 patients. However, there are only a few reports available regarding corneal involvement in this disease. Here we report a case of keratoconjunctivitis as the only symptom of COVID-19 infection. CASE DESCRIPTION: A 27-year-old man who worked as an obstetrics and gynecology resident came to the outpatient clinic with the chief complaints of eye discomfort, foreign body sensation, conjunctival hyperemia, lacrimation, and photophobia in his right eye for the past 3 weeks. Fluorescence test showed a small corneal lesion. The patient was then diagnosed with keratoconjunctivitis. A week after the treatment, all symptoms were resolved. A month later, the patient came to the emergency room with the same eye complaints but with a more severe pain. The fluorescence test showed wider corneal lesion compared to last month. The result from the corneal swab is negative for bacterial or fungal infection, indicating a viral infection. Afterwards, reverse transcriptase polymerase chain reaction test from nasopharyngeal swab was performed and revealed that the patient was positive for COVID-19. CONCLUSIONS: This case report showed that keratoconjunctivitis may occur as the only manifestation of COVID-19 infection. Thus, patient presented with unexplainable eye symptoms should be evaluated for COVID-19 infection.

Phlyctenular Keratoconjunctivitis in a Patient With COVID-19 Infection.

ABSTRACT: The coronavirus disease 2019 global pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several ophthalmic manifestations have been reported to be associated with SARS-CoV-2 infection, including conjunctivitis, acute sixth nerve palsy, and multiple cranial neuropathies. We present a unique case of unilateral phlyctenular keratoconjunctivitis in a 5-year-old boy in the setting of SARS-CoV-2 infection.

Whole-genome analysis to describe a human adenovirus D8 conjunctivitis outbreak in a tertiary hospital.

Conjunctivitis is a frequent ocular disorder caused by human adenoviruses (HAdVs). Only a few of the 45 HAdV-D species are associated with epidemic keratoconjunctivitis, including HAdV-D8. Nosocomial outbreaks due to HAdV-D8 have been rarely described, because keratoconjunctivitis cases are clinically diagnosed and treated without having to characterize the causative agent. Moreover, molecular typing is tedious when using classical techniques. In this study, a hospital outbreak of conjunctivitis caused by HAdV-D8 was characterized using the recently developed whole-genome sequencing (WGS) method. Of the 363 patients attending the Ophthalmology Department between July 13 and August 13, 2018, 36 may have acquired intrahospital conjunctivitis. Also, 11 of 22 samples sent to the Virology section were selected for WGS analysis. The WGS results revealed that 10 out of 11 HAdV-D8 strains were closely related. The remaining strain (Case 28) was more similar to a strain from an outbreak in Germany obtained from a public sequence database. WGS results showed that outbreak HAdV-D8 strains had a minimum percentage of identity of 94.3%. WGS is useful in a clinical setting, because it avoids carrying out viral culture or specific polymerase chain reaction sequencing. The public availability of sequence reads makes it easier to compare clusters in circulation. In conclusion, WGS can play an important role in standard routines to describe viral outbreaks.

The Treatment Models for Adenoviral Keratoconjunctivitis in the Childhood Population.

Purpose: To examine the effects of treatments performed on children with adenoviral conjunctivitis.Methods: 50 children with Adenoviral keratoconjunctivitis (AK) were evaluated. Patients were divided into four groups according to the medical treatment agents that were used previously. AK symptoms were clinically scored and analyzed. The diagnosis of all children was confirmed by an in-office lateral flow immunoassay.Results: Fifty patients with AK were included in the study. 24 (48%) were female and 26 (52%) were male. The mean age was 12.88 ± 2.66 (8-17). In PVP-I groups clinical findings shows faster improvement than other groups (p < .05).Conclusions: Conjunctival irrigation with 2.5% PVP-I is very effective for the treatment of adenoviral conjunctivitis in childhood. Ganciclovir ophthalmic gel 0.15% increases the effect of 2.5% PVP-I on AK, but this was not statistically significant.

Disinfectant potential in inactivation of epidemic keratoconjunctivitis-related adenoviruses by potassium peroxymonosulfate.

PURPOSE: The aim of this study was to test the antiviral effectivity of potassium peroxymonosulfate (RUBYSTA®, KYORIN) against five epidemic keratoconjunctivitis-related types of Human adenovirus D in vitro. METHODS: Five types of Human adenovirus D (8, 37, 53, 54 and 56) were incubated with 1% potassium peroxymonosulfate, 0.1% sodium hypochlorite (NaClO) or alcohol-based disinfectant for 30 s or 1 min. These solutions were subjected to measurements of viral titres by infection assays in A549 cells. At day 6 post-infection, both, supernatants and cells, were collected and the viral genome was assessed by real-time polymerase chain reaction analysis. RESULTS: Treatments with 1% potassium peroxymonosulfate led to significant reduction in all tested Human adenovirus D types comparable to disinfecting effects by 0.1% NaClO. Overall, potassium peroxymonosulfate demonstrated sufficient inactivation of the major epidemic keratoconjunctivitis-causing Human adenovirus D to be considered for disinfection and prevention purposes in ophthalmological clinics and hospitals. CONCLUSION: This study demonstrated that potassium peroxymonosulfate is a promising disinfectant for the prevention of epidemic keratoconjunctivitis nosocomial infections in ophthalmological clinics.

An outbreak of adenovirus D8 keratoconjunctivitis in Leicester, United Kingdom, from March to August 2019.

We report a large epidemic (n = 126) of keratoconjunctivitis predominantly with two lineages of adenovirus (AdV) type D8 in patients seen in eye casualty between march and August 2019. Other AdV species identified by viral sequencing included B, C, and E. Despite various features of more severe eye disease being present, these were not significantly different between the different AdV species, with similar rates of pseudomembrane formation and keratitis observed in patients with AdV species B as for those with AdV species D.

[Outbreak of epidemic keratoconjunctivitis caused by human adenovirus serotype 8 in a nursing home.] / Brote de queratoconjuntivitis epidémica por adenovirus humano serotipo 8 en una residencia de mayores.

OBJECTIVE: Ocular infections caused by human adenovirus are highly contagious and can cause outbreaks, especially in nursing homes. In this work, we describe the epidemiological and analytical research as well as the control measures carried out for a conjunctivitis outbreak. METHODS: Descriptive epidemiological study. Cases with a symptom onset date prior to oficial communication were analyzed retrospectively. The rest was analyzed prospectively. Conjunctival smears were collected for microbiological study. Virological analysis was performed by detecting adenovirus by PCR and genotyping. A data questionnaire that collected clinical and epidemiological information was designed. Possible risk factors associated with infection were studied by calculating the Odds Ratio. RESULTS: On June 11, 2019, the Epidemiological Surveillance Section of the Provincial Health Department of Albacete was notified of the existence of a large number of cases of conjunctivitis in a geriatric center. 54 cases were declared: 43 internal residents, 3 day center assistants and 8 workers. Attack rates were 35.8%, 12.5% and 8.4% respectively. Three risk factors were associated with the disease: patient´s lack of autonomy, being a resident at the nursing home and having their room assigned on the first floor. Human adenovirus serotype 8 was detected in the patients' samples. CONCLUSIONS: A high attack rate was observed in internal residents and the disease was associated with patient´s lack of autonomy and having their room assigned on the first floor of the nursing home. The outbreak was caused by human adenovirus serotype 8.

OBJETIVO: Las infecciones oculares causadas por adenovirus humanos son altamente contagiosas y pueden causar brotes, especialmente en residencias de ancianos. El objetivo de este trabajo fue exponer las investigaciones epidemiológicas y analíticas realizadas para el estudio del brote de queratoconjuntivitis epidémica y las medidas establecidas para su control. METODOS: Se realizó un estudio epidemiológico descriptivo. Se analizaron de forma retrospectiva los casos con fecha de inicio de síntomas anterior a la comunicación oficial, y de forma prospectiva el resto. Se recogieron frotis conjuntivales para estudio microbiológico. El análisis virológico fue realizado mediante la detección de adenovirus por PCR y genotipado. Se diseñó un cuestionario de datos que recogía información clínica y epidemiológica. Se estudiaron posibles factores de riesgo asociados a la infección mediante el cálculo de la Odds Ratio. RESULTADOS: El 11 de junio de 2019 se notificó a la Sección de Vigilancia Epidemiológica de la Dirección Provincial de Sanidad de Albacete la existencia de un número elevado de casos de conjuntivitis en un centro geriátrico. Se declararon 54 casos: 43 entre residentes internos, 3 entre asistentes del centro de día y 8 entre personal laboral. Las tasas de ataque fueron del 35,8%, 12,5% y 8,4%, respectivamente. La falta de autonomía, el ser residente interno y estar ubicado en la primera planta fueron factores asociados a la enfermedad. Se detectó adenovirus humano serotipo 8 en las muestras correspondientes a enfermos. CONCLUSIONES: Se observó una elevada tasa de ataque en residentes internos y la enfermedad se asoció con la falta de autonomía y la localización en la primera planta. El brote fue causado por adenovirus humano serotipo 8.

Relapsing viral keratoconjunctivitis in COVID-19: a case report.

BACKGROUND: Since the outbreak of Coronavirus Disease 2019 (COVID-19) in December 2019, many studies have reported the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the conjunctival sac of patients infected with this virus, with several patients displaying symptoms of viral conjunctivitis. However, to our best knowledge, there is no in-depth report on the course of patients with COVID-19 complicated by relapsing viral conjunctivitis or keratoconjunctivitis. CASE PRESENTATION: A 53-year-old man confirmed with COVID-19 developed symptoms of viral conjunctivitis in the left eye approximately 10 days after the onset of COVID-19. The results of a nucleic acid test were positive for SARS-CoV-2 in the conjunctival sac of the left eye. The symptoms were relieved 6 days after treatment. However, the patient was subsequently diagnosed with viral keratoconjunctivitis in both eyes 5 days after the symptoms in the left eye were satisfactorily relieved. The disease progressed rapidly, with spot staining observed at the periphery of the corneal epithelium. Although SARS-CoV-2 could not be detected in conjunctival secretions, the levels of inflammatory factors, such as interleukin-6, were increased in both eyes. Both eyes were treated with glucocorticoids, and symptoms were controlled within 5 days. There was no recurrence. CONCLUSIONS: In this case report, the pathogenesis, clinical manifestations, treatment, and outcome of a case with COVID-19 complicated by relapsing viral keratoconjunctivitis is described, and the involvement of topical cytokine surge in the pathogenesis of COVID-19 as it relates to viral keratoconjunctivitis is reported.

COVID-19: Ophthalmological Aspects of the SARS-CoV 2 Global Pandemic. / COVID-19: ophthalmologische Aspekte der globalen SARS-CoV-2-Pandemie.

PURPOSE: To perform a systematic analysis of articles on the ophthalmological implications of the global COVID-19 pandemic. METHODS: PubMed.gov was searched for relevant articles using the keywords "COVID-19", "coronavirus", and "SARS-CoV-2" in conjunction with "ophthalmology" and "eye". Moreover, official recommendations of ophthalmological societies were systematically reviewed, with a focus on the American Academy of Ophthalmology (AAO) and the Royal College of Ophthalmologists (RCOphth). RESULTS: As of April 16, 2020, in total, 21 peer-reviewed articles on the ophthalmological aspects of COVID-19 were identified. Of these, 12 (57.1%) were from Asia, 6 (28.6%) from the United States of America, and 3 (14.3%) from Europe. There were 5 (23.8%) original studies, 10 (47.6%) letters, 3 (14.2%) case reports, and 3 (14.2%) reviews. These articles could be classified into the topics "Modes and prevention of (ocular) transmission", "Ophthalmological manifestations of COVID-19", "Clinical guidance concerning ophthalmological practice during the COVID-19 pandemic", and "Practical recommendations for clinical infrastructure". Practical recommendations could be extracted from official statements of the AAO and the RCOphth. CONCLUSION: Within a short period, a growing body of articles has started to elucidate the ophthalmological implications of COVID-19. As the eye can represent a route of infection (actively via tears and passively via the nasoacrimal duct), ophthalmological care has to undergo substantial modifications during this pandemic. In the eye, COVID-19 can manifest as keratoconjunctivitis.

Evaluation of the Anti-Adenoviral Activity of ALTANT, an Ozonated Alcohol Disinfectant.

Seven human mastadenovirus (HAdV) species (A-G) are known with more than 100 reported types. HAdV is highly resistant to common hand sanitizers. Epidemic keratoconjunctivitis and pharyngoconjunctival fever are caused by HAdV, which can be explosively transmitted in a confined space, resulting in outbreaks, such as nosocomial infections. Given the absence of an antiviral agent against the HAdV infection, it is important to prevent the spread of the infection by using disinfectants. Ozone has already been well-known for its bactericidal and virucidal effects. ALTANT is an ozonated alcohol preparation developed by E-TECH Co., Ltd. (Kobe, Hyogo, Japan). In this study, we mixed ALTANT with different HAdV types at a ratio of 9:1 and determined HAdV viability after instantaneous reactions for varying periods (flash to 5 minutes) using the TCID50 assay. The assay results demonstrated that the HAdV viability decreased by 1/10 to 1/100 within 1 minute after the reaction; additionally, slight differences in the reactivity were observed among the HAdV types. HAdV viability decreased by a factor of > 4log10, and the virus was eliminated within 3 minutes. This study demonstrated the potent HAdV disinfection effect of ALTANT.

Application of human lymphoid cells for the evaluation of antivirals against human adenovirus type 19: Zalcitabine has superior activity compared to cidofovir.

Human adenovirus type 19 (HAdV-19) is a major cause of the epidemic keratoconjunctivitis. Outbreaks of keratoconjunctivitis are problematic to human health, especially for infants, the elderly, and immunocompromised individuals. However, the development of anti-HAdV drugs has been hampered by inconvenient screening systems; therefore, development of a simple screening method is highly desirable. In this study, we identified that HAdV-19 can infect a human lymphoid cell line transformed with human T-cell leukemia virus (MT-2 cells). MT-2 cells supported HAdV-19 replication and showed apparent cytopathic effects within five days post-infection. Using a thiazolyl blue tetrazolium bromide (MTT)-based colorimetric assay on MT-2 cells, we were able to detect the anti-HAdV-19 activities of previously reported nucleoside/tide compounds, including (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir), 2',3'-dideoxycytidine (zalcitabine) and 3'-deoxy-3'-fluorothymidine (trifluridine). Compared with previous methods, this system represents a more simple and rapid method to screen anti-HAdV-19 agents.

Characteristic of slow growth in cell culture of adenovirus type 54 causing nationwide outbreak epidemic keratoconjunctivitis in Japan.

PURPOSE: To characterize the virological features of adenovirus type 54 (Ad54) causing nationwide outbreak of severe epidemic keratoconjunctivitis (EKC) in Japan, we comparatively analysed the viral propagation phenotype of Ad54 and other Ads: type 37 (Ad37), 64 (Ad64), and 5 (Ad5), in A549 cells quantitatively. STUDY DESIGN: Laboratory investigation. METHODS: We compared the growth rate of Ads using copy numbers and cytopathic effect observation during propagation in A549 cell lines. Expressions of mRNA of E1 gene were also calculated and compared. Phylogenetic analysis of the region, including putative promoter of E1 gene and E1 open reading frame (ORF), were performed. RESULTS: Increases in viral loads, growth rate, and viral propagation were slower for Ad54 than for other Ads. The expression level of the E1 gene per infected cell was lower for Ad54 than for other Ad types on post-infection day 1. Phylogenetic analysis of the E1 gene putative promoter and ORF revealed Ad54 was the closest to Ad type 8. CONCLUSION: The propagation of Ad54 in A549 is slow compared with Ad37, Ad64 and Ad5. This slow propagation could have been caused by slow genomic replication resulting from delayed viral entry or E1 transcription initiation. The EKC caused by Ad54 needs more attention because the slow propagation of Ad54 may contribute to prolonged disease duration.

Transepithelial Surface Ablation With Mitomycin C for the Treatment of Chronic Central Corneal Scars Following Adenoviral Keratoconjunctivitis.

PURPOSE: To assess visual and refractive outcomes and recurrence rates of subepithelial infiltrates after corneal surface ablation with mitomycin C (MMC) 0.02% for the treatment of chronic corneal scars following epidemic keratoconjunctivitis and to compare these results with a control group receiving only medical treatment. METHODS: This was a retrospective case series enrolling patients with central corneal scars following epidemic keratoconjunctivitis. Patients were divided into two groups: (1) control with clinical follow-up and refractive correction with glasses or rigid gas-permeable contact lenses when necessary and (2) transepithelial phototherapeutic keratectomy (PTK) with MMC 0.02%, combined with photorefractive keratectomy (PRK) in selected cases (treatment group). Signs and symptoms, corrected distance visual acuity (CDVA) in logMAR units, manifest and cycloplegic refraction, and depth of the corneal opacities were assessed. RESULTS: Thirty-five eyes of 27 patients (11 men [40.7%] and 16 women [59.3%]) were enrolled, with a mean follow-up of 54.4 ± 19.7 and 27.5 ± 22.8 months in the control and treatment groups, respectively. Mean improvement in CDVA was 0.13 ± 0.17 logMAR (P = .007) in the control group and 0.29 ± 0.24 logMAR (P = .001) in the treatment group. Intergroup comparison showed a greater improvement in the treatment group (P = .041). Mean hyperopic shift induced in the treatment group was +0.46 ± 1.20 diopters. The recurrence rate of subepithelial infiltrates was 77.7% in the control group and 11.7% in the treatment group throughout the follow-up (54.4 ± 19.7 and 27.5 ± 22.8 months, respectively). CONCLUSIONS: Corneal surface ablation with MMC 0.02% was efficient in treating corneal scars following adenoviral epidemic keratoconjunctivitis, with greater visual improvement in comparison to clinical treatment and a decreased rate of infiltrate recurrence. [J Refract Surg. 2020;36(1):55-61.].

Mystery eye: Human adenovirus and the enigma of epidemic keratoconjunctivitis.

Known to occur in widespread outbreaks, epidemic keratoconjunctivitis (EKC) is a severe ocular surface infection with a strong historical association with human adenovirus (HAdV). While the conjunctival manifestations can vary from mild follicular conjunctivitis to hyper-acute, exudative conjunctivitis with formation of conjunctival membranes, EKC is distinct as the only form of adenovirus conjunctivitis in which the cornea is also involved, likely due to the specific corneal epithelial tropism of its causative viral agents. The initial development of a punctate or geographic epithelial keratitis may herald the later formation of stromal keratitis, and manifest as subepithelial infiltrates which often persist or recur for months to years after the acute infection has resolved. The chronic keratitis in EKC is associated with foreign body sensation, photophobia, glare, and reduced vision. However, over a century since the first clinical descriptions of EKC, and over 60 years since the first causative agent, human adenovirus type 8, was identified, our understanding of this disorder remains limited. This is underscored by a current lack of effective diagnostic tools and treatments. In part, stasis in our knowledge base has been encouraged by the continued acceptance, and indeed propagation of, inaccurate paradigms pertaining to disease etiology and pathogenesis, particularly with regard to mechanisms of innate and adaptive immunity within the cornea. Owing to its often persistent and medically refractory visual sequelae, reconsideration of key aspects of EKC disease biology is warranted to identify new treatment targets to curb its worldwide socioeconomic burden.

Cyclosporin A eye drop and subepithelial adenoviral keratoconjunctivitis infiltrates.

INTRODUCTION: The adenoviral keratoconjunctivitis infiltrates may be a source of significant visual impairment justifying the use of various therapeutic means. AIM: Evaluate the efficiency and safety of use of cyclosporine A 0,5% eye drop in the treatment of subepithelial infiltrates. METHODS: It was a prospective study of 37 eyes of 22 patients with adenoviral keratoconjunctivitis with subepithelial infiltrates treated with cyclosporine A 0,5% eye drop. Cyclosporine A 0,5% was prepared from the injectable form of cyclosporine (Sandimmun®) and artificial tears. The cyclosporine A 0,5% was first administered at 4 drops per day for 15 days, then at a rate of 2 drops per day for a variable period ranging from 15 days to 6 months. The use of this molecule has been motivated by the presence of a persistent dazzlement, by visual acuity under 6/10 or an astigmatism superior to 1 diopter. RESULTS: At the end of follow, dazzlement disappeared in all patients; the final average visual acuity was 8/10 and corneal astigmatism average was of 0.75 diopter. The slit lamp examination showed a marked decrease in the number and density of subepithelial infiltrates from the 15th day. A 29-year-old patient, however, presented some intercostal vesicles due to zonal recrudescence but with spontaneous and quick resolve in the same time of taking topical cyclosporine. No local complications were observed in our patients. The average follow-up was 13 months. CONCLUSION: Topical cyclosporine A is an effective and well-tolerated alternative to corticosteroids in the subepithelial infiltrates occurring as sequelae of adenoviral keratoconjunctivitis.

Genomic foundations of evolution and ocular pathogenesis in human adenovirus species D.

Human adenovirus commonly causes infections of respiratory, gastrointestinal, genitourinary, and ocular surface mucosae. Although most adenovirus eye infections are mild and self-limited, specific viruses within human adenovirus species D are associated with epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular surface infection, which can lead to chronic and/or recurrent, visually disabling keratitis. In this review, we discuss the links between adenovirus ontogeny, genomics, immune responses, and corneal pathogenesis, for those viruses that cause EKC.

Assessment of clinical signs associated with adenoviral epidemic keratoconjunctivitis cases in southern Japan between 2011 and 2014.

Adenoviral epidemic keratoconjunctivitis (EKC) is a major cause of ocular morbidity worldwide and specific antiviral therapies are not available. EKC is primarily caused by Human adenovirus D (HAdV-D) types 8, 37, 53, 54, 56 and 64. Considering the genomic variation in HAdV-D, we hypothesized that clinical signs could be differentiated by virus type. The hypothesis was retrospectively tested with clinical signs recorded from 250 patients with ocular infections visiting an ophthalmological clinic in southern Japan between 2011 and 2014. The results showed that conjunctival opacity, corneal epithelial disorders and pre-auricular lymphadenopathy, were more frequently associated with EKC than other ocular infections. Furthermore, HAdV types 8, 37 and 54, caused corneal complications and longer infections significantly more frequently than infections by types 53 and 56 (P < 0.05). Our descriptive results supported that symptoms severity vary with the infecting type, however, further research is needed to improve diagnosis of EKC.