Mystery eye: Human adenovirus and the enigma of Epidemic Keratoconjunctivitis (EKC)
Highlights
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Epidemic keratoconjunctivitis (EKC) is a severe ocular surface infection.
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EKC causes conjunctivitis of varying severity, but its hallmark is relapsing and remitting corneal inflammation.
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Human adenoviruses, particularly species D, are the main pathogens.
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Models of adenovirus keratitis suggest corneal cells play a key role in the host inflammatory response.
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To date, only topical corticosteroids and tacrolimus appear to alter the course of chronic keratitis following EKC.
Abstract
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.
NovaBay is developing an eye drop formulation of NVC-422 for treating adenoviral conjunctivitis, a highly contagious viral eye infection for which there is no approved acute treatment. Enrollment into a global Phase 2b clinical study has begun, and clinical data results are expected in the second half of 2013.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870914/
SUMMARY
The objective of the study was to identify the extent and cause of an outbreak of epidemic keratoconjunctivitis (EKC). The study design was active case finding and a case-control study of clinic patients who developed symptoms of EKC between 31 December 2005 and 31 March 2006. The main outcome measures were clinical procedures carried out and clinicians seen during clinic visit. Significantly more cases than controls had tonometry with instillation of anaesthetic drops (OR 16·5, 95% CI 3·9–145·1,P<0·01), optical coherence tomography (OR 4·7, 95% CI 1·2–21·9, P=0·01), or instillation of dilating drops by an orthoptist (OR 2·3, 95% CI 1·1–4·7, P=0·01). Significantly more cases than controls were seen by one orthoptist (OR 21·8, 95% CI 8·2–60·0, P<0·01). Transmission of EKC within the clinic was probably due to contamination of either or both the anaesthetic drops and the tonometer head in the room used by an orthoptist. A comprehensive suite of strategies is required to prevent healthcare-associated EKC.
Scientists report discovery of potential new drug for epidemic keratoconjunctivitis
Photorefractive keratectomy with mitomycin-C for the combined treatment of myopia and subepithelial infiltrates after epidemic keratoconjunctivitis
To report the use of photorefractive keratectomy (PRK) with mitomycin-C (MMC) to treat concomitant myopia and visually significant infiltrates associated with epidemic keratoconjunctivitis (EKC).
Consecutive patients with myopia and recalcitrant subepithelial infiltrates after EKC were treated with custom wavefront PRK (Visx S4 IR) and MMC with a target of emmetropia in all cases.
The study evaluated 6 eyes of 3 patients. One year after treatment, all eyes attained an uncorrected distance visual acuity of 20/20 or better. There was no recurrence of infiltrates within the ablation zone in any eye.
Abstract Epidemic keratoconjunctivitis (EKC) outbreaks were reported as early as the 1940s in the United States. Nearly 80 years later, EKC remains a major eye health concern in the US and worldwide. Of particular concern is that a significant number of EKC cluster outbreaks in the US are healthcare acquired infections (HAIs) at ophthalmology offices. Therefore, immediate attention to enhancing best practices of standardization and universal precautions in ophthalmology is paramount.
Sharing Eyedrops between Patients:
When Will It End?
To the Editor– The Centers for Disease Control and Prevention recently released a Morbidity and Mortality Weekly Report on 6 outbreaks of adenovirus-associated keratoconjunctivitis in 4 US states occurring between 2008 and 2010.1 These epidemics occurred in outpatient ophthalmologic clinics and a neonatal intensive care unit, and a total of 411 cases were identified. A goal of the American Academy of Ophthalmology Infection Prevention Statement (2012) is zero tolerance for healthcare-associated infections. The academy acknowledges that adenovirus is the main cause of nosocomial outbreaks of conjunctivitis occurring in eye clinics, nursing homes, and child care centers and that transmission can occur from ophthalmic solutions and instruments
http://onlinelibrary.wiley.com/doi/10.1111/j.1444-0938.2007.00192.x/full
Abstract
Information from peer-reviewed articles, guidelines from professional societies and manufacturers’ instructions were considered to determine the risk factors in optometric practice and to make recommendations for disinfection, sterilisation and reprocessing of instrumentation and other equipment used in practice and measures for personal protection.
Wherever possible, all practitioners should adopt measures to decrease the risk of transmission of infection, such as single use instruments/equipment, appropriate methods of reprocessing where items are reused, routine employment of standard infection control precautions and application of more rigorous procedures for infected or immuno-suppressed individuals.
Adenoviral Keratitis
http://www.aao.org/clinical-statement/infection-prevention-in-eye-care-services-operatin
Adenovirus
Adenovirus has been the main cause of nosocomial outbreaks of conjunctivitis. These outbreaks have mostly occurred in eye clinics or offices, but have also occurred in nursing homes and child care centers. The key transmission occurs from person to person through ophthalmic instruments, medical personnel, or contaminated ophthalmic solutions.5 Adenovirus can survive for long periods on environmental surfaces and ophthalmic instruments can become contaminated and transmit infection.6 Handwashing, glove use and disinfection of instruments can all help to prevent or limit the transmission of adenovirus. Infected personnel shed virus for up to two weeks after onset of symptoms. Because adenoviruses are particularly difficult to eliminate from skin, fomites, and environmental surfaces, assiduous adherence to hand hygiene and use of disposable gloves when caring for infected patients are recommended.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086413/
Risk factors
It has been documented in Heidelberg recently that the prior examination of neonates by ophthalmologists for screening of retinopathy of prematurity was the only significant risk factor for subsequent adenovirus conjunctivitis in the newborn.
http://www.nature.com/eye/journal/v23/n5/full/eye2008234a.html
Outbreak of Gram-positive bacterial keratitis associated with epidemic keratoconjunctivitis in neonates and infants
Conclusions
Infants and neonates show high tendency of MRSA keratitis accompanied with EKC, especially if they were in HCU, applied topical steroid or followed with long interval.
http://www.ajo.com/article/S0002-9394(02)01599-4/abstract?cc=y=
Abstract
PURPOSE: We investigated the potential of a multidose eyedrop bottle used by patients with adenoviral keratoconjunctivitis as a source for spreading infection.
DESIGN: Prospective consecutive case series.
METHODS: The contents of multidose eyedrop bottles given to patients with adenoviral conjunctivitis and in use for 1 week were analyzed by polymerase chain reaction for adenovirus after as long as 9 weeks of preservation at room temperature.
RESULTS: Of 26 patients with adenoviral keratoconjunctivitis, the eyedrop bottles of 19 patients (73%) were positive for adenovirus. The maximum detection interval was 9 weeks. Significantly higher prevalences of intrafamilial infection (P = .0098) and of corneal subepithelial opacity (P = .046) were observed among cases with adenoviral contamination than among cases without contamination.
CONCLUSIONS: Multidose bottles used by patients with adenoviral keratoconjunctivitis are a possible vector for viral transmission for as long as 9 weeks.
http://aac.asm.org/content/50/4/1419.full
ABSTRACT
The inactivation of virus-contaminated nonporous inanimate surfaces was investigated using adenovirus type 8, a common cause of epidemic keratoconjunctivitis. A 10-μl inoculum of adenovirus was placed onto each stainless steel disk (1-cm diameter), and the inoculum was allowed to air dry for 40 min. Twenty-one different germicides (including disinfectants and antiseptics) were selected for this study based on their current uses in health care. After a 1- or 5-minute exposure to 50 μl of the germicide, the virus-germicide test mixture was neutralized and assayed for infectivity. Using an efficacy criterion of a 3-log10reduction in the titer of virus infectivity and regardless of the virus suspending medium (i.e., hard water, sterile water, and hard water with 5% fetal calf serum), only five disinfectants proved to be effective against the test virus at 1 min: 0.55%ortho-phthalaldehyde, 2.4% glutaraldehyde, 2.65% glutaraldehyde, ∼6,000 ppm chlorine, and ∼1,900 ppm chlorine. Four other disinfectants showed effectiveness under four of the five testing conditions: 70% ethanol, 65% ethanol with 0.63% quaternary ammonium compound, 79.6% ethanol with 0.1% quaternary ammonium compound, and 0.2% peracetic acid. Of the germicides suitable for use as an antiseptic, 70% ethanol achieved a 3-log10 reduction under four of the five test conditions. These results emphasize the need for proper selection of germicides for use in disinfecting noncritical surfaces and semicritical medical devices, such as applanation tonometers, in order to prevent outbreaks of epidemic keratoconjunctivitis.
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Conclusion Outbreaks of adenoviral keratoconjunctivitis are a serious public health issue concerning ophthalmic departments. This audit study illustrates several important points: (1) how hospital-acquired infection can account for a significant proportion of the cases seen, (2) how multiple types of adenovirus can be involved in a single outbreak, (3) that severe unilateral disease is associated with a higher rate of misdiagnosis; and (4) how standard viral culture techniques may not be satisfactory in confirming/disproving infection when the diagnosis is in doubt. The potential benefit of infection control procedures in minimising this outbreak could not be proven within this audit.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086413/
Although the beneficial effect of infection control measures has recently been controversially discussed, the mainstream consensus is to pay strict attention to good infection-control practices that may be effective to stop nosocomial outbreaks of adenovirus-associated disease.24, 6, 5
Disinfecting agents proven to be active in vitro against the virus have been listed in the Environmental Protection Agency46 and RKI/Berlin 4 lists of disinfectants. However, the in vitro conditions and interaction between test strains and germicides may not simulate in vivo conditions. For example, HAdV2 and HAdV7, is susceptible to alcohols after 10 minutes of contact time, 47 but adenovirus 8 is resistant to the action of 70% isopropyl alcohol.48 Thus, research results concerning hygiene issues in adenovirus infections have often been confusing for the practicing clinician.
http://www.nature.com/eye/journal/v24/n1/full/eye200939a.html
The reuse of opthalmic minims®: an unacceptable cross-infection risk?
Our study suggests that the practice of reusing PFMs has the potential for bacterial transmission, despite employing precautionary measures. It would be logical to assume that the same should apply for various other micro-organisms including viruses. Inter ocular viral transmission through direct contact with ocular secretions is a well-known phenomenon. Adenoviral keratoconjunctivitis is a common example. In cases where there is obvious ocular infection, preventative measures can be taken to prevent cross contamination. Viral infection may, however, not be apparent and transmission may have much more grave consequences. HSV-1, VZV, CMV, EBV, Hepatitis B and C, and HIV among others have all been shown to appear in the tear film of infected patients. Therefore, the potential exists for inter ocular transmission.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086413/
Ophthalmology – equipment etc:
Dropping bottles and eye ointment should only be used by one patient, and single-use units should be preferred.52
Patient-relevant areas, equipment, instruments, and other devices undergoing patient contact like slit lamp accessories must be disinfected with recommended germicides.46, 4, 49
Tonometry:
Contact tonometry with the Schitz tonometer or the applanation tonometer is a risk factor for EKC, and the pneumotonometer has also has been associated with nosocomial EKC outbreaks.24, 53 Problems regarding disinfection or sterilization of the tonometers particularly the disassemblement have been elucidated.54, 55Tonometers vary in design and material composition; therefore, disinfection or sterilization procedures that are appropriate for one type of tonometer may not be suitable for another.55, 56, 57 Adequate disinfection or sterilization cannot be achieved if the instruments are not initially cleaned thoroughly of any organic material that can impede contact between the disinfectant and the microorganism during the disinfection process.
https://www.ncbi.nlm.nih.gov/pubmed/18952517
Mathematical modelling of epidemics under specific regard of adenoviral keratoconjunctivitis.
Abstract
At first ADV is presented as a typical pandemic. The contagiosity of adenovirus is high because of the viability of the virus on inorganic surfaces in medical offices up to 35 days. Outbreaks and epidemics occur 3-30 days after infection, which is mainly contracted from medical facilities. EKC is considered a notifiable condition in most countries, and outbreaks, suspects and infections must be reported. Symptoms like “pink eye”, foreign body sensations, photophobia, pain, signs such as follicles, hemorrhages and corneal infiltrates, and vision decrease associated with malaise are frequently observed first in one eye, later involving the fellow eye. Unilateral disease has a high rate of misdiagnosis. Currently no vaccine or virustatic is available, which is effective, cost-efficient and tolerable. Treatment is symptomatic and antiinflammatory. Late scarring may be amenable to phototherapeutic keratectomy. Infection control measures focus on the disinfection of equipment and hands of staff, the handling of infected patients with gloves, spatial separation of infected individuals resp. cohorting of infected patients, use of unit-dose eye solutions, and the chlorination of pools by approved and registered disinfectants and germicides. In connection with this it is shown how to handle the dynamics of infections by mathematical models like cellular automation, systems of differential equations and to visualize periodic effects by Fourier Analysis and to calculate costs by mathematical programming. Using mathematical analysis the percentage of a population needing vaccination to prevent spreading of pandemic can be calculated. It is shown here that especially the method of cellular automation is a simple way to simulate complex epidemiological situations without completely knowing the mathematical details
Post infectious dry eye syndrome due to the loss of goblet cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086413/
Any cytopathogenic agents infecting the ocular surface, including the adenovirus, result in a post infectious dry eye syndrome due to the loss of goblet cells. This event is clinically relevant in about one third of patients. This may sometimes be difficult to differentiate from an ongoing infection. The differential diagnosis can be made utilizing tests such as Schirmer’s, Bengal rose stain, break-up time, tear film interference, and impression cytology.
Rarely, (sub)epithelial conjunctival scars can develop particularly in patients that had experienced fulminant and pseudomembraneous disease and lead to persisting corneal irritation and pain sensation [Fig. 9]. Also, as a sequel to the more serious dry eye syndromes with persistent infection and ongoing inflammation, mild symblephara can result.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892586/
Epidemic keratoconjunctivitis (EKC) is an acute eye infection caused by adenovirus. We investigated an outbreak of EKC at an outpatient ophthalmology practice in the context of a suspected community wide increase in EKC activity. A site visit was made to the facility reporting the outbreak. A line list was created of patients clinically diagnosed with EKC at the practice during the previous 5 months. A questionnaire was faxed to all other licensed ophthalmologists in the county regarding recent EKC activity in their facility. Descriptive data analyses were conducted. The outbreak facility reported 37 patients clinically diagnosed with EKC during the previous 5 months. In addition, the single ophthalmologist at the practice also had symptoms compatible with EKC during the outbreak period. Specimens were collected on 4 patients and all were positive for adenovirus serotype 8. Forty percent of ophthalmologists surveyed in the county saw at least one EKC patient in the previous 3 months, and 20% reported a perceived increase in EKC activity in recent months over normal seasonal patterns. The outbreak at the facility likely began as part of a widespread community increase in EKC that may have been amplified at the facility through nosocomial transmission. Medical providers experiencing increases in EKC activity above seasonally expected norms should contact their public health department for assistance with etiologic diagnoses and outbreak control.
http://www.reviewofophthalmology.com/content/d/therapeutic_topics/i/1206/c/22739/
EKC causes chronic dry eyes and conjunctival scarring with reduced tears
EKC is most common during the fall and winter and, in contrast to PCF, presents unilaterally in two-thirds of cases and doesn’t cause fever or sore throat. Keratitis occurs in ap–proximately 80 percent of patients with associated discomfort, photophobia, tearing and mild blepharospasm. Following redness and keratitis, up to 20 uniform, subepithelial corneal infiltrates (the hallmark of EKC) develop on day 11 and are most prevalent during the third and fourth weeks of infection. Approximately 30 to 50 percent of patients with EKC will de-velop these infiltrates, which may contribute to persistent visual loss and light sensitivity and necessitate long-term steroid therapy. The infiltrates are a product of the immune response to the keratitis and are smaller, more numerous, denser, produce greater photophobia and last longer (up to a year) than PCF infiltrates.
In addition, EKC may lead to persistent dry eye or conjunctival scarring.1 – See more at: http://www.reviewofophthalmology.com/content/d/therapeutic_topics/i/1206/c/22739/#sthash.IvgbWMyC.dpuf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086413/
Tonometry:
Contact tonometry with the Schitz tonometer or the applanation tonometer is a risk factor for EKC, and the pneumotonometer has also has been associated with nosocomial EKC outbreaks.24, 53 Problems regarding disinfection or sterilization of the tonometers particularly the disassemblement have been elucidated.54, 55Tonometers vary in design and material composition; therefore, disinfection or sterilization procedures that are appropriate for one type of tonometer may not be suitable for another.55, 56, 57 Adequate disinfection or sterilization cannot be achieved if the instruments are not initially cleaned thoroughly of any organic material that can impede contact between the disinfectant and the microorganism during the disinfection process.
In the absence of controlled studies, specifically on disinfection or sterilization of the pneumotonometer and other tonometers, the tips of such tonometers must be cleaned, then disinfected or sterilized after each patient use.
http://misc.medscape.com/pi/iphone/medscapeapp/html/A1192751-business.html
Often, a recent history of an eye examination or exposure within the family or at work is present.
The incubation period is 2-14 days, and the person may remain infectious for 10-14 days after symptoms develop.
The role of the medical profession in spreading the disease is well documented in the literature. Many epidemics have been initiated in ophthalmology outpatient clinics by direct contact with contaminated diagnostic instruments. Reasons behind the infectious transmission of EKC in hospitals and clinics include the fact that: (1) the virus (adenovirus type 19) remains viable for 5 weeks; (2) the virus is resistant to standard disinfectants, such as 70% isopropyl alcohol and ammonia; and (3) the virus sheds from the eye 3 days before and 14 days after symptom onset
http://novabay.com/blog-post/new-treatment-pinkeye
A New Treatment for Pinkeye?
Posted by Ron Najafi on May 15, 2014
Guest blog by Dr. Kathryn Najafi-Tagol, MD, Founder, Eye Institute of Marin
The recent Winter Olympics in Sochi, Russia, provided plenty of compelling drama, from Mikaela Shriffin’s overwhelming victory in the slalom to Canada’s domination on the curling ice. But viewers also got an up close and personal look at a disease we don’t often think about—pinkeye, or conjunctivitus.
MISCELLANEOUS RESEARCH
http://www.barbercosmo.ca.gov/laws_regs/hsen.pdf
BOARD OF BARBERING AND COSMETOLOGY
Revised Health & Safety Regulations
Title 16, Division 9 of the California Code of Regulations.
Article 12. Health & Safety
http://www.webmd.com/news/20150417/superbugs-what-they-are
Superbugs: What They Are and How You Get Them