Lynda Charters

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Adenovirus conjunctivitis is rolling an age-old infection with potentially new diagnostics and cures.

This article was reviewed by James Chodosh, MD, PhD


	
	Adenovirus conjunctivitis, extremely common, extremely contagious, and extremely expensive, is the cause of from 1% to 2% of all visits to primary care providers in the United States, with $430 million spent on diagnosing and treating the infection.

New and repurposed drugs are being explored to address this infection as well as a specific diagnostic test.

“The profound importance of this infection was underscored by a recent outbreak of adenovirus type 3 pneumonia and conjunctivitis in a neonatal intensive care unit that affected 23 neonates and nine adults, of whom four neonates died,” according to James Chodosh, MD, MPH. “This underscores the importance of treatment over and above just red eye.” 
	
	

Adenovirus keratitis viral pathogenesis: A persistent enigma 

Dr. Chodosh, referenced a study published in 

 2018;Sep 1. pii: S0161-6420(18)31075-3. He is the DG Cogan Professor of Ophthalmology in the Field of Cornea and External Disease, Howe Laboratory, Massachusetts Eye and Ear, Harvard Medical School, Boston.

According to Dr. Chodosh, successful clinical trials to identify treatments for adenovirus conjunctivitis have been stymied for two reasons. 
	
	The first is the relatively low positive predictive value (PPV), i.e., 78%, of the only commercially available rapid diagnostic test for adenovirus that was reported in the clinical trial of Auricloscene (NVC-422, NovaBay Pharmaceuticals) (

“The test did not work in the real world quite as well as we thought it would,”
	Dr. Chodosh said. 

The second reason involves the nonspecific nature of the clinical signs of conjunctivitis, which, Dr. Chodosh noted, when there is no outbreak of the infection and no “truly accurate, rapid diagnostic” test, it is difficult to conduct a clinical trial in the presence of sporadic cases only. 

“Clinical trials for this infection are more likely to be successful if instituted during an outbreak,” he said.

If medications fail, surgery option for treating infectious retinitis 


	These are coming. A recent study reported that an in-office molecular test, not a protein-based test, is in the offing (

“This type of test would be infinitely more sensitive,” Dr. Chodosh said. 

Newly identified antiviral drugs, which include repurposed drugs, also offer hope for a cure. Recently evaluated therapeutics include salicylanilide antihelmintics such as niclosamide, which is FDA-approved (

 2018;159:77-83); and cardiotonic steroids, i.e., digoxin and digitoxin (

“Because these drugs are already FDA approved, there is a shorter path to testing and topical use,” Dr. Chodosh said.

Brincidofovir (CMX001, Chimerix, Inc.), an experimental systemic drug of lower toxicity used systemically to treat patients with systemic adenovirus infections who underwent bone marrow transplants, also has shown very promising results in two studies (

 2017;96:73-9) and may be a candidate for use in the eye.

“If this drug is approved, perhaps it can be repurposed for ocular use,” Dr. Chodosh suggested.
	
	

Managing viral eye infection: What clinicians should know 


	The adenovirus succeeds in infecting host cells by binding of the adenovirus’ fiber knob to one of the host cell receptors that include CAR, CD46, MHC class II alpha chain, and in the corneal epithelium, GD1a glycan.

Dr. Chodosh reported that clinical trials are under way that are targeting the adenovirus receptor on the corneal epithelial cells, for example, APD-209 (Adenovir Pharma), a decoy receptor sulfated glycosaminoglycan. 
	
	In early trials, the drug was shown to be helpful; the investigators reported their findings in 

 2019;11:E247. The phase III trials are ongoing, he noted.

Dr. Chodosh is hopeful for improved diagnostics and a cure for adenovirus conjunctivitis. 
	
	

Conjunctival melanoma: Unlocking mysteries of disease 

 “Considering the avalanche of new molecular diagnostics, eventually we are certain to have rapid, nucleotide-based, in-office testing that works as well as polymerase chain reaction,” he said. “The NovaBay trial confirmed what clinical trialists always knew, that is, that clinical trials are more productive when held in areas where the disease of interest is highly prevalent.”

Dr. Chodosh said if physicians are not sure the patient has the disease and they are enrolled, the value of the trial is diminished. 

“The potential impact of a drug with efficacy against adenovirus conjunctivitis is high and will continue to attract interest from pharma because companies know that such a drug would be used a great deal in primary care settings by pediatricians and family care providers and by ophthalmologists, making this a potentially lucrative investment,” he concluded. “FDA-approved drugs repurposed for ocular use continue to be explored. New drug candidates will emerge as our basic understanding of adenovirus increases.”
	
	

Dr. Chodosh is a past consultant to Shire Pharmaceuticals. 

Articles

Researchers eye cure, diagnostics for adenoviral conjunctivitis 

The World Health Organisation (WHO) announced a new flagship initiative, “a mental health coalition to support system reforms and COVID-19 recovery” in Europe.

This was undertaken because of the organisation’s recognition that “mental health is a key public health concern in the WHO European Region – more than 110 million people are living with some kind of mental health condition, accounting for over 10% of the population.”

“The mental health flagship will bring together a broad coalition of mental health leaders, champions, service users and other partners to improve mental health policies and practices across the region,” the WHO said in a statement.

Considering the COVID-19 virus, focusing on mental health now is especially important given that the measures to prevent the virus from spreading, such as social distancing and quarantining, in addition to the dangerous working conditions for health care workers, are having a psychological impact on the population and exacerbate pre-existing anxiety.

The WHO explained that the Mental Health Initiative will challenge “stigma and discrimination by improving mental health awareness and literacy among not only the public but also service providers and decision makers.”

In addition, it will enhance access to “person-centered, rights-based mental health care in communities. This will expedite progress towards universal health coverage for people with mental health conditions and make the case for a parity of esteem between mental and physical health.”

The Mental Health initiative is one of 4 launched by the WHO. The other 3 priorities for WHO/Europe over the next 5 years are digital health and innovation, behavioural and cultural insights, and immunization.

Organisation is kicking off a flagship initiative as it views mental health as a key public health concern in the WHO European region, where more than 110 million people are living with some type of mental health issue. 

WHO initiative builds a coalition for system reforms, COVID-19 recovery in Europe

This article was reviewed by Mays A. El-Dairi, MD

is popular for use in pediatric neuro-ophthalmology. The fast, non-invasive technology uses optical waves and inferometry, provides in vivo high-resolution tomograms, and displays pathologies that might otherwise go undetected.

“It is the ‘perfect’ non-invasive technology in pediatric neuro-ophthalmology patients with clear media,” said Mays A. El-Dairi, MD, associate professor, Pediatric Ophthalmology and Strabismus, Neuro-Ophthalmology, Duke Eye Center, Durham, NC.
	
	

Therapies, trends make waves in neuro-ophthalmology 

 is used most frequently to obtain measurement of the retinal nerve fiber layer (RNFL). This is associated with a couple of drawbacks, she pointed out, one being that most machines do not have an integrated normative database. 

In some cases, if there is one, the database is extrapolated and it is not highly accurate. The normative database needs to be perfected.

In her neuro-ophthalmology practice, Dr. El-Dairi puts the 

 instrument to use in many ways over and above just evaluating the RNFL. Many diseases can be diagnosed without OCT imaging, but the imaging provides information that might otherwise be impossible to obtain.

Viewing pediatric neuro-ophthalmic disease


	In patients with optic nerve hypoplasia, while 

is not necessarily needed to establish a diagnosis most of the time, 

 facilitates measurement of the opening of Bruch’s membrane, which in optic nerve hypoplasia, is very small (

Optic nerve coloboma also can be diagnosed without use of 

 in most cases. However, in some cases when a tilted nerve is seen, a coloboma cannot always be identified as part of the optic nerve. 

shows a signal that indicates that the nerve is just tilted, she explained.
	
	

OCT artifacts and pitfalls: In the eye of the beholder

In cases of optic nerve head pit, the end of Bruch’s membrane is not visible. 

“OCT is not needed to see the pit, but sometimes the pit can be associated with an area where the ganglion cell area did not form, which can help predict a problem with visual function,” she said, describing a patient who had 20/200 vision and was undergoing treatment for amblyopia. In actuality, she was able to determine that the ganglion cells that facilitate central vision had never formed in this patient.

A myelinated nerve fiber layer seen on an OCT image has a bright, thick, hyperreflective signal that is readily visible. In some cases of subtle pseudopapilledema, visualization of this signal is helpful to the diagnosis.

In all congenital optic nerve anomalies, 

 allows clinicians to evaluate the central ganglion cell layer since it correlates with presence of a central scotoma when the patient is too young for a visual field evaluation, she said. 
	
	

 is useful for examining Bruch’s membrane. When differentiating papilledema from pseudopapilledema, clinicians look for signs of high intracranial pressure and the position of Bruch’s membrane can provide clues. 

“Upward bowing of the membrane can indicate the presence of a retrobulbar process, something that is pushing behind the optic nerve, or high intracranial pressure,” Dr. El-Dairi said. “This is not a very sensitive marker, but it is quite specific; I always look at it when a nerve is elevated.”
	
	

Keys to integrating, interpreting different types of OCT scans

The size of the Bruch’s membrane also can be evaluated using OCT. In patients with pseudopapilledema, the nerves tend to be smaller; the RNFL is under 120 Î¼m and Bruch’s membrane opening is less than 1,500 Î¼m. When compared with true papilledema, the pseudopapilledema nerves are larger; Bruch’s membrane opening exceeds 1,650 Î¼m and the RNFL is thicker than 135 Î¼m. 

In optic neuritis, imaging shows RNFL thickening even when no edema is seen during funduscopy. When optic atrophy becomes apparent, RNFL thinning is seen that is correlated with the final visual outcome. 

“Imaging of the RNFL is not useful for diagnosing optic neuritis, but new baseline images are useful to have six months after resolution to more readily identify a recurrence,” she advised.
	
	

Measuring RNFL with OCT detects subtle differences in glaucoma progression 

Dr. El-Dairi does, however, like to use 

 in children with optic neuritis because in some cases with a bright internal limiting membrane, early-stage neuroretinitis may not be apparent. 

“A macular scan can show changes in the retina, such as subretinal fluid and disrupted photoreceptors,” she explained.

Atrophic nerves are seen as thinning on the RNFL scan and macular map. Cystic lesions also may be visible in the inner nuclear layer. 

“It is important to remember that when there is atrophy on top of papilledema, it is hard to determine how much is atrophy and how much is papilledema,” Dr. El-Dairi noted. 

In a case of hydrocephalus, in which the patient had 20/400 vision, the RNFL measured about 80-plus Î¼m and while the referring physician thought the patient was fine and had non-organic visual loss, the ganglion cell layer was actually absent.

Dr. El-Dairi relies on OCT to monitor the visual fields in young patients. In some cases, imaging will show changes at the macular level and homonymous thinning is seen that is correlated with visual field deficits.
	
	

Making the most of imaging in examinatation of pediatric patients 

In infants with nystagmus, she performs hand-held OCT evaluations to establish the need for electroretinography or neuroimaging. 

Examples include Stargardt’s disease, retinoschisis, Best’s disease, and cone dystrophy, which have pathognomonic findings on the retinal OCT. 
	
	

ssessing quality of OCT scans impacts clinical-decision process 

In an example of Leber congenital amaurosis, Dr. El-Dairi highlighted the normal ganglion cell layer and the significantly attenuated photoreceptor layer. She showed examples of different stages of retinitis pigmentosa that show only rod involvement initially that progresses to both rod and cone involvement. 

Batten disease shows a very specific pattern on imaging-both the outer and inner retina are involved, there is severe attenuation of the ganglion cell layer, and the outer photoreceptors are significantly damaged.

“High-resolution OCT imaging tomograms of the retinal tissues can frequently reveal pathology that is difficult to detect with the naked eye,” Dr. El-Dairi concluded. “With extra anatomic finding, it can help determine the path for further workup.”
	
	

Dr. El-Dairi has no financial interest related to this topic. 

Technology 'perfect' for pediatric neuro-ophthalmology diagnoses

Technology allows ophthalmologists to determine severitiy of disease. 

This article was reviewed by Siamak Yousefi, PhD


	
	Artificial intelligence (AI)-enabled radar may be an improvement over the traditional method of visual field analysis. Investigators note that by using AI-enabled radar they can better assess the functionality of patients with glaucoma and determine which patients have slowly and rapidly progressing visual field damage. 

This technology is designed to address the shortcomings of traditional visual field analysis, specifically, i.e., that they rely on traditional paradigms such as linear regression and do not generate detailed results beyond progression or no progression, do not provide objective identification of progression, and lack advanced visualization and interpretation, according to Siamak Yousefi, PhD.
	
	

Artificial intelligence in medicine: The good, the bad, and the scary 

 radar, a dashboard, that is a pipeline of linear and non-linear data transformations and unsupervised machine learning that provides advanced visualization with three layers of 

 knowledge-including the global visual functional severity, extent of visual functional loss in the hemifields, and local patterns of visual field loss,” explained Dr. Yousefi, assistant professor, Departments of Ophthalmology and Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis.

“The system also provides personalized monitoring, data from thousands of previous 

 patients, and can identify rapid or slow progression,” he added.

Though the basis for this advanced-visualization technology is highly complex, the investigators sought to develop a screen for monitoring 

 that is user-friendly and able to be understood by non-medical individuals. It includes more than 13,000 visual fields cross-sectionally. 

“We applied principle component analysis to linearly reduce the number of dimensions and extracted the global characteristics of the visual fields,” Dr. Yousefi said. “We then applied manifold learning to grab the local patterns of visual field loss and eventually generated this to a map.” 


	To make sense of the data from the collected visual fields, the investigators first identified very dense areas,  and then applied unsupervised clustering to identify 32 non-overlapping clusters that represented different levels of visual field severity.
	
	According to Dr. Yousefi, when the mean deviation of each cluster was computed, the observation was that the severities of the visual fields increased moving from the top right to the bottom left of the screen. 

“The AI pipeline was able to identify the global functional severity of the eyes in the various clusters, i.e., mostly normal eyes on the right and those with severe visual field loss on the left and bottom left of the screen,” he said.

The researchers also computed the glaucomatous severity in the inferior and superior hemifields. 

“We noticed that the AI wisely put eyes with similar hemifield characteristics into different clusters, although statistically their global severity may have been similar,” noted Dr. Yousefi, indicating that the AI was able to differentiate similar damage in different locations and cluster those eyes together.
	
	

The future: Artificial intellignece gains acceptance in ophthalmology


	Investigators conducted a study in which they tested a method to identify and decompose visual fields to 17 different archetypes or patterns. They tried to decompose the visual 

fields at each cluster, Dr. Yousefi explained, to the different archetypes and then identify the dominant pattern attributable to each cluster. 

“Collectively, each region of the dashboard can demonstrate global visual field loss, the extent of visual field loss in the hemifields, and local patterns of visual field loss,” he said.

Because of the capabilities of the radar, the technology can be used for personalized glaucoma monitoring, retention of the history of previously monitored patients, and identification of rapidly and slowly progressing eyes. 
	
	

Predicting glaucoma progression: More than meets the eye 

The availability of this information allows clinicians to easily adjust treatment regimens based on the 

 trajectory in a given patient’s eyes; clinicians will be able to adjust the treatment based on the cluster to which the patient is progressing and possibly positively impact the patient’s quality of life. 

As a proof of concept, Dr. Yousefi and colleagues tracked eyes from benchmark data that indicated that the 

 was not progressing using 10 visual fields for each eye. 

“As expected, most of the eyes did not have substantial changes in the visual fields,” he explained. “Some eyes that had visual field changes that were not in the direction of progression also were considered stable.”

Based on these data, Dr. Yousefi pointed out that the specificity of the radar was about 94%,” he said. 
	
	

Technology traces differences in structure, glaucoma progression 

Investigators also performed the same analysis in eyes based on data from a separate algorithm that indicated that they eyes would progress. Most of these eyes showed glaucomatous changes in the direction of 

Dr. Yousefi concluded that with this method, ophthalmologists can perform better functional assessment of patients with glaucoma compared to the currently available tools. 

“Advanced computational tools can provide more informative objective outcomes,” he said. “While deep learning typically generates black box and yes/no outcomes, our proposal may be helpful for developing models that can be interpreted more. Next-generation glaucoma assessment tools can provide multiple layers of glaucoma knowledge using advanced visualization.”
	
	

Dr. Yousefi has received funding from the National Eye Institute. 

Author | Lynda Charters

Articles

WHO initiative builds a coalition for system reforms, COVID-19 recovery in Europe

Technology 'perfect' for pediatric neuro-ophthalmology diagnoses

AI-enabled radar: Pushing boundaries of glaucoma diagnosing, monitoring

Researchers eye cure, diagnostics for adenoviral conjunctivitis