Lisa Stewart

	Ocular allergy affects millions of people worldwide. It is generally intermittent but sufferers’ quality of life is affected by the resulting ocular discomfort and inflammation: in severe cases they may experience vision disturbance and find that daily activities are hindered.

	Common causes of ocular allergy include mites, animal allergens and moulds, which are found indoors; grass, tree and weed pollens, and mould spores, found outdoors; food allergens such as fruits, vegetables, nuts, milk, eggs, shellfish or fish; and injected allergens including insect venoms and therapeutic proteins.

	Changes to our environment from the combined effects of warming and more CO

 mean that the allergy season is becoming longer from year to year, with pollen seasons starting earlier, lengthier peak-pollen periods and even some pollen presence in the winter.

	Rising temperatures are changing the botanical landscape, increasing the geographic distribution of allergenic plants, and the amount of pollen in the air will continue to increase as climate change worsens.

	As an example of the direct link the environment can have with our health, the number and severity of ocular allergies was observed to increase dramatically in spring 2012 when air pressure, temperature, pollen count and PM10 levels were unusually high. These phenomena seem to increase every year: 2017 was the second-hottest year on record according to NASA data, and was the hottest year that did not have the short-term warming influence of an El Niño event.

	Air pollution constitutes one of the main threats to public health in Europe. Significant impacts on morbidity and mortality have been observed, even in cases of low exposure and when pollutant levels are within limits set by the European Union.

	Focusing on ocular surface diseases, patients commonly present with a type of conjunctivitis that is not strictly of allergic, infectious or dry-eye origin. Clinical studies and experience have shown a cause-and-effect relationship between these allergy-like symptoms and environmental factors, including outdoor air pollutants and poor indoor air quality.

	People with this ‘urban eye allergy syndrome’ experience ocular symptoms that are increased by chemical triggers and pollution in the atmosphere rather than by true allergens.

	Proposed mechanisms for the syndrome include free-radical generation and oxidative stress; increased expression of pro-inflammatory cytokines; modification of key intracellular proteins or the innate immune response; stimulation of autonomic nervous system receptors; adjuvant effects on the immune system; and suppression of normal defence mechanisms.

	It seems likely these all play roles at different stages of the developing syndrome. These individuals certainly appear not to be 

 to pollutants but rather to be experiencing an allergic-type response to pollutants stimulating the mucosal immune system.

	In a recent large survey performed at a national level, focused specifically on ocular allergy, only 40% of subjects diagnosed as affected by allergic conjunctivitis had an associated allergic condition such as rhinitis, asthma or eczema.

 Therefore, it is quite common for patients with eye symptoms to request an ophthalmological evaluation before the allergy consultancy.

	In this survey, pollens were indicated as the most frequent triggers; however, nonspecific environmental conditions, pollutants, cigarette smoke and particular weather conditions were also reported as common factors in inducing ocular symptoms.

	True ocular allergy involves both IgE- and non-IgE-mediated mechanisms. Seasonal and perennial allergic conjunctivitis are primarily IgE-mediated and can be treated using topical and oral antihistamines and topical mast cell stabilisers, whereas non-IgE-mediated disorders such as contact blepharoconjunctivitis require anti-allergic drugs and topical corticosteroids to treat.

	Atopic and vernal keratoconjunctivitis (VKC) have a mixture of IgE-mediated and non-IgE-mediated components and require intense and prolonged anti-allergic drugs, frequently in combination with corticosteroids or topical immunomodulators such as cyclosporine.

	The diagnosis of ocular allergy is relatively simple, being based mostly on clinical history, signs and symptoms, and being confirmed by the results of allergy tests. In general, asking the right questions to patients should reveal not only signs and symptoms but also their frequency, duration and severity.

	VKC is a severe ocular disease that occurs predominantly in children living in warm climates. It is frequently complicated by corneal involvement that manifests in a variety of forms including Tranta’s dots; superficial punctuate keratitis; shield ulcer; corneal plaque; corneal neovascularisation; lipid infiltration; bacterial or fungal keratitis; keratoconus; pseudogerontoxon; and corneal opacification.

	Even though it is relatively easily diagnosed because of its distinct clinical history and ocular manifestations, VKC requires particular attention and is not easy to manage.

	Warm climates and sun exposure probably explain the characteristic north-south gradient prevalence of this form of ocular allergy. VKC is associated with other allergic manifestations in approximately half of patients and often arises in response to exposure to specific allergenic triggers: these observations suggest it does indeed have an allergic component.

	Tear levels of IgE and mast cell mediators are high, which supports this conclusion. However, this does not explain the length of the disease, its typical regression after puberty or the fact that it most often manifests in response to non-allergenic triggers such as sunlight, heat and wind. Antigen-specific Th2 cells have not been demonstrated infiltrating the conjunctiva, and several non-IgE-mediated mechanisms are believed to also be involved.

	Some of the aforementioned mechanisms may involve the integrity of the epithelial barrier. Whereas the junctional complexes are intact in the normal conjunctival epithelium, denying allergens entry, epithelial barrier dysfunction may be induced by endogenous proteases (e.g., metalloproteases) and environmental assailants including some viruses; components of air pollution; cigarette smoke; house dust mites; and pollens, which have intrinsic protease activity.

	Initially, epithelial cells were considered to be a passive barrier impeding allergen penetrance, but we know now that they may recognise allergens and mount an innate immune response with multiple factors such as cytokines, alarmins and endogenous danger signals that activate the dendritic cell (DC) network and other innate immune cells.

 As a consequence, local immune responses may be initiated, beginning the transition from innate to adaptive immunity.

	In particular, allergens induce the production of reactive oxygen species, which activate DC and epithelial cells through NF-kB activation. The innate immunity of epithelial cells not only recognises microbial invasion but may also respond to pollen components from plants, triggering inflammation.

	In fact, in response to allergen recognition, epithelial cells promote Th2 immunity through activation of DCs, by activating innate immune cells such as ILC2s, which can help DCs to polarise Th2 responses in naive T cells.

	Increased expression of heat-shock proteins (HSPs) in VKC patients was recently described by Leonardi 

 The HSP-chaperones are highly conserved during evolution and play essential roles in cell survival; however, they are also implicated in the pathogenesis of various diseases such as some types of cancer and inflammatory and autoimmune disorders.

	Expression of HSPs is induced by environmental and oxidative stress and forms a link between adaptive and innate immunity. Increased HSP levels induced by agents known to initiate or aggravate VKC, such as histamine, cytokines and UV-B, indicate an active interaction between the chaperoning and the immune systems, with perhaps a mutual modulatory role between the two systems.

	HSP27, HSP40, HSP70 and HSP90 seem to be actively involved in VKC, where they may initiate and perpetuate inflammation.

	New mass spectrometric techniques to analyse peptide profiles in human tears may elucidate differences between healthy subjects and patients affected by different phenotypes of ocular allergy and possibly identify target proteins that might be of use in the diagnosis, prognosis and management of VKC and other inflammatory ocular surface conditions.

	For example, hemopexin, transferrin, mammaglobin-B and secretoglobin 1D were found to be significantly overexpressed in VKC samples and dramatically reduced after treatment with topical cyclosporine.

	Recently, collecting and optimally processing sufficient RNA from conjunctival surface cells allowed Dr Leonardi’s group to perform a successful transcriptome-wide expression analysis. Factors involved in both innate and adaptive arms of the immune system, including several Toll-like receptors and other pattern-recognition receptors, were found to be overexpressed in VKC samples.

	In addition, they highlighted the increased expression of multiple chemotactic factors for eosinophils and T cells and multiple co-stimulatory signals required for T-cell activation and survival, confirming that VKC is mostly a cell-mediated pathology.

	Larger studies including different types and severities of ocular allergy should reveal significant gene expression trends that can be targeted to improve the treatments available for ocular allergy.

	Understanding of the role of these different possible mechanisms involved in ocular allergy will open new therapeutic scenarios leading, for example, to the use of specific topical inducers or inhibitors of key proteins in order to prevent the induction of allergic inflammation on the ocular surface and prevent potential severe complications.

	1.     World Meteorological Organization. https://public.wmo.int/en.

	11.  Leonardi A, et al. Presented at ARVO Seattle, 4-9 May 2016; 

	This article was adapted from a presentation given by Dr Andrea Leonardi at the 2017 EuCornea Congress. Dr Leonardi is an associate professor at the Department of Neuroscience, Ophthalmology Unit, University of Padua, Italy, and a board-certified specialist in ophthalmology and in allergy and clinical immunology. Dr Leonardi consulted for Santen; Thea; Novartis; Dompè; Shire (no fee received); Baush & Lomb; and Faes Farma in 2016-17.

Articles

Ocular allergy affects the quality of life of millions of people every year. Understanding the different mechanisms involved will increase their future therapeutic options.

Immune mechanisms in allergic eye disease

	The purpose of corneal angiography is to locate the blood vessels within the cornea and evaluate their condition. The ‘gold standard’ technique used to do this is anterior segment colour imaging, but it is not straightforward and the images acquired are often of poor quality.

	Consequently, Dr Martin Hodson of the St Paul’s Eye Unit, Liverpool, started using dyes to improve the imaging of corneal neovascularisation. After seven years of experience he is well placed to share his expertise and gave a presentation entitled ‘Angiography Within Anterior Imaging’ during the joint Ophthalmic Imaging Association and Ophthalmic Photography Netherlands photographic and imaging session at the European Society of Ophthalmology meeting in Barcelona in June.

	When colour images are required, Mr Hodson uses a Topcon system: a diffuse beam is used, magnification is set at 10 x and the light is set at a 45° angle. The use of the Heidelberg Engineering system when dye has been injected is primarily because it has the capability to record video, which improves the likelihood of recording a useful image compared with a one-shot technique.

	When more in-depth images are required, indocyanine green (ICG) and fluorescein dyes are introduced. There are various considerations, one of which is which lens to use.

	The 30° lens gives the best view of the corneal shoulder and the limbus, but for work on the cornea itself the blue OCT lens is best due to its ability to flatten the image, bringing more of the vessels into focus.

	It is also important to get the focus right, which can of course be difficult because the cornea is completely transparent. Mr Hodson gets the best results by setting the focus to 34 D.

	Lastly, it is important to ensure the eyelids do not interfere with the picture. Many patients find it hard to keep their eyes open when confronted with a bright light and it is likely that it will be necessary for the technician to physically hold the eyelids out of the way.

	Once the dye has been injected and has been seen to appear within the eyelids, a 30-second video is started.

	Figure 1 compares images taken using the different techniques. There is much more detail apparent using ICG compared with the (good) gold standard colour image, because use of the dye in conjunction with infrared light allows one to see past the corneal scarring.

	The ‘early’ (30 seconds) and ‘late’ (about 2–3 minutes) fluoroscein images allow the age of the vessel to be estimated: older vessels, which have better-developed walls, will show leakage in the mid- to late-stage images, whereas younger vessels will leak between 30 seconds and 1 minute.

	The clarity of images taken using these new techniques are such that it is starting to become possible to identify the feeder vessel from a mass of vessels. If the feeder vessel can be identified, fine-needle therapy can be used to block it. Similarly, the Eye Unit is starting to look at vessel structure in papillomas and carcinoma in situ.

	In summary, Dr Hodson reiterated that it is important, every time you go to the camera, to remember that every patient is different so your technique might be slightly different. You should keep an open mind how the camera will be positioned, and remember that most patients cannot focus on the bright light. He is now seeing five to six patients every week and demand for the technique is rising.

	Dr Hodson is senior imaging technician and lead oncology imager at St Paul’s Eye Hospital Liverpool, and world lead in corneal neovascularisation angiography imaging. He is a committee member of the Ophthalmic Imaging Association. He has no conflicts of interest to report with this article.

It is important with corneal angiography to remember that every patient is different so your technique might very slightly from patient to patient.

Angiography within anterior imaging

	Eighty-three children with rapidly progressing myopia have been treated with nightly atropine drops in Tel Aviv since January 2015. Their 2-year results were reported by Professor Yair Morad of the Assaf Herofeh Medical Centre at the recent European Society of Ophthalmology meeting in Barcelona.

	Atropine drops can significantly slow the progression of myopia. Since this was demonstrated in the ‘atropine for the treatment of childhood myopia’ (ATOM) studies,

children have begun to receive treatment in clinics around the world.

	The ATOM1 study showed that 1% atropine administered nightly over a 2-year period slowed myopic progression by 77%.

ATOM2 went on to demonstrate that the effect was dose-dependent and that 0.01% was sufficient to significantly suppress myopia progression.

	A ‘rebound effect’ was evident in both studies: that is, myopia increased when the atropine treatment was stopped, to a greater extent in children who had received higher doses. The least rebound effect was seen with 0.1% atropine; patients receiving this dose had the least overall progression of myopia after 5 years (3 years after the end of treatment).

	Two years of 0.01% atropine treatment provided, after 5 years, a 50% reduction of myopia compared with the predicted value.

	The children treated in the Assaf Herofeh Medical Centre, all of whom were progressing by at least 0.75 D/year, were initially given 0.01% atropine drops in both eyes every night. After 6 months, their myopia had stopped progressing (≤0.25 D) in almost all cases.

	“We were really amazed to see that after 6 months of treatment almost all children really stopped progressing,” Professor Morad said. “This is actually different from the study in Singapore [ATOM1], where the treatment did not have a profound effect in the first year.”

	There were no side effects reported. The mean age of the children at the start of treatment was 9.2 years and their mean refraction was –4.7 D (range –3 to –12 D). Myopia was moderate in 88% and severe (>7 D) in the remaining 12%. Most of the children (72%) had myopic parents.

	Only one child, who had a baseline refraction of –6.5 D and two parents with high myopia, continued to progress (by 0.75 D). His dose of atropine was increased to 0.05%.

	After 12 months (n = 56), most of the patients were still progressing by 0.5 D or less; two children progressed by 0.75 D (relative to baseline) so were switched to 0.05% atropine.

	After 18 months (n = 36), almost all the children had still not progressed more than 0.5 D; only three children progressed more than 0.75 D. And after 2 years (n = 16), 11 children had really stopped progressing, with a decrease of 0.5 D or less.

	The remaining five children continued to progress by 1 or 1.25 D, but this is a great result, Professor Morad said, bearing in mind that all these children progressed by at least 0.75 D per year before treatment, and that some were progressing by 1.5 or even 2 D per year.

	Myopia progression was reduced to <0.5 D per year in two of the three patients whose atropine dose was increased to 0.05%. One patient continued to progress but only by 1 D per year, which was still much better than the progression he had been experiencing before.

	The mean progression across all the children was 0.32 D per year. There were no side effects or discomfort reported, even in those children who received 0.05% atropine.

	The best responders were those who had low myopia and no family history. Those with high myopia and two myopic parents did not see such good results.

	The most difficult question that remains unaddressed is when to stop the treatment, Professor Morad noted. In the ATOM studies, treatment was given for 2 years and then stopped. If the patient continued to progress by >0.5 D per year, treatment could be reinitiated.

	“This seems like a sensible approach but there are other possibilities,” Professor Morad said. “Perhaps treatment should be continued until around 13 years of age, when myopia usually stops progressing.”

	Another important consideration is cost. Atropine is not yet commercially available as 0.01% drops, so the treatment has to be prepared in a pharmacy-in Israel the cost varies from $20 to $80 per bottle, which could place a high burden on the parents.

	Lastly, the long-term side effects are unknown. The studies from the 1970s that looked at 1% atropine showed no significant side effects except for difficulties in accommodation after prolonged treatment.

	Professor Morad pointed out that the dose used in these children is much lower and no side effects were reported, which is “hopeful”.

	Myopia is common and its prevalence is increasing (for example, myopia prevalence, monitored in nearly 1 million people who were joining the Israeli army at the age of 18, increased from 20% in 1990 to 28% in 2002)

. The economic burden is huge, estimated at around 260 billion dollars annually worldwide.

	The main influence on myopia progression is genetics.

More than 20 genetic loci for myopia are known and a child whose parents are both myopic has six times the risk for myopia than a child with non-myopic parents.

	It has recently been explored how time spent outdoors is firmly associated with less myopic refraction. A study from China showed that the prevalence of myopia significantly decreased, from 39% (control group) to 30%, in schoolchildren who had 40 minutes of outdoor activities every day.

	There are many studies showing a definite relation between near work and myopia progression. A meta-analysis of 27 such studies (25,025 children) showed that myopia increased by 2% for every hour of near work per week.

	Atropine drops were first used to arrest myopia in the 1970s: they were initially believed to work by blocking accommodation. However, atropine prevents form myopia from developing in chicks when one eye is blocked, so this cannot be the mechanism.

	Instead, it blocks receptors on the sclera, the scleral muscle and retina, and inhibits the thinning and stretching of the sclera that is characteristic of form myopia.

	1.     Chua WH, et al. Atropine for the treatment of childhood myopia. 

 Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). 

 Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. 

 Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. 

 The changing prevalence of myopia in young adults: a 13-year series of population-based prevalence surveys. 

 Potential lost productivity resulting from the global burden of uncorrected refractive error. 

 Advances in the genomics of common eye diseases. 

Effect of Time Spent Outdoors at School on the Development of Myopia Among Children in China: A Randomized Clinical Trial. 

	9.     Huang HM, Chang D-ST , Wu P-C. The Association between Near Work Activities and Myopia in Children-A Systematic Review and Meta-Analysis. 

	Professor Morad works at Assaf Harofeh Medical Center, Tel Aviv University.

Children in Tel Aviv have been treated with nightly atropine drops, significantly slowing the progression of myopia.

Low-dose atropine for myopia in children: two years of experience

	It is not better to sit up straight to read, a long-term study has concluded. Finnish researchers Olavi Pärssinen and Markku Kauppinen published their results in 

	Who, as a child, was not issued with an ominous warning that reading in an awkward position, under the bedclothes or lolling about on the floor, would "ruin your eyes"? It has long been a popular belief that myopia can be caused by an improper reading posture, by reading too close or by reading in dim light, perhaps with a torch in bed. As long ago as 1864, it was suggested that myopia could be caused by a stooped reading position and use of a horizontal, rather than sloped, writing surface.

	“There is substantial epidemiological evidence of a connection between myopia and reading, without accepted proof of the mechanisms behind this connection”, Professor Pärssinen explained. “Reading is a complex neurophysiological process involving not only accommodation and convergence but also keeping the fixation and regulating saccadic eye movements by varying the tension of six extraocular muscles. The pressure between lids and eye may also vary in reading, not only because of anatomical differences but also with differences in posture and the alignment of the eyes. All of these factors may gradually have an influence on scleral stretching, which is the anatomical change behind myopic progression.”

Genetic, environmental twin studies provide clues to myopia

	This long-term study, analysing the connections between myopia and posture, distance and gaze angle when reading, is part of a trial that began in the early 1980s by recruiting 240 schoolchildren (119 boys and 121 girls; mean age 10.9 years) with previously untreated myopia to a randomised clinical trial of three treatments – continuous use, distance use only or bifocals. No previous studies have compared reading posture at the onset and during the progression of myopia.

	Annual examinations were conducted for three successive years, after which time ordinary fully corrected spectacles were prescribed and continuous use recommended. The next clinical follow-up, in which nearly three-quarters of patients participated, came after a further 10 years when they were in their early 20s. Examinations at all visits included biomicroscopy, ophthalmoscopy and biometric measurements, and measurement of intraocular pressure. Habitual reading distance and gaze direction were also measured.

	A structured questionnaire was used to record average daily time spent reading and performing other types of close work outside school; time spent watching television, playing sports and on outdoor activities; and data on parents’ myopia.

	Mean spherical equivalent at baseline was highest in those who sat to read, as was myopic progression across all follow-up visits. Myopic progression from baseline to their early 20s was lowest for those who reported reading lying on their backs, by a difference of 0.96 D and 1.38 D for men and women, respectively, compared with progression in those who read in a seated position. Overall, there was about one-third less myopic progression in those reading on their backs compared with those whose reading posture was sitting.

	The children were asked to select their habitual reading posture from sitting down, lying on their back, lying on their stomach and varying.

	About half of the respondents varied their reading posture, while about one-third of them preferred to sit to read.

	Twenty children reported lying on their back as their habitual reading posture at the initial visits, 11 of whom answered a follow-up questionnaire in 2015. The questionnaire asked ‘As far you remember, what was your preferred reading posture during childhood?’ and ‘What is your current preferred reading posture?’. Five respondents still preferred to read lying on their back, while the remainder reported a sitting or varied posture.

	Of course, reading for schoolwork and in a professional capacity is mainly performed in a sitting position; reading in other positions is generally possible only when at leisure. The answers to this new questionnaire support the view that many of those who read lying down as children continue to do so as they grow.

High myopia: Global pandemic with genetic and environmental causes

	The researchers found a tendency towards more myopic progression with a steeper downward angle of gaze when reading.

	Although correlations between reading angle and myopic progression at the initial three yearly visits were mainly insigniï¬cant, the mean reading angle of the last two childhood follow-ups correlated with myopic progression in the subjects’ early 20s.

	Elongation of the eye has been suggested to result from the inï¬uence of the extraocular muscles.

 It is known that diï¬erent gaze directions cause diï¬erent tensions in the extraocular muscles, and also that eyelid pressure inï¬uences the shape of the cornea, depending on angle of gaze.

	Gaze direction was measured with an angle scale, starting at zero if the eyes were looking horizontally ahead. The posture of the head during reading was not recorded.

	The correlation between spherical equivalent and reading distance was the only myopia parameter that showed significant diï¬erences between the sexes. Higher myopia was associated with a shorter reading distance in girls at the last two of the three yearly follow-ups, but not at other visits. However, it seems logical that myopes might hold their reading material close, especially when not using spectacles, so it is diï¬cult to conclude whether the association is causal.

	In male subjects a correlation was observed at the fourth visit (early 20s) only, the direction of which opposed that seen in the younger girls: higher myopia was connected with a longer reading distance. It is possible that this was because they had been advised at the childhood visits to adopt a longer reading distance.

	“Larger follow-up studies including a wide distribution of refraction and controlling factors connected with reading, such as reading speed, intensity, pauses, etc, are warranted”, concluded Professor Pärssinen. “Based on our results, one can at least say that there is no need to prohibit children lying down to read.”

			O Pärssinen, M Kauppinen and A Viljanen.

It is not better to sit up straight to read, a long-term study has concluded. Finnish researchers Olavi Pärssinen and Markku Kauppinen published their results in Acta Ophthalmologica this month.

Author | Lisa Stewart

Articles

Immune mechanisms in allergic eye disease

Angiography within anterior imaging

Low-dose atropine for myopia in children: two years of experience

New study finds association between myopic progression and reading position