‘Aye, there's the rub’—Ocular allergy and keratoconus

Affecting 1 in 725 individuals worldwide and up to 1 in 84 Australian young adults, keratoconus is the most common corneal ectatic disorder. It is characterised by progressive, bilateral though often asymmetric thinning of the central or paracentral cornea, leading to coneshaped corneal protrusion and irregular astigmatism. Risk factors classically described have included systemic disorders such as Down syndrome, Ehlers–Danlos syndrome, and osteogenesis imperfecta; atopy and ocular allergy; mechanical factors such as eye rubbing and floppy eyelid syndrome; and family history and ethnicity. We congratulate Seth et al. for the publication of “The association between keratoconus and allergic eye diseases: A systematic review and Meta-analysis” in this issue of Clinical and Experimental Ophthalmology. The authors screened 361 titles and abstracts to include 15 observational studies (10 case–control, 5 cross-sectional) with 708 225 participants (20 336 of them had keratoconus) in quantitative meta-analyses; and 7 studies (6 cross-sectional, 1 basic science) with 899 participants (709 of them had keratoconus) in descriptive analyses. Three meta-analyses were performed to synthesise the associations between keratoconus and allergic eye diseases [13 studies, pooled odds ratio (OR) 1.03, 95% confidence interval (CI) 0.96–1.11], eye rubbing (10 studies, pooled OR 1.59, 95% CI 0.70–3.63), and atopy (3 studies, OR 1.08, 95% CI 0.80–1.44); no significant association was found in all three analyses, although ORs were in the positive direction. The authors assessed included studies to be moderate to high quality, and interestingly deemed heterogeneity as not significant, in contrast to previous meta-analyses pooling similar original articles on this topic. The authors did not provide a table of included studies with variables, measures of interest, and definition of outcome measures to allow the readers to independently assess the degree of clinical heterogeneity and the appropriateness of pooling of results. The authors rightly identified that their study results should be interpreted with limitations. Although it is true that a randomised controlled trial on this topic would be impractical, the low number of prospective crosssectional and case–control studies and the low sample size of three studies in the meta-analysis of keratoconus and atopy limit the certainty of study conclusions. The extremely large confidence intervals of some included odds ratios (with upper bounds of up to 188 752) further highlight the impreciseness and potential methodological limitations of some included studies. As the authors note, with the higher than average prevalence of ocular allergy estimated to be between 11% and 30% of individuals with keratoconus, future high-quality studies are needed to corroborate these meta-analysis findings. Atopy and allergic eye diseases have been linked to chronic habitual eye rubbing. Postulated mechanisms of progression to corneal ectatic disorders, such as keratoconus, have included rubbing-induced frictional microtrauma, elevations in corneal temperature and intraocular pressure, as well as release of inflammatory mediators such as matrix metalloproteinases, interleukins, interferon gamma, and tumour necrosis factor alpha leading to corneal thinning with subsequent remodelling and increased curvature. Other less common anterior segment complications of eye rubbing include acute corneal hydrops, intraocular pressure spikes, and intraocular lens dislocation, to name a few. Clarifying these potential modifiable risk factors of keratoconus is particularly important to prevent ongoing progression and visual loss. Eye rubbing, in particular, is an exposure that is notoriously difficult to measure consistently. There exists no uniform way of eye rubbing—differences arise in style (rubbing with the knuckles, finger pads, fingernails, palms, or otherwise), location (on the globe, below the globe, above the globe, or otherwise), duration, pressure, rhythm, intensity, and frequency. In the context of measurement and reporting error, accurate assessment of rubbing poses understandable challenges, and these differences may lead to differences in outcomes. Observational studies generally utilise self-reporting on questionnaires or history taking as a gross measure of eye rubbing; such approaches rely on patient awareness and memory. Many patients do not remember, realise, or gauge accurately their eye rubbing. From our clinical experience, many patients with keratoconus report that they only realised that they do rub their eyes after it was DOI: 10.1111/ceo.14059