We identified a statistically significant positive association between asthma and increased severity of KC for the first time. Subjects presenting with asthma had a 2.2D steeper corneal curvature compared to subjects having no asthma.
Sabiston in 1966, first described a positive association between asthma and an increased risk of KC[37] and multiple other studies have strengthened the argument for a role of asthma in KC. In a New Zealand study, it was noted that 38% out of 673 KC individuals presented with asthma compared to 18% in the general population[34] and in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study, asthma was reported at 14.9% [53]. In the Dundee University Scottish Keratoconus (DUSK) study in Dundee, KC patients with asthma were diagnosed up to 3.1 years earlier than those without asthma[50]. In addition, in an Israeli study of 662,644 adolescents, an increased risk of asthma in 807 KC patients (OR1.5, 95%CI 1.3–1.6) was reported[31]. Similarly, an association was reported in a Danish nationwide registry study (OR2.21, 95%CI 1.91–2.55)[3] as well as in a United States Nationwide Heath Care Claims Database analysis (OR 1.31, 95% CI, 1.17–1.47)[51]. However, no studies have assessed asthma with effect on severity of KC.
Our finding adds to the growing evidence that asthma not only appears to be associated with KC but also appears to increase severity of the condition. This in an important finding as currently it is estimated that approximately 300 million people in the world have asthma and prevalence in Australia is reported as the highest in the world at 21% for clinical asthma[47].
Asthma & KC in children
Asthma is an inflammatory disease of the small airways of the lung and has been reported to be caused by a combination of genetic predisposition with environmental factors[11]. These environment factors likely include indoor and outdoor allergens, tobacco smoke, chemical irritants as well as air pollution and likely prompt an allergic reaction or airway irritation. Asthma is a common chronic disease that affects people of all ages in all parts of the world. The International Study of Asthma and Allergies in Childhood reported that globally the age distribution of the burden of asthma peaks at age 10–14 years and that asthma is a cause of substantial burden of disease, including both premature death and reduced quality of life in people of all ages[13].
The onset of the KC is usually in the teens to early adulthood, but there are reports of increasing prevalence in children as young as at the age of 4 years[38]. Paediatric KC has also been shown to be more aggressive than adult KC[22]. Our current finding showing asthma has an association with increased severity of KC, is thus important in the examination and systemic management of paediatric KC subjects. While KC in adults has been studied extensively, the disease in the paediatric population has not. Visual impairment in paediatric patients may affect social and educational development, thus negatively impact on their quality of life. Our recent findings show that the quality of life in KC patients is lower than that in patients with later-onset eye diseases such as age-related macular degeneration or diabetic retinopathy,[39] highlighting the significant long-term morbidity associated with KC. It is therefore necessary to consider asthma as a major contributing risk factor in paediatric KC cases, which may lead to a paediatric-specific therapeutic algorithm.
Shared genetic path for Asthma and KC
A large number of genetic loci have been implicated in asthma through the use of linkage, genome wide association studies (GWAS) and animal studies. There is some evidence to support a possible shared genetic contribution between asthma and KC. A previous Genome Wide Association Study (GWAS) conducted on asthma in an Australian population identified significant association with the single nucleotide polymorphism (SNP) rs4129267 (odds ratio 1·09, p = 2·4 × 10− 8) in the interlukin-6 receptor (IL6R) gene [14]. The ligand for this receptor is the interleukin 6 (IL6) gene. IL6 is known to be a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in immune response[20]. Shetty et al recently reported up-regulation of IL6 mRNA in tears of KC patients[44]. Thus, it could be postulated that increased IL6 levels lead to enhanced up-regulation of the immune response through binding with its receptor (IL6R), followed by subsequent activation of the JAK-STAT pathway. While increased IL6 mRNA expression has been detected in tears of KC patients, this does not necessarily confirm IL6 as a causative agent in KC. Interestingly, the cornea is one of the tissues of the eye exhibiting the highest expression of IL6R whereas IL6 has a low expression in this tissue (Ocular Tissue Database, University of Iowa). Ultimately, a direct comparison of gene expression or protein levels will be required in KC compared to non-KC corneal tissue to substantiate these findings. Interestingly, the convergence of immune genes and pathways from different diseases has recently been demonstrated in a meta-analysis of GWAS in ten paediatric autoimmune diseases where such signalling pathways are a common denominator[29].
Other risk factors
In addition to asthma we also assessed several other commonly reported risk factors which haven’t been assessed in KC including age, gender, educational background, birth history, childhood infections, time spent undertaking near work, intermediate work and outdoors, duration of keratoconus, ocular and medical history, smoking and alcohol consumption habits; systemic conditions and eye rubbing. Several of these were significant at the univariate level (BMI, ethnicity, cigarette smoking, arthritis, diabetes and eczema) and suggestive at the multivariate level (eczema, arthritis and diabetes with p values of 0.07, 0.09 0.1 respectively). Interestingly, arthritis showed a positive association with KC whereas diabetes and eczema were associated with a protective effect for KC. The significant “protective effect” of diabetes against KC[2, 24, 25, 26, 27, 32, 35, 42] has been previously described in the literature and researchers have investigated the biochemical properties of cornea to explain this effect[17, 43, 48]. We report findings on time spent on near work, intermediate work and outdoor activities for the first time. As KC typically affects teens to early adults, we were expecting a positive association with near work-related activities as seen in myopia[18]. However, no such trend was evident suggesting that KC is more patho-physiologically driven than by these environmental conditions.
Strengths & Limitations
The main strength of the current study is that it included a wide range of risk factors that could be assessed with their association with KC. To the best of our knowledge, there are no previous studies which looked at the association of hypertension or migraine with KC and there are very few studies that assess potential risk factors such as cigarette smoking and alcohol consumption. The design of this study has addressed several methodological issues found in previous studies on KC, such as small sample size[23], postal questionnaires[34], data from medical record[52] the absence of ocular biometric measures[6, 7, 8, 28, 30, 45] and the lack of a comprehensive environmental risk factor questionnaire[6, 7, 8, 28, 30]. Findings from this study are therefore envisaged to lead to substantial progress in our understanding of the aetiology of KC and classifying it as quasi-inflammatory condition.
The limitation of the study is the lack of a clinically quantified severity risk factor questionnaire for some of the collected measures. Data collected on eczema and asthma did not record severity, number of episodes and length of time presenting with these indicators. It would have been interesting to find out more details about these two conditions including severity of asthma and current treatments as our results and the literature suggest an association of these with KC and with severity of KC.