Eosinophilic esophagitis (EoE) is a chronic, inflammatory disorder of the esophagus, characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal epithelium.1 EoE was first described as a new disease in 1993.2,3 Until then, the presence of esophageal eosinophilia was thought to be associated with gastroesophageal reflux disease (GERD). However, in 1993 and 1994 two studies reported series of young, predominantly male patients with symptoms of dysphagia and a high concentration of esophageal eosinophils, but with normal pH-monitoring and no GERD-related symptoms.2,4 The observations in these two landmark studies laid the foundation for EoE. From that moment, disease awareness among physicians and the number of publications on EoE began to rise. In 2007 the first consensus guidelines were published and, at present the newest insights and recommendations have been gathered in already the fourth guidelines on EoE.5,1
EoE has thus remained unnoticed for decades, but since its recognition in the early 90s awareness increased substantially, and the worldwide incidence and prevalence in both children and adults has risen extremely rapidly.3 The annual prevalence of EoE in the United States is estimated to be 42–53 per 100,000 inhabitants, a rate comparable to that of Crohn’s disease.6 The worldwide emergence of EoE is paralleled by the expansion of PubMed-registered publications on EoE that rose from 3 in the year 1996 to 254 in 2016. With current incidences, EoE can no longer be designated as a rare disease. However, it remains a topic of debate whether the EoE epidemic is caused by a true increase in disease or by the widespread use of endoscopy with biopsy sampling. Furthermore, incidence figures in the literature are highly variable, possibly because most epidemiologic data have been gathered from single-center studies over a short period of time.
In the Netherlands, all pathology reports are stored in the Dutch national pathology database (PALGA). This unique nationwide coverage since 1996 enabled us to accurately estimate the incidence of EoE in the Netherlands over the past two decades and, to determine whether the incidence is influenced by expanding endoscopy rates. The PALGA search enabled us to identify 2161 patients with a histopathologically confirmed diagnosis of EoE, of which 1574 (73%) were males and 365 (17%) were children. The mean age at diagnosis for adults was 37.5 (standard deviation (SD) 18.9) years, and in children the mean age at diagnosis was 10 (SD 5.4) years. EoE was diagnosed in all age groups but most patients (n=798) were diagnosed between 30 and 50 years of age.
The incidence of EoE increased from 0.01 (95% confidence interval (CI) 0–0.02) in 1996 to 2.07 (95% CI 2.05–2.23) per 100,000 inhabitants in 2015. The incidence was higher in males than in females, 3.02 (95% CI 2.66 – 3.41) versus 1.14 (95% CI 0.93 – 1.38), odds ratio (OR) 2.66 (95% CI: 2.10 – 3.36) and higher in adults than in children, 2.23 (95% CI: 1.99 – 2.49) versus 1.46 (95% CI: 1.09 – 1.91), OR 1.78 (95% CI 1.32 – 2.40). In comparison the amount of endoscopies with biopsy sampling rose from 30 per 100,000 in 1996 to 105 per 100,000 in 2015.
The results of this study demonstrated that the incidence of EoE has increased more than 200-fold over the past 20 years and still continues to rise. Whereas, within the same timeframe, we detected only a threefold increase in endoscopy with biopsy sampling rates. Based on current evidence we concluded that the incidence of EoE outpaces the expanding endoscopy rates.
However, although the results of our study provided accurate nation-wide incidence figures, still many epidemiological questions remain to be addressed. For instance, why is the prevalence of EoE in the United States estimated to be comparable of that of Crohn’s disease (42-53 per 100,000 inhabitants) whereas cases from Asia are very scarce (0.01 per 100,000 inhabitants)?6,7 Presumably genetic and environmental/lifestyle influences play an important role in these geographic incidence differences. The rising incidence has been postulated to result from effects of a “modern lifestyle” for several reasons. First, the endemic of EoE coincides simultaneously with the expansion of other allergic diseases over the past decades.8 This sudden increase can be linked to a declined early life exposure to infectious agents in excessive hygienic environments – the hygiene hypothesis.9 Second, early-life perturbations associated with a modern lifestyle, such as the use of antibiotics and formula feeding in infancy and caesarean delivery have all been positively associated with EoE.10 A third theory argues that Helicobacter pylori (H. pylori) infections, which have almost been eradicated in the western world, are inversely associated with EoE. The protective effect of H. pylori against EoE is brought about by induction of a T-helper 1 (Th-1) immune response which blocks the typical EoE associated T- helper 2 (Th-2) immune response.11 Finally, dietary changes associated with a western lifestyle including increased sugar and fat intake have been associated with the rise in several atopic diseases and may possibly play also an allergy provoking role in EoE.12,13 Nevertheless, all aforementioned theories are speculative, and more research is warranted to directly correlate these theories to the rising incidence of EoE.
Another topic of debate is whether the gradual increasing incidence of EoE is based on a true expansion of the disease or whether it is a byproduct of the increased recognition of EoE. Although we described that the incidence rates outpaced the incidence of endoscopy with biopsy sampling rates, we did not investigate the actual disease awareness among gastroenterologists and general practitioners. Despite the fact that significant progress has been made in disease detection, we believe that there is still room for improvement considering the length of the diagnostic delays observed in recently published studies.14 Healthy organizations should therefore further stimulate awareness, not only among physicians but also among patients, to stimulate better disease recognition and early treatment.
- Lucendo AJ, Molina-Infante J, Arias A, et al. Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults. United Eur Gastroenterol J. 2017;1:1-24.
- Attwood SEA, Smyrk TC, Demeester T, et al. Esophageal Eosinophilia with Dysphagia A Distinct Clinicopathologic Syndrome. 1993;38(1):109-116.
- Arias Á, Pérez-Martínez I, Tenías JM, et al. Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther. 2016;43(1):3-15.
- Straumann A, Spichtin HP, Bernoulli R, et al. Idiopathic, eosinophilic esophagitis – A frequently overlooked disease with typical clinical and discrete endoscopic findings. Schweiz Med Wochenschr. 1994;124(33):1419-1429.
- Furuta GT, Liacouras C a, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-1363.
- Dellon ES, Jensen ET, Martin CF, et al. Epidemiology of eosinophilic esophagitis. Gastroenterol Clin North Am 2014;43:201–18
7. Ngiu CS, Low SF. Meta-analysis and systemic review of prevalence of eosinophilic esophagitis in Asia. J Gastroenterol Hepatol. 2012;27:325.
8. Perez Alzate D, Somoza ML, Blanca-Lopez N, et al. Epidemiologyc features in patients with food allergy in an area population from Madrid. Allergy Eur J Allergy Clin Immunol. 2014;69:395.
- Okada H, Kuhn C, Feillet H, et al. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1-9.
- Jensen ET, Kappelman MD, Kim HP, et al. Early life exposures as risk factors for pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2013;57(1):67-71.
- Elitsur Y, Alrazzak BA, Demetieva Y. Does helicobacter pylori protects against eosinophilic esophagitis in children? Helicobacter. 2013;18:117.
- Brigham EP, Kolahdooz F, Hansel N, et al. Association between Western diet pattern and adult asthma: a focused review. Ann Allergy, Asthma Immunol. 2015;114(4):273-280.
- Vlieg-Boerstra BJ, de Kroon MJ, Warners MJ et al. Dietary Intake, Inflammation And Mucosal Integrity In Adult Patients With Eosinophilic Esophagitis. J Allergy Clin Immunol. 2017;1.
- Warners MJ, Oude Nijhuis R.A.B., Wijkerslooth de L.R.H et al. The Natural Course of Eosinophilic Esophagitis (EoE) and Long-term Consequences of Undiagnosed Disease in a Large Cohort. Am J Gastro, 2018, in press.