Sleep in children with eosinophilic esophagitis

Isabela A.Ishikura·Gustavo Moreira·Sergio Tufik ·Monica L.Andersen

Eosinophilic esophagitis (EoE) is a chronic immune-and antigen-mediated disease caused by infiltration of eosinophils in esophagus tissue,which leads to morphological and functional abnormalities at this site [1].This disease was discovered in 1995 by Kelly et al.[2];since then,it has become increasingly recognized and discussed by researchers [2,3].EoE affects children and adults and is three times more prevalent in males than in females.According to a recent systematic review,there are 19.1 cases of EoE per 100,000 children/year,with a higher frequency in Western countries [4].

The pathogenesis of EoE is not well elucidated;however,it has been observed that genetic and environmental factors are associated with occurrence of the disease in 20% and 80% of cases,respectively [5].Symptoms of EoE in children include feeding difficulties,failure to thrive,vomiting,and growth delay [3].Beyond these established symptoms,sleep disturbances,such as obstructive sleep apnea (OSA),are gaining attention as a symptom of children with this disease [6].OSA can have a long-term effect on cardiovascular parameters,height,memory,and learning,resulting in a reduction in quality of life [7].In children,the outcomes of OSA and other sleep disturbances may be worse because the body is still developing.Furthermore,these outcomes can compromise biological functions.Sleep-disturbed children with EoE may be more susceptible to impaired academic performance due to damage in cognitive function.Sleepdisturbed children also have greater difficulty managing the inflammatory events inherent to EoE,and they have delayed growth due to a reduction in growth hormone secreted during sleep.In addition,these children have increased cardiovascular and metabolic risks.

The mechanisms responsible for the sleep disturbances that are prevalent in children with EoE and the complex relationship between sleep and the disease has largely been neglected by researchers.Therefore,we seek to underscore the importance of monitoring the sleep of children with EoE to minimize the deleterious effects on child development that are caused by sleep disturbances associated with EoE.

Physiopathology of EoE

The eosinophilic infiltrate present in EoE is related to Th2(lymphocyte T helper 2) inflammation,and is characterized by a mixed IgE and non-IgE-mediated reaction to food and/or environmental agents driven by thymic stromal lymphopoietin secreted by esophageal epithelial cells under the influence of genetic predisposition [8-10].Increased mucosa permeability and Th2 immune response in the esophagus are the first abnormalities observed in patients with EoE.Altered esophageal mucosa permeability allows food and environmental allergens to enter the subepithelial tissue,inducing allergic reaction following eosinophil infiltration[1].

Esophageal biopsies and blood samples of patients with EoE have high levels of Th2 prototypical cytokines and chemokines,such as IL-5,IL-4,and IL-13,that are secreted by cells involved in allergic inflammation [11-14].The major long-term consequence of chronic inflammation in EoE is esophageal remodeling,followed by the development of irreversible structures.Hence,eosinophil infiltration and activation increase epithelial permeability by damaging epithelial cells and by altering esophageal sensory and motor activities [15].

Sleep in patients with EoE

Symptoms can be present for a long time (mean of 3-5 years)before EoE is diagnosed,especially if the disease appears progressively [16].In infants and toddlers,the most frequent symptoms are feeding difficulties,failure to thrive,vomiting,and sleeping disturbance [3].

Sleep has been poorly studied in the EoE population;however,one study observed that 33% of children with EoE experienced moderate to severe sleep difficulties [17].Corroborating this finding,studies of children aged between 2 and 7 years with the condition found that 25% had sleep problems [18-20].A study using polysomnography (PSG),the gold standard method of investigating sleep architecture and sleep disorders,found that the most common symptom in children with EoE was sleep disorder breathing (SDB-76.5%),followed by problems of sleep onset (51.8%) [6].With respect to sleep architecture,all patients presented a higher percentage of non-rapid eye movements (NREM)stage N2 sleep and reduced rapid eye movements (REM) and NREM stage N3 sleep percentages compared to a control group.Furthermore,patients with EoE exhibited a signifi-cant increase in obstructive and central apnea,arousal,and periodic limb movements (PLM) indexes.Of the 81 patients with EoE in this study,62 presented SDB,with 37% being related to obstructive sleep apnea (OSA) [6].It should be noted that PLM disorder was more prevalent in children with acute symptoms of EoE than in children with EoE without acute symptoms.

How sleep disturbance aggravates the severity of EoE

Sleep is a multidimensional health factor that is affected by circadian rhythms,habits,and behaviors.It is widely accepted that many pathological conditions can influence sleep regulation and that sleep may play a role in the inflammatory response to disease.

The inflammatory process inherent in EoE can affect the immune-sleep response,aggravating the severity of EoE.Less is known about the possible role of cytokines in the homeostatic regulation of sleep in humans,but substantialin vivodata have indicated that inflammatory cytokines function to regulate sleep in animals homeostatically [21].

Sleep disturbances result in persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis,which triggers the production of cortisol.This hormone regulates gene expression in immune cells by inhibiting inflammatory and antiviral immune response genes;however,when there is sustained production of this hormone by the HPA axis,cortisol resistance is developed,reducing the suppression of gene expression in immune cells [21].It is important to consider the architecture of sleep,as shown by PSG,because different stages of sleep regulate nocturnal changes in inflammatory cytokine activity.In children with EoE,there was a significant increase in NREM N2 sleep percentage and a decrease in NREM N3 and REM sleep percentages [6].Although animal studies indicate that most pro-inflammatory cytokines are NREM sleep promoting and that anti-inflammatory cytokines are NREM sleep reducing,human studies related to cytokines in sleep regulation have not yet produced conclusive evidence on this subject[22].The IL-4 and IL-13 observed in esophageal biopsies and in blood samples of patients with EoE are considered anti-inflammatory cytokines;however,IL-5 is a marked proinflammatory cytokine that is responsible for the maturation,proliferation,activation,and migration of eosinophils [23].Taken together,these suggest that the higher levels of IL-5 present in patients with EoE may be the most significant factor responsible for inducing increased NREM N2 sleep percentage in these patients,while increased levels of IL-4 and IL-13 may be responsible for the reduced NREM N3 sleep percentage.This can have a negative influence on the growth development of the child because the NREM N3 sleep stage is associated with growth hormone (GH) secretion.Both NREM N3 and REM sleep are recognized as being important with respect to cognition and memory consolidation[24];thus,alterations in sleep percentages of children with EoE might have cognitive and learning consequences [24].

OSA and cardiovascular complications in children with EoE

OSA is characterized by episodes of complete or partial obstruction of the upper airway,with blood-gas changes and atypical sleep patterns.The respiratory efforts caused by OSA in children are associated with arousal and fragmentation of sleep,resulting in reduced academic performance,daytime irritability,failure to thrive and growth delay.The latter is due to a reduction in GH secretion,which occurs during NREM sleep [25].

A study reported that 37% of children with EoE have OSA [6].The prevalence of allergic rhinitis,a common symptom related to EoE might predispose these children to OSA emergence.This high prevalence of OSA is a significant finding given its intimate association with cardiovascular complications.There is strong evidence that some cardiovascular risk factors may continue from childhood to adulthood.Elevated blood pressure during childhood was associated with hypertension and metabolic syndrome in adults [26 ].Several pediatric studies have described an association between endothelial dysfunction,increased levels of plasma cytokines and OSA [27,28].

OSA is the most severe sleep respiratory disorder and affects about 33% of the adult population [29].Extensive research suggests that lack of treatment of sleep-related breathing disorders increases cardiovascular and metabolic risk [30].OSA is a condition that demands a clear diagnostic definition in children,and differs from adult OSA in terms of physiology,clinical manifestation,PSG features,and sequelae [25].If inadequately diagnosed and treated in children,OSA can cause behavioral problems,learning diffi-culties,cardiovascular complications,and growth retardation[31-33].The treatment of OSA should be part of the EoE treatment protocol to avoid impairments in child development,as well as cardiovascular comorbidities.

OSA and cognitive consequences in children with EoE

Children with habitual snoring (＞ 3/week) without apnea and hypoxemia,also called primary snoring,exhibit a lower percentage of REM sleep and a higher number of arousals as compared to healthy children.The percentage of REM sleep correlates negatively with visuospatial function,suggesting an association between REM sleep and neurobehavioral effects [34].Daytime sleepiness affects from 16 to 28%of children with sleep-disordered breathing and results in learning difficulties,attention deficit,and behavior disorders[32,35].The mechanisms of neurocognitive and behavioral deficits include intermittent hypoxia and sleep fragmentation[30].Deficits in intelligence quotient and executive function of children with OSA were associated with neuronal metabolites in the hippocampus and right frontal cortex,indicating a possible injury in these areas [36].Given the above,these findings show the possible deleterious cognitive effects that OSA can have on the development of children with EoE,leading to an impairment in school performance and quality of life.

In conclusion,this letter describes the recent few studies associating EoE with sleep disturbance in children [6,17-20].Sleep disturbances can occur as one of the symptoms of EoE several years before EoE is diagnosed.Based on these findings,we concluded that sleep disturbance may affect children with EoE by reducing the treatment progression,by impairing cognitive functions and their social and scholarly lives,and by increasing the risk to develop cardiovascular and metabolic diseases.Families with EoE children should change their daily routine and social life to provide a successful treatment to their children.

Thus,it is essential that,in addition to the gastro and immunological support,a sleep professional should be part of the medical team to treat the sleep symptoms of children with EoE.Children with a good sleep quality would be able to have more success in EoE treatment due to appropriate immune response,better scholarly performance as no detriment in cognitive function would be expected,and to show decreased risk of cardiovascular and metabolic diseases.

Author contributionsAll authors made substantial contributions to conception and design,took part in drafting the article or revising it critically for important intellectual content;gave final approval of the version to be published;and agree to be accountable for all aspects of the work.

FundingOur studies are supported by the Associação Fundo de Incentivo à Pesquisa (AFIP) ST and MLA.received CNPq fellowships.No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Compliance with ethical standards

Ethical approvalThis manuscript does not require Ethical approval.

Conflict of interestAll authors of this manuscript declare no conflict of interest.