Wasilewska J

Respiratory response to proton pump inhibitor treatment in children with obstructive sleep apnea syndrome and gastroesophageal reflux disease

OBJECTIVE Evaluation of the respiratory response to proton pump inhibitors (PPI) in children with obstructive sleep apnea syndrome (OSAS) and gastroesophageal reflux disease (GERD). METHODS Of 131 children diagnosed with OSAS (Apnea Hypopnea Index, AHI >1/h), 37 children (6.9 years; 28.24%) with GERD symptoms (>3 times/week) were included. Overnight polysomnography with 24h pH-metry was performed before and after 4-8 weeks of PPI treatment (omeprazole once a day, 1mg/kg). RESULTS Of 37 children, 21 were diagnosed with acid GERD where pre- and post-treatment reflux indexes were 14.09±1.47 vs. 7.73±1.36; (p<0.001). The number of obstructive apneas and hypopneas decreased after PPI treatment, resulting in an AHI reduction from 13.08±3.11/h to 8.22±2.52/h; (p<0.01). Respiratory response to PPI ranged from complete resolution of OSA (three children with mild OSA; AHI<5/h; 10.31years; 14.29%) to lack of significant AHI change (six children with severe OSA; AHI>10/h; 3.62 years; 28.57%). Post-treatment AHI was predicted by pre-treatment reflux index (adjusted R(2)=0.487; p<0.001). CONCLUSIONS Reduction of obstructive respiratory events following short-term PPI treatment in children with both GERD and OSAS may suggest a causal relationship between apnea and reflux in some children. Questionnaire screening for GERD in children with OSAS may be of benefit.

Influence of candidate polymorphisms on the dipeptidyl peptidase IV and μ-opioid receptor genes expression in aspect of the β-casomorphin-7 modulation functions in autism

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with population prevalence of approximately 60-70 per 10,000. Data shows that both opioid system function enhancement and opiate administration can result in autistic-like symptoms. Cow milk opioid peptides, including β-casomorphin-7 (BCM7, Tyr-Pro-Phe-Pro-Gly-Pro-Ile), affect the μ-opioid receptor (MOR) and are subjected to degradation resulting from the proline dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme activity. The presence of MOR and DPPIV activity are crucial factors determining biological activity of BCM7 in the human body. Our study examined the effect of β-casomorphin-7 on the MOR and DPPIV genes expression according to specific point mutations in these genes. In addition, we investigated frequency of A118G SNP in the MOR gene and rs7608798 of the DPPIV (A/G) gene in healthy and autistic children. Our research indicated correlation in DPPIV gene expression under the influence of BCM7 and hydrolyzed milk between healthy and ASD-affected children with genotype GG (P<0.0001). We also observed increased MOR gene expression in healthy children with genotype AG at polymorphic site A118G under influence of BCM7 and hydrolyzed milk. The G allele frequency was 0.09 in MOR gene and 0.68 in the DPPIV gene. But our results suggest no association between presence of the alleles G and A at position rs7608798 in DPPIV gene nor alleles A and G at position A118G of the MOR and increased incidence of ASD. Our studies emphasize the compulsion for genetic analysis in correlation with genetic factors affecting development and enhancement of autism symptoms.

Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old.

Introduction Immune system dysfunction is considered to be one of many medical disorders found in children with autism. The primary objective of the study was to assess if blood tests reflecting humoral immunity (IgA, IgG, IgM, IgE) are useful in identifying children with regressive autism. The secondary objective was to evaluate a part of the cellular arm of immunity (CD4/CD25 Tregs, CD4/CD23 cells) in those children. Material and methods Using a clinical case-control design, the systemic levels of immunoglobulins and lymphocyte subpopulations analysed by flow cytometry were compared in children aged 3-6 years old with a new diagnosis of regressive autism (n = 24; mean age: 4.25 ±1.70 years; male 23/24) and in sex- and age-matched healthy children (n = 24; aged 4.25 ±2.20 years; male 23/24). Results The humoral immunity profile, described by three binary variables, IgA < 0.97 g/l, IgE > 36 IU/ml, and IgG > 6.3 g/l, with a sensitivity of 79% and a specificity of 83% (p < 0.0001), was able to identify children with autism. The highest risk of autism diagnosis was associated with IgA < 0.97g/l (OR – 23.0; p < 0.001). A higher number of CD19/CD23 was found in children diagnosed with autism than in the control group (36.82 ±6.72% vs. 18.20 ±3.95%; p < 0.02). No correlation between the number of CD23-positive cells and serum IgE levels was observed. Conclusions A subtle shift of serum immunoglobulins consisting of low-normal IgA and B cell activation expressed by an increase of CD23-positive cells may characterize children with regressive autism aged 3-6 years old.

Cow's-milk-induced infant apnoea with increased serum content of bovine β-casomorphin-5.

772 S uddenly occurring life-threatening events with symptoms such as apnoea, changes in skin colour (eg, blue or cyanotic), altered muscle tone (eg, floppy, stiff), coughing, choking, or gagging are called apparent life-threatening events (ALTE). About 7.4% to 10% of infants with ALTE, mostly in its recurring form, cannot be saved and they die of sudden infant death syndrome (SIDS) (1–3). A number of different and independent causes of ALTE pathogenesis have been described. Those causes include diseases of various organs and systems, infections, nonaccidental traumas, and Münchausen syndrome by proxy (1,4,5). A coexistence of digestive tract disorders is also diagnosed in >50% of infants with ALTE. Gastro-oesophageal reflux is 1 of the most often diagnosed disorders; however, its role in the genesis of infantile apnoea has not been fully explained (6). ALTE aetiology is explainable and diagnosable only in half of all of the cases (2,3). The causes of ALTE described before do not include an opioid action of the exogenous peptides released from milk b-caseins. We report a case of a breast-fed infant with recurrent apnoea episodes, which have always been preceded by his mother’s consumption of fresh cow’s milk. A biochemical examination has revealed a high level of b-casomorphin-5 (BCM-5) in the child’s serum. We speculate that it is an opioid activity that may have a depressive effect on the respiratory centre in the central nervous system and induce a phenomenon called milk apnoea. A full-term male infant from a rural family, age 7 weeks, was referred to a macroregional SIDS prevention centre to diagnose the cause of his recurrent ALTE. Apnoea had been occurring since the child was 3 weeks old and its clinical course kept getting more serious. The infant’s mother noticed that those events occurred only after her consumption of cow’s milk, particularly when she had consumed large amounts of it (up to 2 L/d). Before and during her pregnancy, the mother drank milk with no adverse effects. The boy’s ALTE occurred during breast-feeding or directly after that, and was manifested as sudden, 20-, 30-, or 40-second-long apnoea with generally lowered muscle tone. Most of the episodes required

Brief Report: Eosinophilic Esophagitis as a Cause of Feeding Problems in Autistic Boy. The First Reported Case

Unrecognized gastrointestinal disorders may contribute to the behavioral problems in non-verbal patients, but they are often overlooked since the clinical symptoms are nonspecific. Eosinophilic esophagitis (EE) is a chronic inflammatory disorder manifesting itself predominantly in reflux-type symptoms that do not respond to standard anti-reflux pharmacotherapy. Here we report the first case of EE in an autistic patient with feeding difficulties caused by exacerbated EE symptoms.

Obstructive hypopnea and gastroesophageal reflux as factors associated with residual obstructive sleep apnea syndrome

OBJECTIVE The mechanism of persisting obstructive sleep apnea (OSA) after adenotonsillectomy is not fully explained. The purpose of this study was to evaluate factors associated with residual OSA. The primary outcome measures were metabolic tests and polysomnographic respiratory indices in children with residual disease compared with children who were diagnosed with OSA but were untreated. Secondary outcome measures were acid gastroesophageal reflux indices recorded parallel to the sleep study. METHODS In the one-year study consecutive series of patients with sleep disordered breathing hospitalized in a tertiary pediatric center were evaluated. Following the study protocol a sleep interview, physical examination, metabolic blood tests (serum leptin and the homeostasis model assessment index for insulin resistance, HOMA-IR) and an overnight polysomnography with pH-metry recording were performed. Children diagnosed with OSA were analyzed in two groups: I - residual OSA (after surgery), II - non-residual OSA (newly diagnosed). Logistic regression analysis was applied to obtain significant risk factors for prediction of OSA. RESULTS Fifty-seven children (mean age ± SE, 6.9 ± 0.5 years; 66.7% boys) met the inclusion criteria and were enrolled in the study as residual (n=19) or non-residual OSA (n=38). The groups differed significantly in mean oxygen saturation, SpO₂ (94.3% vs. 96.2%; p=0.018 respectively), in the Apnea Hypopnea Index, (20.6/h vs. 9.1/h; p<0.03), the number of respiratory arousals with desaturation (2.2/h vs. 0.8/h; p<0.03); mean intraluminal esophageal pH (5.36 vs. 5.86; p=0.007) and the Reflux Index (9.61% vs. 4.35%; p=0.003). The groups did not differ in total sleep time, tonsil size, BMI z-score and blood metabolic indices. Logistic regression analysis showed that residual OSA was significantly predicted by two polygraphic findings: the obstructive hypopnea index (OR 1.15; 95% CI 1.02-1.28; p=0.014) and by the Reflux Index (OR 1.01; 95% CI 1.00-1.34; p=0.042). CONCLUSIONS 1. Obstructive hypopneas, rather than obstructive apneas, persist after adenotonsillar surgery resulting in residual OSA. 2. Children with residual OSA are at higher risk of acid gastroesophageal reflux and should be evaluated for gastroesophageal reflux disease.

The natural history of cow's milk allergy in north-eastern Poland

PURPOSE The rate of cows milk allergy diminishes with age. There is not enough information concerning geographical trends in persistent cows milk allergy in children. The objective of the study was to evaluate the prevalence of persistent cows milk allergy in children previously diagnosed with IgE-mediated cows milk allergy (CMA). MATERIAL/METHODS Diagnosis of cows milk allergy was established by a medical history of symptoms associated with exposure to cows milk, positive skin prick tests with cows milk, the presence of milk-specific IgE, and by a positive double- or single-blind placebo-controlled food challenge with milk confirmed by a positive open-controlled milk challenge. A second oral challenge was performed after at least one year of a milk-free diet and children with a positive oral milk rechallenge were diagnosed as having a persistent CMA. RESULTS Two hundred ninety-one children, 2-14 years of age (mean 5.30±3.16 years, 95% CI, 5.02-5.62 years) completed the study. Persistent CMA was diagnosed in 79 patients (27.1%). Two hundred twelve children (72.9%) outgrew their allergy to cows milk at a mean age of 5 years after an average time of 16.4±0.8 months on an elimination diet. Eighty percent of children below 3 years of age became milk tolerant. Milk-specific IgE (p=0.018) and history of paternal bronchial asthma and/or rhinitis (p=0.020) were associated with persistence of cows milk allergy in regression analysis. CONCLUSIONS An age above 3 years, as well as features of atopy, individual and familial, may be associated with a risk of delayed tolerance to milk in children.

Gastrointestinal symptoms and autism spectrum disorder: links and risks - a possible new overlap syndrome

Autism spectrum disorder (ASD) is a genetically determined neurodevelopmental brain disorder presenting with restricted, repetitive patterns of behaviors, interests, and activities, or persistent deficits in social communication and social interaction. ASD is characterized by many different clinical endophenotypes and is potentially linked with certain comorbidities. According to current recommendations, children with ASD are at risk of having alimentary tract disorders – mainly, they are at a greater risk of general gastrointestinal (GI) concerns, constipation, diarrhea, and abdominal pain. GI symptoms may overlap with ASD core symptoms through different mechanisms. These mechanisms include multilevel pathways in the gut–brain axis contributing to alterations in behavior and cognition. Shared pathogenetic factors and pathophysiological mechanisms possibly linking ASD and GI disturbances, as shown by most recent studies, include intestinal inflammation with or without autoimmunity, immunoglobulin E-mediated and/or cell-mediated GI food allergies as well as gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity linked with functional abdominal pain, and dysautonomia linked with GI dysmotility and gastroesophageal reflux. Dysregulation of the gut microbiome has also been shown to be involved in modulating GI functions with the ability to affect intestinal permeability, mucosal immune function, and intestinal motility and sensitivity. Metabolic activity of the microbiome and dietary components are currently suspected to be associated with alterations in behavior and cognition also in patients with other neurodegenerative diseases. All the above-listed GI factors may contribute to brain dysfunction and neuroinflammation depending upon an individual patient’s genetic vulnerability. Due to a possible clinical endophenotype presenting as comorbidity of ASD and GI disorders, we propose treating this situation as an “overlap syndrome”. Practical use of the concept of an overlap syndrome of ASD and GI disorders may help in identifying those children with ASD who suffer from an alimentary tract disease. Unexplained worsening of nonverbal behaviors (agitation, anxiety, aggression, self-injury, sleep deprivation) should alert professionals about this possibility. This may shorten the time to diagnosis and treatment commencement, and thereby alleviate both GI and ASD symptoms through reducing pain, stress, or discomfort. Furthermore, this may also protect children against unnecessary dietary experiments and restrictions that have no medical indications. A personalized approach to each patient is necessary. Our understanding of ASDs has come a long way, but further studies and more systematic research are warranted.

Cross allergic reactions in infants and toddlers with atopic dermatitis

PURPOSE Prevalence and clinical significance of cross sensitization in children up to 3 years old, diagnosed with atopic dermatitis. MATERIAL AND METHOD The retrospective study included 69 children up to 3 years old with atopic dermatitis. Allergological diagnostics was performed based on skin tests, determination of total IgE concentration and allergen-specific IgE. RESULTS Cross sensitization was found in 26% of children. Other patients were qualified to the control group. The sensitization to trees pollen and fruits as well as grass pollen and vegetables were the most frequent types of cross allergy. The patients family history was positive with regard to atopy in 72% of children from the study group vs. 31% of children from the control group. The statistically higher prevalence of allergic rhinitis and bronchial asthma as well as co-existence of sensitization to house dust mite and animal dander were revealed in the study group. The total concentration of IgE, eosinophilia and SCORAD values were statistically higher in the study group. Children with cross sensitization required systemic steroid therapy more frequently. CONCLUSION In children up to 3 years with atopic dermatitis and sensitization to plant pollen, the role of a pollen-food allergy syndrome must be taken into account in the pathogenesis of the disease. In children with cross sensitization, the course of atopic dermatitis is more severe; the symptoms from the respiratory and digestive system co-exist. The positive family history is a factor, predisposing to the development of cross sensitization in infants and toddlers.

Serum gastrin concentrations in children with primary gastroesophageal reflux and gastroesophageal reflux secondary to cow's milk allergy

PURPOSE The assessment of the serum gastrin concentrations and the role of enterohormone in children with primary acid gastroesophageal reflux (GER) and GER secondary to cows milk allergy (CMA). MATERIALS/METHODS 138 children were diagnosed with pathological acid GER on the basis of pH-metric examination. 76 (28.8%) patients had primary GER and 62 (23.5%) patients had GER secondary to CMA.Serum gastrin concentration (fasting and postprandial) was assessed before treatment and 1 and 2 years after initiation of the therapy. RESULTS The children with primary GER had the fasting gastrin concentration 69.46 ± 11.87 μU/ml before treatment, 77.86 ± 26.35 μU/ml after 1 year and 83.78 ± 25.21 μU/ml after 2 years of treatment. The children with GER secondary to CMA had gastrin concentrations 89.61 ± 26.75, 73.17 ± 19.49 and 73.90 ± 20.31 μU/ml respectively. The mean postprandial gastrin concentration after treatment was higher than before treatment in children with both primary and secondary GER. The primary GER group had postprandial gastrin concentration 96.07 ± 33.51 μU/ml before treatment and 116.06 ± 33.95 μU/ml and 118.48 ± 33.96 μU/ml after 1st and 2nd year of therapy respectively. The secondary GER group had postprandial gastrin concentration 85.33 ± 14.12 μU/ml before treatment and 106.55 ± 24.51 μU/ml and 110.36 ± 24.67 μU/ml after 1st and 2nd year of therapy respectively. CONCLUSIONS The mean fasting serum gastrin concentrations in patients with primary and secondary GER were similar and mean postprandial concentrations were higher than fasting concentrations in both study groups.