Extensively hydrolysed infant formulas: Need for aligned definition of peptide size characteristics and standardisation of analytical methods.

Letter by Nutten et al. on article by Levin et al. (Levin ME, Blackhurst DM, Kirstein F, Kok D, van der Watt GF, Marais AD. Residual allergenicity of amino acid-based and extensively hydrolysed cow's milk formulas. S Afr Med J 2017;107(9):763-767. S Afr Med J 2017;107(3):258-263. https://doi.org/10.7196/SAMJ.2017.v107i9.12137); and response by Levin et al.

Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice.

We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.

Chest physiotherapy, gastro-oesophageal reflux, and arousal in infants with cystic fibrosis.

BACKGROUND: Postural drainage chest physiotherapy in infants with cystic fibrosis (CF) exacerbates gastro-oesophageal reflux (GOR) and may contribute to a more rapid deterioration in lung function. AIMS: To compare standard postural drainage chest physiotherapy (SPT) and a modified physiotherapy regimen (MPT) without head-down tilt, with regard to GOR, arousal state, and cardiorespiratory function. METHODS: Twenty infants with CF underwent 30 hour oesophageal pH monitoring, during which four chest physiotherapy sessions were administered (day 1: MPT-SPT; day 2: SPT-MPT). Arousal state, heart rate, and oxygen saturation were documented for each of the physiotherapy positions (supine, prone, right lateral, and left lateral with (SPT) or without (MPT) 30 degrees head-down tilt). RESULTS: Significantly more reflux episodes occurred during SPT than during MPT, but there were no significant differences in median episode duration or fractional reflux time. During SPT, left lateral positioning was associated with fewer reflux episodes compared to other positions. During supine and prone positioning, more reflux episodes occurred during SPT than during MPT. Infants were significantly more likely to be awake or cry during SPT. There was a significant association between crying and reflux episodes for SPT. Non-nutritive sucking was associated with a significant reduction in reflux episodes during SPT. Oxygen saturation during SPT was significantly lower during crying and other waking, and non-nutritive sucking during SPT was associated with a significant increase in oxygen saturation. CONCLUSIONS: SPT is associated with GOR, distressed behaviour, and lower oxygen saturation.

New approaches to parenteral nutrition in infants and children.

Parenteral nutrition (PN) has become a mainstay in the treatment of children with intestinal failure or conditions that preclude enteral feeding. Estimated energy and protein requirements can usually be met, unless the patient is fluid volume restricted or glucose intolerant. Although PN is generally well tolerated, in some patients it is still associated with a significant morbidity. Complications include metabolic disturbances, venous access device infection or dysfunction, venous thrombosis and cholestatic liver disease. Patients need to be carefully monitored for evidence of micronutrient deficiencies or excesses. There is a close relationship between line sepsis and thrombosis. Strict aseptic technique is the key to preventing line infections. Recurrent sepsis and thrombosis may eventually lead to loss of venous access and may jeopardize the long-term delivery of PN. Chronic cholestatic liver disease is common in premature infants with gastrointestinal problems, recurrent sepsis and lack of enteral feeding. The aetiology is multifactorial. Early enteral feeding is the most effective strategy in preventing PN-associated liver disease. New specialized nutrient solutions and lipid emulsions promise improved clinical outcomes. However, long-term clinical data are not yet available in children. In recent years, nutrition support teams have improved clinical and economic outcomes by encouraging the appropriate use and monitoring of PN therapy. In patients with intestinal failure, parent-administered home PN has become an alternative to long-term hospitalization. Apart from a positive effect on the quality of life of patient and family, home PN is cost-effective and reduces the risk of nosocomial infections and catheter-related complications.

Brachyspira aalborgi infection in four Australian children.

AIM: The clinical presentation of four children and adolescents (two males and two females with a mean age of 12.4 years; range 9-16 years) with colorectal spirochetosis is discussed. RESULTS: Symptoms included persistent diarrhea (n = 2), rectal bleeding (n = 1) and abdominal pain (n = 2). In all patients, colorectal spirochetosis was an unanticipated finding on colonic histology, and the presence of spirochetes was confirmed by the use of electron microscopy. Spirochetes were identified as Brachyspira aalborgi by using PCR amplification of the bacterial 16S rRNA and nicotinamide adenine dinucleotide oxidase sequences in all four patients. No other enteric pathogens were found. CONCLUSIONS: Although all patients appeared to respond to antibiotic treatment, the clinical significance of B. aalborgi as a human pathogen requires further investigation.

Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis.

BACKGROUND: Distressed behavior is common in infants and is often attributed to gastroesophageal reflux (GER) or food protein intolerance. OBJECTIVE: To examine the effect of a hypoallergenic amino acid-based infant formula (AAF) on distressed behavior and GER symptoms in infants who failed to respond to extensively hydrolyzed formula and antireflux medications. STUDY DESIGN: Nineteen distressed infants (9 boys and 10 girls; median age, 5.0 months) with presumed GER underwent gastroscopy (n = 17) and esophageal 24-hour pH monitoring (n = 14). Double-blind placebo-controlled (DBPC) formula challenges of AAF versus previously besttolerated formula were conducted. RESULTS: Nine infants had histologic evidence of esophagitis, and 9 had inflammatory changes in the stomach and/or duodenum. Symptoms remitted in all infants within 2 weeks of the start of feeding with AAF. On DBPC challenge after a median period of 3 months of receiving AAF, 12 infants were intolerant to active formula (distress score, 287 vs 580 min/wk,P =. 01; symptom score, 23.1 vs 36.1, P =.03). Seven infants did not relapse and were considered tolerant (distress score, 470 vs 581, P =.77; symptom score, 29.5 vs 20.2; P =.89). CONCLUSION: Treatment with AAF may reduce distressed behavior and symptoms of GER in infants with food protein intolerance.

Campylobacter upsaliensis gastroenteritis in childhood.

BACKGROUND: Campylobacter upsaliensis can cause gastroenteritis and bacteremia. Data on its epidemiology and role in pediatric gastroenteritis are limited. OBJECTIVE: To describe the incidence and clinical features of enteric C. upsaliensis infection in children and to compare these with similar data for Campylobacter jejuni. DESIGN AND METHODS: Medical records of all patients with enteric C. upsaliensis infection between 1992 and 1999 at the Royal Children's Hospital, Melbourne, were reviewed. A case-control study (age-matched 1:2) was performed to compare the severity of clinical disease and associated risk factors for infection with C. upsaliensis and C. jejuni. RESULTS: Of 18,516 specimens 666 (3.6%) were positive for C. jejuni and 19 (0.1%) were positive for C. upsaliensis. Records were available for 18 patients with C. upsaliensis gastroenteritis (mean age, 1.6 years; median age, 1.3 years; range, 3 months to 7 years; 14 male). Eleven patients (61%) presented with acute and 7 (39%) with chronic or intermittent diarrhea. The case-control study showed that fever (P = 0.03), acute diarrhea (P = 0.05) and rectal bleeding (P = 0.0006) were significantly less common in C. upsaliensis than in C. jejuni infection. CONCLUSION: C. upsaliensis is a rare cause of gastroenteritis in young children and, compared with C. jejuni infection, is associated with significantly lower rates of fever, acute diarrhea and rectal bleeding.

Clinical spectrum of food allergy in children in Australia and South-East Asia: identification and targets for treatment.

The prevalence of atopic diseases is increasing worldwide for reasons that are not clear. Food allergies are the earliest manifestations of atopy. This review defines the foods most commonly involved in allergic reactions and identifies an emerging group of syndromes in which food allergy is involved. A study of the frequency of food allergies in Australia and South-East Asia has recently shown that egg, cow's milk and peanut are the most common food allergens in Australia, but there were divergent results from different regions of South-East Asia. It is not clear whether the differences in reactivity to foods are due to genetic or cultural factors, but the findings raise the possibility that genetic susceptibility to food allergy may operate at the T-cell level modulated by the major histocompatibility complex. The Melbourne Milk Allergy Study defined a wide range of clinical symptoms and syndromes that could be reproduced by dietary challenge. A subsequent analysis of the infants with hypersensitivity to cow's milk and other multiple food proteins identified a new syndrome, multiple food protein intolerance of infancy. Food challenges demonstrated reactions developing slowly days after commencement of low-allergen soy formula or extensively hydrolysed formula. Follow-up at the age of 3 years showed that most children with this disorder tolerated most foods apart from cow's milk, egg and peanut. Atopic dermatitis affects about 18% of infants in the first 2 years of life. In a community-based study we have shown a very strong association (RR 3.5) between atopic dermatitis and infants with immunoglobulin E allergy to cow's milk, egg or peanut. Family studies on these infants have shown a link between atopic dermatitis and the genomic region 5q31 adjacent to the interleukin-4 gene cluster. Infantile colic (distress) affects 15-40% of infants in the first 4 months of life. Many theories of causation have been proposed, but a study from our centre showed that dietary modification, particularly that of breastfeeding mothers whose infants present with colic before the age of 6 weeks, alleviated symptoms. Colic associated with vomiting has been attributed to gastro-oesophageal reflux (GOR). This has been considered primarily a motility disorder, but a secondary form resulting from food protein intolerance has been described recently. We have also recently identified a group of infants with distressed behaviour attributed to GOR who have failed to respond to H2-receptor antagonists, prokinetic agents and multiple formula changes. Symptoms resolved on commencement of an elemental amino acid-based formula. In two-thirds of the patients, symptoms relapsed when challenged with low-allergen soy formula or extensively hydrolysed formula. We propose that a period of food protein intolerance is a part of the normal development of the immune system as it encounters common dietary proteins in infancy and early childhood. Future targets for research are development of appropriate dietary and management strategies for these entities and identification of genetic markers for these disorders.

The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance.

Infants (n = 18) with intolerance to extensively hydrolyzed formulas and soy who responded to an L-amino acid-based elemental formula (AAF) were studied until 3 years of age. By 2 years of age most tolerated non-formula foods, and by 3 years only 3 required AAF. Growth normalized during AAF feeding in 4 infants with failure to thrive.

PCR amplification from fixed tissue indicates frequent involvement of Brachyspira aalborgi in human intestinal spirochetosis.

PCR procedures amplifying portions of the 16S rRNA and NADH oxidase genes of Brachyspira aalborgi and Serpulina pilosicoli were applied to DNA extracted from paraffin-embedded human colonic or rectal tissues from 30 Norwegian, Australian, and U.S. patients, 16 of whom had histologic evidence of intestinal spirochetosis (IS). B. aalborgi-specific sequences were identified by PCR in 10 of the IS patients (62.5%) but none of the others, while S. pilosicoli sequences were not detected in tissues from any patient. Direct sequencing of products from three of the positive samples provided further confirmation of the presence of B. aalborgi. B. aalborgi may be a more common cause of intestinal spirochetosis than has been previously thought.

Postural drainage in cystic fibrosis: is there a link with gastro-oesophageal reflux?

OBJECTIVES: To determine the clinical effects of a change from postural drainage (PD) to positive expiratory pressure chest physiotherapy (PEP) in children with cystic fibrosis (CF) and symptoms of gastro-oesophageal reflux (GOR). To measure the effects of PD on GOR in children with CF. METHODS: Study 1: Six adolescents with CF and symptoms of GOR during PD were changed to upright PEP physiotherapy. The effects on lung function, reflux symptom scores and annual hospital days were measured. Study 2: Twenty-four children with CF (mean age 11 years) and symptoms suggestive of GOR underwent 24-h pH monitoring, including periods of chest physiotherapy. RESULTS: Study 1: All six patients reported a reduction in reflux symptoms during PEP therapy (P < 0.001). Lung function parameters improved during the first 6 months of PEP (P < 0.001). This improvement was sustained for a further 18 months. Annual hospital days decreased significantly (P < 0.0005). Study 2: Nine of 24 patients (37.5%) had pathological GOR. Reflux episodes were significantly increased during PD (P < 0.0001), as was fractional reflux time (P < 0.01). CONCLUSIONS: Upright PEP physiotherapy may be more appropriate than PD in selected patients with CF and symptomatic GOR. The role of GOR as a cofactor in the progression of pulmonary disease in CF needs further evaluation.

Multiresistant Pseudomonas aeruginosa outbreak in a pediatric oncology ward related to bath toys.

BACKGROUND: Nosocomial outbreaks of Pseudomonas aeruginosa in pediatric hospitals frequently involve neonates and immunosuppressed patients and can cause significant morbidity and mortality. OBJECTIVE: To describe the investigation of a multidrug-resistant P. aeruginosa outbreak in a pediatric oncology ward at the Royal Children's Hospital, Melbourne, Australia. DESIGN AND METHODS: Specimens were collected from infected patients and the ward environment. Bacterial isolates were characterized by antibiotic susceptibility patterns and bacterial DNA fingerprinting performed by pulsed-field gel electrophoresis (PFGE). A case-control study was carried out to assess possible risk factors for infection. RESULTS: Eight patients had clinical illnesses including bacteremia (n = 5) and infections of skin (n = 2), central venous catheter site (n = 1) and urinary tract (n = 1). The environmental ward survey yielded isolates of multiresistant P. aeruginosa from a toy box containing water-retaining bath toys, as well as from three of these toys. Pulsed-field gel electrophoresis of bacterial DNA demonstrated identical band patterns of the isolates from patients, toys and toy box water. A case-control study involving the 8 cases and 24 disease-matched controls demonstrated a significant association between P. aeruginosa infection and use of bath toys (P = 0.004), use of bubble bath (P = 0.014), duration of stay (P = 0.007) and previous antibiotic exposure (P = 0.026). Cultures from the bubble bath liquid were negative. CONCLUSION: This is the first description of a nosocomial outbreak associated with toys. We caution against the use of water-retaining bath toys in wards treating immunocompromised children.

Gastro-oesophageal reflux in infants under 6 months with cystic fibrosis.

AIM: To establish the incidence of pathological gastro-oesophageal reflux (GOR) in newly diagnosed infants with cystic fibrosis and to identify clinical predictors of increased reflux. METHODS: 26 infants with cystic fibrosis less than 6 months of age (14 male, 12 female; mean (SEM) age 2.1 (0.21) months, range 0.8 to 5.6 months) underwent prolonged oesophageal pH monitoring (mean duration 27.1 (0.49) hours; range 21.3 to 30.2 hours). Reflux symptoms, anthropometric variables, pancreatic status, meconium ileus, genotype, and chest x ray findings were correlated with pH monitoring data. RESULTS: Five infants (19.2%) had an abnormal fractional reflux time of greater than 10%, seven (26.9%) of 5-10%, and 14 (53.8%) of below 5%. Infants who presented with frequent vomiting had a significantly higher fractional reflux time than infants who had infrequent or no vomiting. There was no significant association between abnormal chest x rays and pathological GOR. Sex, genotype, nutritional status, meconium ileus, and pancreatic enzyme supplementation were not significantly associated with pathological GOR. CONCLUSIONS: About one in five newly diagnosed infants with cystic fibrosis had pathological GOR. Pathologically increased reflux was present before radiological lung disease was established. Apart from frequent vomiting, no useful clinical predictors of pathological reflux were found.

Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis.

UNLABELLED: Gastro-oesophageal reflux is increased in cystic fibrosis and it is possible that postural drainage techniques may exacerbate reflux, potentially resulting in aspiration and further impairment of pulmonary function. AIM: To evaluate the effects of physiotherapy with head down tilt (standard physiotherapy, SPT) on gastroesophageal reflux and to compare this with physiotherapy without head down tilt (modified physiotherapy, MPT). METHOD: Twenty (mean age 2.1 months) infants with cystic fibrosis underwent 30 hour oesophageal pH monitoring during which SPT and MPT were carried out for two sessions each on consecutive days. RESULTS: The number of reflux episodes per hour, but not their duration, was significantly increased during SPT compared with MPT (SPT 2.5 (0.4) v MPT 1.6 (0.3), p = 0.007) and to background (1.1 (0.)1, p = 0.0005). Fractional reflux time was also increased during SPT (11.7 (2.6)%) compared with background (6.9 (1.3)%) p = 0.03) but not compared with MPT (10.7 (2.7)%). There was no significant difference between MPT and background for number of reflux episodes, their duration, or fractional reflux time. CONCLUSIONS: SPT, but not MPT, was associated with a significant increase in gastro-oesophageal reflux in infants with cystic fibrosis.

Effect of antireflux medication on salivary drooling in children with cerebral palsy.

Salivary drooling is a common and debilitating problem in cerebral palsy (CP). We hypothesised that gastro-oesophageal reflux (GOR) may exacerbate drooling by stimulation of the oesophago-salivary reflex. The aim of our study was to assess the role of GOR in children with CP and severe drooling. Twenty-four children with CP and severe drooling underwent oesophageal pH monitoring (N = 23) or oesophagoscopy (N = 1). Nine had pathological GOR and were enrolled in a double blinded, placebo controlled cross-over trial of medical antireflux therapy (ranitidine plus cisapride) versus placebo. Drooling was measured by semi-quantitative observation (drooling quotient) and a questionnaire-based scoring system (rated by the child's caregivers). Mean drooling quotients and scores for drooling severity and frequency were not significantly different between active medication and placebo. In our study, treatment of pathological GOR did not improve salivary drooling in children with CP.