The recognition of constipation as a possible non-Immunoglobulin E (IgE)-mediated allergic condition is challenging because functional constipation (unrelated to food allergies) is a common health problem with a reported worldwide prevalence rate of up to 32.2% in children. However, many studies in children report challenge proven cow's milk allergy and constipation as a primary symptom and have found that between 28% and 78% of children improve on a cow's milk elimination diet. Due to the paucity of data and a focus on IgE-mediated allergy, not all food allergy guidelines list constipation as a symptom of food allergy. Yet, it is included in all cow's milk allergy guidelines available in English language. The Exploring Non-IgE-Mediated Allergy (ENIGMA) Task Force (TF) of the European Academy for Allergy and Clinical Immunology (EAACI) considers in this paper constipation in the context of failure of standard treatment and discuss the role of food allergens as culprit in constipation in children. This position paper used the Delphi approach in reaching consensus on both diagnosis and management, as currently published data are insufficient to support a systematic review.

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, etc. The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.

Constipation is a very common disorder, mostly functional in nature, that may persist for years in up to 35-52% of children. Food allergy prevalence, severity and persistence are increasing over time, and cows' milk protein is the commonest food allergen recognised to affect gastrointestinal motility in children. There is mounting evidence of the role of cows' milk (CM) allergy (CMA) in children with constipation. With this narrative review, we aim to provide clinicians with an updated and critical overview of food allergy-associated constipation. We searched Embase, Medline and the Cochrane Library, using keywords related to the topic. Only reviews and studies including children aged 0-17 years that were published in English were considered. Constipation has been reported in 4.6% of infants with CMA; the prevalence of food allergy underlying chronic constipation in children resistant to conventional treatment and presenting to tertiary clinics ranges between 28% and 78%. The identification of predisposing risk factors and of a specific phenotype of food allergy-induced constipation remains elusive. No allergic tests, radiological or motility investigations achieve sufficient sensitivity and specificity to screen children for CMA-related constipation. A 4-week cows' milk protein (CMP) elimination diet may be considered for children with chronic constipation resistant to conventional treatment and who lack alarm sign/symptoms of organic diseases. In subjects with ameliorated symptoms on CMP elimination, the diagnosis of CMA should be confirmed by a food challenge to avoid an unnecessary protracted diet.

Allergic colitis (AC) is one of the most common etiologies of rectal bleeding in infants aged one to six months.

The aim of this study is to apply step-by-step dietary restrictions in the mother's diet or change of infant formula fed thereby, to evaluate the subsequent clinical response.

Sixty healthy infants whose clinical and evaluation results indicated proctocolitis in our outpatient gastroenterology clinic were included in this. They were divided into three groups according to the type of feeding; group 1 were exclusively breast fed, group 2 were exclusively formula fed and group 3 were fed with combination of both. In breast feeding women, discontinuation was allergenic food was studied in four stages; cow-related dairy products, soy, sesame and fast food (stage A), egg (stage B), corn, nuts and fish (stage C) and wheat (stage D).

Sixty newborns with age at symptom onset 3 days-20 days participated in the study. Up to the time of our initial evaluation, the mean age and weight of infants was 73.34 ± 1.00 day and 3292.71 ± 367.93 g, respectively. There was no significant difference in sex and the type of labor between the groups. Thirty-three infants had a history of eczema and the parents of 47 infants had a history of allergy, with the greatest prevalence in group one. Rectal bleeding in 50% of infants was halted after the elimination of allergenic feed in mother (15 in stage A, 8 in stage B and 7 in stage C). Ten infants needed extensive hydrolyzed formula and 20 needed amino acid-based formulas.

There is no need for immediate use of amino acid or extensive hydrolyzed formulas in the first stage of blood in stool, perhaps discontinuing allergenic food in mothers could be the primary measure.

Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones.

A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor.

Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD.

Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation.

To review the literature for clinical data on infants with allergic or eosinophilic colitis.

MEDLINE search of all indexes was performed using the words "colitis or proctocolitis and eosinophilic" or "colitis or proctocolitis and allergic" between 1966 and February of 2013. All articles that described patients' characteristics were selected.

A total of 770 articles were identified, of which 32 met the inclusion criteria. The 32 articles included a total of 314 infants. According to the available information, 61.6% of infants were male and 78.6% were younger than 6 months. Of the 314 patients, 49.0% were fed exclusively breast milk, 44.2% received cow's milk protein, and 6.8% received soy protein. Diarrheal stools were described in 28.3% of patients. Eosinophilia was found in 43.8% (115/263) of infants. Colonic or rectal biopsy showed infiltration by eosinophils (between 5 and 25 per high-power field) in 89.3% (236/264) of patients. Most patients showed improvement with the removal of the protein in cow's milk from their diet or the mother's diet. Allergy challenge tests with cow's milk protein were cited by 12 of the 32 articles (66 patients).

Eosinophilic colitis occurs predominantly in the first six months of life and in males. Allergy to cow's milk was considered the main cause of eosinophilic colitis. Exclusion of cow's milk from the diet of the lactating mother or from the infant's diet is generally an effective therapeutic measure.

Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field.

Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance.

The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

Intestinal biopsies constitute an ever-increasing portion of the pathologist's workload, accounting for nearly two-thirds of specimens accessioned yearly by the pathology department at The Children's Hospital of Philadelphia. The widespread use of endoscopy and gastrointestinal biopsies in current clinical practice presents the pathologist with a diversity of intestinal mucosal appearances corresponding to disease states of variable clinical severity, requiring close collaboration between clinician and pathologist for optimal interpretation. Many of the entities resulting in severe diarrhea of infancy have been recognized only in the last several decades, and although rare, the study of these disorders, especially when combined with the powerful methods of present-day genetics and molecular biology, has afforded important insights into enterocyte development and function, and intestinal immunity and tolerance. Other conditions once considered infrequent, such as celiac disease, have now been recognized to be much more common and can present with a wide range of pathologic features.

To determine the incidence and clinical aspects of allergic proctitis (AP) in infants with symptoms that mimic Hirschsprung's disease (HD).

One hundred and five patients less than 6 months of age, who underwent barium enema, anorectal manometry and rectal suction biopsy due to suspicion of HD, were enrolled. Comparison of the patient characteristics associated with each disease was based on the results of the triple testing. The sensitivity and specificity of the three tests, for the diagnosis of HD, were evaluated.

The mean age of enrolled patients was 2.1+/-0.9 months. Based on the three tests, 39 patients (37.1%) were diagnosed with HD, seven patients (6.7%) with AP, and 53 (50.5%) had normal results. Of the 54 patients with transitional zone and a reversed rectosigmoid index on the barium enema, four (7.4%) were patients with AP. The mean age of the AP patients (3.1+/-1.5 months old) was older than the HD children (1.4+/-0.9 months old). The sensitivity of the three tests for HD was 97.4%, 87.2% and 92.3% and the specificity was: 74.2%, 78.8% and 100%, respectively.

In the infants with severe abdominal distention, the incidence of AP mimicking HD was relatively high. Therefore, consideration of AP should be part of the differential diagnosis in infants with severe abdominal distention or findings that mimic HD. For differentiation of these disorders, a rectal suction biopsy is very useful.

Pediatric surgeons often encounter neonates who present with Hirschsprung's disease (HD)-like symptoms and plain x-ray findings, but respond well to conservative treatment. During our investigation of the etiology of this condition, which we named "benign transient nonorganic ileus of neonates" (BTNIN), we noticed that BTNIN included cases of cow's milk allergy (CMA). Therefore, a prospective study of the identity of BTNIN and CMA was conducted.

Cow's milk allergy was diagnosed when a baby showed HD-like symptoms after oral feeding, and a drug-induced lymphocyte stimulation test was positive for cow's milk with a titer of more than 300%.

Of 38 neonates with suspected HD, a surgical disorder was excluded by plain x-ray in 9, intestinal atresia was diagnosed in 3, and the remaining 26 were enrolled in this study.

Of 26 cases, 9 were diagnosed as HD by manometric studies and 17 as CMA. Thirteen of 17 CMA cases had been fed with breast milk and 4 with formula milk.

The proportion of CMA in the cases presenting with HD-like symptoms in the neonatal period is much higher than what we expected, and most cases of BTNIN are caused by CMA. If HD is ruled out, CMA should be considered.

Two neonatal cases of cow's milk allergy showing bilous vomiting and massive bloody stool are presented. In both cases, laboratory data on admission showed no eosinophilia. The immediate upper gastrointestinal series of both cases demonstrated no evidence of intestinal malrotation, but revealed a narrowing of the duodenum and upper jejunal loops and marked stasis of barium in one case, suggesting an edema with inflammation. Rectal mucosal punch biopsy of the other case showed eosinophilic infiltration in the lamina propria. These findings suggested an allergic origin, useful information for avoiding confusion with some diseases requiring emergency surgery. In both cases, bleeding resolved soon after elimination of cow's milk from the diet. Thereafter both cases showed a moderate to marked increase in peripheral eosinophilia, while serum radioallergosorbent tests for cow's milk protein were negative. Definitive diagnosis of allergic enterocolitis is difficult because there is neither specific laboratory data nor tests. Allergic enterocolitis can occur in the early neonatal period and should be considered in differential diagnosis of any newborn developing gastrointestinal bleeding.

Chronic constipation is common in the general population. Some studies have shown that in children cow's milk protein hypersensitivity can cause chronic constipation unresponsive to laxative treatment.

To review the literature and summarize the data that point to a relationship between refractory chronic constipation and food hypersensitivity, and to discuss the hypothesis that the pathogenesis of constipation due to food hypersensitivity.

A search in the U.S. National Library of Medicine was performed, matching the key words 'chronic constipation, food intolerance and allergy'.

Thirty-three papers were found but only 19 of them were related to the topic of this review. Most of the data indicated a relationship between constipation and food allergy in a subgroup of paediatric patients with 'idiopathic' constipation unresponsive to laxative treatment. There was only one study in adults that demonstrated the resolution of chronic constipation on hypoallergenic diet in four patients.

An increasing number of reports suggest a relationship between refractory chronic constipation and food allergy in children. Similar data in adults are scarce and need to be confirmed. Further studies should be performed to obtain firmer evidence for the role of allergy in constipation and clarify the pathogenetic mechanisms involved.

The authors present a neonatal case of allergic colitis, which manifested the difficulty of spontaneous defecation and irregular narrowing of distal rectum in contrast enema. Rectal suction biopsy showed positive acetylcholinesterase activity. These clinical, radiological and histological findings were indistinguishable from Hirschsprung's disease. Gastrointestinal symptoms were improved by the cessation of cow's milk formula. The present findings may impact on the less recognizable gastrointestinal manifestation of allergic colitis.

Cow's milk allergic enterocolitis is a common paediatric gastrointestinal disease. However, radiological findings from contrast studies have rarely been reported. We report two Japanese neonate patients with cow's milk allergic enterocolitis with vomiting, bloody stool and unique findings on upper gastrointestinal contrast study. Upper gastrointestinal contrast study showed folds of the small intestine to be thickened, such as in spasm, or ribbon-like cords in both cases. There was also poor passage from the duodenum to the jejunum in one case. In addition, there were spastic findings on lower gastrointestinal contrast study in part of the large colon in one case. Clinicians, including paediatric surgeons, treating neonates with bloody stool and/or vomiting should thus be aware that unique findings on upper and lower gastrointestinal contrast studies may be useful in suspecting cases with cow's milk allergic enterocolitis.

To examine daily cows milk consumption and duration of breastfeeding in infants and young children with anal fissure and constipation.

Two groups of 30 consecutive children aged between 4 months and 3 years were evaluated retrospectively. Group I comprised children with chronic constipation and anal fissure in whom surgical causes were excluded, and group II comprised normal children. The daily consumption of cows milk, duration of breastfeeding and other clinical features of the children were investigated

The mean daily consumption of cows milk was significantly higher in group I (756 mL, range 200-1500 mL) than group II (253 mL, range 0-1000 mL) (P < 0.001). Group I children were breastfed for a significantly shorter period (5.8 months, range 0-18 months) than group II (10.1 months, range 2-24 months) (P < 0.006). The odds ratios for the two factors - children consuming more than 200 mL of cows milk per day (25 children in group I, 11 children in group II) and breastfeeding for less than 4 months (16 children in group I, 5 children in group II) - were calculated to be 8.6 (95% confidence interval [CI]: 0.23-0.74, P = 0.0005) and 5.7 (95% CI: 0.37-0.66, P = 0.007), respectively.

Infants and young children with chronic constipation and anal fissure may consume larger amounts of cows milk than children with a normal bowel habit. Additionally, shorter duration of breastfeeding and early bottle feeding with cows milk may play a role in the development of constipation and anal fissure in infants and young children.

Gastroesophageal reflux (GER) and cow milk allergy (CMA) occur frequently in infants younger than 1 year. In recent years, the relation between these 2 entities has been investigated and some important conclusions have been reached: in up to half of the cases of GER in infants younger than 1 year, there may be an association with CMA. In a high proportion of cases, GER is not only CMA associated but also CMA induced. The frequency of this association should induce pediatricians to screen for possible concomitant CMA in all infants who have GER and are younger than 1 year. With the exception of some patients with mild typical CMA manifestations (diarrhea, dermatitis, or rhinitis), the symptoms of GER associated with CMA are the same as those observed in primary GER. Immunologic tests and esophageal pH monitoring (with a typical pH pattern characterized by a progressive, slow decrease in esophageal pH between feedings) may be helpful if an association between GER and CMA is suspected, although the clinical response to an elimination diet and challenge is the only clue to the diagnosis. This article reviews the main features of GER and CMA, focusing on the aspects in common and the discrepancies between both conditions.