Search Results (276)

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in preterm infants, yet it remains one of the most challenging neonatal diagnoses to establish with certainty. No single clinical, laboratory, or radiographic finding is pathognomonic, and the modified Bell’s staging system is limited because features such as abdominal distension, bloody stools, pneumatosis intestinalis, and portal venous gas are common in preterm infants or are mimicked by other conditions. A wide range of disorders in preterm and term neonates can therefore resemble NEC, including spontaneous intestinal perforation, sepsis-associated ileus, dysmotility of prematurity, malrotation with or without volvulus, cow’s milk protein allergy, Hirschsprung-associated enterocolitis, cardiogenic colitis, viral enterocolitis, intussusception, neonatal appendicitis, meconium obstruction, incarcerated inguinal hernia, and food protein-induced enterocolitis syndrome. Misclassification of these mimics leads to over- and under-estimation of NEC incidence, contaminates outcome data, and may delay surgical intervention. This review summarizes the epidemiology, risk factors, pathophysiology, and distinguishing clinical, radiographic, and histopathological features of the common mimics of NEC, with particular emphasis on spontaneous intestinal perforation. We also highlight the inherent diagnostic challenges and future directions, including the need for reliable biomarkers and the evolving role of artificial intelligence. Full article

Introduction: Restrictive diets are increasingly encountered in pediatric practice and may be adopted voluntarily or prescribed for medical conditions. Although they can support normal growth when appropriately planned, exclusion of nutritionally important foods may increase the risk of nutrient inadequacy. This narrative review examined nutritional deficiencies and laboratory monitoring in children following plant-based, food-allergy elimination, gluten-free, ketogenic, and protein-restricted diets for inherited metabolic disorders. Methods: Targeted searches of PubMed, Scopus, and Web of Science were conducted through 30 June 2026 using pediatric, diet-specific, nutritional-status, and biomarker terms. Because this was a narrative review, the literature was selected and synthesized qualitatively rather than through a formal systematic-screening process; no fixed study count, duplicate independent screening, or formal risk-of-bias assessment was performed. Professional guidelines and position papers were prioritized when discussing monitoring considerations, while pediatric studies were used to describe dietary intake, biochemical findings, clinically manifest deficiency, and growth outcomes. Results: Nutritional risks differed according to the foods or nutrients restricted. Vitamin B12 and iron were major concerns in plant-based diets, whereas cow’s milk and multiple-food elimination increased the risk of inadequate calcium, vitamin D, iodine, protein, and energy intake. Gluten-free diets were commonly associated with low fiber, iron, folate, and B-vitamin intake, particularly when refined, non-fortified products predominated. Ketogenic dietary therapy required attention to selenium, vitamin D, bone-related minerals, carnitine in selected patients, and linear growth. In phenylketonuria and related disorders, nutritional adequacy depended strongly on protein-substitute adherence and appropriate provision of essential amino acids and micronutrients. Across all dietary patterns, laboratory results required interpretation in relation to dietary intake, growth, supplementation, inflammation, medication, and the underlying condition. Across dietary patterns, inadequate intake, biochemical abnormalities, clinically manifest deficiency, and impaired growth were considered related but distinct outcomes. Conclusions: Nutritional monitoring should be individualized and based on the actual dietary restriction and clinical risk. The principal contribution of this review is a practical, risk-based framework that links the specific dietary restriction and adequacy of replacement foods with growth, symptoms, supplementation, and targeted laboratory biomarkers. Full article

Cow’s milk allergy (CMA) is the most common food allergy in infants. Goat milk exhibits relatively low allergenicity and is widely regarded as a potential substitute for cow milk. However, the high sequence homology between cow and goat milk proteins may trigger cross-reactivity, significantly restricting the practical application of goat milk. This study aims to disrupt cross-linear epitopes of cow and goat milk proteins through enzymatic hydrolysis. We prepare hypoallergenic goat milk protein hydrolysates and systematically evaluate their desensitization effects. Bioinformatics methods were employed to predict the B-cell linear epitopes of six major allergens (α_S1-casein, α_S2-casein, β-casein, κ-casein, α-lactalbumin, and β-lactoglobulin) from cow, goat, and sheep milk, and sequence homology was analyzed through protein-protein Basic Local Alignment Search Tool (BLASTP). The results showed that the sequence similarity of homologous allergens among the three milk sources all exceeded 30%. Subsequently, six proteases (protamex, alcalase, pepsin, trypsin, papain and bromelain) were used to hydrolyze whole goat milk protein. Indirect enzyme-linked immunosorbent assay (ELISA) results indicated that all six hydrolysates significantly reduced immunoreactivity with antibodies against the five major cow’s milk allergens. Among them, alcalase exhibited significant efficacy against all five allergens; papain and protamex were particularly effective against β-casein; trypsin showed pronounced efficacy against α-lactalbumin and β-lactoglobulin; and bromelain and pepsin also significantly reduced immunoreactivity against certain allergens. Mass spectrometry revealed the peptide composition and epitope coverage of the hydrolysates: bromelain yielded two overlapping peptides (FAWPQY, LKDLKDY), protamex one (LAMAAS), Alcalase three (PPQSVLS, IPIQYVLS, LPYPYY), trypsin two (YLGYLEQL, AMAASDISLL), papain three (NEINQFYQK, FQSEEQQQTEDELQDK, AMAASDISL); and no matching peptide was detected for pepsin. These results confirmed at the molecular level that enzymatic hydrolysis can effectively disrupt cross-reactive epitopes. Full article

Background/Objectives: Cow’s milk allergy (CMA) is one of the most frequent food allergies in early childhood, yet its diagnosis remains a challenge. The Parent-Specific Cow’s Milk-Related Symptom Score (Pre-CoMiSS™) was developed in 2024 to assist parents in tracking possible cow’s milk-related symptoms in their infants. The aim of this qualitative study was to explore users’ experience with the Pre-CoMiSS™ tool, learn from their experience and identify areas for improvement. Methods: Participants were parents of infants aged up to 12 months who felt that their babies were experiencing possible feeding-related symptoms. Participants were selected from a local panel of potential parents in the UK and Sweden. Forty-five-minute interviews, led by experienced qualitative research moderators, were conducted using dedicated discussion guides and a frame-by-frame PDF version of the Pre-CoMiSS™ tool. Thematic analysis of the data was undertaken. Results: A total of 20 parents participated, 10 from the UK and 10 from Sweden. The Pre-CoMiSS™ tool was well received by parents from both countries. Parents found the tool’s results clear, useful, and easy to understand. However, some parents, especially from Sweden, expressed the need for additional guidance on next steps. Conclusions: Parents found the Pre-CoMiSS™ tool acceptable and easy to use, although some requested clearer guidance on next steps. These findings support further refinement and formal validation before clinical implementation. Full article

Background/Objectives: Although cow’s milk allergy is the most common food allergy in infants, its diagnosis remains challenging. Conventional allergy tests, including skin-prick testing and serum-specific IgE, can support the diagnosis in cases with a clear clinical history; however, neither positive nor negative results are sufficient for a definitive diagnosis without confirmation via an oral food challenge or reintroduction. The basophil activation test has emerged as a promising adjunctive tool in the diagnosis of cow’s milk allergy. Methods: We searched in the electronic databases PubMed/MEDLINE and Google Scholar for English articles published up to March 2026, using combinations of the following keywords: “cow’s milk allergy,” “basophil activation test, “BAT”, “food allergy,” “oral food challenge,” “IgE-mediated,” “children,” and “pediatric.” Results: While its widespread use is currently limited by the lack of standardized protocols, the need for fresh blood samples, and restricted availability outside specialized centers, the basophil activation test has the potential to improve diagnostic accuracy and support clinical decision-making in IgE-mediated cow’s milk allergy. Importantly, basophil activation test may also reduce the number of oral food challenges by providing a safe, functional assessment of allergen reactivity, thereby minimizing patient risk and the burden of invasive testing. Conclusions: Further studies and validation are needed before the basophil activation test can be implemented as a routine diagnostic tool. Full article

Background: To investigate the diagnostic value of the SPT-to-histamine ratio, casein-specific immunoglobulin E (IgE), and cow’s milk-specific IgE in predicting oral food challenge (OFC) positivity in children with suspected cow’s milk allergy. Methods: In this single-center retrospective observational study, 126 children evaluated for suspected cow’s milk allergy who underwent OFC between January 2019 and July 2024 at a tertiary pediatric allergy and immunology center were included. Demographic and clinical characteristics, SPT parameters, and laboratory biomarkers were analyzed. Discriminatory performance was assessed using receiver operating characteristic (ROC) analysis, and independent predictors were identified using multivariable logistic regression. Results: OFC was positive in 66 patients (52.4%). Casein-specific IgE demonstrated strong discriminatory performance (AUC = 0.878), with 80.3% sensitivity and 85.0% specificity at a cutoff value of ≥2.55 kUA/L. The SPT-to-histamine ratio showed moderate discriminatory performance (AUC = 0.758). In multivariable analysis, only casein-specific IgE remained an independent predictor of OFC positivity (adjusted OR = 1.317, p < 0.001). Conclusions: Casein-specific IgE is a strong independent predictor of OFC positivity. Although SPT-derived ratios may provide complementary diagnostic information, their independent predictive contribution appears limited. These findings support the role of component-resolved diagnostics in pre-challenge risk stratification. Full article

Background/Objectives: Cow’s milk protein allergy (CMPA), one of the most common allergies in early life, can present psychological, financial, and social challenges for caregivers. For mothers, this burden may be compounded by the fact that experiences with pediatric CMPA typically coincide with the perinatal period, which itself may be challenging. Our study aimed to explore the concerns, experiences, and needs of mothers navigating pediatric CMPA. Methods: We conducted a qualitative study involving three groups: mothers of children (18 months to 4 years) with, or who previously had, CMPA; mothers of infants (<18 months) with CMPA; and pregnant women concerned about their baby developing CMPA. All mothers completed a demographic questionnaire and participated in a virtual focus group or interview that was recorded, transcribed verbatim, and analyzed according to reflexive thematic analysis. Questionnaire data were described (n/N, %) to summarize participant characteristics. Results: In total, 16 mothers participated. Three themes were identified: (1) perceived negative psychosocial impacts, (2) perceived inadequacy of support from healthcare professionals, and (3) perceived negative dietary and financial implications. Conclusions: This study provides valuable insights into the perceived psychosocial implications and unmet management needs of CMPA. Full article

Background: Oral food challenge (OFC) remains the gold standard for diagnosing food allergy; however, it is time-consuming and associated with the risk of allergic reactions. The identification of reliable biomarkers capable of predicting OFC outcomes could improve patient selection and reduce the number of OFCs required in clinical practice. Among the most widely used biomarkers are skin prick tests (SPTs) and serum-specific IgE (sIgE) measurements, including component-resolved diagnostics. However, their diagnostic utility, as well as the comparability of different diagnostic platforms, remains incompletely defined in cow’s milk (CM) and hen’s egg (HE) allergy. Methods: We retrospectively analyzed results of diagnostic tests obtained in children undergoing OFCs to baked milk, raw milk, baked egg, and boiled egg. Diagnostic performance of SPTs to either allergen extracts or native food allergens, as well as sIgE measured using ImmunoCAP and ALEX2 platforms, was evaluated using receiver operating characteristic (ROC) analysis and logistic regression models. Results: Diagnostic performance varied across allergy phenotypes. SPTs to native food allergens demonstrated good discriminative capacity for raw milk and boiled egg allergy, whereas SPTs to standardized extracts showed limited diagnostic utility overall. In baked milk allergy, casein-sIgE measured by ImmunoCAP demonstrated the best diagnostic performance. In raw milk allergy, α-lactalbumin-sIgE measured using ALEX2 platform and β-lactoglobulin-sIgE measured by ImmunoCAP showed greater diagnostic relevance than casein-sIgE. In boiled egg allergy, SPT to raw egg yolk demonstrated the highest diagnostic value. In baked egg allergy, ovalbumin-sIgE measured using the ALEX2 platform showed the best performance, while ovomucoid-sIgE did not demonstrate clear superiority. ALEX2 showed good concordance with ImmunoCAP despite systematic differences in absolute sIgE values. Combined multivariable models provided only modest improvements over single predictors and did not achieve sufficient accuracy to replace OFCs. Conclusions: SPTs to either allergen extracts or native food allergens, as well as sIgE measurements, demonstrate moderate and heterogeneous utility in predicting OFC outcomes for CM and HE allergy. Although ALEX2 and ImmunoCAP showed comparable overall performance, platform-specific interpretation may be required. OFC remains indispensable for definitive diagnosis. Full article

Background: Hydrolyzed rice formulas (HRFs) are increasingly recognized as an alternative nutritional option for infants with cow’s milk protein allergy (CMPA), but real-world data on prescribing patterns and early clinical evolution remain limited. Objective: This study aimed to describe real-world use and prescribing patterns of HRF and eHF in infants with CMPA, identify factors associated with HRF recommendation, and assess short-term clinical evolution after formula use. Methods: This observational analysis from the ETAPA project included two mutually exclusive infant-level cohorts: a prospective recommendation cohort assessing variables associated with HRF versus eHF recommendation, and a retrospective treated cohort assessing 7-day clinical evolution after formula use. In the retrospective cohort, the main clinical outcome was absolute change in CoMiSS from day 0 to day 7. A propensity score-weighted sensitivity analysis was performed to address measured confounding by indication. Results: Overall, 1505 valid infant-level records were analyzed: 1094 in the prospective cohort and 411 in the retrospective cohort. In the prospective cohort, HRF was recommended in 214/1094 records (19.6%). In multi-variable analysis, older infant age was associated with higher odds of HRF recommendation (OR 1.034 per month, 95% CI 1.002–1.067; p = 0.036), whereas IgE-mediated CMPA was associated with lower odds (OR 0.673, 95% CI 0.459–0.988; p = 0.043). In the retrospective cohort, CoMiSS decreased markedly in both groups (eHF: median reduction 7.0 [IQR 4.0–10.0] points; HRF: 6.5 [4.0–10.0] points; p = 0.661). After adjustment, HRF was not associated with a statistically significant difference in absolute CoMiSS reduction compared with eHF (β −0.513 points, 95% CI −1.108 to 0.082; p = 0.091). Conclusions: In routine pediatric practice, HRF was used across a broad range of CMPA profiles and was associated with clinically relevant short-term symptom improvement. These findings support HRF as an additional nutritional option for CMPA management, while the observational design precludes conclusions of equivalence or non-inferiority versus eHF. Full article

Necrotizing enterocolitis (NEC) remains one of the most devastating gastrointestinal emergencies in neonates and also presents major diagnostic challenges. Despite extensive research, NEC still lacks a practical definition and relies on a set of nonspecific clinical, laboratory, and radiological findings rather than a single pathognomonic presentation or test. The modified Bell staging system remains the most widely used framework in clinical practice and research, but it was originally developed to guide treatment decisions rather than aid diagnosis and has important limitations when applied as a diagnostic aid. Clinical and radiological criteria used for early stages of NEC are nonspecific, disease progression is not always linear, radiographic signs are inconsistently present, and histopathological confirmation is unavailable in most of the cases as surgery is not undertaken in all the cases. These limitations have led to the opinion that even the modified Bell staging is “broken” when it is used to define the disease itself. At the same time, increased understanding about gut immunity and microbiome progression, and neonatal hemodynamics make it increasingly clear that NEC is not a single uniform disease. It is now regarded as a heterogeneous syndrome comprising multiple phenotypes that share a final common pathway of intestinal injury and necrosis differing in timing, predisposing factors, mechanism, and clinical course. These presentations overlap with several neonatal conditions including spontaneous intestinal perforation, septic ileus, cow’s milk protein allergy, congenital heart disease-related intestinal hypoperfusion, viral enterocolitis, malrotation with volvulus, and intussusception. This review discusses controversies in the definition and staging of NEC, consolidates alternative diagnostic criteria beyond Bell’s system, and elaborates on a phenotype-based framework for clinical distinction. Also, the review sheds light on the clinical mimickers, practical bedside diagnosis using serial clinical assessment and imaging, consequences of NEC, and emerging precision medicine approaches. A shift from stage-based labeling toward a practical, phenotype-informed framework may improve diagnostic precision, reduce misclassification, and enhance both clinical care and research. Full article

Background: Food protein-induced allergic proctocolitis (FPIAP) is generally considered a benign and self-limited condition; however, both its natural course and the impact of management strategies on prognosis remain controversial. Data on modifiable factors influencing tolerance acquisition are limited. Methods: We conducted a retrospective cohort study including 180 infants with cow’s milk-induced FPIAP. Clinical characteristics, management strategies, and outcomes were analysed. Logistic regression was used to identify factors associated with delayed tolerance, and Kaplan–Meier and Cox regression analyses were performed to evaluate time to tolerance. Results: Tolerance was achieved in 91.2% of infants, with a median time from diagnosis to tolerance of 31.1 weeks. In multivariable logistic regression, multi-food elimination at presentation (OR, 2.58; 95% CI, 1.02–6.54; p = 0.046) and a longer interval from diagnosis to reintroduction (OR per week, 1.08; 95% CI, 1.02–1.14; p = 0.022) were independently associated with delayed tolerance. Exclusive breastfeeding was associated with lower odds of delayed tolerance in univariable analysis but not after adjustment. In unadjusted time-to-event analyses, observation-first management was associated with earlier tolerance acquisition (HR, 0.37; 95% CI, 0.22–0.62; p < 0.001), whereas multiple food allergy was associated with a lower probability of tolerance acquisition over time (HR, 0.60; 95% CI, 0.41–0.88; p = 0.009). Feeding modality also showed an unadjusted temporal association with tolerance acquisition, with exclusively breastfed infants demonstrating a more favorable pattern than formula-fed infants. Conclusions: The course of FPIAP appears to be influenced not only by clinical characteristics but also by management strategies. Delayed reintroduction and multi-food elimination were associated with later tolerance, while observation-first management was associated with earlier tolerance acquisition. These findings suggest that commonly used strategies such as prolonged elimination or delayed reintroduction may warrant reconsideration in selected infants and support a more individualized and less restrictive approach to management. Full article

Approximately 1–2% of infants have cow’s milk protein allergy (CMPA). From a clinical perspective, diagnosing CMPA using the oral food challenge (OFC) is high risk, necessitating safer alternatives. One possible alternative is component-resolved diagnostics (CRD). This narrative review examines specific IgE (sIgE) thresholds for cow’s milk protein in predicting outcomes of OFCs in European children. Eligible studies focusing on CRD in European pediatric populations were identified through PubMed and Scopus databases. Our findings highlight the crucial role of Bos d 8 (casein) in the diagnostic process. Among the analyzed milk components, Bos d 8 appeared to be a promising marker for predicting positive OFC outcomes in several cohorts. However, due to significant population heterogeneity, conflicting findings exist, with some studies indicating that no single molecular component is consistently superior to whole cow’s milk specific IgE. While other molecules, such as Bos d 6 and lactoferrin, showed limited diagnostic utility, specific IgE to Bos d 8 demonstrated the highest clinical value. Although the double-blind, placebo-controlled food challenge (DBPCFC) remains the gold standard for CMPA diagnosis, the use of Bos d 8 in CRD is a key step toward risk stratification and may help reduce the need for high-risk OFCs in selected patients. Full article

Introduction: Cow’s milk protein allergy (CMPA) is one of the most common food allergies in early infancy and poses important clinical and economic challenges for affected children, their families, and healthcare systems. In Latin America, variability in diagnostic and therapeutic approaches remains substantial. Objective: We aim to systematically review the available evidence on CMPA, with emphasis on clinical characteristics, diagnosis, management, and economic impact, and to provide a complementary cost analysis of specialized formulas in the Colombian context. Methods: A systematic review was conducted according to PRISMA guidelines to synthesize current evidence on CMPA in pediatric populations. Studies published between 2010 and 2023 were screened using predefined eligibility criteria, and 46 studies were included in the qualitative synthesis. A complementary cost analysis was also performed to estimate the six-month costs associated with specialized infant formulas in Colombia, based on average age-specific formula consumption and standardized 2025 market prices. Results: The reviewed evidence confirms that CMPA is a heterogeneous condition with variable clinical manifestations and persistent diagnostic challenges, particularly in non-IgE-mediated presentations. Elimination of cow’s milk protein followed by oral food challenge remains the reference diagnostic approach. Breastfeeding with maternal dairy exclusion is consistently recommended as the preferred first-line strategy, whereas extensively hydrolyzed and amino-acid-based formulas are used when breastfeeding is not feasible or is insufficient. Estimated six-month costs ranged from COP 4,337,640 to COP 14,480,700 (approximately USD 1100–3600), depending on formula type. Conclusions: CMPA requires early recognition, careful clinical evaluation, individualized nutritional management, and improved access to effective and affordable treatment strategies. Full article

Background: Cow’s milk protein allergy (CMPA) is a common cause of gastrointestinal and dermatologic symptoms in infancy. In clinical practice, infants with atopic dermatitis (AD) and suspected non-IgE-mediated CMPA are frequently managed with formula modification, although real-world comparative data across different formula strategies remain limited. Aim: To evaluate gastrointestinal symptom resolution, improvement in AD, and growth outcomes following formula modification in infants with AD and suspected non-IgE-mediated CMPA. Methods: This retrospective comparative cohort study included 107 infants aged ≤12 months with documented AD and suspected non-IgE-mediated CMPA evaluated at a tertiary academic center between January 2024 and December 2025. Infants were categorized according to initial management strategy: switch to extensively hydrolyzed formula (eHF; n = 63), switch to amino acid formula (AAF; n = 29), or continued standard cow’s milk-based formula (n = 15). The primary outcome was resolution of gastrointestinal symptoms within 2–4 weeks. Secondary outcomes included improvement in AD, weight gain, and need for further formula escalation. Multivariable logistic regression was performed to adjust for potential confounders. Results: Overall, gastrointestinal symptom resolution occurred in 74 of 107 infants (69.2%). Resolution rates were 71.4% in the eHF group, 79.3% in the AAF group, and 40% in the standard formula group (p = 0.01). In adjusted analysis, switching to eHF (aOR 2.8; 95% CI 1.1–7.3; p = 0.03) and AAF (aOR 4.1; 95% CI 1.3–12.5; p = 0.01) was independently associated with higher odds of symptom resolution compared with continued standard formula. Improvement in AD was observed in 57.9% of infants overall and differed significantly across groups (p = 0.04). Mean weight gain during follow-up did not differ significantly between groups (p = 0.63). Subsequent formula escalation was more frequent in the standard formula group (46.7%) compared with eHF (17.5%) and AAF (13.8%) groups (p = 0.004). Conclusions: In infants with AD and suspected non-IgE-mediated CMPA, substitution with extensively hydrolyzed or amino acid formula was independently associated with greater gastrointestinal symptom resolution and improvement in dermatitis compared with continued standard formula, without evidence of compromised growth. These findings provide supportive real-world evidence consistent with current international guidelines; however, given the observational design and potential for residual confounding, they should be interpreted as hypothesis-generating rather than confirmatory evidence of causal treatment effects. Full article

Cow’s milk allergy (CMA) remains one of the most common food allergies in infancy, requiring the avoidance of cow’s milk and its derivatives. Breast milk is the best source of nutrition for infants. For those infants with CMA whose mothers are unable to breastfeed or choose not to, extensively hydrolysed formulas (eHFs) are widely recommended as first-line milk substitutes, whereas hydrolysed rice formulas (HRFs) are increasingly recognised as a viable alternative. This concept paper provides a healthcare professional (HCP) perspective on HRF, drawing on expert consensus from two meetings convened in 2025. Discussions noted the long history of safe and effective HRF use in Europe, its nutritional adequacy, and the evolving international guidelines supporting HRF as an alternative first-line option. A key meeting outcome was the development of a practical decision tree to help UK clinicians decide when HRF should be the preferred choice. Key considerations for its use in non-breastfed infants include the following: parental/caregiver stress related to persistent symptoms; ongoing symptoms despite multiple interventions; cultural and lifestyle choices; religious dietary requirements; and specialists’ recommendations. Secondary considerations highlighted by HCPs include the following: proven reactions whilst infants are breast-milk-fed together with parental request for formula; faltering growth; multiple symptoms; taste acceptance (older infants); and parental preference based on experience. The role of functional components, such as prebiotics and human milk oligosaccharides (HMOs), was noted in regard to the emerging evidence of benefits to the microbiome and immune development. The experts emphasised the importance of engaging HCPs across all levels of CMA care and addressing challenges in translating current guidance into treatment practice. It was concluded that, overall, HRF represents a nutritionally complete, plant-based alternative that has been shown to be well tolerated (taste, symptoms) in clinical studies. It can be used to broaden therapeutic options for infants with CMA in the UK who are not exclusively fed breast milk. Full article