Inpatient management of iron deficiency anemia in pediatric patients with inflammatory bowel disease: A single center experience.

BACKGROUND: Screening for iron deficiency anemia (IDA) is important in managing pediatric patients with inflammatory bowel disease (IBD). Concerns related to adverse reactions may contribute to a reluctance to prescribe intravenous (IV) iron to treat IDA in this population. AIM: To track the efficacy and safety of IV iron therapy in treating IDA in pediatric IBD patients admitted to our center. METHODS: A longitudinal observational cohort study was performed on 236 consecutive pediatric patients admitted to our tertiary IBD care center between September 2017 and December 2019. 92 patients met study criteria for IDA, of which 57 received IV iron, 17 received oral iron, and 18 were discharged prior to receiving iron therapy. RESULTS: Patients treated with IV iron during their hospitalization experienced a significant increase of 1.9 (± 0.2) g/dL in mean (± SE) hemoglobin (Hb) concentration by the first ambulatory follow-up, compared to patients who received oral iron 0.8 (± 0.3) g/dL or no iron 0.8 (± 0.3) g/dL (P = 0.03). One out of 57 (1.8%) patients that received IV iron therapy experienced an adverse reaction. CONCLUSION: Our findings demonstrate that treatment with IV iron therapy is safe and efficacious in improving Hb and iron levels in pediatric patients with IDA and active IBD.

Analysis of missed clinic visits, preferred languages, and telemedicine in a pediatric gastroenterology practice.

OBJECTIVES: Previous studies have demonstrated a relationship between socioeconomic disparities and missed clinic visits (MCV). However, the relationship between patient-preferred language and MCVs, particularly with respect to telemedicine, remains relatively underexplored. We sought to characterize the associations between MCV and patient-level predictors, including preferred language, in a large single-center pediatric gastroenterology, hepatology, and nutrition practice. METHODS: This retrospective longitudinal cohort study included all missed or completed outpatient visits in the Gastroenterology, Hepatology, and Nutrition Programs at Boston Children's Hospital from January 1, 2016 to May 20, 2022. Univariate and multivariate hierarchical generalized linear mixed models were employed to identify associations between visit- and patient-level predictors and an MCV outcome. RESULTS: A total of 300,201 visits from 70,710 patients residing in Massachusetts were included. Univariate analyses revealed higher MCV odds for Hispanic patients and those from areas with the highest Social Vulnerability Index (SVI), and these odds increased with telemedicine (Hispanic in-person odds ratio [OR] 5.21 [(95% confidence interval) 4.93-5.52] vs. telemedicine OR 8.79 [7.85-9.83]; highest SVI in-person OR 5.28 [4.95-5.64] vs. telemedicine OR 7.82 [6.84-8.96]). Controlled multivariate analyses revealed that among six language groups, only Spanish language preference was associated with higher MCV odds, which increased with telemedicine (Spanish in-person adjusted OR [aOR] 1.35 [1.24-1.48] vs. telemedicine aOR 2.1 [1.83-2.44]). CONCLUSIONS: Patients preferring Spanish experience unique barriers to care beyond those faced by other language preference groups, and telemedicine may exacerbate these barriers.

Efficacy and Safety of Tacrolimus or Infliximab Therapy in Children and Young Adults With Acute Severe Colitis.

INTRODUCTION: One-third of children and young adults admitted for management of acute severe colitis (ASC) fail intravenous corticosteroids. Infliximab (IFX) or tacrolimus (TAC) is often used to prevent urgent colectomy in these patients. However, no prior studies have reviewed the outcome of pediatric patients with ASC who were treated with either IFX or TAC. METHODS: We retrospectively identified 170 pediatric patients with ASC admitted to our institution who did not respond to intravenous corticosteroids and were subsequently treated with either IFX or TAC. We compared 6-month colectomy rates, time to colectomy, improvement in disease activity indices, and adverse effects. RESULTS: The mean age of patients in the IFX (n = 84) and TAC (n = 86) groups were 14 and 13.8 years, respectively. The median study follow-up time was 23 months. The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53). The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63). Three patients treated with IFX experienced infusion reactions. Six patients treated with TAC experienced changes in renal function or electrolytes, and 4 patients reported neurologic symptoms. CONCLUSIONS: There were no significant differences in the likelihood of colectomy 6 months after initiating IFX or TAC rescue therapy. Efficacy of both agents was comparable. The types of adverse effects differed by therapy. These data support the use of either TAC or IFX in children with ASC refractory to intravenous corticosteroids.

Higher alpha diversity and Lactobacillus blooms are associated with better engraftment after Fecal Microbiota Transplant in Inflammatory Bowel Disease.

Background: Fecal Microbiota Transplant (FMT) has proven effective in treating recurrent Clostridioides difficile infection (rCDI) and has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. However, there is little known regarding predictors of engraftment. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Results: Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. The treatment arm received seven days of antibiotics followed by FMT enema and then capsules weekly for seven weeks. We enrolled four subjects with CD and 11 with UC, ages 14-29 years. Due to weekly stool sampling, we were able to create a time series of alpha diversity, beta diversity and engraftment as they related to clinical response. Subjects exhibited a wide range of microbial diversity and donor engraftment as FMT progressed. Specifically, engraftment ranged from 26% to 90% at week 2 and 3% to 92% at two months. Consistent with the current literature, increases over time of both alpha diversity (p< 0.05) and donor engraftment (p< 0.05) correlated with improved clinical response. Additionally, our weekly time series enabled an investigation into the clinical and microbial correlates of engraftment at various time points. We discovered that the post-antibiotic but pre-FMT time point, often overlooked in FMT trials, was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial with publicly available weekly sequencing data. Conclusions: We found that higher residual alpha diversity and Lactobacillus blooms after antibiotic treatment correlated with improved engraftment and clinical response to FMT. Future studies should closely examine the host microbial communities pre-FMT and the impact of antibiotic preconditioning on engraftment and response.

Efficacy and Safety of Sulfasalazine Suspension in Children With Ulcerative Colitis.

BACKGROUND: Sulfasalazine (SZ) is commonly used to treat pediatric ulcerative colitis (UC). SZ can be compounded into a suspension form which is beneficial for children with difficulty swallowing a pill. Despite being utilized for over 40 years, there is a lack of published data on the efficacy and safety of SZ suspension in children with UC. Recently, third-party payors have begun refusing to pay for SZ suspension due to lack of data. METHODS: In this retrospective study, we reviewed the electronic medical records of patients ages <18 years diagnosed with UC from June 1999 to December 2019 at Boston Children's Hospital and treated with SZ suspension as a first-line agent. We obtained demographics, clinical, and endoscopic data to measure outcomes at 1 year and long term. RESULTS: Of 57 patients treated with SZ suspension, 52 (91%) had a follow-up and 26 of 52 (50%) remained in steroid-free remission at 1 year. Two patients were switched to SZ tablets due to nonmedical reasons and 11 (21%) required rescue treatment (2 infliximab, 1 tacrolimus, 8 6-mercaptopurine/azathioprine) within a year. Three required colectomy within a year and 5 in long term. Four (8%) developed nonserious adverse reactions and switched to 5-aminosalicylates (5-ASA) by 1 year. The median duration of long-term follow-up was 36 months (range, 2-205 months) with 28 requiring treatment escalation in long term. CONCLUSIONS: SZ suspension is a safe and effective treatment for UC in children with difficulty swallowing a pill. The 1-year remission rate on this treatment is comparable to 5-ASA utilized in children.

Efficacy and Safety of High-dose Cholecalciferol in Patients With Inflammatory Bowel Disease Receiving Infliximab.

OBJECTIVE: Vitamin D deficiency is prevalent in patients with inflammatory bowel disease (IBD). The goal of this study was to assess the efficacy and safety of high-dose, interval cholecalciferol administration in patients with IBD receiving infliximab. METHODS: This prospective, longitudinal, open-label study enrolled pediatric and young adult patients with IBD and vitamin D deficiency. Subjects received 50,000 IU every 4 to 5 weeks (n = 11) or 100,000 IU every 6 to 8 weeks (n = 32) of oral cholecalciferol for 1 year. Dosing was directly observed and administered in conjunction with infliximab infusions. The primary endpoint was vitamin D sufficiency, defined as a 25-hydroxy-vitamin D (25-OHD) level ≥30 ng/mL. RESULTS: Forty-three participants constituted the primary analysis population. 25-OHD levels reached steady-state after the third dose, and mean increases in 25-OHD levels were 8 vs. 4.5 ng/mL in the 100,000 IU vs. 50,000 IU treatment groups, respectively. Only 43.8% of patients receiving 100,000 IU and 18.2% of patients receiving 50,000 IU achieved sufficiency. There was no difference in the 25-OHD level responsiveness in patients with Crohn disease versus those with ulcerative colitis (P = 0.72). There was no correlation between 25-OHD levels and clinical disease activity in patients with Crohn disease (P = 0.85) or ulcerative colitis (P = 0.24). CONCLUSIONS: Supplementation with cholecalciferol was well-tolerated and direct observation is a promising paradigm for ensuring compliance with therapy. Patients with IBD, however, appear to require high doses of cholecalciferol, with less than half of patients (37% overall) achieving vitamin D sufficiency. Additional studies are necessary to determine the optimal treatment regimens.

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.

Analysis of Using the Total White Blood Cell Count to Define Severe New-onset Ulcerative Colitis in Children.

OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis). RESULTS: Mean age was 12.7 years; 49.6% (n = 212) were girls, and 83% (n = 351) were Caucasian. Severe total Mayo score was present in 28% (n = 120), mean PUCAI score was 49.8 ±â€Š20.1, and 33% (n = 142) had severe mucosal disease with extensive involvement in 82% (n = 353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%. CONCLUSIONS: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.

Pediatric Collagenous Gastroenterocolitis Successfully Treated with Methotrexate.

A two-and-one-half-year-old previously healthy female presented with a ten-week history of watery diarrhea, nonbilious and nonbloody emesis, and low-grade fevers. She was found to have severe hypoalbuminemia and hypogammaglobulinemia. Her symptoms persisted, and she became dependent on parenteral nutrition. Biopsies obtained during subsequent endoscopic and colonoscopic studies revealed findings consistent with collagenous gastroenterocolitis. She responded to an empiric course of prednisone, but her symptoms recurred shortly after transitioning to oral budesonide. After successful reinduction with intravenous prednisone, intramuscular methotrexate was initiated. She remained asymptomatic during a 15-month course of therapy, and she continued to do well clinically until approximately nine months after weaning off methotrexate. At that point, she experienced a recurrence of diarrhea, and repeat endoscopic evaluation confirmed collagenous colitis. This responded nicely to a short course of oral budesonide, and she has since remained asymptomatic and off any therapy.

Protein-Losing Enteropathy in the Setting of Iron Deficiency Anemia: A Case Series.

Protein-losing enteropathy (PLE) in the setting of severe iron deficiency anemia (IDA) and excessive cow milk intake is an uncommonly recognized phenomenon. Here, we describe a series of 7 toddlers who presented for evaluation of edema in the setting of excessive cow milk intake between November 2016 and January 2019. Laboratory studies in each patient were consistent with IDA and hypoalbuminemia with evidence of PLE. Diagnostic evaluation and treatment of each patient differed, although all were instructed to restrict cow milk and provided with oral iron supplementation. The edema had resolved, and the IDA had improved in all 7 patients by the time of their follow-up outpatient appointments. Iron deficiency and PLE should be considered in patients who present with anasarca.

Screening and Counseling for Alcohol Use in Adolescents With Chronic Medical Conditions in the Ambulatory Setting.

PURPOSE: We seek to determine how youth with chronic medical conditions experience alcohol screening and counseling. METHODS: Adolescents with type I diabetes, juvenile idiopathic arthritis, moderate persistent asthma, cystic fibrosis, attention deficit hyperactivity disorder, or inflammatory bowel disease were surveyed. Descriptive statistics and regression analysis quantified rates of asking and counseling about alcohol. RESULTS: Of 390 participants (75.1% white/non-Hispanic, 51.8% female, average age 16.4 years), 70% reported being asked about their alcohol use by a healthcare provider, and 76% reported receiving at least one message regarding alcohol and health. Of past year drinkers, 54% disclosed use to their provider. Only 2.0% of youth reported receiving the message "I should not drink." CONCLUSIONS: Most youth with chronic medical conditions were asked and counseled about alcohol use although few heard unambiguous recommendations to avoid alcohol consumption.

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study.

BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.

Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response.

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4ß7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course.

Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care.

Serologic Reactivity Reflects Clinical Expression of Ulcerative Colitis in Children.

Background: In contrast to pediatric Crohn's disease (CD), little is known in pediatric ulcerative colitis (UC) about the relationship between disease phenotype and serologic reactivity to microbial and other antigens. Aim: The aim of this study was to examine disease phenotype and serology in a well-characterized inception cohort of children newly diagnosed with UC during the PROTECT Study (Predicting Response to Standardized Pediatric Colitis Therapy). Methods: Patients were recruited from 29 participating centers. Demographic, clinical, laboratory, and serologic (pANCA, ASCA IgA/IgG, Anti-CBir1, and Anti-OmpC) data were obtained from children 4-17 years old with UC. Results: Sixty-five percent of the patients had positive serology for pANCA, with 62% less than 12 years old and 66% 12 years old or older. Perinuclear anti-neutrophil cytoplasmic antibodies did not correspond to a specific phenotype though pANCA ≥100, found in 19%, was strongly associated with pancolitis (P = 0.003). Anti-CBir1 was positive in 19% and more common in younger children with 32% less than 12 years old as compared with 14% 12 years old or older (P < 0.001). No association was found in any age group between pANCA and Anti-CBir1. Relative rectal sparing was more common in +CBir1, 16% versus 7% (P = 0.02). Calprotectin was lower in Anti-CBir1+ (Median [IQR] 1495 mcg/g [973-3333] vs 2648 mcg/g [1343-4038]; P = 0.04). Vitamin D 25-OH sufficiency was associated with Anti-CBir1+ (P = 0.0009). Conclusions: The frequency of pANCA in children was consistent with adult observations. High titer pANCA was associated with more extensive disease, supporting the idea that the magnitude of immune reactivity may reflect disease severity. Anti-CBir1+ was more common in younger ages, suggesting host-microbial interactions may differ by patient age.

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

Background: The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method: To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results: HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). Conclusion: In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Protein-Losing Enteropathy in the Setting of Severe Iron Deficiency Anemia.

A 20-month-old boy presented with a 2-week history of pallor and progressive abdominal distention. Nutritional history revealed long-standing excessive cow milk intake. He was subsequently found to be profoundly iron deficient and hypoproteinemic, with an elevated fecal α-1-antitrypsin level and occult blood positive stool, consistent with protein-losing enteropathy. He was treated with cow milk restriction and oral iron supplements, which resulted in resolution of his edema and laboratory anomalies. While small numbers of previous case reports have described the potential association between excessive cow milk intake and severe iron deficiency and protein-losing enteropathy, this constellation of clinical symptoms is infrequently recognized in clinical practice. As iron deficiency is recognized as the most common nutritional deficiency in the United States, it is important to keep excessive cow milk intake in mind when evaluating young children presenting with severe iron deficiency and protein-losing enteropathy.