Increased expression of proton pump and allergic inflammation genes predicts PPI failure in pediatric eosinophilic esophagitis.

Proton pump inhibitors (PPIs) are one of the standards of care of eosinophilic esophagitis (EoE) treatment, though PPI response rates are variable ranging from 23 to 63% in pediatric studies. We sought to determine if expression of select genes in esophageal mucosa can predict PPI responsiveness in EoE. Children with a new diagnosis of EoE (15 or more eosinophils/hpf on esophageal biopsy) were prospectively treated with 8 weeks of PPI therapy before follow-up esophagogastroduodenoscopy (EGD). Children with <15 eosinophils/hpf on follow-up were classified as having PPI-Responsive EoE (PPI-R) and ≥ 15 eosinophils/hpf as PPI-Nonresponsive EoE (PPI-NR). Using the Nanostring nCounter Analysis System, mRNA expression of a custom panel of genes was measured in esophageal biopsies. Immunohistochemical staining of biopsies was performed. Among children with EoE, 32% (8/25) had PPI-R EoE. ATP12A, ATP4A, tryptase-beta 2 (TPSB2), CLC and IL13 had higher expression in PPI-NR EoE compared to PPI-R EoE or controls. Immunohistochemical staining of ATP12A was higher among PPI-R EoE and PPI-NR EoE, compared to non-EoE controls. In this study, PPI-NR EoE had significantly higher baseline gene expression of mast cell, cytokine, proton pump, and eosinophil genes compared to PPI-R EoE. PPIs may be involved in an inflammatory cascade of mast cell activation that stimulates IL-13 release, which upregulates ATP12A and ATP4A that leads to eosinophil recruitment. Histologic PPI failure may occur when increased gene expression of these components is high and cannot be overcome pharmacologically, especially in the case of proton pump genes.

Effects of Mirikizumab on Histologic Resolution of Crohn's Disease in a Randomized Controlled Phase 2 Trial.

BACKGROUND & AIMS: Histologic evaluation of mucosal healing in Crohn's disease is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes. METHODS: Biopsy specimens from 1 ileal and 4 colonic segments were evaluated at weeks 0, 12, and 52 from each of the 170 SERENITY participants. Criteria for the weeks 12 and 52 histologic response were no epithelial neutrophils or epithelial damage, or >50% decrease in either the Robarts Histopathology Index or the active Global Histologic Disease Activity Score, and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsy specimens. Agreement was evaluated between histologic and endoscopic end points. Associations between 1-year outcomes and week 12 histologic and endoscopic response were evaluated. RESULTS: At week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%; P < .001) and remission (26% vs 6%; P < .01) than placebo. Rates were numerically similar at 1 year (mirikizumab pooled response, 46%-69%; remission, 13%-31%). Agreement between week 12 histologic and endoscopic response was 69% (Cohen's kappa coefficient [κ] = 0.40) and remission was 83% (κ = 0.38) in all pooled arms, including placebo. At 1 year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (P = .003). CONCLUSIONS: In a post hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in Crohn's disease over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226).

Eosinophilic Esophagitis Symptom Scores Are High in Children Without Eosinophilic Disease.

OBJECTIVES: The Pediatric Eosinophilic Esophagitis (EoE) Symptom Score version 2 (PEESSv2.0) is an EoE-specific validated metric for disease monitoring, but its use has not been explored outside of EoE. Our aim was to determine if PEESSv2.0 scores differentiate between children with EoE and non-EoE esophageal dysfunction undergoing initial esophagogastroduodenoscopy (EGD). METHODS: A prospective cohort study of pediatric subjects was conducted. Children ages 1-18 undergoing initial EGD for esophageal dysfunction were enrolled. Demographics, clinical history, and child self-report and parent-proxy report PEESSv2.0 symptom scores were collected at the time of EGD. Esophageal biopsies were reviewed, and EoE was defined as >15 eosinophils/high powered field (hpf) seen in any level of the esophagus. Non-EoE was defined as <15 eosinophils/hpf. RESULTS: Seventy-one children were included in the study from 2015 to 2018 [59% (42/71) males; mean age 9.2 years; range 1-17 years]. Fifty-eight percent (41/71) met criteria for EoE, and 42% (30/71) were labeled non-EoE. Non-EoE children and their parents had higher/worse median PEESSv2.0 total scores than those with EoE [47.0 vs 28.0 (P = 0.001) and 40.5 vs 26.5 (P = 0.012), respectively]. Non-EoE children reported higher median GERD [9.0 vs 4.0 (P = 0.003)], nausea/vomiting [9.0 vs 4.0 (P = 0.003)], and pain [11.0 vs 6.0 (P = 0.001)] subdomain scores compared to those with EoE. PEESSv2.0 dysphagia subdomain scores (child and parent-proxy) did not differ between EoE and non-EoE groups [22.0 vs 15.0 (P = 0.184) and 18.5 vs 17.4 (P = 0.330), respectively]. DISCUSSION: Total PEESSv2.0 scores were worse in non-EoE group compared to EoE group. Although PEESSv2.0 is validated for use in monitoring EoE therapy, it does not distinguish children with EoE from non-EoE esophageal dysfunction at the time of diagnostic EGD.

The Effects of Patient Demographics on Outpatient Endoscopy Utilization in Children With Eosinophilic Esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that requires esophagogastroduodenoscopy (EGD) for diagnosis and treatment monitoring. We aimed to identify the frequency of endoscopic monitoring in children with EoE and observe the effect of age, race, socioeconomic factors, and atopy on the rate of endoscopy. METHODS: We queried the Pediatric Health Information System over a 15-year period for ambulatory EGDs in children with EoE. Subjects with at least 1 year of data were included. Age, sex, ethnicity, race, insurance type, median household income, and atopy were collected for each subject. RESULTS: 16,517 subjects were included (mean age 8.5 years). 3211 (19%) of subjects had ≥1 EGD per subject year (EGD/SY). Subjects >13 years old were more likely to have ≥1 EGD/SY compared to children 6-12 years (odds ratio [OR] 2.29, P < 0.001, 95% confidence interval [CI] = 2.06-2.54). Males were more likely to have ≥1 EGD/SY compared to females (OR 1.19, P < 0.001, 95% CI = 1.08-1.31). African-American subjects were 16% less likely than Caucasian subjects to have ≥1 EGD/SY (OR 0.84, P = 0.05, 95% CI = 0.71-1.00). Subjects with allergic rhinitis or anaphylaxis, food allergy, and/or oral allergy syndrome were more likely to have ≥1 EGD/SY (OR 1.67, P < 0.001, 95% CI = 1.47-1.90 and OR 3.65, P < 0.001, 95% CI = 3.25-4.11, respectively). CONCLUSIONS: Nineteen percent of subjects had ≥1 EGD/SY. Older age, male sex, allergic rhinitis, and food allergies were associated with more frequent endoscopic monitoring in children with EoE. Caucasian subjects had more frequent endoscopy than African-American subjects. This study raises awareness about underrecognized variation in the care of children with EoE.

Inadequate Bowel Preparation in Pediatric Colonoscopy-Prospective Study of Potential Causes.

OBJECTIVES: Inadequate bowel preparation (IBP) for colonoscopy leads to missed diagnosis, longer anesthesia time, higher chance of complications and increased costs. Adult studies have demonstrated that patient characteristics such as male gender and obesity are associated with IBP. Little is known about factors affecting bowel preparation in children. Our aim was to determine factors associated with IBP in children. METHODS: We prospectively enrolled children undergoing outpatient colonoscopy. Quality of bowel preparation was assessed using Boston Bowel Preparation Scale (BBPS) score (range 0-9). Data collected included patient demographics, indication, and type of insurance. Patients were divided into two groups based on BBPS score-adequate (BBPS score > 5) and inadequate (BBPS score < 5) and groups were compared using Student t-test and chi-square test. Possible predictors were analyzed using multivariate logistic regression models. RESULTS: A total of 334 children were prospectively enrolled of whom 321 were studied further (age range 2-18 years; mean age 12.4 years; 60.4% female; 85.9% Caucasian). The mean BBPS score was 6.8 (standard deviation of ±2). IBP was reported in 12.8% (41/321). Multivariable logistic regression analysis did not show statistical differences between the groups in studied patient factors including age, gender, obesity, race, insurance type, and indication for colonoscopy. CONCLUSION: Contrary to several adult studies, the results of our prospective study did not show any relationship between examined patient factors and IBP in children. Interestingly, IBP was less prevalent in our pediatric study compared to published adult data (12.8% vs 20-40%).

Adrenal Insufficiency in Children With Eosinophilic Esophagitis Treated With Topical Corticosteroids.

OBJECTIVES: The aim of the study was to identify practices of gastroenterologists screening for adrenal insufficiency (AI) and report prevalence of AI in children with eosinophilic esophagitis (EoE) treated with topical corticosteroids (TCS); compare serum dehydroepiandrosterone sulfate (DHEA-S) levels to morning serum cortisol (MSC) levels as screening tool for AI. METHODS: A multipart study was conducted. In part 1, a survey about screening practices for AI in children with EoE on TCS was sent to gastroenterologists belonging to a PedsGI listserv and to EoE consortia. In part 2, children with EoE on TCS for ≥6 months were prospectively screened for AI with MSC levels. For subjects with a MSC level of <10 µg/dL, a repeat MSC level and/or confirmatory adrenocorticotropic hormone (ACTH) stimulation testing was offered. AI was defined by peak serum cortisol level <18 µg/dL. In part 3, DHEA-S levels were drawn with MSC levels. RESULTS: Seven percent (16/238) of gastroenterologists screened for AI. Providers in EoE consortia were more likely to screen than nonconsortia providers [9/21(43%) vs 7/217(3%); P = 0.0001]. Thirty-seven children were prospectively screened for AI, and 51% (19/37) had a low MSC level. Ten patients had a low-dose ACTH stimulation test (LDST) after 1 or more low MSC levels. Five percent (2/37) of patients were diagnosed with AI. DHEA-S and MSC levels had a moderate correlation (rs = 0.44, P = 0.03). CONCLUSIONS: Gastroenterologists belonging to EoE consortia were more likely to screen for AI. Prevalence of AI in our prospective cohort was 5%. DHEA-S has a moderate correlation with MSC levels, but more data is required to assess utility as a screening tool for AI.

Implementation of guidelines in eosinophilic esophagitis at an academic pediatric practice.

Guidelines for eosinophilic esophagitis (EoE) require high-dose PPI (HD-PPI) trial to evaluate for PPI-responsive esophageal eosinophilia (PPI-REE) prior to EoE diagnosis and dedicated therapy. This involves a second esophagogastroduodenoscopy (EGD) to assess for PPI-REE. This study is to evaluate adherence to current guidelines in evaluation of PPI-REE and EoE. Retrospective review of new patients treated with HD-PPI after an index EGD showing >15 eos/hpf in esophageal biopsies. One hundred and eighty patients had an index EGD with esophageal eosinophilia of >15 eos/hpf. Of these, 97/180 (53.8%) received HD-PPI; remaining 83/180 were prescribed other interventions without a HD-PPI trial. Of the 180 patients, 143 (79.4%) patients returned for follow-up and of whom 96/143 (67.1%) underwent repeat EGD. Adherence to guidelines improves with time. Patients are vested in care.

Incidence of Low Seroimmunity to Hepatitis B Virus in Children With Inflammatory Bowel Disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often receive immunosuppressive therapy, which may make them vulnerable to infections such as hepatitis B. We hypothesized that hepatitis B virus titers are low in the vaccinated pediatric population with IBD. The aims of our study were to identify the incidence of lower titers of hepatitis B surface antibody (HBsAb) and determine which patient factors may be associated with lower HBsAb titers. METHODS: Patients with diagnosis of IBD, ages 5 to 18 years, were prospectively enrolled. Patients were confirmed to have had a full series of hepatitis B vaccination. Quantitative serum HBsAb titers were measured and logistic regression analysis with independent variables of age, sex, race, disease phenotype, surgery, medications and a dependent variable of adequate HBsAb titers (> 10 mIU/mL) was performed. RESULTS: Of the 116 patients enrolled, 57 were boys and 59 were girls. 75 patients had a diagnosis of Crohn disease; 32 had a diagnosis of ulcerative colitis; and 9 patients had been diagnosed as having indeterminate colitis. At the time of the study, 15 patients were taking corticosteroid, 66 on an immunomodulator, and 53 on a biologic. Sixty percent of patients in the 5- to 10-year age group had protective titers versus 22% to 27% in the older groups, P = 0.04. Only 28% of the 116 patients had HBsAb titers of >10m IU/mL. Twenty percent of the patients taking corticosteroids, 27% taking immunomodulators, and 24% taking biologics were found to be seroimmune. CONCLUSIONS: Nearly two-thirds of pediatric patients with IBD have low titers against hepatitis B virus. Titers were highest in the younger patients. No patient-specific variable, such as the use of immunosuppressants, appeared to influence these low titers.

The Effect of Amantadine on Agitation in the Pediatric Traumatic Brain Injury Population: A Case Series.

In this report, we present a case series involving four pediatric patients who sustained a traumatic brain injury (TBI) and required intensive care unit admission immediately after the injury. In each of the four cases, amantadine was started during the acute care hospital admission to address agitation. Cases were retrieved from the electronic medical record at the Children's Hospital of Philadelphia between July 1, 2020, and October 31, 2022. This case series describes clinical data on TBI presentation, amantadine administration, patient behavior, and hospital course relating to agitation. This is the first publication that reports the effect of amantadine on agitation in the acute phase of recovery in the pediatric TBI population. Improvement in agitation was observed within 48 hours of amantadine initiation in all four cases based on the primary team progress notes, as well as the quantity of pro re nata medications given for agitation. Resolution of agitation was also observed in all cases, though the time scale varied. No adverse events were reported in relation to amantadine use, supporting other reports that the medication may be well tolerated in the pediatric population. More research is needed to determine the optimal dose of amantadine for the pediatric population and whether amantadine hastens agitation resolution compared to the current standard of care.

Gastrointestinal Food Allergies and Intolerances.

Adverse reactions to food include immune-mediated food allergies, celiac disease, and nonimmune-mediated food intolerances. Differentiating between these many disorders is important to guide us toward appropriate testing and management. Double-blind placebo-controlled food challenges are the gold standard for food allergy diagnosis but are difficult and time-consuming. In place of this, strong clinical history, other supportive tests, and oral food challenges are helpful. Some commonly available tests for food allergy and intolerances lack sufficient evidence for efficacy. Food intolerance diagnosis is largely based on history and supported by symptom improvement with appropriate dietary manipulation.

Rehabilitation After Complete Hemisensory Loss: Report of Two Cases.

The role and function that proprioception plays in movement and motor learning have been debated since the 19th century but can be difficult to isolate and study. Lesions at various points along the proprioceptive pathway result in afferent paresis that can be significantly disabling. Compensatory mechanisms can help with successful rehabilitation and provide an opportunity to study the role of these mechanisms in sensory feedback. Here, we present two cases of adult patients with complete hemisensory loss after a stroke: one patient with a cortical stroke and the other one with a thalamic stroke. First, we see that that motor learning can occur without proprioception, with the help of visual feedback. Second, proprioception plays an important role in movement: in the upper limb, it can facilitate individual finger movements, and in the lower limb, it maintains sufficient knee flexion to prevent the knee from going into recurvatum (backward bending) during ambulation.

Environmental Design for End-of-Life Care: An Integrative Review on Improving the Quality of Life and Managing Symptoms for Patients in Institutional Settings.

CONTEXT: The environment in which end-of-life (EOL) care is delivered can support or detract from the physical, psychological, social, and spiritual needs of patients, their families, and their caretakers. OBJECTIVES: This review aims to organize and analyze the existing evidence related to environmental design factors that improve the quality of life and total well-being of people involved in EOL care and to clarify directions for future research. METHODS: This integrated literature review synthesized and summarized research evidence from the fields of medicine, environmental psychology, nursing, palliative care, architecture, interior design, and evidence-based design. RESULTS: This synthesis analyzed 225 documents, including nine systematic literature reviews, 40 integrative reviews, three randomized controlled trials, 118 empirical research studies, and 55 anecdotal evidence. Of the documents, 192 were peer-reviewed, whereas 33 were not. The key environmental factors shown to affect EOL care were those that improved 1) social interaction, 2) positive distractions, 3) privacy, 4) personalization and creation of a home-like environment, and 5) the ambient environment. Possible design interventions relating to these topics are discussed. Examples include improvement of visibility and line of sight, view of nature, hidden medical equipment, and optimization of light and temperature. CONCLUSION: Studies indicate several critical components of the physical environment that can reduce total suffering and improve quality of life for EOL patients, their families, and their caregivers. These factors should be considered when making design decisions for care facilities to improve physical, psychological, social, and spiritual needs at EOL.