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Dr. Neha Santucci: Management of DGBIs in the Post-Pandemic Era (Part 1)

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Recently, Dr. Neha Santucci gave our group an excellent update on disorders of gut-brain interaction.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.

John Apley’s monograph The Child with Abdominal Pains provided an early understanding of the prevalence of DGBIs.
An increase in DGBIs occurred with COVID.
This study in adults showed a greater increase in functional dyspepsia compared to IBS.

DGBIs occur in Children with Down syndrome. This cohort showed high rates of functional constipation (36%), irritable bowel syndrome (14.9%), functional dyspepsia (12.3%) and aerophagia (5.3%).
DGBIs were common after surgery for malrotation
  • Development of DGBIs is influenced by psychological factors, early life events, chronic stress, gut motility, inflammation, mucosal immune activation and altered gut microbiota
  • DGBIs are associated with altered brain networks
  • DGBIs are associated with a number of comorbidities including mental health disorders, joint hypermobility, headaches, POTS, musculoskeletal pain, disordered eating, and poor sleep
  • Individuals with DGBIs are at increased risk of eating disorders including ARFID. Presence of ARFID with DGBIs has been associated with more anxiety, depression, ADHD and sleep disturbance
  • Poor sleep in previous night is associated with increased pain the next day in individuals with DGBIs
  • DGBIs are common in children with organic diseases, including IBD, EoE, Celiac disease, Recurrent Pancreatitis, Malrotation and Anorectal disorders
  • Up to 50% of pediatric GI visits are for functional disorders and ~25% of all children have DGBIs
  • Strive to make a positive diagnosis (rather than simply a diagnosis of exclusion)
  • Avoid excessive testing
  • Dyspepsia and gastroparesis are not distinct disorders and likely exist on a spectrum (some of the same treatments for both)
  • First treatment goals: develop a good rapport with family and focus on improved functioning
Children with DGBIs had more problems with coping skills.
Individuals with DGBIs are at increased risk of eating disorders including ARFID. Presence of ARFID with DGBIs has been associated with more anxiety, depression, ADHD and sleep disturbance.
Initial treatment needs to address these questions

Related blog posts:

-“The more time the doctor spends on the history, the less time he is likely to spend on treatment.”

-“Doctors who treat the symptoms tend to file a prescription. Doctors who treat the patient are more likely to offer guidance.”

-“It is a fallacy that a physical symptoms always has a physical cause and needs a physical treatment.”

-“Anxiety like courage is contagious.”

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Case Report: Cat Scratch Colon in a Young Patient

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A Watson et al. JPGN 2024;79:1081–1083. Cat scratch colon in a patient with very early-onset Crohn’s disease with diverting ileostomy

Case report: This image is from the ascending colon of a 12 yo with Crohn’s disease sp diverting ileostomy.

“Cat scratch colon refers to the rare endoscopic finding of erythematous linear breaks that arise spontaneously, typically in the ascending colon and/or cecum, resembling scratches made by a cat, on otherwise unremarkable mucosa…It is presumed to be a benign condition likely caused by barotrauma from air insufflation during colonoscopy in a colon with altered elasticity or when the rate of insufflation exceeds the rate of air passage, such as in a diverted colon.2, 3“

My take: Surprisingly, the cat scratch colon finding is not consequential.

One Family’s Tragic Loss Prompted Widespread Interest in Organ Donation

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Los Angeles Times, Corinne Purtill, September 24, 2024: 30 years later, a family’s loss gives life to others

An excerpt:

For the Green family, the memory of Oct. 1, 1994 is many things at once: the date of their greatest pain and their finest hour; a day of unspeakable loss and life-giving gifts.

It is the date their 7-year-old son, Nicholas, died in an Italian hospital, two days after being shot during an attempted robbery on a family vacation from California…

Seven people, five of them teenagers, received Nicholas’ corneas, kidneys, liver, heart and pancreas. The family’s story prompted a surge in interest that continues to drive new donor registrations in Italy…

At the time, Italy had one of the lowest organ donation rates in Western Europe. The Greens’ decision, along with the awful circumstances of the boy’s death, led to a swell of media attention across Italy…The year before Nicholas’ death, 6.2 people per million in Italy donated their organs. Ten years later, as the story circulated and the numbers of parks, playgrounds and streets in Italy named after Nicholas grew, the number had tripled to nearly 20 people per million…

Over the years, members of the family have made dozens of trips to Italy to speak on behalf of organ donation and to check in on the people whose lives were saved by their loss…five are still living. His liver recipient, who was 19 at the time of the transplant, went on to marry and have children. The Greens have met her eldest son. His name is Nicholas.

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Risk of Eating Disorders with Dietary Therapy of Functional Abdominal Pain

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L Sims et al. JPGN 2024;79:1040–1046 Open Access! Eating concerns in youth with functional abdominal pain disorders

This retrospective cohort included 270 adolescents/young adults who attended an intensive, interdisciplinary pain treatment program, including 135 youth with functional abdominal pain (FAP) and an age- and gender-matched control group with a primary pain diagnosis of chronic headache.

Key findings:

  • Limitation of this study: The population attending this intensive pain program is NOT representative of typical outpatient setting
  • A history of an eating disorder was more common with FAP than in those with chronic headache (15.4% vs. 5.9%)
  • In this cohort, patients with FAP compared to patients with chronic headache had higher rates of prior exclusion diets to manage their symptoms (46% vs. 22%, p = 0.007), and prior requirement enteral or parenteral feeds (18% vs. 1.5%, p = 0.001)
  • The study found a significant association between a history of exclusion diets and meeting criteria for ARFID. “With regard to ARFID, the prevalence of patients in both groups who met diagnostic criteria (FAP: 50%; chronic headache: 36%) was also significantly higher than estimates from the general school-aged population (3%)”
  • Patients with FAP were also more likely than patients with chronic headache to be diagnosed with postural orthostatic tachycardia syndrome ([POTS]; 46% vs. 30%) and have a history of food allergies or intolerances (43% vs. 25%)
  • Significantly more adolescents with FAP (n = 68) than chronic headache (n = 45) had lost 4.5 kg or more, p = 0.004

My take: Most treatments for FAP, including dietary treatment, have some inherent risks. In patients placed on dietary therapies, screening and/or discussing the risk of dietary restriction need to be considered.

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Boats Leaving Harbor -Claude Monet, National Gallery of Art (Washington, D.C.)

Home Parenteral Nutrition in Children with Severe Neurological Impairment

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D D’Arienzo et al. JPGN 2024; 79:1031–1039. Open Access! Characteristics and outcomes of home parenteral nutrition among children with severe neurological impairment

Background:  “A subset of patients with SNI may not tolerate enteral feeding due to gastrointestinal (GI) issues, resulting in pain, feeding intolerance, and malnutrition, despite the absence of primary digestive disorders.3–5 In these cases, home parenteral nutrition (HPN) can be considered…The decision to initiate HPN in children with SNI is challenging. The lack of evidence, absence of definitive etiologies for GI symptoms, known complications, and psychosocial burden of HPN create ethical hurdles for clinicians when partnering with caregivers in this decision.12, 18, 20“

Methods: This was a retrospective review from Canada’s largest tertiary care pediatric hospital of all children with severe neurologic impairment (SNI, n=18) and primary digestive disorders (n=187), where home parenteral nutrition (HPN) was initiated between January 2010 and September 2023.

Key findings:

  • Compared with the primary digestive disorders group, children with SNI with non-primary digestive disorders were less likely to achieve enteral autonomy (p < 0.0001).
  • There was a higher mortality rate were observed in the SNI cohort, though this did not reach statistical significance (22% in SNI group vs. 8% those primary digestive disorders; p = 0.09). Only one death in the SNI group was attributed to HPN-related complications.
  • “CRBSI rate of 1.7 per 1000 catheter days among the SNI and non-primary digestive disorder population on HPN indicates no increased risk in this population. Similarly, our observed rate for catheter-related mechanical problems (occlusion, leakage, dislodgement) of 4.3 per 1000 catheter days is similar to the report of 3.4 per 1000 catheter-days in children with intestinal failure on HPN.28 “

In the discussion, the authors note that “HPN initiation was found to not influence utilization acute care hospital resources, with no difference in ED visits, hospitalizations, ICU admissions or days in hospital in the year before initiating HPN, compared to the following year…the high usage of acute care that is characteristic of this population persisted, suggesting that HPN also did not meaningfully decrease health care use for these children.”

My take: HPN may improve symptoms and nutrition in some children with SNI. This comes with a substantial burden. Prior to starting PN, careful exploration of long-term goals is essential. The decision to use of PN is fraught with ethical issues in children with SNI and could be considered a ‘heroic’ measure; some families will opt for palliative care.

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Fields in the Month of June by Charles-Francois Daubigny at National Gallery of Art (Washington, D.C.)

Frequency of Erythema Nodosum and Pyoderma Gangrenosum in 32,497 Pediatric Patients with Inflammatory Bowel Disease

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MY Yousif et al. JPGN 2024; 79:1009–1016. Open Access! The association between erythema nodosum and pyoderma gangrenosum and pediatric inflammatory bowel disease

Using the ImproveCareNow prospective registry, the authors analyzed a total of 285,913 visits from 32,497 patients aged ≤ 21 years.

Key findings:

  • The occurrence of erythema nodousm (EN) was 1.57% and the occurrence of pyoderma gangrenosum (PG) was 0.90%. Co-occurrence of EN and PG was reported in 0.30% patients.
  • Both EN and PG were associated (p < 0.0001) with worse intestinal disease, lower remission, higher inflammatory markers, and extraintestinal manifestations (EIMs) arthritis and uveitis. 
  • Limitations: “imperfect and incomplete data entry that may introduce bias. However, due to the extensive longitudinal data, we expect any bias to be minimal.”

My take: This study clarifies how common these dermatologic findings occur in pediatric patients with IBD. Prompt recognition of these disorders is important. Recently, our group cared for a 20 yo patient with inadequately-treated PG by multiple internal medicine physicians; this led to prolonged hospitalization.

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The Dancer by Auguste Renoir, National Gallery of Art

Is There a Residual Impact of a Tethered Cord on Colonic Motility

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JM van der Zande et al. JPGN 2024; 79:976–982. Open Access! Anorectal physiology and colonic motility in children with a history of tethered cord syndrome

This retrospective review of 24 children with tethered cord syndrome (TCS) (50% female) who had ARM testing (median age at ARM 6.0 years). 19 children had prior TCS repair.

Key findings:

  •  No significant differences in ARM parameters were found between children who had detethering surgery before ARM and children with functional constipation (FC). The children with TCS did have lower resting pressures though this was attributed to most having their ARM while under GA for concurrent procedures. The resting pressures were still normal.
  • Among the 14 children who also had a colonic manometry (CM) performed (13/14 after detethering surgery), there were no significant differences in colonic motility were found between children with a history of TCS and children with FC.

My take: The vast majority of children with a history of TCS (following detethering) should be treated akin to children with functional constipation.

Impression, Sunrise by Claude Monet at National Gallery of Art (Washington, D.C.)

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Cefdinir Stool in Infants

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A D’Agrosa et al. J Pediatr 2024; 273; DOI: 10.1016/j.jpeds.2024.114129. Cefdinir Stool

This 5 month old infant was brought to ED due to diarrhea and dark stools for 2 weeks. She had completed cefdinir for a UTI.

Cefdinir may cause red or maroon stools when administered with iron or products that contain iron, such as infant formula. This typically occurs within two days of antibiotic administration.

My take: Familiarity with this reaction is helpful to avoid extensive evaluations. Also, it is worthwhile to keep in mind that false-positive testing with guaiac testing is common (up to 34% in healthy infants).

Other references:

From: E Khalid et al. Journal of Infection and Chemotherapy; 2020; 26: 286-288. Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report

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1-Food vs 4-Food Elimination Diet for Eosinophilic Esophagitis

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KL Kliewer et al. Journal of Allergy and Clinical Immunology, 2024; One-food versus 4-food elimination diet for pediatric eosinophilic esophagitis: A multisite randomized trial

Methods: This was a multisite, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE. The 12-week study enrolled 63 patients (6-17 yrs). Primary end point was symptom improvement by Pediatric Eosinophilic Esophagitis Symptom Score (PEESS).

Key findings:

  • 1FED vs 4FED: The mean PEESS improved −25.0 versus −14.5 (P = .04), but remission rates (41% vs 44%; P = 1.00), histology scoring system (−0.25 vs −0.29; P = .77), endoscopic reference score (−1.10 vs −0.58; P = .47), and QoL scores were similar between groups.
  • The 4FED withdrawal rate (32%) exceeded that of 1FED (11%) (P = .0496).

My take: A 4FED diet is difficult to maintain. In this 12 week study, more than 30% of patients withdrew from the 4FED diet. In addition, dairy elimination alone resulted in similar response rates.

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Dr. Sana Syed: AI Advancements in Pediatric Gastroenterology

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Recently, Dr. Sana Syed gave Children’s Healthcare of Atlanta Grand Rounds. She provided an excellent update on the development of artificial intelligence (AI) to select targeted therapies for pediatric gastroenterology diseases.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.

Key points:

  • One of the goals of using AI is to identify the right therapy at the time of diagnosis. Currently, diseases like eosinophilic esophagitis (EoE) and Crohn’s disease have multiple treatment options. However, many patients do not respond to first-line treatments; many develop complications due to not responding to treatment.
  • Currently we are lacking adequate biomarkers for individualized therapy. AI has the potential to sort through massive amounts of data (histologic, genetic, pharmacokinetics, transcriptome, metabolomics, etc) to allow for precision therapy.
  • For EoE, machine-learning has already identified three subtypes that may affect clinical management. EoE1 is associated with a normal-appearing esophagus. EoE2 is associated with being steroid refractory. EoE3, when compared to the other two endotypes, is associated with adult-onset and narrow-caliber esophagus or stricturing.
  • For Crohn’s disease, research has shown that younger age has been associated with an increased risk of not responding to anti-TNF therapy
This is a quote from President Obama when his administration announced massive funding
toward precision medicine in January of 2015, that the promise of precision medicine is
”delivering the right treatments at the right time, every time to the right person.” This figure illustrates some of the kinds of data that Dr. Syed had access to as faculty at UVA, including
genomics, epigenome, transcriptomics, proteomics, metabolomics, etc.
Shoda and colleagues, used a combination of histology data, endoscopic features, histologic and endoscopic scoring indices, and transcripts that make up the eosinophilic esophagitis diagnostic
panel, a quantitative PCR assay with 96 EoE representative genes. The key message from all of those visualizations is that they found that EoE can be divided into three distinct endotypes after analyzing transcriptomics changes via partition-around-medoid clustering, a machine-learning method.
In this project, the researcher intend to curate a novel metabolic network specific to the ileum,
which is relevant to Crohn’s disease, link metabolic processes with Crohn’s disease phenotypes
using in silico metabolic network modeling and ‘omics and characterize and target metabolic
pathways in an organoid model generated from patient-derived Crohn’s disease tissue.
In CoMPAS, the researchers aim to leverage artificial intelligence methods (AI) methods to build predictive
models for CD using histology slides and single-cell RNA sequencing, allowing for risk
stratification of B1 patients who will respond to anti-TNF therapy
The goal of our project is to create a multi-omics reference dataset with scRNA-seq data
coupled with contextual data on tissue morphology, ancestry, social determinants of health, and
the environment. The cohort for this study is enrolling patients who have clinical indications for endoscopy like foreign body removal, reflux, abdominal pain

My take: This work is necessary to identify the right treatments for each patient and will lead to better outcomes. We are already seeing the early stages of machine-learning’s impact on clinical care. In many other fields, AI work is much further along (especially in oncology). A recent study in Nature identified JAK inhibitors as potential life-saving therapy with toxic epidermal necrolysis (TEN).

Reference: Nordmann, T.M., Anderton, H., Hasegawa, A. et al. Spatial proteomics identifies JAKi as treatment for a lethal skin disease. Nature (2024). https://doi.org/10.1038/s41586-024-08061-0

Summary from Eric Topol (Ground Truths) focusing on spatial omics: Thierry Nordmann, Matthias Mann and their international consortium, used deep visual proteomics from 3μm PPFE sections of skin biopsies in patients affected by TEN…

More than 5,000 proteins were quantified from single cells—keratinocyte and immune cells—using mass spec, for the 4 different skin conditions (proteome cluster in Figure below, left panel). This led to the finding that the TEN patients had marked increased in Type 1 and 2 interferon signaling and activation of phosphorylated STAT1, which invoked the janus kinase (JAK/STAT) pathway. Subsequent steps were to test JAK inhibitors in cell culture (with live cell imaging) and in two different mouse models, all showing highly potent, dose-dependent impact on inhibition of the intense inflammatory process and disease severity…

They went on to treat seven patients at Fuian Medical University, the course of one patient shown below, treated with a JAKi on day 4 after diagnosis, and manifesting a marked response starting within 48 hours. All 7 patients fully resolved, with no side effects…

For spatial medicine, there are multiple analytical challenges that invoke the need for machine learning and A.I., including segmentation of cell types, automated capture of cells of microdissection, extracting useful information from the >5,000 proteins quantified per cell, and ultimately, as we’ll see more in the future, A.I. powering the construction of high-resolution 3D maps.

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