Category Archives: Uncategorized

Population-Based Study: Prevalence of Bowel and Bladder Dysfunction in Early Childhood (Good Bowel Control is Happening Later)

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SJ Verkuijl et al. JPGN 2023; 77: 47-54. Open Access! The Prevalence of Bowel and Bladder Function During Early Childhood: A Population-Based Study

Methods: This cross-sectional questionnaire study (n=791 Dutch children) up to age 7 yrs of age.

Key findings:

  • The mean age at which parents/caregivers considered their child fully toilet-trained was 5.1 ± 1.5 years. “Compared to studies performed 15 years ago, we found toilet training to be completed at an older age (23,26–28).”
  • Prevalence of fecal incontinence among toilet-trained children was 12%.
  • Prevalence of constipation was 14%, with excessive stool retention (75.9%) and painful/hard stools (78.7%) as the 2 most common symptoms.
  • The prevalence of urinary incontinence among all toilet-trained children was 40%. The majority of these urinary incontinent children suffered from daytime incontinence (56%). Enuresis occurred in 22% and the other 22% suffered from combined daytime incontinence and enuresis.
  • There were significant associations between fecal incontinence and constipation [odds ratio (OR) = 3.88], fecal incontinence and urinary incontinence (OR = 5.26), and constipation and urinary incontinence (OR = 2.06)
  • Half of the children with constipation and almost all the children with fecal incontinence remained untreated.
Stool Frequency by age (Figure 1 B)

In the discussion, the authors note “treatment of constipation and/or fecal incontinence often leads to the resolution of urinary incontinence (34).”

In my experience, many families sent by urologists have been told that the constipation is causing urinary incontinence. For many children, the explanation is more complicated; association of constipation does not indicate causation. A lot of children have limited sensation of response to both bowel and bladder, rather than the rectum pushing on the bladder. Most children that I see with constipation/encopresis do not have urinary incontinence. However, behavior approaches to toileting can be helpful for both.

My take: This is a useful study providing an updated view on when to expect good toileting and highlighting the frequency of bowel/bladder dysfunction (which is often untreated).

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Understanding Reflux/Airway Disease and Potential Role of Airway Impedance

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A recent blog post, Airway Impedance to Objectively Assess Airway Mucosal Integrity, reviewed a study by Rosen et al (R Rosen et al. J Pediatr 2023; 256: 5-10) which used a novel approach in assessing airway disease using airway impedance.

This month’s Journal of Pediatrics provides a terrific commentary by my partner, Jose Garza. Open Access: Airway Impedance: In Search of a New Tool (DOI:https://doi.org/10.1016/j.jpeds.2023.01.007).

The article first describes the history of identifying gastroesophageal reflux: “the first attempt to detect GER was in 1884 by Reichman, who lowered a sponge into the esophagus of a patient with heartburn and showed that it contained acid when retrieved. He found that fluid expressed from the sponge was acidic in persons with heartburn and alkaline in normal controls. The first in situ measurement of acid reflux in the esophagus is credited to Tuttle and Grossman 2 in 1958.”

With the development of multi-channel impedance, the concept of reflux has shifted in young children: “non-acid reflux events are more important to the development of symptoms than acid events.”

With regard to Rosen et al, the commentary reiterates that “measuring laryngeal mucosal integrity [using impedance] is safe and feasible in children with extraesophageal symptoms.” The study showed “no correlation between otolaryngology airway inflammation scores with airway impedance, further emphasizing the fact that we need to move away from these scores, as they have failed to show correlation with GERD and with laryngeal mucosal integrity.”

“The authors did find a decrease in airway impedance in patients with history of aspiration; those who aspirated more textures had lower median airway impedance. Therefore, not all airway inflammation is the result of reflux and oropharyngeal dysphagia–associated aspiration can cause GER-like symptoms and airway inflammation. Aspiration can be silent, and if we do not look for it, we are not going to find it.”

“Another group of patients with low airway impedance comprised patients receiving PPIs, which makes it clear that acid is not what is affecting the airway. Otherwise, PPIs would improve airway impedance.” 

My take (borrowed from author): “It is not yet clear whether measuring airway impedance will eventually become a widespread test with clinical applicability. However, the concepts advanced in this report are clearly a step in the right direction.”

Place Massena, Nice, France

Understanding Racial Differences in Response to IBD Treatment — Golimumab in Ulcerative Colitis

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R Greywoode et al. Inflamm Bowel Dis 2023; 29: 843-849. Open Access! Racial Difference in Efficacy of Golimumab in Ulcerative Colitis

The authors analyzed pooled individual-level data (n=1066) from induction and maintenance trials of golimumab in adults with moderate-to-severe UC. Key findings:

  • Compared with White participants, participants from racial minority groups had significantly lower clinical response (adjusted odds ratio [aOR], 0.43), clinical remission (aOR, 0.41), and endoscopic healing (aOR, 0.48) at week 6.
  • Participants from racial minority groups also had significantly lower clinical remission (aOR, 0.46) and endoscopic healing (aOR, 0.63) at week 30.
  • There were no racial differences in placebo response rates.

Discussion:

This is a fascinating study. Most of the differences in response to IBD treatment have been attributed to social determinants of health including access to care (geography, insurance), and adherence to medical care. This study implicates biological factors rather than social factors for driving the difference in response. “There is also a growing body of research uncovering differences in the frequencies of genetic variants in diseases, which may contribute to differences in observed health outcomes among divergent ancestral populations.32,33“

“One of the challenges in further understanding how race may affect response to IBD biologic drugs is the relatively small number of participants from racial minority groups included in clinical trials. There is a longstanding disparity in clinical trial participation in the United States, whereby racial and ethnic minority groups have disproportionately low representation.34-37“

While the differences in the disease phenotype may account for the response to treatment, there may be other factors as well. With hepatitis C infection, those of us who remember the frequent use of Peg-interferon therapy will recollect that specific mutations in Interleukin-28B (IL28B) gene predicted lower response rates in African-American populations (related post: Understanding IL28B).

My take: Most of the changes in outcomes to treatment are likely driven by socioeconomic factors. This study is a good reminder that biological factors play a big role as well.

This figure shows the treatment responses compared to 1.00 (white population)

Oral GLP-1 Receptor Agonist for Obesity: Orforglipron

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S Wharton et al. NEJM 2023; DOI: 10.1056/NEJMoa2302392. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

In this phase 2 randomized, double-blind trial with 272 adults with obesity (mean weight at baseline 108 kg), participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. “The pharmacokinetic profile of orforglipron, with a half-life of 29 to 49 hours, supports once-daily oral administration.”

Key findings:

  • At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo.
  • A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo.
  • Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists.

Weight reduction of at least 10% at week 36:

My take: This is an exciting time for drug development for obesity. Given the low success rates of traditional ‘lifestyle’ management approaches, these medications have the potential to reduce a great deal of morbidity. Oral agents, rather than injections, would hasten the use of these agents more broadly. Long term outcomes are still unclear.

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When to Use Dupilumab for Eosinophilic Esophagitis: Multispecialty Guidelines

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SS Aceves et al. Annals of Allergy, Asthma, and Immunology. 2023; 130: 371-378. Open Access! Clinical guidance for the use of dupilumab in eosinophilic esophagitis

This article summarizes updated recommendations for eosinophilic esophagitis from the Joint Task Force for the American Academy of Allergy Asthma Immunology and American College of Allergy Asthma Immunology and the American Gastroenterology Association (JTF-AGA). It offers a good number of recommendations regarding when using dupilumab should be considered.

Other Key Points:

  • “Dupilumab can be considered as first-line therapy in patients presenting with severe EoE”and in patients with multiple atopic diseases.
  • In addition, it recommends “performing a repeat EGD, along with obtaining biopsies, 5 to 6 months after either starting dupilumab therapy or whenever adjusting the dupilumab dose.” In some cases, like stricture dilatation, the authors indicate that earlier EGD may be appropriate.
  • The advantages/disadvantages of current treatment options are summarized in Table 3. For dupiliumab, the disadvantages include its high price of dupilumab and weekly injections. Conjunctivitis has been an adverse effect identified in its usage with other indications.

My take: Dupilumab is a major advance for patients with EoE. Due to the need for weekly injections and its costs, it is likely a 2nd line agent for most kids with EoE.

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Mel Heyman: Past, Present and Future of ARFID

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Recently, at the Georgia AAP Pediatrics by the Sea meeting, Mel Heyman presented a terrific lecture reviewing ARFID. This lecture delved into the historical backgrounds of eating disorders and described the subtypes of ARFID along with evaluation/management. This lecture was presented in honor of Stan Cohen who recently retired from our group. Here are many of the slides:

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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.

The Expanding Adalimumab Options

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S White, R Morrow, I Pan, EF de Zoeten. JPGN 2023; 76: 701-703.
Riding the Wave of Adalimumab Biosimilars: Considerations for Pediatric Gastroenterologists

This article is a very handy update on approved adalimumab biosimilars, though even more biosimilars are expected to become available soon. The table below which is similar to a table in the article outlines the similarities and differences in these products compared to the reference product.

These biosimilars are FDA-approved for the treatment of adult and pediatric patients aged 6 and older with Crohn disease. “However, the biosimilar products are only approved for treatment of adult patients” (18 and older) with ulcerative colitis. “This may be due to the recent change in pediatric ulcerative colitis Humira FDA-approved dosing.”

My take (borrowed in part from authors): Insurance coverage decisions are likely to overlook some of these factors which are very important for pediatric patients. “The adalimumab biosimilars will likely provide a clinically effective, cost saving option for our patients, but consideration of a number of factors will be key when selecting between” them.

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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.

Which is a More Effective First-Line for Crohn’s Disease: Ustekinumab or anti-TNF agents?

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P Riviere et al. Inflamm Bowel Dis 2023; 29: 923-931. Comparative Effectiveness of Ustekinumab and Anti-TNF Agent as First-Line Biological Therapy in Luminal Crohn’s Disease: A Retrospective Study From 2 Referral Centers

A previous study (SEAVUE) has suggested similar efficacy of ustekinumab and adalimumab in biologic-naive patients (post: SEAVUE: Head-to-Head Ustekimumab vs. Adalimumab) with ~60-65% clinical response at 52 weeks and ~30% endoscopic remission.

This current retrospective study sought to obtain ‘real-world’ data comparing anti-TNF agents (95 adalimumab, 61 infliximab) to ustekinumab (n=50). In the anti-TNF group, 44% (n=68) received concomitant immunomodulator therapy. Key findings:

  •  At 3 months, clinical response rates were 86% in anti-TNF groups and 64% in the ustekinumab.
  • At 12 months, in adjusted multivariate analysis, clinical remission (based on Harvey-Bradshaw Index) was independently associated with the biological therapy received (odds ratio, 2.6 for anti-TNF agent vs ustekinumab; P = .02).
  • “In our sensitivity analysis, a significant difference in terms of efficacy was only found between infliximab and ustekinumab.”
  • In those with ileocolonoscopy, endoscopic healing was similar (between 6-18 months): 58% of anti-TNF group and 61% of ustekinumab group.
  • 2% of patients in the anti-TNF group had severe adverse events compared to none in the ustekinumab group; among patients receiving adalimumab, 1 patient had cerebral aspergillosis, 1 had a postinfectious macrophage activation syndrome, and 1 had severe folliculitis needing abscess drainage.
  • Drug persistence at 12 months was 87% in anti-TNF group and 88% in ustekinumab group.

The discussion notes that ‘real-world’ data is important as only ~30% of patients in a regular practice would fulfill the criteria to be included in clinical trials. However, in this retrospective (non-randomized) study, there were differences in the patient population that could affect response to treatment, including a higher rate of smokers in the anti-TNF group (29% compared to 12% in the ustekinumab group).

My take: While anti-TNF therapy, particularly infliximab, may be a little better based on clinical remission, the most objective marker of efficacy, endoscopic healing, was similar. Thus, it is not clear if anti-TNF therapy is more effective than ustekinumab. To achieve optimal results, many in the anti-TNF group received immunomodulator cotherapy and dose escalation.

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Joel Andres, Chef & Philanthropist, World Central Kitchen

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.

A Treatment For Gastroparesis with a 30% Response: Placebo

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JL Wise et al. Clin Gastroenterol Hepatol 2023; 21: 1447-1461. Open Access! Response and Adverse Event Rates With Placebo in Gastroparesis: A Systematic Review and Meta-analysis

In this meta-analysis, the key findings:

  • The pooled placebo response rate was 29.3% (95% CI, 23.7%–35.2%) in 23 trials (n=1011)
  • Pooled placebo response rates were higher in idiopathic compared with diabetic gastroparesis (34.2% vs 28.1%).
  • Pooled responses were also higher in RCTs of shorter duration (<4 weeks, 32.6% vs ≥9 weeks, 23.2%) and in trials that did not use validated symptom questionnaires (31.2% vs 27.4%)
  • Adverse events occurred in 33.8% (95% CI, 26.4%–41.8%) of patients with placebo, in 27 trials, and were less common in idiopathic compared with diabetic gastroparesis (17.9% vs 43.4%)

My take: The relatively high placebo response joins the list of factors which make the management of gastroparesis difficult. This list includes trouble with diagnosis/variable results with gastric emptying studies and limited response to current treatments.

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Harbor in Nice, France

Early Postoperative Anti-TNF Therapy

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JE Axelrad et al. Inflamm Bowel Dis 2023; 29: 888-897. Early Initiation of Antitumor Necrosis Factor Therapy Reduces Postoperative Recurrence of Crohn’s Disease Following Ileocecal Resection

This retrospective cohort study identified 1037 patients with Crohn’s disease who underwent ileocecal resection (ICR). Only 5.4% were younger than 18 yrs at the time of surgery. In this cohort, 278 (26%) received a biologic agent as prophylaxis to prevent recurrence with 80% receiving an anti-TNF agent. In those receiving an anti-TNF agent, 35% were started on therapy within 4 weeks of surgery and 65% were started between 4 and 12 weeks. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum). Key findings:

  • After adjusting for factors associated with postoperative recurrence (POR), compared with no biologic prophylaxis, the initiation of an anti-TNF agent (n=223) within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61).
  • Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis –though sample size with vedolizumab (n=27) and ustekinumab (n=28) was very limited
  • Most patients receiving biologic prophylaxis had prior anti-TNF exposure including 73% of the anti-TNF group, 96% of the vedolizumab group, and 93% of the ustekinumab group.

In their discussion, the authors note that their findings reinforce previous studies which showed beneficial effects of anti-TNF therapy for POR, including the PREVENT trial. This randomized controlled trial with infliximab initiation within 45 days postoperatively in high risk individuals reduced endoscopic recurrence at 18 months (22.4% compared with 51% in placebo group).

My take: Anti-TNF therapy, even in those with prior exposure, likely improves outcomes in patients with Crohn’s disease following ileocecal resection. This study indicates that starting therapy within the first 4 weeks is more beneficial.

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Watersound, FL