Acid Suppression and Antibiotics in Infancy Associated with Increased Risk of Celiac Disease

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M Boechler et al. J Pediatr 2023; 254: 61-67. Acid Suppression and Antibiotics Administered during Infancy Are Associated with Celiac Disease

Methods: A retrospective cohort study was performed using the Military Healthcare System database. N=968,524 children with 1704 cases of celiac disease (CD) in this group (from 2001 to 2013) with prescription for PPIs, H2RAs or antibiotics in first 6 months of life.

Key findings:

  • PPIs (HR, 2.23; 95% CI, 1.76-2.83), H2RAs (HR, 1.94; 95% CI, 1.67-2.26), and antibiotics (HR, 1.14; 95% CI, 1.02-1.28) were all associated with an increased hazard of CD.
  • The risk is increased by use of multiple categories of these medications and/or if acid suppression medications are used for longer periods

There have been previous studies indicating an increased risk of CD in patients given acid suppression (Lebwohl et al. Dig Liver Dis 2014; 46: 36-40) and conflicting data regarding the use of antibiotics. With regard to acid suppression, recent studies have indicated that these medications in infancy may increase the risk of food allergies as well. The authors speculate in their discussion that the increased risk for CD could be related to changes in protein degradation, mucosal permeability, microbiome changes, and immune reactivity. The authors note that their dataset did NOT show an increased risk of CD associated with C-section delivery.

One of the limitations of this study is that early presentations of CD could lead to prescriptions of agents to to help reduce symptoms rather than the medications increasing the risk of developing CD. However, this is unlikely as gluten introduction is often later in infancy.

My take: Better stewardship of antibiotics and acid blockers is needed. Use of acid suppression medications is associated with an increased risk of celiac disease as well as food allergies.

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Additional posts on Celiac Disease

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Florida Narrative Ignoring Inconvenient Data with COVID-19 Vaccine Safety

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From MedPage Today (4/12/23): Data Omitted From FL Vax Report?

The Florida Surgeon General’s recommendation that young men shouldn’t get the COVID-19 vaccine was made “despite the state having contradictory data,” according to the Tampa Bay Times.

In October, Florida Surgeon General Joseph Ladapo, MD, PhD, announced that young men shouldn’t get the COVID-19 vaccine, countering CDC guidance. His recommendation was based on an analysis that purported to show an increased risk of cardiac-related death for men ages 18 to 39.

However, draft versions of the analysis obtained by the Tampa Bay Times show that “catching COVID-19 could increase the chances of a cardiac-related death much more than getting the vaccine,” the article stated.

“That data was included in an earlier version of the state’s analysis but was missing from the final version compiled and posted online by the Florida Department of Health,” the Times reported. “Ladapo did not reference the contradictory data in a release posted by the state.”

My take: The approach taken by Florida’s “surgeon general” is one of making sure the facts don’t get in the way of a perfectly good narrative.

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Is It a Mistake to Use Budesonide for Autoimmune Hepatitis?

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A Diaz-Gonzalez et al. Hepatology 2023; 77: 1095-1105. Open Access! Budesonide as first-line treatment in patients with autoimmune hepatitis seems inferior to standard predniso(lo)ne administration

Background: AASLD guidelines also suggest the use of budesonide with azathioprine as an alternative agent (to prednisone with azathioprine) in patients without cirrhosis or a severe acute presentation.1–3 However, particularly in pediatrics, there is concern that it is not as effective.

Methods: This was a retrospective, multicenter study of 105 naive AIH patients treated with budesonide as the first-line drug. The control group included 276 patients treated with prednisone.

Key findings:

  • The biochemical response (BR) rate was significantly higher in patients treated with prednisone (87% vs. 49% of patients with budesonide, p < 0.001). BR was defined as normalization of both serum transaminases and IgG.
  • The probability of achieving BR was significantly lower in the budesonide group (OR = 0.20) at any time during follow-up, and at 6 (OR = 0.51) and 12 months after starting treatment (0.41)
  • Prednisone treatment was significantly associated with a higher risk of adverse events (24.2% vs. 15.9%). These differences vanished when patients with cirrhosis were excluded from the analysis, showing a similar incidence of AEs in both groups (p = 0.119). Of the specific adverse effects, only the presence of osteoporosis was significantly higher in the prednisone group (mainly in those older than 60 years)
  • The authors note that budesonide was “only indicated in 5.4% of patients newly diagnosed with AIH… Budesonide was mainly employed in patients with low baseline transaminases, suggesting that this drug is preferred in patients with less severe disease.”

My take: “The use of budesonide in the real-life setting was low and was associated with a lower probability of achieving BR with respect to prednisone.” It likely needs to be restricted to those with mild disease, and those with adverse events with prednisone. Cost is less of an issue as budesonide can be obtained as a generic (Mark Cuban Costplus pharmacy: Budesonide).

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If a Gastroparesis Medication Works in the Forest But No One Sees It, Did It Really Work?

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MR Ingrosso et al. Gastroenterol 2023; 164: 642-654. Open Access! Efficacy and Safety of Drugs for Gastroparesis: Systematic Review and Network Meta-analysis

The authors examined  29 RCTs (3772 patients). Key findings:

  • Only two medications (neither available in U.S.) were identified as being more effective than placebo for global symptoms of gastroparesis: clebopride (RR, 0.30) followed by domperidone (RR, 0.68) 
  • Oral metoclopramide ranked first for nausea (RR 0.46), fullness (RR 0.67), and bloating. Though, use may result extrapyramidal adverse effects

In the associated editorial (pg 522-524, Drug Treatments for Gastroparesis—Why Is the Cupboard So Bare?), the authors note that the label “gastroparesis” applies to a heterogeneous population.

Key points:

  • I tend to abide by the recommendation proposed by Masaoka and Tack10 some years ago that one should use the term gastroparesis only “when persistently and severely delayed gastric emptying is found in the absence of mechanical obstruction.” 
  • An obsession with gastroparesis as the basic issue among patients with “gastroparesis-like” symptoms has translated into a therapeutic fixation on the acceleration of gastric emptying. This too has led to frustration and disappointment. As already mentioned, symptoms are a poor predictor of the rate of gastric emptying, and a normalization of delayed emptying has not consistently correlated with symptom responses and vice versa.11,12
  • Oblivious to research illustrating how upper gastrointestinal symptoms can result from several other derangements in foregut physiology, such as impaired accommodation of the upper stomach, visceral hypersensitivity, and antropyloric distensibility and dysmotility,13, 14, 15, 16

My take: Currently, pharmaceutical agents geared towards symptoms like nausea and sensory disorders are much more promising than prokinetic agents for gastroparesis

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Thrombosis in Pediatric Patients with Intestinal Failure

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G Keefe et al. J Pediatr 2023; 253: 152-157. High Rate of Venous Thromboembolism in Severe Pediatric Intestinal Failure

This retrospective study (n=263) examined the rate of venous thromboembolism (VTE) in pediatric patients who required parenteral nutrition for at least 90 consecutive days.

Key findings:

  • The cumulative incidence of VTE was 28.1%, with a rate of 0.32 VTEs per 1000 catheter-days
  • The number of catheters and early gestational age were noted to be independent risk factors for VTE
  • No patients had progression of thrombus while receiving therapeutic anticoagulation
  • Of those with acute DVTs (n=47), 24 (51%)resolved on repeat imaging, 14 (30%)were stable, and and 9 (19%) had decreased
  • 4.4% (2 of 45) had a major bleed while on anticoagulation

The authors note that the true rate of VTE is likely even higher because only 42% categorized as not having a VTE had undergone dedicated venous imaging.

My take: A lot of patients with intestinal failure develop VTE. Given the risks of treatment, the role of prophylactic anticoagulation remains unclear. This is where a prospective study would be helpful.

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“Tug” Sign For Eosinophilic Esophagitis and EoE Bowel Sounds Tips

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EA Pasman et al. Clin Gastroenterol Hepatol 2023; 21: 1108-1110. Quantitative Analysis of Tug Sign: An Endoscopic Finding of Eosinophilic Esophagitis

Background: “Chronic inflammation can lead to tissue remodeling in the esophagus with fibrosis in the lamina propria that is partially responsible for symptoms and complications of EoE.3,4 At times, a firmness to the esophagus can be appreciated with a noticeable force required to obtain biopsies from EoE. This sensation has been described as the “tug” or “pull” sign.5,6“

Methods: in this prospective study with 159 patients (128 pediatric, 31 adult), the authors devised a digital force gauge to measure the force required to take biopsy specimens. The study included 88 patients with EoE and 71 controls.

Key finding:

  • EoE patients showed an increase in the mean force required to obtain biopsies: 14.9 Newton (N) compared to 11.6 in control group
  • Peak force was greater in EoE patients: 20.4 N compared to 15 N in control group.
  • The pediatric subgroup had higher peak force in EoE patients: 22.4 N compered to 16.1 N for control group

My take: I had not heard of the term “Tug” sign for EoE, though it is something that is intuitive for GI providers who care for these patients. This study quantifies this problem.

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

Related topic: Recent bowel sounds episode with Amanda Muir discussed eosinophilic esophagitis. A few pointers:

  • Useful YouTube video explaining how to swallow inhaled steroid (from Glen Furuta/Colorado Chilren’s): How to Use an Inhaler for EoE
  • Budesonide can be administered with 1 tsp honey, 1 tsp maple syrup or with 1 tsp apple sauce
  • Approximate equivalent dose of Flovent 4 puffs of 220 mcg =~1 mg budesonide
  • Elemental feedings are difficult to maintain and used much less, mainly in children who already have enteral tubes.
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HooDoo Rocks, Mount Lemmon. Tucson, AZ

Synergistic Dangers: Helicobacter Pylori and Cancer Genes

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Y Usui et al. NEJM 2023; 388: 1181-1190. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer

Background: Gastric cancer is the fifth most common neoplasm and the fourth leading cause of death from cancer worldwide.1 Helicobacter pylori has been classified as a group I carcinogen and is an environmental risk factor for gastric cancer.2 Although H. pylori infection affects more than half the world population

Methods: This study evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. This retrospective study also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).

Key findings:

  • Germline pathogenic variants in nine genes: (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer.
  • At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% vs. 14.4%).
  • Limitation: The study population was from East Asia and thus, the findings may be different in other populations.

My take: H. pylori infection has a synergistic effect in increasing the risk of gastric cancer in individuals with germline pathogenic variants in homologous-recombination genes. To minimize the risk of gastric cancer, H pylori eradication is important; however, it is especially in those with cancer-predisposing variants.

From NEJM Twitter Feed

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FDA Treatment for Rett Syndrome

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FDA 3/13/23: FDA approves first treatment for Rett Syndrome

Action

FDA has approved Daybue (trofinetide) oral solution as the first treatment for Rett syndrome, a rare, genetic neurological disorder. Daybue is approved for the treatment of Rett syndrome in adults and children 2 years of age and older.

Patients take Daybue either orally or via gastrostomy tube. The recommended dose is based on patient weight. Daybue is taken twice daily, morning and evening, with or without food.

Disease or Condition

Rett syndrome is a rare, genetic neurological and developmental disorder that affects the way the brain develops. Patients with Rett syndrome experience a progressive loss of motor skills and language. Most babies with Rett syndrome seem to develop as expected for the first six months of life. These babies then lose skills they previously had attained at approximately six to 18 months of age — such as the ability to crawl, walk, communicate, or use their hands. The hallmark of Rett syndrome is near constant repetitive hand movements, such as rubbing or clapping. Rett syndrome leads to severe impairments affecting nearly every aspect of life, including the ability to speak, walk, eat, and breathe.

The syndrome primarily affects females (1 in 10,000) and even more rarely affects males.

Effectiveness

The efficacy and safety of Daybue was evaluated in a randomized, double-blind, placebo-controlled, 12-week study (Study 1; NCT04181723) of patients with Rett syndrome five to 20 years of age. Patients were randomized to receive Daybue (N=93) or matching placebo (N=94) for 12 weeks. The dose of Daybue was based on patient weight to achieve similar exposure in all patients.

The co-primary efficacy measures were change from baseline in the Rett Syndrome Behavior Questionnaire (RSBQ) total score and the Clinical Global Impression-Improvement (CGI-I) score at week 12. The RSBQ is a 45-item rating scale completed by the caregiver that assesses a range of signs and symptoms of Rett syndrome. Lower scores represented lesser severity in signs and symptoms of Rett syndrome. The CGI-I is a 7-point scale rated by clinicians to assess how much a patient’s illness has improved or worsened. A decrease in CGI-I score indicates improvement.

Patients treated with Daybue demonstrated a statistically significant difference compared to placebo on the co-primary efficacy endpoints, as measured by the change from baseline in the RSBQ total score and the CGI-I score at week 12.

Safety Information

Most common adverse reactions, occurring in at least 10% of Daybue-treated patients and twice the rate of placebo, included diarrhea (81%) and vomiting (27%).

See full prescribing information for additional information on risks associated with Daybue.

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Dried Blood Spot Testing for Biliary Atresia

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C-S Lee el al. JPGN 2023; 76: 418-423. A Pilot Study of Biliary Atresia Newborn Screening Using Dried Blood Spot Matrix Metalloproteinase-7

Methods: The study used stored DBS samples collected from 48 to 72 hours of life were retrieved from newborn screening centers in Taiwan (n=25 biliary atresia (BA), 107 non-BA)

Key findings:

  • MMP-7 levels of BA patients on the DBS were significantly higher than those of non-BA patients (19.2 ± 10.4 vs 5.6 ± 2.7 ng/mL, P value < 0.0001).
  • BA patients in this cohort underwent Kasai operation at a mean of 43 days. 32% (n=8) had surgery before 30 days of life, and 24% (n=6) had surgery after 60 days.
  • In this cohort, at time of publication, 9 (36%) of BA patients had received a liver transplantation at a mean of 2.4 years. Patients with their native liver tended to have had an earlier Kasai (38 days vs 54 days, P=0.057).

In their discussion, the authors note that BA starts very early in life. Increase in MMP-7 within 3 days of birth, supports “speculation that most BA ” may start before birth (JPGN 2019; 69: 396-403, What Is The Evidence That Biliary Atresia Starts in Utero?).

My take: Incorporating MMP-7 testing with newborn screening needs to be looked at in a bigger study. Efforts to identify BA cases earlier have largely been unsuccessful over the past several decades despite the knowledge that delayed diagnosis leads to worse outcomes.

Figure from JPGN Twitter Feed

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