Category Archives: Uncategorized

Effective and Durable Hepatitis E Vaccine (Phase III Study)

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Background (from MedPage Today): HEV is a leading cause of acute viral hepatitis worldwide, resulting in an estimated 20 million infections worldwide and 70,000 deaths every year. HEV primarily occurs in Africa, Central America, and Asia…U.S. incidence of HEV infection is largely unknow in part because of a lack of surveillance or an FDA-approved, commercially available HEV assay. However, an analysis of seroprevalence of HEV among blood donors in the U.S. showed approximately 10% seropositivity for HEV immunoglobulin G (IgG), reflecting past infection, and 0.58% for HEV IgM, indicating recent infection.

Genotypes HEV-1 and HEV-2 are transmitted via contaminated water and are specific to humans. However, HEV-3 and HEV-4 are zoonotically transmitted, often by eating uncooked or undercooked meat and offal of boar, deer, and pig. 

Safety data of the vaccine were reported in an earlier study, showing no serious adverse effects attributed to the vaccine (though data is scarce in vulnerable populations including pregnant women and children)

S Huang et al. The Lancet 2024: DOI:https://doi.org/10.1016/S0140-6736(23)02234-1. Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial

In this randomized placebo-controlled study with 112 604 healthy Chinese adults aged 16–65 years, the key findings:

  • During the 10-year study period, there were 13 infections in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% in the modified intention-to-treat analysis and 86·6% in the per-protocol analysis.
  • In a subset of patients, 254 (87·3%) of 291 vaccinees had vaccine-induced antibodies detectable at the 8·5-year mark.

My take: This HEV vaccine markedly decreases the likelihood of acquiring HEV infection.

Related blog posts:

View from Ram Head Trail, St John

Is It RISKy Not To Use Anti-TNF Therapy for Pediatric Crohn’s Disease?

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D Geem et al (Senior author: Subra Kugasthasan). Clin Gastroenterol Hepatol 2024; 22: 368-376. Progression of Pediatric Crohn’s Disease Is Associated With Anti–Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization

Congratulations to my colleagues at Emory who led/participated in this study.

This study examined 5-year longitudinal data from the pediatric multicenter RISK cohort (n=1075). RISK=risk stratification and identification of immunogenetic and microbial markers of rapid disease progression in children

Key findings:

  • For children with a low BMIz at diagnosis (n = 294), BMIz normalization within 6 months of diagnosis were associated with a decreased risk for surgery (HR 0.47). Patients without BMIz normalization were enriched for genes in cytokine production and inflammation.
  • Unsurprisingly, baseline B2 (stricturing disease) and B2+B3 (stricturing and penetrating disease) were associated with increased risk of surgery with HR, 4.20 and HR, 8.24 respectively
  • Earlier anti-TNF therapy was associated with a lower hazard rate (HR) of needing surgery


My take: It appears that early anti-TNF therapy lowers the risk of surgery. Improved BMI with treatment is another good prognostic variable. There may be an early window in which effective treatment prevents long-term damage to the GI tract in pediatric patients with Crohn’s disease.

This study has overlapping findings (also with RISK cohort) by Adler et al showing early treatment preventing perianal fistulas. Blog post: Early Treatment Can Prevent Fistulas in Pediatric Crohn’s Disease

Related article: JC McCurdy et al. Clin Gastroenterol Hepatol 2024; 22: 377-385. Open Access! Comparative Effectiveness of Biologic Therapies in Preventing Penetrating Complications in Patients With Crohn’s Disease

In this observational retrospective study with 40,693 patients: 93% anti-TNF, 3% UST (ustekinumab), and 4% VDZ (vedolizumab), “Anti-TNF therapy was associated with a lower risk of LPD and PPD [luminal and perianal penetrating disease] compared with VDZ, and lower risk of LPD compared with UST.”

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Practical Tips for Eosinophilic Esophagitis

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We recently had Glenn Furuta, MD give our group a terrific lecture on eosinophilic esophagitis (EoE).

Some of the key points:

  • The burden of EoE continues to increase.
  • There are clearly several phenotypes of EoE. Some patients may never develop stricturing/fibrostenotic disease  but natural history data continues to evolve.
  • After treatment response, many patients can continue with symptoms. In adults and adolescents, this has been termed ‘esophageal hypervigilance.’ Feeding therapy may be helpful in this circumstance.
  • Adrenal insufficiency: Currently their group tries to screen for this after 4 months of topical corticosteroids and then yearly. It is unusual for them identify adrenal insufficiency if the patient is receiving only a single steroid agent; patients receiving steroids for other conditions like asthma are at higher risk.
  • An esophagram with a barium coated pill can be a useful adjunct to determine if there is esophageal narrowing (this can be missed on endoscopy).
  • For select patients, endoFLIP can characterize distensibility/esophageal function
  • Esophageal strictures: Their group uses Bougie dilators and has had a good experience. No perforations. ~15% with chest pain afterwards.
  • Corticosteroids (topical) can reduce the risk of food impactions in adults.
  • Reviewed use of Dupilimab and its recent approval in EoE for children as young as 1 yr of age (>15 kg)

Some selected slides:

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IBD Updates: Dual Advanced Therapies in Pediatrics, IL23 agents/Psoriasis

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A Yerushalmy-Feler et al. Inflammatory Bowel Diseases, Volume 30, Issue 2, February 2024, Pages 159–166. Open Access! Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN

In this retrospective study with 62 children (35 Crohn’s disease, 27 ulcerative colitis) with extensive and severe IBD that was refractory to various therapies, the authors examined the outcomes of combination therapies: the dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children.

Key findings:

  • Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively.
  • Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months 
  • Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6.
  • Among the 43% that were receiving steroids at the start of dual therapy, twenty (74%) of them could be successfully weaned within 3 months after the initiation of dual therapy.
  • Only 2 of 23 (8.7%) had endoscopic healing

My take (borrowed partly from authors):

  1. “Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events” and affordability.
  2. “There are currently no data for identifying the patients that are more likely to benefit from dual therapy….The ideal selection of dual biologic regimens remains to be determined.”

A Al-Janabi et al. JAMA Dermatol. 2024;160(1):71-79. doi:10.1001/jamadermatol.2023.4846 Open Access! Risk of Paradoxical Eczema in Patients Receiving Biologics for Psoriasis

This study examined more than 13,000 patients enrolled in a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis.

Key findings:

  •  A total of 273 exposures (1%) were associated with paradoxical eczema.
  • The adjusted incidence rates were 0.94 per 100 000 person-years for TNF inhibitors, 0.80 per 100 000 person-years for IL-12/23 inhibitors, and 0.56 per 100 000 person-years for IL-23 inhibitors.  IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39)

My take (from authors): The overall incidence of paradoxical eczema was low in biologic-treated patients with psoriasis. The risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema.

Chattahoochee River in Sandy Springs, GA

IBD Updates: Preventing Inflammatory Bowel Disease with a Healthy Diet and Medication Safety Pyramid

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Guo A, Ludvigsson J, Brantsæter AL, et al. Gut Published Online First: 30 January 2024. doi: 10.1136/gutjnl-2023-330971 Open Access! Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts Thanks to Mike Hart for this reference.

Methods: This study used prospectively collected data in children borne in Sweden from 1997-1999 as part of the ABIS (All Babies in Southeast Sweden, n=16,419) and in a similar study from Norway 1999-2008 as part of the MoBa (Norwegian Mother, Father and Child Cohort, n=113,106) study. Food data was recorded at 1 and 3 years. At the 1 year timepoint, there were 81,280 participants and 307 with IBD. At the 3 year timepoint, there were 65,692 participants and 266 with IBD.

Diet quality was examined using a modified Health Eating Index (HEI) (measure 1). ”The modified HEI reflects the child’s overall dietary quality, rather than food quantity and energy intake. This index included the intake of seven food groups: ‘fruits and vegetables’, ‘dairy foods’, ‘meat’, ‘fish and eggs’, ‘soft drinks’, ‘salty snacks’ and ‘sweet snacks’ (online supplemental tables 2 and 3). The intake of each food group was categorized by ranking weekly intake frequency by quartiles with a score of 1–4. Based on WHO dietary recommendations for children, being in the lowest intake category for ‘healthy food groups’ (eg, fruits and vegetables and fish and eggs) was assigned 1 point, the highest intake category was assigned 4 points, and vice versa for unhealthy foods, such as salty snacks and sweet snacks. Finally, the total HEI score, ranging from 7 to 28, with a higher score indicating a higher dietary quality, was divided into thirds representing low, medium and high diet quality.”

Key findings:

  • Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 and and 0.75 respectively)
  • Pooled aHR for children 1 year old with high versus low fish intake was 0.70  for IBD , and showed association with reduced risk of UC (pooled aHR=0.46)

In their discussion, the authors note several other studies (references 28,38, and 39) have shown an association with diet and development of IBD. A higher adherence to a Mediterranean diet was associated with a lower risk of developing IBD. The authors speculate that the reduction in IBD may be mediated by changes in the microbiome and and “early-life diet has a significant impact on gut microbiota composition.”

My take:

  1. This study shows an association between better early-life diet quality, particularly more veggies and fish and less sugar-sweetened beverages, and a lower risk of developing IBD.
  2. Diet studies are very difficult to perform due to wide variations and lack of control. This type of prospective data with a large cohort is likely to be one of the most valuable in improving our understanding.

Related blog posts:

From Miguel Regureiro and Marcus Banks. Gastroenterology & Endoscopy News. Nov 20, 2023. Moving From IV to Subcutaneous Infliximab, and an Updated Look at Advanced Therapy Safety

Early Treatment Can Prevent Fistulas in Pediatric Crohn’s Disease

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J Adler et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae020.056. EARLY TUMOR NECROSIS FACTOR ANTAGONIST TREATMENT PREVENTS PERIANAL FISTULA IN PEDIATRIC CROHN’S DISEASE

The authors utilized the prospectively-enrolled RISK cohort to assess the effect of early ANTI-TNF therapy and the development of perianal fistulizing complications (PFCs); this included 621 propensity-matched pediatric patients without PFCs at enrollment. ”The study included a moderately ill population, including 21% with growth delay, 43% with deep ulcers, and 70% with weighted pediatric Crohn’s disease activity index (wPCDAI) >30.”

Key findings:

  • Anti-TNF therapy was associated with 79% reduced odds of developing PFCs
  • The presence of perianal lesions increased the risk of PFCs more than 3-fold

My take: This study, in agreement with others (see below), shows that early treatment with effective therapy reduces the risk of disease complications like perianal fistulas.

Related blog posts:

How Not to Console an Irritable Infant

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A Berkwitt et al. NEJM 2024; 390: 358-366.Case 3-2024: An 8-Week-Old Male Infant with Inconsolable Crying and Weakness

This case report describes an 8 week old who been well until 7 days before the current presentation, when irritability, less frequent stooling and frequent crying developed. He was seen by his primary care clinic and symptoms were attributed to gas. Several days later, he presented to the emergency department with persistent crying but he had developed lethargy and weakness.

This case report details potential reasons for irritability in infants:

  • Infections
  • Neurologic causes including hydrocephalus
  • Ocular/skin such as a corneal abrasion and hair tourniquet
  • Cardiopulmonary causes such as heart failure and myocarditis
  • Gastrointestinal causes like colic, constipation gas, and reflux
  • Genitourinary like hernia and torsion
  • Musculoskeletal like fractures
  • Cancer including neuroblastoma and leukemia
  • Metabolic causes
  • Ingestions/Toxins

Then, the authors turn their attention to potential reasons for hypotonia:

  • CNS disease -accounts for 60 to 80% of cases of hypotonia, specifically hypoxic–ischemic encephalopathy and cerebral palsy
  • PNS disease -need to be considered in those with normal neuroimaging. To have an acquired PNS disease, the authors considered mainly botulism and Guillain-Barre syndrome.

Ultimately, the authors concluded that the infant likely had botulism which was in fact the correct diagnosis, confirmed by a stool test for Clostridium botulinum toxin type A (generally available only through local public health departments). Also, “On further interviewing, the patient’s family members reported that he typically had hard stools every 2 to 3 days. Two days before admission, the infant appeared to have abdominal discomfort, which his family members presumed was from constipation or gas. Honey was given to try to soothe him.”

Teaching points:

  1. Don’t give honey or corn syrup to a baby, though “clearly defined food exposures, such as exposures to honey or corn syrup, account for only a minority of cases.8..Often, there is a history involving rural living, dust production, or nearby soil perturbation.9“
  2. Give Baby BIG (infant botulism immune globulin) while waiting for results.
  3. Try to ascertain dietary exposures when obtaining a history.

Fortunately, this infant fully recovered.

Related blog post: Why call it botulinum?

View from The Windmill Bar in St John  

IBD Updates: Extending Mirkizumab Induction, Best Biologic, Fatigue in Pediatric IBD, Adalimumab Success in Patients with Abdominal Abscess

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  1. G D’Haens et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae004. Extended Induction and Prognostic Indicators of Response in Patients Treated with Mirikizumab with Moderately to Severely Active Ulcerative Colitis in the LUCENT Trials

Key findings:

  • Of patients not achieving clinical response during 12-week induction, 53.7% achieved response following extended induction (additional 3 doses of IV infusion every 4 weeks)
  • With “extended induction,” total of 80.3% mirikizumab-treated patients achieved clinical response by W24

2. S Schreiber et al. Inflamm Bowel Dis 2024; 30: S7. NETWORK META-ANALYSIS TO EVALUATE THE COMPARATIVE EFFICACY OF BIOLOGICS FOR MAINTENANCE TREATMENT OF ADULT PATIENTS WITH CROHN’S DISEASE

Methods: A network meta-analysis (NMA) was conducted to evaluate comparative efficacy of licensed biologics. Phase 3 randomized controlled-trials (RCTs) evaluating biologics approved by the European Medicines Agency or United States Food and Drug Administration as of 31 March 2023 for maintenance treatment of adult patients with moderate-to-severe CD were included, i.e. infliximab (IFX) intravenous (IV) and SC, adalimumab (ADL) SC, vedolizumab (VDZ) IV and SC, ustekinumab (UST) SC, and risankizumab (RZB) SC.

Key findings:

  • Among 8 comparator arms, IFX SC 120 mg every 2 weeks (Q2W) showed the highest odds ratio (95% credible interval) vs. PBO for clinical remission during the maintenance phase (3.52 [2.18–5.65]).

My take: This meta-analysis shows a favorable response for IFX SC; however, head-to-head trials are needed to really determine which biologic has the highest efficacy.

3. N Bevers et al. JPGN 2024; 2023; 77: 628-633. Fatigue and Physical Activity Patterns in Children With Inflammatory Bowel Disease

In this cross-sectional study with 104 children (24 with fatigue), biological parameters (CRP, fecal calprotectin) did not discriminate fatigued from non-fatigued patient

4. Y Bouhnik et al. Clin Gastroenterol Hepatol 2023; 21: 3365-3378. Adalimumab in Biologic-naïve Patients With Crohn’s Disease After Resolution of an Intra-abdominal Abscess: A Prospective Study From the GETAID

In this multicenter prospective study with 117 patients, the authors examined the success rate of adalimumab (ADA) in patients with CD with an intra-abdominal abscess resolved without surgery.

Key findings:

  • At W24, the survival rate without abscess recurrence or surgery was 74% (n=87)
  • Abscess drainage was significantly associated with ADA failure at W24 (odds ratio, 4.18)

My take (borrowed from authors): Provided that the abscess was carefully managed before initiating medical treatment, this study showed the high efficacy of ADA in the short and long term in biologic-naïve patients with CD complicated by an intra-abdominal abscess

Adjacent to Honeymoon Beach, St John

Medical Diagnostic Errors

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Eric Topol 1/28/24: Toward the eradication of medical diagnostic error

Key points/excerpts:

  • There is little evidence that we are reducing diagnostic errors despite more lab testing and more imaging. “One of the important reasons for these errors is failure to consider the diagnosis when evaluating the patient.” This, in turn, may be related to brief office visits.
  • There are a few ways that artificial intelligence (AI) is emerging to make a difference to diagnostic accuracy. ..A systematic analysis of 33 randomized trials of colonoscopy, with or without real-time AI machine vision, indicated there was more than a 50% reduction in missing polyps and adenomas, and the inspection time added by AI to achieve this enhanced accuracy averaged only 10 s. 
  • AI support to radiologists for a large mammography study “showed improvement in accuracy with a considerable 44% reduction of screen-reading workload.” The cancer detection rate was 6.1 per 1000 compared to 5.1 per 1000 in the control group.
  • In difficult NEJM CPC cases, large language AI model (LLM) outperformed clinicians (see slide below).” The LLM was nearly twice as accurate as physicians for accuracy of diagnosis, 59.1 versus 33.6%, respectively.”
  • “Likewise, the cofounder of OpenAI, Ilya Sutskever, was emphatic about AI’s future medical superintelligence: ‘If you have an intelligent computer, an AGI [artificial general intelligence], that is built to be a doctor, it will have complete and exhaustive knowledge of all medical literature, it will have billions of hours of clinical experience.’ “

My take (borrowed from Dr. Topol): “We are certainly not there yet. But in the years ahead, …it will become increasingly likely that AI will play an invaluable role in providing second opinions with automated, System 2 machine-thinking, to help us move toward the unattainable but worthy goal of eradicating diagnostic errors.”

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IBD Update -Stem Cells for Perianal Disease, Medicine-Induced VEO-IBD, and Thalidomide for VEO-IBD

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AL Lightner et al. Inflamm Bowel Dis 2023; 29: 1912-1919. A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow–Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn’s Disease

Seven pediatric patients with perianal Crohn’s disease were treated with mesenchymal stem cells. Key finding: At 6 months, 83% had complete clinical and radiographic healing. This healing rate is higher than “the 50% efficacy reported by the only completed randomized control phase III clinical trial.[ADMIRE study].”

MA Baarslag et al. NEJM 2023; 389: 1790-1796. Severe Immune-Related Enteritis after In Utero Exposure to Pembrolizumab

This case report details severe immune-related gastroenterocolitis after in utero exposure to pembrolizumab, an anti–PD-1 agent; the infant presented at 4 months of life. Extensive testing did not identify any underlying causes of VEO-IBD. This infant required TPN for a short period, but subsequently responded to treatment with glucocorticosteroids and infliximab (with plans to continue until at least 3 years of age). Both programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint inhibitors are negative regulators of T-cell immune function. Inhibition of these targets, resulting in increased activation of the immune system and can result in medication-induced colitis in the patients who take them and potentially in infants exposed to these agents in utero.

M Bramuzzo et al. Inflamm Bowel Dis 2024; 30: 20-28. https://doi.org/10.1093/ibd/izad018. Efficacy and Tolerance of Thalidomide in Patients With Very Early Onset Inflammatory Bowel Disease

This retrospective study with 39 patients with VEO and 39 patients with pediatric IBD.

Key findings:

  • The treatment persistence at 1, 2, and 3 years was 68.2%, 57.0%, and 50.9% for VEOIBD patients and 81.7%, 60.0% and 33.0% for pIBD patients, respectively 
  • A significantly higher proportion of VEOIBD patients discontinued therapy due to lack of efficacy (48.2% vs 17.2%; P = .03), while AEs were the main reason for discontinuation in pIBD patients
  • A significatively lower number of VEOIBD patients experienced AEs compared with pIBD patients (14 [35.9%] vs 30 [76.9%]; P = .0005).

Treatment persistence:

Treatment persistence

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