Primary Prevention of Obesity Still Needed

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SL Gortmaker, SN Bleich, DR Williams. NEJM 2024; 390: 681-683. Childhood Obesity Prevention — Focusing on Population-Level Interventions and Equity

Despite the exciting advances in obesity pharmacology, most children and adults are unlikely to benefit from these expensive therapies anytime in the near future.

This commentary’s key points:

  • “Scholars and policymakers shouldn’t lose sight of population-level strategies that can prevent excess weight gain and obesity among children in the first place.”
  • The authors identify three successful policy examples: 1. Revision of WIC food packages to improve nutritional quality at a cost about $18 per child. 2. Improving school lunch standards (2010 Healthy, Hunger-Free Kids Act) at a cost of about $30 per child. 3. Excise tax on sugar-sweetened beverages. “In California, an analysis found that such a tax would be cost-saving, would prevent 42,700 cases of obesity in children and 223,000 cases in adults statewide over 10 years because of projected reductions in consumption of sugar-sweetened beverages.”
  • “Leveraging these strategies won’t fix the problem of childhood obesity overnight, but it could (and has already begun to) slow the development of new cases, particularly among members of historically underserved populations — a major public health achievement.”

My take: There is not a simple solution for widespread obesity in children and adults. We need to chip away at this problem from every angle. It is crucial to use public policy changes as one of our tools.

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Near Leduck Island off St John

When Is It Safe To Replace a Central Line in the Setting of Candida Infection?

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D Katz et al. JPGN Reports 4(4):p e358, November 2023. | DOI: 10.1097/PG9.0000000000000358 Open Access! Early Central Venous Catheter Replacement After Candida in Pediatric Intestinal Failure Patients.

Background:

  • The Infectious Diseases Society of America (IDSA) recommends the removal of both short- and long-term catheters in patients with catheter-related bloodstream infection (CRBSI) due to fungi (1). 
  • In addition to source control, antifungal treatment and blood culture-confirmed clearance are recommended for all cases of CRBSI due to candida…In contrast, little is known about the optimal timing for the replacement of a CVC in the setting of candidemia (5–7). As a result, practices greatly vary between practitioners.

Methods: This was a retrospective, single-center review of children with intestinal failure (IF). Patients were divided into early (<7 days after their first negative culture), and late (≥7 days after their first negative culture) CVC replacement following uncomplicated candidemia. 

Key findings:

  • Early replacement occurred in 18 encounters and late replacement in 21 encounters. The median time to CVC replacement or exchange in the early group was 4 days, compared to 10 days in the late group (P < 0.001).
  • The median duration of the hospitalization in the early group was 12 days compared to 21 days in the late group (P = 0.011).
  • None of the patients were reinfected with candida within 30 days.

My take: This small study provides reassurance that earlier replacement of  CVCs after clearance of uncomplicated candidemia is beneficial.

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Income and Health Outcomes in Pediatric Short Bowel Syndrome

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Clarification: Yesterday’s post on the safe use of polyethylene glycol (Long Term Use of Polyethylene Glycol (PEG 3350)) noted the labeling indicates “‘to not use these medications for more than 7 days.” However, Ben Enav pointed out that the label also states the following in bold: “do not take more than directed unless advised by your doctor.” The actual label is shown below.

———

SA Gutierrez et al. J Pediatr 2024; 265: 113819. Neighborhood Income Is Associated with Health Care Use in Pediatric Short Bowel Syndrome

Methods: The authors used the Pediatric Health Information System (PHIS) database to evaluate associations between neighborhood income and hospitalization data for children with short bowel syndrome (SBS). This included 4289 children with 16,347 hospitalizations from 43 institutions.

Key findings:

  • 2153 of the 4289 (50%) patients were readmitted during the study period (2006-2015)
  • Children living in low-income neighborhoods were more likely to be Black, Hispanic, have public health insurance, and live in the Southern U.S.
  • Children from low-income neighborhoods had a 38% increased risk for all-cause hospitalizations (rate ratio [RR] 1.38), an 83% increased risk for CLABSI hospitalizations (RR 1.83) and increased hospital length of stay.
  • 2.4% of patients in this cohort experienced 10 or more CLABSI hospitalizations

One of the study’s limitations is that ‘there is no singular ICD-9 code for SBS.’

My take: It is speculation about the reasons why children in low income neighborhoods have higher rates of hospitalizations and CLABSI hospitalizations. It could be that more parents in these households have less time and resources to manage a child with SBS. It is possible that these households have more chaotic environments. Regardless of the reason, it takes a lot of work and meticulous care to prevent CLABSI hospitalizations in children with SBS.

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A lot of Turk’s Cap Cacti along the Ram Head Trail, St John

Long Term Use of Polyethylene Glycol (PEG 3350)

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A Bautista-Casasnovas et al. JPGN Reports 4(4):p e353, November 2023. Open access! Multicentre Study Into the Use of Polyethylene Glycol With Electrolytes Over at Least 6 Months to Treat Constipation in Paediatric Populations

Background: PEG 3350 with electrolytes (PEG+E) is the most widely used osmotic laxative in Europe, and it is normally prescribed for short or limited periods in children, such that there is little information regarding its long-term use (≥6 months).

Methods: This was a retrospective, observational, descriptive, longitudinal, and multicentre study was carried out on 74 children diagnosed with functional constipation.

Patient characteristics:  The mean (±SD) duration of the symptoms of constipation before starting PEG+E treatment was >1 year (15.6 ± 8.4 months). Fecal disimpaction was necessary in 49 children (66.2%) .

Key findings:

  • The mean PEG+E dose used was 1.0 (±0.8) g/kg.
  • The mean duration of PEG+E use was 18.6 (±13.4) months (range 8–73 months), and 59.45% (n = 44) of the patients took the treatment for more than 1 year.
  • 81% (n = 60) of the patients achieved 4 or more weekly bowel movements after having taken PEG+E for at least 3 weeks.
  •  All clinical symptoms (abdominal pain, gassiness/bloating) were reduced considerably, with the resolution of the anal fissures, bleeding, and soiling in all patients.

Polyethylene glycol (the active ingredient in Miralax) is considered a first-line treatment for pediatric constipation and for fecal impaction. “However, caregivers may be hesitant to administer medication over long periods due to a fear of a rebound effect or addiction (23). Indeed, early withdrawal of laxatives is the commonest cause of recurrence (4,5), highlighting the need for longer follow-up studies (8).”

My take: It is helpful to have long term studies of PEG 3350 showing its effectiveness and safety, especially as the medication labels state to not use these medications for more than 7 days.

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Clarification: However, Ben Enav pointed out that the label also states the following in bold: “do not take more than directed unless advised by your doctor.” The actual label is shown below.

Delayed Commentary

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I was a little disappointed (aka first world problem) that this commentary appeared in the February print edition of The Journal of Pediatrics about 4 months after the publication of the analyzed study. This blog commented on this study in October: Disparities Are Abundant in Pediatrics -4 Studies on IBD, SUID, Specialty Referrals and in the NICU re: J Smith et al. J Pediatr 2023; 260: 113522.

DJ Spencer. J Pediatr 2024; DOI:https://doi.org/10.1016/j.jpeds.2023.113839. Open Access! Understanding Health Outcomes in Pediatric Inflammatory Bowel Diseases: Contributing Factors that Aren’t so Black and White

“In this issue of The Journal, Smith et al report the results of an historical cohort analysis of 519 children and adolescents with newly diagnosed IBD (2013-2020)… Smith et al ask the question of whether the greater rate of complicated disease in Black patients is related more to delayed diagnosis or access to therapy rather than inherent race-based differences in response to treatment.”

Key points:

  • “In this study, Smith et al importantly identified no difference in initiating standard medical therapies based on race. Specifically, they report no difference in initial corticosteroid usage, time to initiation of maintenance therapy, or time to initiate antitumor necrosis factor therapy. In patients receiving biologics, both Black and White patients received similar loading doses and frequency of therapeutic drug monitoring.”
  • “Despite comparable disease presentation and approach to medical therapy in this study cohort, Black patients strikingly remained only one-half as likely to reach corticosteroid-free remission at 12 months compared with White patients (OR 0.52, 95% CI 0.3-0.9).”
  • ” Black patients were less likely to be seen in gastroenterology specialty clinic for follow-up, more likely to present to the emergency department, and more likely to be hospitalized.”
  • “This study described poorer outcomes in Black patients despite similar treatments. However, the authors fail to arrive at a definitive answer as to why this is the case.”

My take: Black patients, even when offered similar IBD treatment, clearly experience inferior outcomes. While access and social determinants of health are important, there may be biological/phenotypic factors (eg. more aggressive disease) that are involved as well. More studies are needed. This editorial is a helpful review -the timing of the editorial in the print edition many months later, though, is a head-scratcher.

Unrelated topic: CDC COVID-19 Recommendation

The Centers for Disease Control and Prevention announced new isolation guidance for Covid-19 this week. At the start of the pandemic, people were recommended to stay home for 10 days after testing positive. At the height of the Omicron wave, that was revised to 5 days. This week, isolation time was revised to 24 hours without a fever and symptoms improving, which is similar to the recommendations for other illnesses.

St Johns Honeymoon Beach

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How Much of a Drug Markup is Reasonable (for hospitals)?

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JC Robinson et al. NEJM 2024; 390: 338-345. Hospital Prices for Physician-Administered Drugs for Patients with Private Insurance

In this study, the authors used 2020–2021 national Blue Cross Blue Shield claims data regarding patients in the United States who had drug-infusion visits. This included 404,443 patients in the United States who had 4,727,189 drug-infusion visits.  The authors examined 57 medications which represent the most expensive physician-administered drugs.

Background:

“Approximately one third of hospitals, including all specialized cancer hospitals, are also eligible for large discounts off drug acquisition prices under the federal 340B Drug Pricing Program.Hospitals thus have two means to generate profits from physician-administered drugs. Hospitals can reduce what they pay to manufacturers for the drugs, especially if they are eligible for 340B discounts, and can increase what they are paid for the drugs by imposing markups on the reimbursement prices they charge to insurers.”

Key findings:

  • The median price markup (defined as the ratio of the reimbursement price to the acquisition price) for hospitals eligible for 340B discounts was 3.08
  • After adjustment for drug, patient, and geographic factors, price markups at hospitals eligible for 340B discounts were 6.59 times as high as those in independent physician practices; price markups at noneligible hospitals were 4.34 times as high as those in independent physician practices
  • Hospitals eligible for 340B discounts retained 64.3% of insurer drug expenditures, whereas hospitals not eligible for 340B discounts retained 44.8% and independent physician practices retained 19.1%.
  • When we look at high drug costs, much is due to price markups NOT due to the manufacturers (which is already a lot). In this study, hospitals eligible for 340B discounts “retained almost two thirds of insurer drug expenditures, passing on only one third to the drug companies.”

My take: In my view, the health care market is messed up.

  • Hospitals charge exorbitant amounts for infusions (and other care) and this is worsening with consolidation
  • Insurance companies are difficult to work with and often deny needed care. Patients and physicians have little leverage to get them to fulfill their obligations.
  • Pharmaceutical companies use a myriad of tricks to increase the costs of their medications (see blog posts below) and charge U.S. consumers much more than what patients pay in other countries
  • Physicians are not incentivized to limit costs for patients/insurers. Many worry their reputations will suffer and they will be exposed to legal liability if thorough evaluations are not performed.
               From NEJM Twitter feed

Related issue:

This tweet from Bernie Sanders illustrates the additional costs that U.S. consumers pay for medications and indicates that legislation may be needed as the ‘market’ is not working well to control costs.

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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.

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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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“Real-World” Dupilumab for Eosinophilic Esophagitis

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CJ Lee, DS Dellon. Clin Gastroenterol Hepatol 2024; 22: 252-258. Open Access! Real-World Efficacy of Dupilumab in Severe, Treatment-Refractory, and Fibrostenotic Patients With Eosinophilic Esophagitis

Rationale for the retrospective study: ” Although it is the first Food and Drug Administration–approved treatment for EoE, eligibility criteria for the clinical trial program excluded several characteristics of the most severe EoE patients seen in clinical practice…Therefore, the purpose of this study was to determine the real-world efficacy of dupilumab in patients with severe, treatment-refractory, and fibrostenotic EoE.”

This cohort of 46 patients with severe disease including 39 (85%) who had prior esophageal dilatation (mean of 9). Patients had a mean age of 39 and had had symptoms for a mean of 13 years. Patients were considered treatment-refractory as all had received PPIs and topical steroids; in addition, most (87%) had tried elimination diets.

Key findings:

  • The peak eosinophil counts decreased markedly, and postdupilumab histologic response rates were 80% and 57% for fewer than 15 eosinophils per high-power field and 6 or fewer eosinophils per high-power field, respectively. Mean eosinophil count dropped from 70 to 9 following dupilumab treatment.
  • The Endoscopic Reference Score (EREFS) decreased from 4.62 to 1.89 with improvement in all categories: exudates, rings, edema, furrows and strictures.
  • Global symptom improvement was reported in 91% (P < .001).

My take: Many clinical studies are not representative of typical patients with various ailments, often excluding those with the most severe manifestations. This study indicates that dupilumab is an effective agent for patients with severe fibrostenotic eosinophilic esophagitis.

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Where I Want to Be Right Now (Honeymoon Beach, St Johns)

Spice It Up! Curcumin for Ulcerative Colitis (2024)

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S Ben-Horin et al. Clin Gastroenterol Hepatol 2024; 22: 347-356. Open Access! Curcumin-QingDai Combination for Patients With Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial

This two part study involved a small open-label trial of combination curcumin-QingDai (CurQD) with 10 patients and a placebo-controlled trial with 42 patients with active ulcerative colitis (UC) over 8 weeks.

Background: “Curcumin and QingDai (QD, Indigo) are herbal compounds previously found to be effective in mild–moderate and moderate–severe ulcerative colitis (UC), respectively, but data on their use still are limited.” Curcumin has purported anti-inflammatory and antioxidant properties through downregulation of nuclear factor-kB, regulation the JAK/STAT pathways, and through its effects on the NLRP3 inflammasome. Qing Dai, also known as indigo naturalis, is a traditional Chinese medicine that has demonstrated efficacy in promoting recovery from colitis in animal models and prior human trials, potentially acting through activation of the aryl hydrocarbon receptor.

Methods: CurQD was administered as 3 capsules of 500 mg herbal extract dry powder QD (a total of 1.5 g) and 3 capsules of 500 mg dry powder curcumin (a total of 1.5 g)

Key findings:

  • Clinical response was observed in 85.7% vs 30.7% (P < .001), clinical remission in 14 of 28 (50%) vs 1 of 13 (8%; P = .01), a 50% calprotectin reduction in 46.4% vs 15.4% (P = .08), and endoscopic improvement in 75% vs 20% (P = .036) in the CurQD and placebo groups, respectively. 
  • In the maintenance arm, 11/15 responders in the CurQD arm maintained remission for an additional 8 weeks with just curcumin alone.

The editorial (pg 235 ) notes the following:

  • The number of patients in the study is small and safety and effectiveness of these agents is not certain. Qing Dai has been associated with a rare risk of pulmonary arterial hypertension (especially with long-term use). Thus, further studies are needed.
  • “Although it may be preferrable to use these agents in combination with therapies with established efficacy, should the patients’ choice be to use alternative therapy as sole agents for treatment, it is important for us to continue to maintain a trusting physician-patient relationship to ensure that our patients are achieving the treatment targets they need to maximize long-term favorable outcomes, irrespective of the therapeutic agent of choice.”

My take: Curcumin (with combination of Qing Dai for induction) was superior to placebo in achieving meaningful clinical outcomes including clinical response, remission, calprotectin improvement and endoscopic improvement. For future studies, I would favor an active comparator like mesalamine rather than placebo.

Related blog post: Spice It Up? Curcumin for Ulcerative Colitis (2015)