“Crushing it:” Two More Pediatric Hepatitis C Trials

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Before today’s planned blog post, I wanted to mention a good NY Times article which highlights how long the virus which causes COVID-19 can be present on surfaces:

Full link from NY Times: How Long Will Coronavirus Live on Surfaces or in the Air Around You?

An excerpt:

The virus lives longest on plastic and steel, surviving for up to 72 hours. But the amount of viable virus decreases sharply over this time. It also does poorly on copper and cardboard, surviving four to eight hours; the latter finding suggests packages that arrive in the mail should be safe — unless the delivery person has coughed or sneezed on it or has handled it with contaminated hands.

That the virus can survive and stay infectious in aerosols is also important for health care workers.

For weeks experts have maintained that the virus is not airborne. But in fact, it can travel through the air and stay suspended for that period of about a half-hour.

The virus does not linger in the air at high enough levels to be a risk to most people who are not physically near an infected person. But the procedures health care workers use to care for infected patients are likely to generate aerosols.

The original article from NEJM:  Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

——–

This “C” virus was hard to cure until recently.  More good news from recently published studies for pediatric hepatitis c virus (HCV) treatment:

  • KB Schwarz et al. Hepatology 2020; 71: 422-30. 
  • MM Jonas et al. Hepatology 2020; 71: 456-62.
  • AASLD-IDSA Practice Guidance Panel. Hepatology 2020; 71: 686-721

In the first study of an all oral regimen of ledipasvir-sofosbuvir, sustained virological response at 12 weeks after dosing (SVR12) was achieved in 33 of 34 (97%) of children 3-<6 yrs of age with genotypes 1 or 4 (only 1 with type 4). No serious adverse effects were reported. Dosing: 33.75 mg/150 mg if <17 kg or 45 mg/200 mg if ≥17 kg. The one non-responder discontinued treatment due to drug taste.  Pharmokinetic studies in 13 patients confirmed appropriate medication dosing.

In the second study of glecaprevir/pibrentasvir (G/P), as part of the DORA phase 2/3 nonrandomized, open-label trial, adolescents 12-17 received the ‘adult’ regimen of 300 mg/120 mg daily for 8-12 weeks in accordance with indication duration based on adult data.  Among the 47 patients (genotypes 1, 2, 3, 4), 100% achieved SVR12. Safety profile was consistent with prior studies in adults.

The third publication, which is quite lengthy, highlights updated recommendations for HCV in adults and children (this will be reviewed in tomorrow’s post).

Related blog posts:

More Advice on Coronavirus for Pediatric GIs: NASPGHAN and CCFA

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For Georgia:

NASPGHAN statement regarding Coronavirus (SARS-CoV-2) Associated Infectious Disease (COVID -19) and Pediatric GI Patient Care and Providers.

Dear Members,

In view of the COVID -19 pandemic, care of our pediatric GI patients and at the same time our pediatric GI providers (i.e. physicians and other members of the healthcare team) is an utmost priority at NASPGHAN. NASPGHAN is working on several initiatives concurrently, and we are writing at this time to make you aware.

1. The Endoscopy Committee and the Clinical Practice Committee are working on a statement regarding elective procedures for pediatric GI patients with respect to this highly contagious pathogen, COVID to both preserve Personal Protective Equipment (PPE) as well as limit potential exposure.

2. A task force of leaders from NASPGHAN, ESPGHAN, LASPGHAN, and Asia (Hangzhou, China) will be writing a commentary to be published in the JPGN, our journal, with what COVID-19 means to the pediatric gastroenterologist.

3. Mike Kappleman of UNC, ICN, NASPGHAN and in particular the IBD Committee, are launching a prospective, real-time monitoring study of COVID-19 in IBD patients. The study is IRB and HIPAA approved and will link its data with that collected by the European Porto group’s study of coronavirus in IBD patients in Europe and Asia, thereby allowing an operational real-time active surveillance network for children and adolescents with IBD (our patients).

4. Jason Silverman, Jennifer Lee, and Peter Lu are putting together a special episode of the Bowel Sounds Podcast™ including relevant up-to-date guidelines and information about COVID-19 as it relates to our members and our patients.

5. The Endoscopy Committee and Clinical Practice Committee are working on information and options for telemedicine and virtual health, given the more recent announcement by CMS and the White House/President Trump in terms of changes in reimbursement given the coronavirus pandemic.

6. Within the next 24 hours, the NASPGHAN Website, as well as GIKids.org will house resources and links to the Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics (AAP), Crohn’s and Colitis Foundation (CCF), the Canadian Association of Gastroenterology (CAG) and the Joint GI Societies Statement (adult-based), including ASGE, ACG, AGA on Endoscopic procedures in the face of COVID-19.

7. Finally, please feel free to send us suggestions that would help our pediatric GI community work towards creative solutions during this time.

Sincerely,

Karen F. Murray MD
President, NASPGHAN

James Heubi MD
Past President, NASPGHAN

Benjamin Gold MD
President Elect, NASPGHAN

Jeannie S. Huang MD
Secretary Treasurer, NASPGHAN

Rina Sanghavi MD

Underlying Genetic Disease in Pediatric Inflammatory Bowel Disease

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Link to text of accepted study (Gastroenterology, ahead of publication): Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated with Monogenic Variants, Identified by Whole-exome Sequencing in 1000 Children at a Single Center 

Abstract:

Background & Aims: A proportion of infants and young children with inflammatory bowel diseases (IBD) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

Methods: We performed whole-exome sequencing analyses of blood samples from an
unselected cohort of 1005 children with IBD, 0–18 y old (median age at diagnosis, 11.96 y) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses.

Results: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 y and 2.3% of children 6–18 y old. Of the 17 patients with monogenic Crohn’s disease, 35% had abdominal pain, 24% had non-bloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 y (odds ratio [OR], 6.30; P=.020), family history of autoimmune disease (OR, 5.12; P=.002), extraintestinal manifestations (OR, 15.36; P<.0001), and surgery (OR, 3.42; P=.042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation.

Conclusions: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare but should be considered in analysis of all patients with pediatric onset of IBD.
KEY WORDS: HSCT, genetics, risk factor, prevalence

 

VEO-IBD -Useful “Position” Paper is Really a Review

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A recent publication (Full text: NASPGHAN Position Paper on the Evaluation and Management for Patients with Very Early-onset Inflammatory Bowel Disease. JR Kelsen et al. JPGN 2020; 70: 389-403) is more of a review than a true position paper. A related upcoming study (highlighted tomorrow) indicates that ~8% of VEO-IBD patients have underlying monogenetic forms of IBD.

While the article makes numerous useful points, explicit recommendations are not clearly stated.

Key Points:

  • Epidemiology: 6-15% of pediatric IBD population presents at <6 years of age
  • Children with VEO-IBD need careful immunologic evaluation.  Some of the specific disorders that need to be considered include Chronic Granulomatous Disease (can check DHR) and XIAP (can check a flow cytometry-based assay).
  • Besides panendoscopy, the article recommends close collaboration with the pathologist to identify specific features of the numerous VEO-IBD disorders (most listed/described in Table 1)
  • Identification of VEO-IBD disorders with genetic testing (either whole exome or targeted gene panel) helps determine specific medical therapies and/or stem cell transplantation for disorders like CTLA4B deficiency, LRBA defects, IL-10 deficiency, XIAP, STXBP2, and FOXP3 deficiency.
  • Infliximab does not work as well in VEO-IBD patients.  A recent study found only 12% remained on infliximab 3 years after initiation.
  • VEO-IBD were much more likely to need surgery with rates of 50% for those with onset before 1 year and ~30% for those after 1 year of age.  Colectomy should be considered with caution due to the overlapping presentation of Crohn’s disease and ulcerative colitis in this age group.

One topic that was not discussed was the potential role for dietary therapy in this age group.

Related blog posts:

The following related images are from Eric Topol’s twitter feed and share figures from a Nature review.

Seen on Eric Benchimol’s twitter feed

Briefly Noted: Parent Preference: MiniONE over MIC-KEY

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In a prospective, randomized cross-over trial (RA Abdelhad et al. JPGN 2020; 70: 386-8) that compared two low profile gastrostomy buttons, caregiver preference favored AMT’s MiniONE over Avanos Medical’s MIC-KEY.  It is worth noting that the authors reported no conflict of interests.

Among 185 patients, 65 with MIC-KEY and 43 with MiniONE completed crossover study; GT buttons were placed laparoscopically.

  • In this group, 69% preferred MiniONE.
  • There were no differences in objective outcomes: adverse effects, emergency room/clinic visits, leavage, granulation tissue or dislodgements.
  • Caregiver preference was based on smaller size of external bolster and its ability to glow in the dark.

Some limitations of this study included a lack of long-term followup and an imbalance in the crossover groups completing the study.  Lack of blinding of the investigators and caregivers could have allowed bias to affect evaluations as well.

UNC Campus Pic (Chapel Hill)

 

Today’s Children in Crisis: YOYO

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Predictive Modeling on COVID19 in U.S. from NYTimes: How Much Worse the Coronavirus Could Get, in Charts

Modeling comments from Nate Silver: It’s important to keep in mind that many of these models describe projections *without* changes in behavior. This is mentioned in the article (good for NYT, a lot of articles omit this context). So behavioral changes and testing are key. I slightly worry that some of the headlines contribute to a sense of fatalism, when the real message is more like “this is probably gonna be bad, but it could be considerably less bad if we get our act together and much worse if we don’t.”

———-

Besides the current outbreak, what else has been happening to children:

So, is it surprising at all that there is no interest in limiting products shown to be dangerous for children?  Today’s children are being told: ‘you’re on your own’ (YOYO)

An ongoing concern for pediatric gastroenterologists, magnet ingestions, was highlighted in a Politco report -thanks to Ben Gold for sharing this report: Toddlers eat shiny objects….

Here are a few excerpts:

Once ingested, high-powered magnets find each other inside the body and shred any tissue, such as bowel, trapped in between….

In early 2012, this coalition [led by NASPGHAN] approached the Consumer Product Safety Commission with one simple ask: eliminate these high-powered magnet sets from the market…the agency ultimately recalled high-powered magnet sets …

One company, Zen Magnets, remained unconvinced, and sued the CPSC, fighting… the recall on existing magnets…

The rule [ban] set was struck down by two judges on the 10th Circuit Court of Appeals with the deciding vote cast by now-Supreme Court Justice Neil Gorsuch. These judges ignored the expertise of the CPSC epidemiologists and economists; ignored the compelling medical testimony, overwhelming expert evidence and dire safety consequences and substituted their own opinion in favor of promoting “government restraint” on regulating industry…

The nation’s poison control centers recorded six times more magnet ingestions―totaling nearly 1,600 cases in 2019 alone—after the 10th circuit court decision allowed magnets back on the market…

The article details how the CPSC’s change in regulation has also led to deaths related to delays in recalling faulty infant inclined sleeps, with defective RZR All Terrain Vehicles, and the mismanaged recall of IKEA’s Malm dressers.

A related article was published in USA Today this week by Dr. Bryan Rudolph: Children can easily swallow high-powered magnets, it’s time to ban them for good

My take: What’s next up for our children? Outlawing lifeguards for pools? Repealing seat belt laws?  Perhaps it won’t matter –there are so many bigger threats that are not even on the radar.  YOYO.

Related blog posts:

Image from Politico

Biliary Atresia Biomarkers 2020

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Two recent studies provide more information on biliary atresia (BA) biomarkers.

  • OG Behairy et al. JPGN 2020; 70: 344-9.
  • S Shamkar et al. JPGN 2020; 70: 350-5.

Behairy et al report on the use of serum IL-33 in a cohort of 90 infants, 30 with BA, 30 with cholestasis due to other causes, and 30 healthy infants.

  • Using a cut-off of 20.8 pg/mL, IL-33 had a specificity of 95% and sensitivity of 96.7% for identifying BA.
  • Interestingly, the test performed better in those with advanced fibrosis.  The mean value of IL-33 in those with grade 3/6 was 88.2 compared to 37.2 for 1/6 and 70.9 for 2/6. In comparison, the children with cholestasis due to other liver disease had a level of 18.5 for those with 3/6 fibrosis

The authors note in a prior study that IL-33 was higher in BA infants than those with a choledochal cyst.

While this is a small study, I disagree with the editorial (pg 278-9) which largely discounted the potential role of IL-33.  “IL-33 is elevated with many other diseases (bronchopulmonary dysplasia, asthma, allergy, and more) It, therefore, cannot easily be used as a highly specific marker for fibrosis. Furthermore, the use of IL-33 as a prognostic marker, is from a clinical point of view not of great importance, as follow-up clinical decisions are generally made based on patients’ clinical course.”

Shankar et al provide data on GGT values in BA (n=113 infants).

These infants underwent Kasai procedure at a median of 61 days

  • 12.3% had normal (<200) GGT values.
  • Those with normal GGT had worse outcomes: earlier need for liver transplantation (14 vs 20 months) and poorer transplant survival.
  • 9/14 (64%) with normal GGT and 53/99 (53.5%) of elevated GGT underwent liver transplantation

The authors note that decreased levels of GGT has been associated with reduced glutathione metabolism which could impari adaptive response to oxidative stress, leading to further hepatocyte injury.

My take: In my experience, I have had very few BA patients with GGT values <200 (lower than 10%).  The development of other biomarkers like MMP-7 and IL-33 increase the likelihood that BA will be recognized sooner and if elevated, could obviate the need for a liver biopsy prior to operative cholangiogram.  Nevertheless, practitioners cannot wholly rely on any the current biomarkers.

Related blog posts:

Fall on UNC Campus, Chapel Hill

It’s Complicated: The Relationship Between Milk and Health

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  • GutsandGrowth Milestone: this is the 3000th blog post
  • New COVID19/IBD worldwide registry (so far zero cases reported.  Can report cases at the following: SECURE-IBD Registry

——

A provocative review (WC Willett, DS Ludwig. NEJM 2020; 182: 644-54) provides a rationale for why a healthy diet may not need milk.

Key points:

  • “The current recommendation to greatly increase consumption of dairy foods to 3 or more servings per day does not appear to be justified.”
  • All the nutrients in milk can be obtained from other sources (including calcium and vitamin D). If diet quality is low, especially for children, dairy foods can improve nutrition. “If diet quality is high, increased intake is unlikely to provide substantial benefits, and harms are possible.”
  • Overall evidence does not support high dairy consumption will reduce fractures
  • Total dairy consumption has not been clearly related to weight control or to risks of diabetes or cardiovascular disease
  • The reported health benefits of milk depend strongly on what food it is being compared to; dairy intake is generally more favorable than processed red meat or sugar-sweetened beverages but less compared to plant-protein sources (eg. nuts)
  • No clear benefit of consuming reduced-fat milk compared to whole milk
  • Milk intake in childhood is associated with greater attained height which confers both risks and benefits

More details:

The authors review the composition of cow’s milk and compare it to human milk and cheddar cheese (Table 1). They note that cows have been bred to produce higher levels of insulin-like growth factor 1 (IGF-1) and that they are pregnant for most of the time they are milked; this greatly increases hormones like progestins and estrogens in milk.

The authors review how milk can promote growth and development in children.  Tall stature, associated with milk intake, is associated with lower risks of cardiovascular disease but with higher risks of many cancers, hip fractures, and pulmonary emboli.

Bone health and fracture risk: “paradoxically, countries with the highest intakes of milk and calcium tend to have the highest rates of hip fractures;” this, however, may not be causal as their are a lot of confounding factors (eg. Vitamin D status, ethnicity).  The authors also note that U.S. studies have shown calcium intake was unrelated to bone mineral density in the hip.  Further, the authors point out the discrepancies between U.S. and U.K with regard to daily calcium requirements; at age 4-8 yrs, U.S RDA is 1000 mg per day compared to 450-550 mg in UK.  Estimation of the calcium requirement is “problematic.”

Body weight and obesity.  “Studies of milk consumption and body weight in children are few and are subject to confounding and reverse causation.”  Available studies, however, have shown that whole milk and 2% milk are associated with lower risk of obesity than low-fat or skim milk.

Blood pressure, lipids, and cardiovascular disease in relation to milk consumption:  Ultimately, whether milk is beneficial is mainly related to the comparison foods.

Milk and the development of diabetes:  intake of dairy products has been associated with a modestly lower risk of type 2 diabetes.  Despite some hypothetical risks for type 1 diabetes, children weaned to “hydrolyzed protein instead of cow’s milk did not have fewer autoantibodies to beta cells after 7 years than children who drank cow’s milk.”

Milk intake and cancer.  Milk consumption is associated with a lower risk of colorectal cancer (likely due to its high calcium intake) and an increased risk of breast cancer, prostate cancer, and endometrial cancer; these effects may be mediated by the sex-hormones in milk.

Allergies to milk may affect up to 4% of infants.  In addition, lactose intolerance “limits consumption of milk worldwide.”

Total mortality and its association with milk intake:  “in a meta-analysis that included 29 cohort studies, intake of milk (total, high-fat, and low-fat) were not associated with overall mortality.”  Again, the risk is related to what food is substituted for milk intake.

Organic/grass-fed production and potential detrimental environmental effects from milk production; the latter includes pollution, antibiotic resistance, and greenhouse gas production.

My take: These authors are not going to get any funding from the dairy industry.  Dairy is typically an important nutrient source in children. Particularly in adults, lower intakes of dairy may be warranted.

Related blog posts:

 

Island Ford, Sandy Springs

Silent Anal Fistulas –Sounds Bad, Is It?

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A recent prospective study (PH Kim et al. Clin Gastroenterol Hepatol 2020; 18: 415-23) with 440 consecutive adults (mean age 29.6 years) with Crohn’s disease (CD) identified asymptomatic anal fistulas with MRE (including anal MRI) studies. 36 patients were newly diagnosed and the remainder had established CD.

Key findings:

  • In all of these patients, none of whom had clinical fistulas, an MRE identified “perianal tracts” in 53 (12%).
  • 37 of 290 (12.8%) of patients without a perianal fistula history and 16 of 150 (10.7%) with a history of healed perianal fistula had perianal tracts identified on MRE
  • No patients had any lesions that required treatment after examination by a surgeon
  • MRE detection of asymptomatic tracts was independently associated with later need for perianal treatment: 17.8% cumulative incidence at 37 months (aHR 3.06)

My take: Abnormal perianal tracts on MRE in asymptomatic patients indicate an increased risk of developing clinically-significant perianal disease –though most do not.

More on COVID19:

  • No children with IBD have been reported thus far from ESPGHAN which includes a 100 sites (mainly Europe) (as of March 10th); to report cases: ESPGHAN COVID19 Case Report Page
  • There is some discussion that biologic therapy for IBD may have some protective effects