Gene Replacement Therapy for Spinal Muscular Atrophy and Subacute Liver Failure

Posted on October 28, 2020 by gutsandgrowth

A recent study (AG Feldman et al. J Pediatr 2020; 225: 252-258. Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1) describes two children who developed subacute liver failure after treatment with onasemnogene (AVXS-101). This gene therapy was approved by the FDA in 2019 and more than 335 children have been treated. Both children presented about 3-8 weeks after their AVXS-101 infusion (despite steroid therapy), at 6 months of age and 20 months of age respectively, with ALT values above 1600 and INR of at least 1.5 (despite Vitamin K). Both had liver biospies and then were treated with methylprednisolone, starting at 20 mg/kg/day.

Key points:

The authors speculate that subacute liver failure was due to a systemic hyperinflammatory reaction
The authors recommend screening prior to AVXS-101 therapy with LFTs, GGT, and INR; if baseline labs are elevated, further workup is recommended (eg. A1AT, HBV, HCV, ANA, anti-SMA, anti-LKM, and ultraound)
While this reaction has been with AVXS-101, there are other gene therapies with adenovirus-vector which could trigger similar reactions
The authors note that the “package insert for onasemnogene recommends prednisolone (1 mg/kg/day) should be given in the 24 hours before infusion and should be continued for 30 days after infusion.”
After infusion, it is “necessary to monitor liver tests frequently in the first 2 months”

My take: This new therapy’s risks are substantial; however, the benefits from treatment can be life-altering as well.

Anemia in IBD -NASPGHAN Position Paper

Posted on October 27, 2020 by gutsandgrowth

A Goyal et al. JPGN 2020; 71: 563-582 Full text (free). Anemia in Children With Inflammatory Bowel Disease: A Position Paper by the IBD Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition.

Main Types of Anemia in Inflammatory Bowel Disease:

“IDA is the most common cause of anemia in children with IBD. True iron deficiency results from a number of factors, including chronic blood loss secondary to gastrointestinal bleeding, decreased iron absorption because of tissue or systemic inflammation and from reduced absorptive surface area. “
“Functional iron deficiency (FID) results from high levels of circulating hepcidin, which binds to and disables the iron transporter, ferroportin. Under the influence of hepcidin, ferroportin-mediated export of intracellular iron is stalled, leaving the iron trapped within the enterocytes and macrophages… the underlying inflammation, which induces hepcidin production can result in anemia secondary to FID.”
Anemia of chronic disease (ACD) “occurs from various downstream pathways secondary to inflammation.”

Table 4:

Recommended Testing

Screening Tests: “initially a complete blood count (CBC), CRP, and ferritin levels should be performed. If a patient is found to be anemic, then testing should include CBC with differential, including mean corpuscular volume (MCV), mean corpuscular Hgb concentration (MCHC), red cell distribution width (RDW), reticulocyte count, CRP, serum ferritin, and transferrin saturation (TSAT)”
Serum iron level … is … unreliable in the assessment of iron deficiency as the level fluctuates with several variables.
Transferrin saturation (TSAT) is a measure of the iron content in the circulating transferrin and reflects the availability of utilizable iron

Treatment of Anemia

In mild anemia (Hgb ≥10 g/dL) and/or quiescent disease, oral iron should be tried first.
Parenteral iron is indicated when oral iron is ineffective or poorly tolerated, in patients with moderate-severe anemia and/or with active inflammation.
According to ECCO guidelines, an IV replacement goal of achieving of ferritin level of up to 400 μg/L is more likely to prevent recurrence of anemia…a transferrin saturation of 50% and serum ferritin of 800 μg/L should not be exceeded
Regarding iron effects on microbiome: studies indicate that dysbiosis at baseline worsens the unfavorable shifts in microbiome with oral iron therapy…Our position, however, is that further studies are required in humans before any reliable conclusions can be drawn. [My question: have the effects of oral iron supplementation on the microbiome been compared to IV iron supplementation on the microbiome?]
Table 6 lists various iron products including costs and dosing.
The hypersensitivity reactions to parenteral iron are mostly secondary to iron nanoparticles that trigger complement activation-related pseudo-allergy (CARPA)….It is important that parenteral iron be administered by trained personnel. Emergency medications and resuscitative equipment should be available during these infusions.

My take: This is a useful resource for a very common problem.

Related blog posts:

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

More Evidence That A Proinflammatory Diet May Increase the Risk of Crohn’s Disease

Posted on October 26, 2020 by gutsandgrowth

C-H Lo et al. Gastroenterol 2020; 159: 873-883. Full Text Link Dietary Inflammatory Potential and Risk of Crohn’s Disease and Ulcerative Colitis

The authors used Empirical dietary inflammatory pattern (EDIP) scores which were calculated based on the weighted sums of 18 food groups obtained via food frequency questionnaires. n=166,903 women and 41,931 men

Key findings:

“In an analysis of 3 large prospective cohorts, we found dietary patterns with high inflammatory potential to be associated with increased risk of CD but not UC.”
- Compared with participants in the lowest quartile of cumulative average EDIP score, those in the highest quartile (highest dietary inflammatory potential) had a 51% higher risk of CD (HR 1.51; 95% CI 1.10–2.07; P_trend = .01).
There were 328 cases of CD and 428 cases of UC over 4,949,938 person-years of follow-up. The median age at IBD diagnosis was 55 years (range 29–85 years)

Discussion points:

Food groups that are associated with unfavorable EDIP scores “are characterized by calorie-dense foods high in animal proteins, saturated fats, and glycemic carbohydrates, such as red meat, refined grain, and high-energy soft drinks.”
- “Dietary patterns resembling the Western diet, characterized by higher intake of red meat, high-fat dairy, and refined grains, have been proposed to trigger the onset of intestinal inflammation by inducing changes in gut microbiome, altering host homeostasis, and regulating T-cell immune response.”
“In contrast, diets rich in fruit, vegetables, legumes, whole grains, fish, and poultry, resembling a more prudent and Mediterranean dietary pattern with high fiber and marine ω-3 content, may have anti-inflammatory effects.”

Related blog posts:

Vedolizumab -Not Likely to Help Primary Sclerosing Cholangitis

Posted on October 25, 2020 by gutsandgrowth

A recent retrospective study (TJ Laborda et al. JPGN 2020; 71: 459-464 Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium) indicates that vedolizumab (VDZ) is unlikely to be helpful for primary sclerosing cholangits (PSC).

VDZ was initiated at median age of 16 years [IQR 15–18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis.

Key findings:

Overall, there was a mild increase in median GGT after initiation of VDZ. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response (defined as GGT <50 or at least a 75% decline) after 9 to 12 months
For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response

In the discussion, the authors note that their findings are in agreement with three retrospective studies in adults which have shown that VDZ is not effective for PSC in patients with IBD.

My take: This study indicates that VDZ is not likely to help with PSC, though 62% of IBD patients had improvement in their GI disease.

Cholangitis After Kasai Procedure for Biliary Atresia

Posted on October 24, 2020 by gutsandgrowth

K Cheng et al. JPGN 2020; 71: 452-458. Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study

This study, which relied on data from a pediatric database (PHIS) with 48 pediatric centers, identified 1112 subjects with biliary atresia (2004-2013).

Key findings:

Median age at time of Kasai (hepatoportoenterostomy) procedure: 63 days
Median number of admissions for cholangitis within 2 years was 2 episodes. The presence of portal hypertension (OR 2.24) and black race (OR 1.51) were associated with higher risk of cholangitis
When Kasai was performed at >90 days, this lowered the likelihood of cholangitis (OR 0.46)
With regards to those with 5 or more bouts of cholangitis, risk factors included Asian ethnicity (OR 2.66), public insurance (OR 1.72), and portal hypertension (OR 2.88)
56% of patients had portal hypertension and 15.6% had esophageal varices
Neither steroids nor ursodeoxycholic acid were found to affect patient outcome
Limitations: lack of clear definition for cholangitis diagnosis and episodes of cholangitis may not have been captured if patients received care outside the participating centers

My take: Cholangitis is a common problem following hepatoportoenterostomy. Earlier diagnosis of biliary atresia provides the best opportunity for improving long-term outcomes.

Related blog posts:

Latest on Masks & Rural Hospitals Closing

Posted on October 23, 2020 by gutsandgrowth

AAP Behind the Scenes (Fall 2020)

Posted on October 23, 2020 by gutsandgrowth

This Georgia AAP (virtual) board meeting started with a brief review from Dr. Kathleen Tomey (Department of Health)

Some slides:

This data should be interpreted based on limited testing in this age group

AAP Update from Dr. Scornik:

Toolkit available at Georgia AAP Website

Full link: Race, Postoperative Complications, and Death in Apparently Healthy Children

Safe sleep initiatives briefly discussed by Dr. Sarah Lazarus which aligns with Strong4Life campaign:

From Dr. Evan Anderson’s presentation to AAP Board Meeting

Dr. Anderson notes that COVID-19 mortality and morbidity IN CHILDREN exceeding other conditions with vaccines like Varicella and Influenza.

Letter from AAP President to FDA (Dr. Hahn) and HHS (Alex Azar)

Other information:

Update on E-Cigarettes Webinar*+: Wednesday, October 28 at 12:30 pm
Please note new date! Here’s a chance to still register.
First in a series of three webinars offered to Georgia Pediatricians on the growing epidemic of youth e-cigarette use
Faculty: Alice Little Caldwell, MD, FAAP
https://register.gotowebinar.com/register/8457518617359610381

Stelara (Ustekinumab) Safety

Posted on October 22, 2020 by gutsandgrowth

F Poizeau et al. JAMA Dermatol. Published online September 9, 2020. doi:10.1001/jamadermatol.2020.2977. Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti–Interleukin 12/23p40 Antibody Ustekinumab

Methods: “This case-time-control study used data from the French national health insurance database, covering 66 million individuals, on all patients exposed to ustekinumab between April 1, 2010, and December 31, 2016, classified according to their cardiovascular risk level (high- and low-risk strata). The risk period was the 6 months before the SCE, defined as acute coronary syndrome or stroke, and the reference period was the 6 months before the risk period. Statistical analysis was performed from September 20, 2017, to July 6, 2018.”

Key findings:

Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced SCEs (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke).
Among patients with a high cardiovascular risk, a statisically significant association between initiaton of ustekinumab treatment and SCE occurrence was identified (odds ratio, 4.17; 95% CI, 1.19-14.59).
Conversely, no statistically significant association was found among patients with a low cardiovascular risk (odds ratio, 0.30; 95% CI, 0.03-3.13).

My take: This study suggests that the initiation of ustekinumab treatment may trigger SCEs among patients at high cardiovascular risk; however, the study conclusions are limited as this was an observational study (not a randomized trial).

Be Kind & the 21st Century Cures Act

Posted on October 21, 2020 by gutsandgrowth

I remember when I was first taught to dictate consultations. I was a resident doing a genetics rotation. My mentor, Peter Dignan, made several suggestions. One was to try to always include something nice about the patient. Many of my current colleagues are amused how many of my patients are ‘delightful.’ While there are a lot reasons for putting some kind information in the medical record, Dr. Dignan emphasized that patients and families can get hold of their records and undoubtedly they would appreciate a friendly word. Now with the 21st Century Cures Act Final Rule, access to records and notes will expand considerably and Dr. Dignan’s advice is probably even more important.

A good source of information on this new law, which is in effect Nov 2nd, 2020, is from the 33charts blog—Cures Act Final Rule – How It Will Change Medicine: “The ONC Cures Act Final Rule (Cures Rule) is the biggest health care law you’ve never heard of. But it’s a law that’s going to fundamentally shift the way we see patients and their information. It will change how physicians talk to patients about information. It will shift the way health professionals connect patients to their information.” This blog post details how this change is going to affect both healthcare providers and families. The two key changes are

Access to clinical notes (ie, ‘open notes’)
Immediate release of tests and studies.

The key point: “The Cures Rule will force health systems to be better stewards of information on behalf of our patients. I think this is going to force health professionals to help patients think about information and what they do with it. It will force patients to recognize the difference between information and knowledge and wisdom. I suspect that the most critical ultimate change will be transparent conversations and more timely physician follow-up on high stakes studies.”

Another take on the 21st Century Cures Act: C Blease et al. Annals of Internal Medicine; 2020: https://doi.org/10.7326/M20-5370. New U.S. Law Mandates Access to Clinical Notes: Implications for Patients and Clinicians

Some additional information (from EPIC training) — there are limited exceptions for note sharing:

Another reference:

My take: When this rolls out, a lot of physicians (myself included) will need to make some adjustments; since it is the law, don’t expect to avoid these changes. I expect early on this will generate a lot of additional questions and phone calls. In the long run, this is likely to improve communication, transparency, and availability of patient information. For example, it is more likely that needed lab results from referring physicians will be more available after this law is in effect.

PPD (TB Skin Test) or Interferon-Gamma Release Assay (TB Blood Test)?

Posted on October 20, 2020 by gutsandgrowth

A recent editorial (JG Hashash et al. Inflamm Bowel Dis 2020; 26: 1315-1318. Approach to Latent Tuberculosis Infection Screening Before Biologic Therapy in IBD Patients: PPD or IGRA?) provides some guidance on screening for tuberculosis prior to biologic therapy as well as background on how these tests work.

Key points:

The authors state that both a PPD or TB Blood Test (aka Quantiferon-TB Gold) are reasonable for most individuals, though they have a preference for the TB Blood Test.
For those with history of BCG vaccination, the TB Blood Test is recommended
Steroids are associated with negative PPD and indeterminate TB Blood Test.
The authors advocate baseline testing prior to biologic therapy for everyone.
Annual testing: For those in high TB endemic areas, “we propose yearly chest x-ray in addition to IGRA [TB Blood Test]…in low endemic areas…we do not perform yearly chest x-rays nor do we check yearly IGRA unless mandated by a patient’s insurance.”

My take: TB blood testing is more convenient but more costly. The authors indicate that for patients from low endemic areas, yearly TB testing is mainly to check boxes mandated by insurance companies rather than improving care.