Inconclusive Screening for Cystic Fibrosis and Outcomes

T Gonska et al. Pediatrics 2021; 148: e2021051740. Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age

Background: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis

Methods: Prospective, longitudinal, multicenter, Canada-wide cohort study of CFSPID for a mean of 7.7 years

Key findings:

  • A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) — either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. Those with initial sweat chloride concentration ≥40 mmol/L were most likely to receive a diagnosis of cystic fibrosis.
  • Children with CFSPID were pancreatic sufficient and showed normal growth until school age and had good pulmonary outcomes (similar to healthy controls)
  • In the associated commentary by P Chakraborty et al (Maximizing Benefits and Minimizing Harms: Diagnostic Uncertainty Arising From Newborn Screening), the authors note that while newborn screening (NBS) offers benefit of early diagnosis, some families can be harmed by false-positive tests or inconclusive results. Furthermore, “these issues of uncertainty are increasingly important to consider as the scope of NBS programs and their use of genomic technologies expands.”

My take: With CF, this study shows the need to monitor those with inconclusive studies. More broadly, the use of genomic testing is leading to more frequent inconclusive results in many areas and sometimes leaving more questions than answers.

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From NPR, December 2021

CHOA Nutrition Support Lecture: Cystic Fibrosis Nutrition -Changing in the Age of ‘Miracle Drug’

Recently a terrific review of Cystic Fibrosis and Nutrition was presented at our CHOA nutritional colloquium.

To access this ~45 minute webinar: Next Nutrition Support Colloquium Webex on Tuesday, 2/23, at 1300-1400: “Nutrition and Cystic Fibrosis”-20210223 1812-1

Password: 5DgsMXqY

Key points:

  • Advances in Cystic Fibrosis (CF) have led to improvement in longevity, now ~46 years in 2019
  • Newer CFTR modulator therapies need to be aligned to the specific mutations. With new therapies, a high calorie diet may not be required and instead follow a standard healthy balanced diet.
    • These agents appear to be driving a big drop in hospitalizations
    • Now some patients need counseling for obesity and NAFLD
  • Better nutrition has been linked to better lung outcomes.
  • Pancreatic enzyme replacement therapy needed for 85-90% of patients with CF
    • CFTR modulator therapies may allow lower dosing PERT dosing
  • Fat soluble vitamin supplementation (A, D, E, K) is needed
    • Vitamin D (25-OH) goal (by CF Foundation) is >30 ng/mL
  • High salt diet is recommended due to excessive losses
  • Targeted nutritional support needs to be based on nutritional status; some patients may need G-Tube placement. CHOA algorithm developed.
  • High sugar diet may increase the development of CF related diabetes (CFRD)
  • Fibrosing colonopathy is a very rare effect of high dose pancreatic enzymes and may have been in part due to impurities in older preparations of panrcreatic enzymes.

Some of the slides:

Related blog posts:

Data on Immobilized Lipase Cartridge for Patients with Cystic Fibrosis

Full text: M Sathe et al. JPGN 2021; 72: 18-23. Evaluation of the Effectiveness of In-line Immobilized Lipase Cartridge in Enterally Fed Patients With Cystic Fibrosis

Background: Traditional pancreatic enzyme replacement therapy is not designed for use with enteral feedings. “Only 1 FDA-approved PERT (PERTZYE, Cheisi, Inc.) has a package insert with instructions on how to deliver the contents of the lowest dose capsule (4000 USP lipase unit) through gastrostomy tubes 14 French or larger…Two recently published studies demonstrated the safety, tolerability, and effect on FA absorption of a new enzyme strategy to aid fat digestion with continuous enteral feedings, a single use digestive cartridge containing immobilized lipase (RELiZORB; Alcresta Therapeutics, Newton, MA). The cartridge connects in-line with an enteral feeding set. As enteral formula flows through the cartridge, immobilized lipase enzyme hydrolyzes intact triglyceride fats within the formula into more absorbable forms, whereas the lipase is retained within the cartridge.”

Key findngs:

  • Weight percentiles reached 50% in 18%, 25.5%, and 28.9% of patients at 0, 6, and 12, respectively.
  • BMI reached 50% in 37.1%, 49.1%, and 50.0% in patients at 0, 6, and 12 months, respectively.

My take: “Immobilized lipase cartridge use demonstrated statistically significant improvements in growth in patients with cystic fibrosis requiring enteral feedings.” Newer and more effective therapies for Cystic Fibrosis may decrease the need for enteral supplementation along with lipase cartridge.

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Intestinal Inflammation in Patients with Cystic Fibrosis

An interesting study (C Tetard et al. JPGN 2020; 71: 778-781. Reduced Intestinal Inflammation With Lumacaftor/Ivacaftor in Adolescents With Cystic Fibrosis) describes the association of Lumacaftor/Ivacaftor and improvement in intestinal inflammation based on calprotectin levels.

This was a small study with 15 patients, with 9 patients having very elevated fecal calprotectin (FC) (>250) and the median level was 713 mcg/g for the entire cohort at baseline. After treatment with lumacaftor/Ivacaftor, median FC level was 102 mcg/g.

This pilot study is intriguing and makes the point that intestinal inflammation is commonly seen in children with cystic fibrosis. However, this study has some striking differences from prior studies.

My take: This study suggests that Lumacaftor/Ivacaftor is associated with a significant decrease in intestinal inflammation. When one looks at prior studies, the FC values presented in this study at baseline are much greater which could indicate significant selection bias.

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Nutrition Pearls -Fiber in Short Bowel and Good Growth with Cystic Fibrosis

One useful resource for NASPGHAN members (NASPGHAN Nutrition Pearls) has been the short monthly nutrition pearl videos (about 10 of them so far). Here are some pointers from the most recent of these.

In October: Fiber for Short Bowel Syndrome –Beneficial for those with a colon in continuity:

Commercial products with limited data supporting use in short bowel syndrome
All of the fiber products are fermented in colon and may be beneficial. Highlighted products are more likely to help with stool consistency (thickening).

In September: Growth in Cystic Fibrosis

Related blog posts for Short Bowel Syndrome:

Related blog posts for Cystic Fibrosis:

Stratifying Cystic Fibrosis Liver Disease with Ultrasonography

A recent multicenter case-controlled study (MJ Siegel, J Freeman, W Ye et al. J Pediatr 2020; 219: 62-9) show that ultrasonography can identify children with cystic fibrosis (CF) at increased risk for developing advanced CF liver disease; it is well-recognized that currently advanced CF liver disease occurs predominantly in children.

Among 722 participants who underwent ultrasonography as part of a planned 9 year research study, 65 had heterogeneous liver pattern and 592 had a normal liver pattern at baseline.

Key findings at planned 4-year interim analysis in a subgroup of 55 with (baseline) heterogeneous liver pattern and 116 with (baseline) normal liver pattern:

  • Those with heterogeneous liver pattern had higher median biochemical markers of liver disease: ALT 42 vs 32, GGT 36 vs 15, AST to platelet ratio index: 0.7 vs 0.4
  • Those with heterogeneous liver pattern were at ~9-fold increased risk of developing a nodular liver pattern (23% vs. 2.6%).
  • The authors did not identify specific clinical risk factors that predict the development of nodular liver ultrasound pattern

My take: Even among those with a heterogeneous pattern, the majority will not develop a ultrasonography (nodular) pattern of advanced liver disease.  Much more insight in this area is needed with the advancement in medical treatments and with the more availability of elastography.

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In the News, New Cystic Fibrosis Study

More information related to today’s earlier post: In the News: Big Therapeutic Advance for Cystic Fibrosis



Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.


We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor–tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del–minimal function genotypes. Patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.


A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor–tezacaftor–ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor–tezacaftor–ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group.


Elexacaftor–tezacaftor–ivacaftor was efficacious in patients with cystic fibrosis with Phe508del–minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 number, NCT03525444. opens in new tab.)

In the News: Big Therapeutic Advance for Cystic Fibrosis

Washington Post: Long-Awaited Drug Could Turn Deadly Disease into Manageable Condition

An excerpt:

A new cystic fibrosis therapy dramatically improved patients’ lung function and showed clear signs of targeting the genetic root of the disease, instead of just alleviating symptoms — a breakthrough so long-sought that many doctors and patients are moved to tears when talking about it.

The data, being unveiled Thursday at a national conference in Tennessee and simultaneously published in two leading medical journals, was so persuasive that the Food and Drug Administration last week approved the three-drug combination, called Trikafta — five months ahead of the agency’s deadline. The drug could benefit 90 percent of patients with the disease, a major advance over previous drugs that worked in a tiny fraction of the people with the disease or had more modest effects

Sarah Carollo, 28, a special needs teacher in Lee’s Summit, Mo., started Trikafta through a clinical trial in late 2018. Carollo… couldn’t walk down a hallway without stopping to rest and catch her breath…

A few days after she began taking the pill, her doctors tested her lung function and were so stunned at the improvement that they had to check whether they were really looking at the results from the right patient. Two weeks ago, Carollo ran a 5K race with another patient, Laurana Blackburn, who was also taking the drug through the clinical trial…

There are more than 1,700 gene mutations that can cause the protein to malfunction, but in the most common mutation, the protein is misfolded and can’t reach the right spot in the cell — and even if it does reach that spot, it doesn’t work properly. The new combination therapy includes one drug that corrects the misfolded protein and two that activate the correctly folded protein when it reaches the right spot in the cell.

In the largest trial, reported in the New England Journal of Medicine, 403 patients who had at least one copy of the most common gene mutation underlying cystic fibrosis received either Trikafta or a placebo. There were improvements in objective tests of lung function, decreases in lung problems and hospitalizations and an increase in people’s quality of life…

It also remains to be seen whether patients have an easy time gaining access to the drug, which will cost $311,000 a year. While that is a tremendous amount, orphan drugs for small patient populations typically carry very large price tags, and physicians are optimistic that insurers will cover the drug.

The NY Times reported on the FDA approval (October 2019), Studies Yield ‘Impressive’ Results in Fight Against Cystic Fibrosis, and noted that the “Institute for Clinical and Economic Review, which evaluates the cost-effectiveness of drugs, found that the cystic fibrosis drugs the company sells should cost as much as 77 percent less. ”

#NASPGHAN19 Postgraduate Course (Part 2)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course. My notes from these lectures may contain errors of omission or transcription.

Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)

9:00 – 10:20 “Potpourri”

46 Alessio Fasano, MD, MassGeneral Hospital for Children  Celiac disease: Beyond diagnosis

  • Reviewed potential non-biopsy option for diagnosis if anti-TG2 >10 x normal. Pediatricians are not following recommendations –>many children placed on gluten-free diet at lower titer antibody-positivity.
  • Recommends checking Hepatitis B antibody because many children with celiac disease do not seroconvert.
  • TTG levels are good for diagnosis but not as helpful for monitoring after diagnosis.
  • Only 10 out of 1000 are true refractory, about 100 out of 1000 are exquisitely sensitive to gluten

56 Meghana Sathe, MD, UT Southwestern Medical Center The role of the gastroenterologist and hepatologist in Cystic Fibrosis (CF) care today

  • Fecal elastase monitoring useful for determining need for PERT.
  • Discussed CF liver involvement.  Multilobular cirrhosis, 7% of individuals, is most important liver disease in CF.
  • Modulator therapy can elevate liver enzymes and may need to hold if ALT >5 ULN or lower elevation if elevated bilirubin (see Stop Rules -Practical Advice on DILI)
  • DIOS -for partial obstruction, polyethylene glycol and/or gastrogastrin enemas could be used.
  • Consider treatment of SBBO as well which is frequent with CF.

67 Sonia Michail, MD, Children’s Hospital Los Angeles Update on C. difficile

The slide I liked the best was showing a change in microbiome after FMT which is not in syllabus.

82 Ed Hoffenberg, MD, Children’s Hospital Colorado  What the pediatric GI provider needs to know about cannabis

Disclaimer: NASPGHAN/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. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society 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. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

PEG Placement in Cystic Fibrosis

A small retrospective study (RT Khalaf et al.NCP 2018; LINK: showed that PEG placement was associated with a trend (not statistically significant) towards improved lung function in children with cystic fibrosis (CF). Reference from Kipp Ellsworth twitter feed.  There were 20 patients who had PEG placed compared to 40 patients who did not.


  • BMI percentile increased per month for those with PEG (0.51, 95% confidence interval (CI) = −0.05–1.08, P = .08), but decreased for those without PEG (−0.03, 95% CI = −0.33–0.28, P = .86); however, the difference (0.54; 95% CI = −0.10–1.18, P = .10) was not statistically significant.
  • FEV1 change with time showed a decrease for patients with PEG (−0.04; 95% CI = −0.30–0.22, P = .74) and those without PEG (−.22; 95% CI = −0.45–0.01, P = .06). Although the FEVdecrease for those without PEG was higher than those with PEG, the difference between the groups was not statistically significant (0.18; 95% CI = −0.17–0.52, P = .32)

My take: While the differences are not statistically-significant, this study indicates that PEG placement is NOT detrimental to lung function in CF and may be beneficial.

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