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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Near Banff

Big Advance in Cystic Fibrosis –Who Will Benefit?

Recent studies point to huge advances in cystic fibrosis (CF) therapy. Though as noted in a previous blog (Why Do Canadians with Cystic Fibrosis Live Longer?), medical advances may have limited effect based on a lot of issues including access to care.

Despite that note of caution, it is hard not to be excited about a couple of recent publications which show that triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has great potential to improve outcomes for CF patients.

  • JC Davies et al. NEJM 2018; 379: 1599-611.
  • D Keating et al. NEJM 2018; 379: 1612-20.
  • Editorial: F Holguin, 1671-2

Background: In the editorial, the pathophysiology of the defect of CF is discussed and how the newer medicines either act as a potentiator of the CFTR (ivacaftor) or as corrector (lumacaftor and tezacaftor).  Potentiators increase CFTR channel opening at the cell surface whereas correctors increase the amount of CFTR protein at the cell surface. One caveat has been that these therapies had not been proven effective, individually, for Phe508del CFTR mutation which occurs in “approximately two thirds of patients.”  Combination therapy has helped in most of this group but not in those with Phe508del-minimal function (MF).

The new studies examine triple therapy with the addition of two new-generation small molecule correctors: VX-445 and VX-659. These new correctors target different sites of the CFTR protein.

Key findings:

  • in the Davies (VX-659) trial, “4 weeks of triple therapy …increased the primary end point of predicted percentage of FEV1, in the Phe508del-MF and Phe508del-Phe508del groups by an averae of 13.3% and 9.7% respectively”
  • In the Keating (VX-445) trial, triple therapy “significantly increased FEV1 in patients with those genotypes by 13.8% and 11.0% respectively.”
  • Overall, triple therapy “improved the percentage of predicted FEV1 more than double-combination therapy” in patients with a Phe508del-Phe508del mutation.  And reported efficacy in the patients with Phe508del-MF CFTR mutation.
  • The majority of patients had at least one adverse event. 3 of the 122 in the VX-445 trial discontinue treatment due to severe adverse events.

My take: These reports “represent a major breakthrough…for improving health and possibly survival in all patients who carry the most common CFTR mutation.”  Long-term outcomes will need to be followed to confirm these findings.

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This is Figure 2 from Davies study showing immunoblot findings, densitometry findings, and chloride transport in bronchial cells. The most robust responses were with triple therapy


Screening for Colorectal Cancer in Cystic Fibrosis

Briefly noted:

A Gini, et al. “Cost Effectiveness of Screening Individuals with Cystic Fibrosis for Colorectal Cancer” Gastroenterol 2018; 154: 556-67.

  • Key point: “Colonoscopy every 5 years, starting at age of 40 years was the optimal colonoscopy strategy for patients with cystic fibrosis” without prior organ transplantation.

D Hadjuliais, et al. “Cystic Fibrosis Colorectal Cancer Screening Consensus Recommendations: Gastroenterol 2018; 154: 736-45.

  • There are 10 Task Force recommendations. These include “initiation of screening at 40 years” in those without organ transplantation. Among those who have had organ transplantation, CRC screening is recommended at age 30 years and/or within 2 years of transplantation. Link: Abstract

My take: Fortunately, more individuals with cystic fibrosis are living long enough to benefit from CRC screening.  Due to increased risk, these guidelines recommend screening at a younger age than the general population.

More pics from Hoover Dam. The figure in this picture is a art piece honoring those who died while working on the construction


CFTR Modulators for Cystic Fibrosis

Two more studies have shown the effectiveness of CFTR modulators for subsets of patients with cystic fibrosis.

  • JL Taylor-Cousar et al. NEJM 2017; 377: 2013-23
  • SM Rowe et al. NEJM 2017; 377: 2024-35.

In the Taylor-Cousar study, the authors treated patients with homozygous Phe508del cystic fibrosis with either combination tezacaftor-ivacaftor or placebo for 24 weeks. Combination therapy resulted in FEV1 that was 4% higher along with a 35% lower rate of pulmonary exacerbations than placebo.

In the Rowe study which examined patients some retained CFTR function (which occurs ~5% of CF patients), a prospective trial of tezacaftor-ivacaftor had a greater effect on increasing FEV1 than ivacaftor alone.  Ivacaftor monotherapy and tezacaftor-ivacaftor combination therapy were both more effective than placebo.

A related editorial (H Grasemann. pgs: 2085-8) helps provide context to help understand the importance of these studies.  His key point:

“Although CFTR modulator therapies have measurable beneficial effects on some aspects of the disease, there is still an unmet need for truly effective new therapies to be developed for all persons with cystic fibrosis.  The clinical efficacy of the current combination therapies for patients with cystic fibrosis who have the most common CFTR genotype (Phe508del/Phe508del) is suboptimal and falls within the range of established symptomatic therapies, such as nebulized inhaled hypertonic saline or recombinant human DNAse.”

This figure depicts the types of molecular defects: No functional CFTR with framshifts for deletions or insertions (class 1), CFTR trafficking defect due to misfolded protein (class II), defective channel regulation (class III), reduced cholirde conductance (class IV) , reduced synthessis (class V) or decreased CFTR stability (class VI)

#NASPGHAN17 Annual Meeting Notes (Part 2): Year in Review

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

This first slide shows the growth in NASPGHAN membership:

Year in Review

Melvin Heyman  Editor, JPGN

This lecture reviewed a number of influential studies that have been published in the past year.  After brief review of the study, Dr. Heyman summarized the key take-home point.


Why Do Canadians with Cystic Fibrosis Live Longer than Patients in U.S.?

NY Times Summarizes the reasons why Canadians with Cystic Fibrosis Live Longer: Link:  Canadians With Cystic Fibrosis Live 10 Years Longer Than Americans With the Disease

Cystic fibrosis is an inherited disease that causes recurrent lung infections and other problems. The average lifespan for an American with the illness is 37 years. In Canada, it is 49.

Researchers studied records of 5,941 Canadian and 45,448 American cystic fibrosis patients between 1990 and 2013. After controlling for severity of disease, age and other factors, they found that overall death rates were 34 percent lower in Canada than in the United States.

There was no difference in death rates between Canadians and Americans with private health insurance. But Canada provides universal health care coverage under a single-payer system, so every Canadian has some kind of health insurance. The Canadian death rate was 44 percent lower than that of Americans on Medicaid or Medicare, and 77 percent lower than Americans without insurance.

 AL Stephenson et al.  Ann Intern Med. 2017. DOI: 10.7326/M16-0858


Background:In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias.
Objective:To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States.
Design:Population-based study.
Setting:42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers.
Patients:Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013.
Measurements:Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival.
Results:Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients’ insurance status.
Limitation:Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results.
Conclusion:Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage.
Primary Funding Source:U.S. Cystic Fibrosis Foundation.

Sainte-Chapelle, Paris

Complexity in Cystic Fibrosis Diagnosis

The availability of multiple diagnostic techniques for cystic fibrosis has increased the complexity and created areas of uncertainty.  A recent supplement (J Pediatr 2017; 181S: 1-55) delve into these issues.

“The diagnosis of CF has become increasingly complex, as CFTR mutations resulting in a wide spectrum of dysfunction have been increasingly identified.”

On page S6, 27 consensus recommendations are given.

The article S45-51, reviews cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) and cystic fibrosis screen positive, inconclusive diagnosis (CFSPID).  Key points:

  • CRMS and CFSPID are equivalent entities with CRMS being the preferred terminology in the US
  • CRMS/CFSPID are relatively frequent; for every 3 to 5 cases of CF, there is one case of CRMS/CFSPID.
  • The majority of CRMS/CFSPID do NOT develop CF. Approximately 10-20% develop clinical features concerning for CF.


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