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
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)
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.
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.
Wilschanski et al (JPGN 2016; 63: 671-5) provide a summary (“highlights”) of a full report (Turck D et al. Clin Nutr 2016; 35: 557-77) on nutritional recommendations for infant and children with cystic fibrosis.
What’s in here:
Table 1: criteria for adequate nutritional status including
Age <2 yrs: 50% for weight & height compared to healthy-age peers
Age 2-18 yrs: 50% BMI compared to healthy peers
Table 2: nutritional assessment and followup
Assess elastase-1 annually if pancreatic sufficient
0-1 yr: 2000-4000 units lipase/120 mL of formula/breast milk & 2000 units lipase/gram of dietary fat
1-4 yrs: 2000-4000 units of lipase/gram of dietary fat (max 10,000 units lipase/kg/day)
>4 yrs: starting dose; 500 units lipase/kg/meal -titrate up to 1000-2500 units lipase/kg/meal (max 10,000 units lipase/kg/day)
Table 5: Fat-soluble vitamin/vitamin guidelines
Table 6: Sodium supplementation
0-6 months: 1-2 mmol/kg/day –give salt in small portions throughout the day, “diluted in water or fruit juice”. In some infants, up to 4 mmol/kg/day if increased losses (eg. due to heat, gastrointestinal losses)
Older children: anticipate need for additional salty foods or use sodium chloride capsules, especially when excessive sweating (eg. fever, sports, hot weather)
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. 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.
A recent study (C Colombo et al. J Pediatr 2016; 177: 59-65) examined 20 patients with cystic fibrosis-associated liver disease (CFLD) who were receiving ursodeoxycholic acid (UDCA) for at least 2 years. Specifically, they wanted to focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid. The possibility that long-term UDCA therapy could be detrimental was propelled by a primary sclerosing cholangitis study (K Lindor et al. Hepatology 2009; 50: 808) which indicated that high doses of UDCA resulted in worse outcomes despite better “liver function tests.”
Dosing of UDCA: 20 mg/kg/day
Key findings: UDCA became the predominant serum bile acid; 2 hours after UDCA administration, “both UDA and chenodeoxycholic acid significantly increase (P< .01), but no significant changes in serum lithocholic acid concentrations were observed.”
What does this study prove?
Well, not very much. There are other potential mechanisms for UDCA toxicity and as the editorial notes, “we still lack the necessary endpoints in CF liver disease with which to assess the efficacy of UDCA or any therapy that is on the horizon.”
My take: Because our surrogate markers are unreliable for CFLD, there really is no way to know with certainty whether UDCA therapy is beneficial.