Challenging barriers to an option for improved provision of enteral nutrition

CF clinicians have long recognized the negative effect of malnutrition on outcomes in people with CF [[1]Sproul A. Huang N. Growth patterns in children with cystic fibrosis.J Pediatr. 1964; 65: 664-676Abstract Full Text PDF PubMed Scopus (134) Google Scholar] and the importance of a high-calorie diet to support weight gain and growth [[2]Corey M. McLaughlin F.J. Williams M. Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto.J Clin Epidemiol. 1988; 41: 583-591Abstract Full Text PDF PubMed Scopus (638) Google Scholar] . Nutritional status has been widely accepted as one of the critical metrics for health in people with CF. Low BMI has been identified as one factor associated with larger mean annual lung function decline [[3]Cogen J. Emerson J. Sanders D.B. Ren C. Schechter M.S. Gibson R.L. et al.Risk factors for lung function decline in a large cohort of young cystic fibrosis patients.Pediatr Pulmonol. 2015; 50: 763-770Crossref PubMed Scopus (79) Google Scholar]. Enteral feedings to increase caloric intake are used to support optimal weight gain in those at nutritional risk. Recent evidence-informed enteral feeding guidelines recommend continuous nocturnal infusions for individuals with CF who are receiving supplemental enteral tube feedings [[4]Schwarzenberg S.J. Hempstead S.E. McDonald C.M. Powers S.W. Wooldridge J. Blair S. et al.Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.J Cyst Fibros. 2016; 15: 724-735Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] . Even though the majority of those receiving enteral feedings are pancreatic insufficient, a recommendation for or against a specific method of providing pancreatic enzyme replacement therapy (PERT) during these continuous feedings could not be made because of a lack of evidence. PERTs are only approved for use with oral snacks and meals; in fact, patients receiving enteral feedings were excluded from studies done to obtain regulatory approval. A common practice is to provide PERT capsules orally at the beginning and the end of nocturnal enteral feedings [[5]Ferrie S. Graham C. Hoyle M. Pancreatic enzyme supplementation for patients receiving enteral feeds.Nutr Clin Pract. 2011; 26: 349-351Crossref PubMed Scopus (33) Google Scholar] . It makes little physiologic sense to provide a bolus of PERT to digest fats in a continuous feeding; nonetheless, until now this off-label use has been the only therapeutic option. Using this method, weight gain is achieved in some but not all patients, and many have ongoing abdominal pain, bloating, or other undesirable symptoms. Recently, an immobilized lipase cartridge (ILC) was developed specifically to support nutrient absorption for tube-fed patients. This product is unique because it contains lipase in a device used in-line with the tube through which the enteral feeding flows. Thus, it continuously breaks down long-chain triglycerides into absorbable components outside of the body throughout the entire duration of an enteral feeding. The non-porcine lipase in the ILC is not a new chemical entity; it is derived from Rhizopus oryzae, which was granted Generally Recognized as Safe (GRAS) status by the FDA in 2006. The continuous pairing of lipase contemporaneously with nutrient delivery increases the amount of absorbable fat in the gut lumen. Patients with CF are deficient in long-chain polyunsaturated fatty acids (LCPUFA), critical building blocks of cell membranes and other tissues, and notably deficient in metabolites of omega-3 fatty acids, LCPUFAs with anti-inflammatory effects [[6]Freedman S.D. Blanco P.G. Zaman M.M. Shea J.C. Ollero M. Hopper I.K. et al.Association of cystic fibrosis with abnormalities in fatty acid metabolism.N Engl J Med. 2004; 350: 560-569Crossref PubMed Scopus (333) Google Scholar]. A randomized study of the ILC used over a one-week period provides evidence that the standard of care is sub-optimal with respect to nutrient absorption. Enrolled subjects had been receiving enteral feeding with oral PERT supplementation for a mean of 6.6 years and had baseline plasma omega-3 fatty acid concentrations that were well below the range observed in healthy subjects. As one indication of the improved absorption of fat, CF patients who used the ILC had plasma omega-3 fatty acid concentrations come into the range of normal compared to no change in those receiving PERT alone with enteral feedings [[7]Freedman S. Orenstein D. Black P. Brown P. McCoy K. Stevens J. et al.Increased fat absorption from enteral formula through an in-line digestive cartridge in patients with cystic fibrosis.J Pediatr Gastroenterol Nutr. 2017; 65: 97-101Crossref PubMed Scopus (29) Google Scholar]. When the ILC was used in an open-label fashion, erythrocyte membrane omega-3 fatty acid composition rose steadily over the course of 3 months [[8]Stevens J. Wyatt C. Brown P. Patel D. Grujic D. Freedman S.D. Absorption and safety with sustained use of RELiZORB evaluation (ASSURE) study in patients with cystic fibrosis receiving enteral feeding.J Pediatr Gastroenterol Nutr. 2018; 67: 527-532Crossref PubMed Scopus (25) Google Scholar]. Weight gain would be the most highly relevant clinical proof that the ILC improves macronutrient absorption, but it would be unethical to provide placebo for the length of time it would take to observe weight gain [[9]Konstan M.W. Borowitz D. Mayer-Hamblett N. Milla C. Hendeles L. Murray S. et al.Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis.Clin Investig (Lond). 2013; 3: 731-741Crossref PubMed Google Scholar]. Several retrospective, single-center chart reviews have provided evidence that the ILC supports weight gain (Table 1). The continuous release of lipase contemporaneously paired with nutrient delivery will decrease undigested nutrients in the gut lumen. In addition to being unavailable for absorption, these undigested nutrients likely contribute to symptoms such as bloating, nausea and loose stools. Real world evidence of the benefits of ILC include improvements in gastrointestinal symptoms as well as reduced treatment burden and a positive safety two of the top four priorities for people with CF, and tolerability profile [10Hendrix S. Flume P. Michel S. Jump C. Use of an in-line digestive enzyme cartridge in pediatric patients.Pediatr Pulmonol. 2017; 52 ([abstract]): 461Google Scholar, 11Iwanicki C. Bouma S. Nasr S. Use of immobilized lipase cartridge with overnight enteral feeds improves symptoms and results in weight gain in children with cystic fibrosis.Pediatr Pulmonol. 2017; 52 ([abstract]): 452Google Scholar, 12Minor M. Nemastil C.J. Gemma S. Rice A. Shaikhkhalil A. Digestive enzyme cartridge (Relizorb™) during continuous enteral feeds among individuals with cystic fibrosis.Pediatr Pulmonol. 2017; 52 ([abstract]): 259Google Scholar, 13Hollin I.L. Donaldson S.H. Roman C. Aliaj E. Riva D. Boyle M. Borowitz D. Beyond the expected: Identifying broad research priorities of researchers and the cystic fibrosis community.J Cyst Fibros. 2019; 18: 375-377Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Combined, the signatories of this communication have treated approximately 450 CF subjects with the ILC and view this as a valuable therapeutic option for their CF patients who require tube feedings. In total, these findings imply that the ILC can produce measurable, clinically relevant benefits.Table 1Clinical outcomes in unique single-center studies of an immobilized lipase cartridge (ILC).StudyNAge range (yrs)Weight changeSymptom changeIwanicki et al. [[11]Iwanicki C. Bouma S. Nasr S. Use of immobilized lipase cartridge with overnight enteral feeds improves symptoms and results in weight gain in children with cystic fibrosis.Pediatr Pulmonol. 2017; 52 ([abstract]): 452Google Scholar]162–20Wt z-score was −0.08 in the 3 months before and + 0.16 in the 3 months after starting ILC53% had improvement in at least one symptomstool quality, stomach aches, nausea and vomiting.Minor et al. [[12]Minor M. Nemastil C.J. Gemma S. Rice A. Shaikhkhalil A. Digestive enzyme cartridge (Relizorb™) during continuous enteral feeds among individuals with cystic fibrosis.Pediatr Pulmonol. 2017; 52 ([abstract]): 259Google Scholar]191–30BMI z-score but not wt z-score improved 6 months after ILC; 4 subjects > age 21 had no wt gain in the 6 months prior to ILC and gained 1.58 kg in the 6 months afterNot reportedHendrix et al. [[10]Hendrix S. Flume P. Michel S. Jump C. Use of an in-line digestive enzyme cartridge in pediatric patients.Pediatr Pulmonol. 2017; 52 ([abstract]): 461Google Scholar]13Mean age 8 (4 subjects <5 years of age)All those >2 yrs. of age had higher BMI %ile at 3 and 6 months after starting compared to baseline. Only 3 month data presented for those <2 yrs. but showed dramatic improvement in wt-for-lt %ile at 3 months.46% had improvement in GI symptomsStevens et al. [[8]Stevens J. Wyatt C. Brown P. Patel D. Grujic D. Freedman S.D. Absorption and safety with sustained use of RELiZORB evaluation (ASSURE) study in patients with cystic fibrosis receiving enteral feeding.J Pediatr Gastroenterol Nutr. 2018; 67: 527-532Crossref PubMed Scopus (25) Google Scholar]395–33GI symptoms declined from 59% to 30.8% over 3 months of use of ILC; gas, abdominal pain, nausea decreased by 50%; none reported diarrhea, steatorrhea or vomiting at the end of the open-label period stool quality, stomach aches, nausea and vomiting. Open table in a new tab Since the lipase activity is ex vivo, the ILC was evaluated as a device and not as a drug, thus the type of randomized, placebo-controlled trials used for drug approval were never done. Assuring patient safety and being a good steward of resources are part of a physician's duty. During the three years the ILC has been available, >725,000 cartridges have been used by nearly 2000 patients. Despite that widespread usage, there have been no medical device reports or adverse events reported to the US Food and Drug Administration (FDA) and there have been no device recalls. In the US, these devices have been offered to patients primarily through a fund established by the manufacturer since insurers have argued that this is an experimental device. This is despite the fact that the FDA has cleared its use in both adults and children. This physiologically superior product is available and has proven successful in a real-world setting but is unavailable to patients because of the vicissitudes of insurance approvals in the US. While we agree that additional data needs to be generated, our obligation as advocates for our patients is to support access to this innovation. Use of an immobilized lipase cartridge to support enteral feedings is making a positive difference for many patients with CF and is a rational alternative to the historical but illogical current standard of care. Our goal in this editorial is to alert the CF community to the need to advocate with insurance providers to reimburse for this device. Its use has the potential to improve health for people with CF, and its cost may be mitigated by the real possibility of reduced pulmonary decline in a well-nourished person with CF. Our CF teams struggle every day to improve nutrition in their patients to improve their well-being and survival. A new, effective tool is tantalizingly within reach and we call on insurance providers to make it possible for us to use it. Co-signatories The following individuals who provide care to people with cystic fibrosis support this editorial: Gastroenterologists: Julian Abrams, MD, MS, Columbia University Medical Center, New York, NY; James M. Abraham, MD, University of Minnesota, Minneapolis MN; David Assis MD, Yale University School of Medicine, New Haven CT; Molly A. Bozic MD, Riley Children's Hospital, Indianapolis IN; Jill Dorsey, MD, MS, Nemours Children's Specialty Care, Jacksonville FL; A. Jay Freeman, MD, MSc, Emory University School of Medicine, Atlanta GA; Megan Gabel, MD, University of Rochester, Rochester NY; Candi Jump, DO, MSEd, Medical University of South Carolina, Charlston, SC; Daniel H. Leung, MD, FAASLD, Baylor College of Medicine, Houston TX; Sarah Shrager Lusman, MD, Morgan Stanley Children's Hospital of New York Presbyterian, New York NY; Asim Maqbool, MD, The Children's Hospital of Philadelphia, Philadelphia PA; Baha Moshiree, MD, Carolinas Medical Center, Charlotte NC; Sirish Palle, MBBS MD, Oklahoma University Health Sciences Center, Oklahoma City, OK; Jacob Robson, MD, MS, University of Utah Primary Children's Hospital, Salt Lake City UT; Sabina Sabharwal MD MPH, Boston Children's Hospital, Boston MA; Meghana Sathe, MD, University of Texas Southwestern, Children's Medical Center, Dallas TX; Ala K. Shaikhkhalil, MD, Nationwide Children's Hospital, Columbus, OH; Adam Stein, MD, Northwestern University Feinberg School of Medicine, Chicago IL; Jillian Sullivan, MD MSCS, The University of Vermont Children's Hospital, Burlington, VT; Field F. Willingham MD, MPH, FASGE, Emory University School of Medicine, Atlanta GA Cystic Fibrosis Pulmonary Providers: Cynthia Brown, MD, Indiana University, Indianapolis, IN; Perry Brown, MD, FAAP, University of Washington School of Medicine, Boise NY; Elisabeth Dellon, MD, MPH, UNC School of Medicine, Chapel Hill, NC; Scott H. Donaldson, MD, University of North Carolina at Chapel Hill, Chapel Hill, NC; Amy Filbrun MD, MS, University of Michigan, Ann Arbor MI; Jennifer L. Goralski, MD, The University of North Carolina at Chapel Hill, Chapel Hill NC; Benjamin Kopp, MD, MPH, FAAP, Nationwide Children's Hospital, Columbus, Ohio; Noah Lechtzin, M.D.; M.H.S., Johns Hopkins University School of Medicine, Baltimore MD; Karen S. McCoy, MD, Nationwide Children's Hospital, Columbus, OH; Samya Nasr, MD, CPI, University of Michigan Health System,Ann Arbor, MI; Jerry Nick, MD, National Jewish Health, Denver, CO; David Orenstein MD, Childrens Hospital of Pittsburgh, Pittsburgh PA; Christopher M Oermann MD, Children's Mercy – Kansas City, Kansas City MO; Clement L. Ren, MD, MBA, ATSF, Riley Hospital for Children, Indianapolis, IN; George Retsch-Bogart, MD, University of North Carolina at Chapel Hill, Chapel Hill, NC; Ronald C. Rubenstein, MD, PhD, Childrens Hospital of Philadelphia, Philadelphia PA; Scott Sagel, MD, PhD, Children's Hospital Colorado, Aurora, CO; Gregory Sawicki MD, Boston Children's Hospital, Boston MA; Preeti Sharma, MD, University Texas Southwestern and Children's Medical Center, Dallas TX; Jennifer L. Taylor-Cousar, MD, MSCS, ATSF, University of Colorado Anschutz Medical Campus, Aurora CO; James Tolle, MD, Vanderbilt University, Nashville TN; Donna Beth Willey-Courand MD, University of Texas Health Science Center, San Antonio TX; Edith Zemanick, MD, University of Colorado, Aurora, CO; Dietitians: Kelly Baumberger RD, University of North Carolina, Chapel Hill NC; Sandra Bourna MS, RD, CSP, Michigan Medicine, Ann Arbor MIRuth DeVoogd, MSN, CPNP – AC/PC, Children's Hospital Colorado, Aurora, CO; Katie Hinton, dietitian, Vanderbilt University, Nashville TN; Courtney Iwanicki, MS, RD, CSP, Michigan Medicine, Ann Arbor MI; Amanda Radmer Leonard MPH, RD, LDN, CDE, Johns Hopkins Children's Center, Baltimore, MD; Jessica Leonard, RD, LDN, Boston Children's Hospital, Boston MA; Karen M. Maguiness, MS, RD, CSP, Riley Hospital for Children at IU Health, Indianapolis, IN; Morgan Myrick, dietitian, Vanderbilt University, Nashville TN; Veronica Niedzinski, MS, RDN, National Jewish Health, Denver, CO; Laura Padula, MS, RD, CSP, LDN, Children's Hospital of Philadelphia, Philadelphia PA; Kanan Patel, MS RD CSP, Children's Healthcare of Atlanta, Atlanta GA; Elizabeth Reid MS, RDN, LDN Children's Hospital of Philadelphia, Philadelphia PA; Terri Schindler MS, RDN, Rainbow Babies and Children's Hospital, Cleveland OH; Bekah Sommer, MS, Indiana University, Indianapolis, IN; Kimberly Stephenson, MS, RD, CSP, University of North Carolina at Chapel Hill, Chapel Hill NC; PharmD: Cameron J. McKinzie, PharmD, BCPPS, BCPS, University of North Carolina at Chapel Hill, Chapel Hill NC, Kay Vavrina RD, LD, CNSC, University of Texas Health Science Center, San Antonio TX. The Cystic Fibrosis Foundation has provided financial support to Alcresta in support of the development of the immobilized lipase inline cartridge, Relizorb®, and has an ongoing financial interest in royalties based on sales of the cartridge. Additionally, CFF has advocated for insurance coverage of the cartridge.

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