Providing good nutrition is a pillar of cystic fibrosis (CF) care as malnutrition is associated with a worse clinical prognosis, including a more rapid decline in pulmonary function.¹ Considering this aspect of clinical care as background, five recent articles have been chosen to represent new knowledge in the setting of CF and nutrition. We have reviewed articles looking at pancreatic enzyme replacement therapy (PERT) dosing in relation to body mass index (BMI) in children with CF, the oft-missed consideration of protein malabsorption in those with CF, health-related quality of life (HRQOL) in CF specifically related to nutritional status, prognostic markers of mortality in adolescents with CF (which include low BMI), and the potential use of appetite stimulants in relation to CF nutrition care.

Haupt et al evaluated PERT dosing in relation to CF BMI. One hundred seventy-nine United States CF programs that entered data into the national CF Foundation Patient Registry were divided into quartiles based on BMI. A significant difference in PERT dosing existed between top and bottom CF quartile centers for BMI, suggesting that PERT dosing should be followed closely for all those with CF, especially for children with CF who should be expected to have good gain weight as they grow. The authors do point out that high-performing centers were more likely to have more patients with CF diagnosed by newborn screening, were more likely to use supplemental feeding by nasogastric or gastrostomy access, and were more likely to use acid blockade therapy (such as proton pump inhibitors) to potentially enhance PERT efficacy. Thus, it could be argued that high-performing centers were more likely to meticulously follow nutritional outcomes. As always, care should be taken to make sure PERT dosing is not more than 10,000 units lipase/kg/day or 2500 units lipase/kg/meal to prevent fibrosing colonopathy, and frequent review of PERT dosing should occur in patients with CF by members of the CF care team to prevent risk of malnutrition.²

Engelen et al used a unique method for determining protein malabsorption in patients with CF, a nutritional issue not always considered in their care. Specifically, the ratio of serum levels of 15N-labeled spirulina protein (broken down to 15N-labeled phenylalanine) and 2H5-labeled phenylalanine was measured every 20 minutes as patients underwent a six-hour feeding protocol with an enteral formula commonly used in CF care. PERT dosing was given two hours into the feeding protocol. Protein malabsorption was significantly reduced in patients with CF compared to a healthy control group, although protein absorption in the patients with CF improved to levels close to those of controls with use of PERT. Citrulline (a nonessential amino acid produced by enterocytes) levels were not significantly different between CF and control subjects, suggesting normal gut mucosal function in patients with CF.³ Thus, while protein digestion appears to be impaired in people with CF, this defect can probably be reversed with PERT. This technique of determining protein absorption may be able to answer further questions about CF protein absorption. For example, this study brings up the intriguing question about whether growth hormone (which has been shown to reverse a protein catabolic state in people with CF) may also improve protein absorption.⁴ Proton pump inhibitor (PPI) use did not improve protein absorption in those with CF; however, only a small number of CF patients in the study were not on a PPI, and more data is needed to answer questions about the effectiveness of PPI therapy for enhancing weight gain. Finally, longer duration of enteral feeding using various techniques (such as oral versus gastrostomy feeding), various times in which PERT is given, and other aspects of feeding must be studied to see how protein absorption in patients with CF occurs in a 24-hour setting. This study is a good first step toward answering such questions.

Shoff et al studied HRQOL in children with CF in relation to their nutritional status. HRQOL questionnaires are based on item-response theory, which is a way of modeling using scale responses to single-item questions to determine a symptom response of a patient with a disease process compared to a control group.⁵ This study used patients from the Wisconsin Randomized Clinical Trial of CF Newborn Screening, in which all study subjects underwent annual HRQOL testing for three years using the Cystic Fibrosis Questionnaire tool. Improved dimensions of physical functioning and body image were improved as height z-scores and BMI z-scores increased. Physical functioning and body image dimensions significantly improved with higher weight z-scores. HRQOL scores were categorized as "mostly low," "mostly good," and "perfect" to prevent any potential statistical ceiling effect, and a Cystic Fibrosis Questionnaire score consistent with "mostly low" was seen between short stature and an eating disturbance as well as between a BMI below goal and body image. It should be pointed out that this study occurred in one region of the midwestern United States, and it is unknown if findings are replicable nationally or internationally. Also, the authors state that the categories ("mostly low", etc.) have not been validated in other studies, so it is somewhat unclear if these categories closely match scoring of the Cystic Fibrosis Questionnaire. However, this study does suggest the HRQOL is impaired in children with CF simply as a result of poor nutrition and resultant downstream effects such as body image.

Hulzebos et al tried to determine whether mathematical modeling could predict risk of mortality in adolescents with CF. A multivariate model to determine risk of mortality included cardiopulmonary exercise testing using a cycle ergometer (CPET), resting lung function, and nutritional status (BMI). Univariate analysis demonstrated that FEV₁%_predicted breathing reserve (calculated from results of the ergometer), BMI, and peak aerobic activity were significantly associated with an increased risk of mortality. A multivariate analysis model of three risk factors, including FEV₁%_predicted, peak ventilatory equivalent ratio, and BMI, was predictive of mortality. Adolescents with CF with two or three risk factors from the multivariate model had a significantly increased risk of mortality. Those with three risk factors had a significantly greater risk of mortality than patients with only one or two risk factors. Although these results make sense clinically, the findings are based on a modeling study, and multivariate analysis can potentially oversimplify results by decreasing the number of variables to obtain simpler results. The authors acknowledge that Pseudomonas aeruginosa infection can increase mortality; however, they did not include infection risk because of a strong correlation found with the peak ventilatory equivalent ratio for oxygen in the model for predicting mortality.⁶ Other infections known to increase mortality, such as Burkholderia cepacia, were not considered in this model.⁷

Finally, Chinuck et al evaluated the effectiveness of appetite stimulants as a therapeutic option for CF nutrition care. This study was done as a Cochrane analysis, and as is often the case in such studies, minimal data were available for evaluation. Three studies involving appetite stimulants were placebo-controlled, with one study using cyproheptadine hydrochloride and two studies using megestrol acetate. When the studies were combined, appetite stimulant use was significantly associated with increased mean weight at three and six months, while weight z-score showed a significant improvement at three months. Side effects were minimal. The authors conclude that these two appetite stimulants may be a helpful short-term option in improving appetite and weight in individuals with CF; however, there are no long-term data. Further, there are still no good data for other appetite stimulants such as dronabinol or mirtazapine. Finally, side effects of appetite stimulants are still not fully understood. As an example, megestrol acetate has been associated with life-threatening adrenal insufficiency, although data on this side effect is limited to case reports.⁸

These studies suggest that we still have much to learn in the realm on nutrition care for patients with CF. There appears to be a correlation between appropriate PERT use and improved nutrition in patients with CF as evidenced by BMI outcomes, and there are data showing that good BMI improves HRQOL and reduces the risk of mortality in children with CF. It is unclear if appetite stimulant use is an effective medical adjunct therapy for improving nutrition in the CF population. Longitudinal, long-term studies are needed to clarify these issues.

Commentary References
1. Umlawska W, Krzyzanowska M, Zielinska A, et al. Effect of selected factors associated with the clinical course of the disease on nutritional status in children with cystic fibrosis. Adv Clin Exp Med 2014; 23: 775-783.
2. Borowitz D, Grand R, Durie P. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy, consensus committee. J Pediatr 1995; 127: 681-684.
3. Stultz J, Tillman E, Hemls R. Plasma citrulline concentration as a biomarker for bowel loss and adaption in hospitalized patients requiring parenteral nutrition. Nutr Clin Pract 2011; 26: 681-687. 4. Hardin D. GH improves growth and clinical status in children with cystic fibrosis: a review of published studies. Eur J Endocrinol 2004; 151 Suppl 1: S81-S85.
5. Langer M, Thissen D, Burwinkle T, et al. Item response theory detected differential item functioning between health and ill children in quality-of-life measures. J Clin Epidemiol 2008; 61: 268-276.
6. van de Weert-van Leeuwen P, Slieker M, Hulzebos H, et al. Chronic infection and inflammation affect exercise capacity in cystic fibrosis. Eur Respir J 2012; 39: 893-898.
7. Frangolias D, Mahenthiralingam E, Rae S, et al. Burkholderia cepacia in cystic fibrosis. Variable disease course. Am J Respir Crit Care Med 1999; 160: 1572-1577.
8. Li J and Winkler M. Decompensated septic shock in the setting of megace-induced severe adrenal suppression in an otherwise healthy pediatric patient: a case report. Pediatr Emerg Care 2012; 28: 802-804.

Engelen M, Com G, Anderson P, et al. New stable isotope method to measure protein digestibility and response to pancreatic enzyme intake in cystic fibrosis. Clin Nutr. 2014;33:1024-1032.

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When we think about cystic fibrosis (CF), we often think about fat malabsorption due to associated exocrine pancreatic insufficiency. However, people with CF are also at risk of a negative nitrogen balance due to protein malabsorption, although testing for protein malabsorption is difficult to perform. The authors of this study evaluated a novel method of testing for protein malabsorption as a marker of pancreatic protease function. Specifically, subjects were given a meal with ¹⁵N-labeled spirulina protein (a protein from blue-green algae) and ²H₅-labeled phenylalanine. The proteolytic breakdown product of ¹⁵N-labeled spirulina is ¹⁵N-labeled phenylalanine and can be compared to the ²H₅-labeled phenylalanine, which is not broken down by pancreatic proteases. This ratio determination testing is not affected by phenylalanine metabolism.

Nineteen study subjects (10 children and nine adults with CF) and eight healthy control subjects were evaluated for this study, with a majority of the patients with CF admitted to the hospital for a pulmonary exacerbation. The homozygous F508del CFTR mutation was present in 90% of the children and 25% of the adults with CF. Subjects received standard formula often used in CF nutrition care given over six hours either by the oral or gastrostomy route with the addition of ¹⁵N-labeled spirulina and ²H₅-labeled phenylalanine. Pancreatic enzyme replacement therapy (PERT) dosing occurred two hours into the feeding regimen of subjects with CF. Protein digestion was calculated by the 15N-labeled spirulina/²H₅-labeled phenylalanine ratio, and these protein levels were obtained every 20 minutes after feeds were started. Additionally, citrulline levels were obtained during the study after a pulse dose of L-[5-13C-2H2]-citrulline to determine intestinal mucosal function.

Mean body mass index (BMI) was not different between adults with CF and the control group, although three adults and three children with CF were in nutritional failure. Control subjects were able to break down approximately 80% of the spirulina protein, which is considered normal for protease function. However, the patients with CF had significantly lower protease function, measured at 46.5% of control function (P < 0.001). After PERT use in subjects with CF, spirulina protein absorption increased to 90.3% of control absorption with a maximum digestion time of 80 minutes. No significant difference was seen in protein digestion between adult and pediatric subjects with CF, and no significant difference in protein digestion was noted between those with CF, regardless of F508del mutation status, history of nutritional failure, or lung function. No difference was seen in protein absorption in the subjects with CF, regardless of proton pump inhibitor use, although the number of subjects with CF who were not using proton pump inhibitors was small (n = 3). Plasma citrulline levels were not significantly different between control and patients with CF, suggesting normal gut mucosal function in subjects with CF.

This study demonstrates that protein malabsorption can be measured in people with CF, and importantly, protein absorption is low in this patient population, although malabsorption can be corrected with PERT.