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Nutritional status, nutrient intake and use of enzyme supplements in paediatric patients with Cystic Fibrosis; a European multicentre study with reference to current guidelines

Open ArchivePublished:March 18, 2017DOI:https://doi.org/10.1016/j.jcf.2017.03.005

      Abstract

      Background

      The New European guidelines have established the most updated recommendations on nutrition and pancreatic enzyme replacement therapy (PERT) in CF. In the context of MyCyFAPP project - a European study in children with CF aimed at developing specific tools for improvement of self-management - the objective of the current study was to assess nutritional status, daily energy and macronutrient intake, and PERT dosing with reference to these new guidelines.

      Methods

      Cross sectional study in paediatric patients with CF from 6 European centres. SD-scores for weight-for-age (WFA), height-for-age (HFA) and body mass index-for-age (BMI) were obtained. Through a specific 4-day food and enzyme-dose record, energy and macronutrients intake and PERT-use (LU/g lipids) were automatically calculated by the MyCyFAPP system. Comparisons were made using linear regression models.

      Results

      The lowest quartiles for BMI and HFA were between 0 and -1SD in all the centres with no significant differences, and 33.5% of the patients had a SD-score <0 for all three parameters. The minimum energy intake recommendation was not reached by 40% of the children and mean nutrients intake values were 14%, 51% and 34% of the total energy for protein, carbohydrates and lipids respectively. When assessed per centre, reported PERT doses were in the recommended range in only 13.8% to 46.6% of the patients; from 5.6% up to 82.7% of children were above the recommended doses and 3.3% to 75% were below.

      Conclusion

      Among the 6 centres, a large variability and inconsistency with new guidelines on nutrition and PERT-use was found. Our findings document the lack of a general criterion to adjust PERT and suggest the potential benefit of educational and self-managerial tools to ensure adherence to therapies, both for clinical staff and families. They will be taken into account when developing these new tools during the next stages of MyCyFAPP Project.

      Abbreviations:

      BMI (body mass index for age), CI (confidence interval), CF (Cystic Fibrosis), E/S (enzyme to substrate ratio), ECFS (European Cystic Fibrosis Society), ESPEN (European Society for Parenteral and Enteral Nutrition), ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), FER (food and enzymes record), HFA (height for age), kcal (kilocalorie), LU (lipase units), mHealth (mobile health), PERT (pancreatic enzyme replacement therapy), PI (pancreatic insufficiency), PS (pancreatic sufficiency), SD (standard deviation), WFA (weight for age)

      Keywords

      1. Introduction

      Antibiotics, physiotherapy and nutrition are considered the three pillars in the treatment of Cystic Fibrosis (CF) according to the most recent standards of care [
      • Yen E.H.
      • Ms H.Q.
      • Borowitz D.
      Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis.
      ]. Whilst therapies for lung disease have been a continuous focus of research in recent years [
      • Amin R.
      • Ratjen F.
      Emerging drugs for cystic fibrosis.
      ] less high-impact studies have addressed the improvement of the nutritional and pancreas-related aspects.
      The importance of a good nutritional status has clearly emerged over the last few decades with its direct relationship to a better lung function and consequently a better overall prognosis and survival [
      • Yen E.H.
      • Ms H.Q.
      • Borowitz D.
      Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis.
      ,
      • Corey M.
      • Mclaughlin F.J.
      • Williams M.
      • Levkon H.
      A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto.
      ]. Obtaining and keeping a good nutritional status is, however, a challenge in most patients with CF. This has several reasons, i.e. the increased energy requirements secondary to chronic inflammation and pancreatic insufficiency (PI) (present in almost 80% of patients) on one side and the decreased energy intake and loss of nutrients due to maldigestion and malabsorption on the other side [
      • Woestenenk J.W.
      • Van Der Ent C.K.
      • Houwen R.H.J.
      Pancreatic enzyme replacement therapy and coefficient cystic fibrosis.
      ].
      Therefore, the main nutritional goal in children with CF is to avoid inadequate nutrient intake and to follow a normal growth pattern according to age. Nutritional follow-up and intervention is essential and should aim at achieving an optimal adjustment of pancreatic enzyme replacement therapy (PERT) to correct pancreatic insufficiency as well as at prescribing a balanced diet according to nutritional needs [
      • Haupt M.E.
      • Kwasny M.J.
      • Schechter M.S.
      • Mccolley S.A.
      Pancreatic enzyme replacement therapy dosing and nutritional outcomes in children with cystic fibrosis.
      ,
      • Schall J.I.
      • Bentley T.
      • Stallings V.
      Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis.
      ]. The recently published guidelines on nutrition care for infants, children and adults with CF compile the most recent scientific evidence and establish recommendations regarding nutritional goals and PERT dosage [
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ].
      In comparison with antibiotics or physiotherapy treatments, nutrition and PERT are more likely to be mainly managed by the patients or parents themselves, outside the care of the CF team. Eating and drinking is a daily need and patients are supposed to comply with a balanced diet and adjust the dose of enzymes accordingly. However, if an incorrect nutritional behaviour or an inadequate enzyme dosage occurs, it will most likely not be detected and corrected until the next contact or visit to the CF centre. Consequently, one of the ultimate goals of the medical care in CF – achieving and maintaining an adequate nutritional status – will be jeopardised rather than potentiated.
      Therefore, nutritional education and treatment in CF can be considered as one of the ideal targets of mobile health (mHealth) and patients' self-management. These concepts have been pointed out as main priorities in the current European Union's research and innovation programme, Horizon 2020. They strongly suggest that the current and future lines of medical investigation should be focused on this area [
      • Horizon 2020
      Work Programme 2014–2015. Health, Demographic change and wellbeing.
      ].
      In this scenario, MyCyFAPP Project (www.mycyfapp.eu) came to fruition as an innovative approach towards the self-management of nutrition and PERT in paediatric patients with CF by means of a mobile APP. The whole project includes various studies in order to generate educational resources and supporting tools addressed to patients, to ultimately achieve the overall goal.
      The present study was carried out to obtain baseline information about nutrient and PERT intake and identify possible discrepancies with the current recommendations. This information will help to develop CF-specific, tailored evidence-based tools to allow for the self-management of nutrition and PERT in order to facilitate adherence to current recommendations. We therefore assessed nutritional status, daily energy and macronutrient intake, and enzyme dosing of a European population of children with CF and related these findings to the new ESPGHAN/ECFS/ESPEN nutritional guidelines [
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ].

      2. Methods

      2.1 Subjects and study design

      Patients with CF considered for enrolment in this cross-sectional study were regularly followed in the 6 MyCyFAPP participating European CF Centres: Lisbon (Portugal), Madrid (Spain), Valencia (Spain), Milan (Italy), Leuven (Belgium) and Rotterdam (The Netherlands). Inclusion criteria required a confirmed diagnosis of CF for at least 6 months and age between 1.0 to 17.9 years. Patients who had undergone organ transplantation were excluded. Presence of pancreatic sufficiency (PS) was not considered an exclusion criterion.
      The anthropometric measurements were taken and clinical data registered. Prospectively, participants completed a newly developed 4-day food and pancreatic enzymes record. The collected information was securely stored in the online MyCyFAPP project system, allowing for data storage and automatic calculations. Participants followed their usual diet and took their regular enzyme dose as prescribed by the specialists in their centres.
      The study protocol was approved by the ethical committee of each CF centre and conducted according to the Declaration of Helsinki guidelines. All parents and patients were informed about the purpose and ultimate aim of the study and were asked to sign the informed consent.

      2.2 Clinical and anthropometric data

      The anthropometric data were obtained by trained personnel of the CF centres. After calibration of the equipment, weight was measured using a digital scale to the nearest 0.1 kg and height was obtained with either a measuring board (supine length) or stadiometer (standing height). Body mass index was calculated as weight (kg)/height (m2). Anthropometric measurements were converted to standard deviations scores e.g. “height for age” (HFA), “weight for age” (WFA), and “body mass index for age” (BMI) using the CDC references [
      • Kuczmarski R.J.
      • Ogden C.L.
      • Guo S.S.
      • Grummer-Strawn L.M.
      • Flegal K.M.
      • Mei Z.
      • et al.
      CDC growth charts for the United States: methods and development.
      ].

      2.3 Nutritional data collection and calculation

      The specific 4 days food and enzymes record form (FER) was developed, based on current recommendation that a 3 to 5 day diet record is necessary for a quantitative evaluation of nutrient intake [
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ]. The FER was structured in six sections: 3 main meals (breakfast, lunch and dinner) and 3 snacks (morning, afternoon and night). Patients were asked to indicate the exact time of each meal, the name of the dish, ingredients/food products it contained and the amount taken, as well as the PERT dose. The FER also included a household measure table with equivalences in grams and an example of a completed food record, both in order to help participants to register everything the most accurate way. The food record is the regular tool to assess dietary intake in all the centres, so all the patients were familiar with its use. Regarding the specific FER for this study, dieticians were the personnel in charge of explaining it to the patients and their families according to a common consensus criterion among the centres. Patients were advised to follow their normal diet and to take their regular enzyme doses.
      The nutritional composition databases used for the energy and nutrient intake calculation were purchased from EuroFIR® (Spain, Italy, Portugal, and Netherlands), and Nubel® (Belgium), since they were country specific and contained the nutritional facts of the particular food products in each region. Calculations were automatically performed by the system through the specifically developed calculation tools. The total daily energy intake was calculated and expressed as kcal/kg/day. Macronutrient intake was calculated in grams of lipids, carbohydrates and protein per day and expressed as percentage of total daily energy intake. The dosage of PERT was evaluated by considering the Enzyme/Substrate ratio (E/S) as the unit of dosage quantification, which was calculated as lipase units (LU) per gram of dietary fat (g fat) per meal (LU/g fat/meal). Additionally, the dose was calculated in terms of LU per kilogram of body weight per day (LU/kg/day) and reported as mean daily intake (LU/day).

      2.4 Comparison to current recommendations

      All data were compared according to the recommendations of the new nutritional guidelines for CF for nutritional status, energy and macronutrient intake and PERT dose [
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ]. The recommended value for the nutritional status indicators HFA, WFA and BMI SD-scores is 0 SD, which corresponds to the mean value of age-matched healthy population. The current recommendation for total energy intake is 110–200% of the recommended energy intake of healthy age-matched population. For macronutrient intake the recommendations are 20% of total daily energy intake from protein, 35–40% from lipids, and 40–45% from carbohydrates. Recommended PERT dose is between 2.000 and 4.000 LU/g of dietary fat and below 10.000 LU/kg/day.
      Analysis of energy intake considered the mean energy intake minus the lower recommended limit (110%) to evaluate if patients were at least fulfilling the lowest recommendation: 0 means the recommendation is achieved whilst negative values mean the patient has achieved a lower intake than the recommended.
      In order to classify patients according to the enzyme dosage recommendations, three groups were established according to their mean daily PERT intake: below the recommended range (<2.000 LU/g), within the recommended range (2.000–4.000 LU/g) and above the recommended range (>4.000 LU/g). Intra-patient variability in the E/S ratio intake was assessed; this value expresses the spectrum of enzyme dosage for a certain amount of fat used by the patient at a concrete mealtime along the 4 days record.

      2.5 Statistical analyses

      The sample size was estimated using Monte Carlo simulations assuming normally distributed variables and aiming for a precision of ±10% for each variable. The estimations for performing the simulations were based on data from Schall, Bentley and Stallings (2006) [
      • Schall J.I.
      • Bentley T.
      • Stallings V.
      Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis.
      ].
      The data were summarized using mean (standard deviation) or median (interquartile range) in the case of continuous variables and with relative and absolute frequencies in the case of categorical variables. The association between nutritional status, age, pancreatic insufficiency, diagnosis through neonatal screening (NBS) and time lapsed from diagnosis till the present study was assessed using linear mixed models, adding the centre as a random effect. The Pearson correlation coefficient was calculated to assess age effect on SD-scores of BMI, HFA and WFA. Beta regression mixed models were used for the nutrient intake analyses. For the analyses on PERT-dosage, for each patient (4 days each, 6 meals/day) the mean daily dosage was calculated together with the standard deviation of the mean per patient representing the intra-patient variability. A p value ≤0.05 was considered statistically significant. 95% confidence intervals (95% CI) were provided for all estimates. The statistics' analyses were performed using R software (version 3.3.2).

      3. Results

      A total of 207 paediatric patients with CF from 6 different participating European CF centres were enrolled. Table 1 shows the patients' characteristics according to centre. There was a slight predominance of male patients (53.3%). Only 33% of the patients had been diagnosed through new born screening (NBS), with remarkable differences among centres. Ninety-one per cent of the patients suffered from PI.
      Table 1Clinical and demographic characteristics of the study cohort.
      Lisbon

      (n = 30)
      Madrid

      (n = 33)
      Valencia (n = 36)Milan

      (n = 30)
      Leuven (n = 29)Rotterdam (n = 49)TOTAL

      (n = 207)
      Mean age, years (SD)10.6 (4.8)7.6 (5.9)8.4 (5.1)7.9 (5.5)8.2 (5.7)7.1 (4.0)8.3 (1.2)
      Male % (n)43.3 (13)60.6 (20)50 (18)63.3 (19)62.1 (18)46.2 (24)53.3 (112)
      Newborn screening, % (n)0 (0)72.7 (24)13.9 (5)90.0 (27)3.4 (1)23.1 (12)32.9 (69)
      Mean age at diagnosis (years) (SD)2.5 (3.0)0.1 (0.2)1.3 (2.0)0.4 (1.8)0.6 (1.0)1.0 (2.5)1.1 (1.0)
      Pancreatic insufficiency % (n)90.0 (27)81.8 (27)100 (36)100 (30)100 (29)80.8 (42)91.0 (191)
      SD, standard deviation.

      3.1 Nutritional status

      Fig. 1 shows the median values of anthropometric parameters (BMI, WFA, HFA in SD-scores) and their relative positions as compared to age-matched healthy population (0 SD) for the different centres. First quartiles for BMI and HFA, (i.e. 25% of patients) were between 0 and −1SD except from one centre (Valencia, BMI), and third quartiles (i.e. 75% of children) for the three indicators were comprised between 0 and +1 SD in all centres (except for Milan, WFA). Some patients (33.5%) had a SD-score <0 for the three parameters, but only 4 patients had SD values <−2 SD for all of them. No correlations were found between any of the parameters (BMI, HFA or WFA) and age and no statistically significant differences were found among the centres for any of the parameters.
      Fig. 1
      Fig. 1Boxplots of anthropometric parameters in the different CF centers: BMI SD-scores, HFA SD-scores and WFA SD-scores. BMI: body mass index for age; HFA: height for age; WFA: weight for age.
      Being diagnosed by NBS, was not associated with a significantly better nutritional status outcome, in terms of BMI, WFA and HFA, when considering both age of diagnosis and time since diagnosis. The nutritional status of patients with PS was similar to that of the children with PI in terms of mean SD-scores (mean SD-scores for HFA p = 0.65, 95% CI [−0.353, 0.537]), WFA p = 0.43, 95% CI [−0.246, 0.587]) and BMI p = 0.44 [−0.239, 0.564]).

      3.2 Energy and Nutrient intake

      Overall, the mean daily protein intake varied from 10% to 17% of the total daily energy intake with a mean consumption of 14% (Fig. 2A ), not reaching the recommendation of 20%. The mean value of carbohydrate intake was 51% (Fig. 2B), with mean values for all centres above the recommended range. Altogether, the mean lipid intake of all centres was close to the lower threshold (34%) and ranging between 27 and 38% of the total daily energy intake. Only 3 centres fulfilled the recommendation for lipids (Fig. 2C).
      Fig. 2
      Fig. 2Mean values (with 95% confidence interval) of macronutrients intake as percentage of total daily energy intake: carbohydrates (2A), protein (2B) and lipids (2C). Vertical dotted lines represent the recommended intake range or value; vertical line represents the mean value of all the centres. Total daily energy intake (2D) represented as mean daily energy intake per patient minus the minimum amount recommended (110% from the recommendation in an age-matched healthy population).
      Overall, the recommended lower limit of daily energy intake was not reached by 46% of the patients. Fig. 2D represents the mean value and 95% confidence interval of the daily energy intake per centre as compared to the lowest recommendations. For all the centres the mean value was slightly higher than the recommendation (+50 kcal). However, the mean energy intake in two centres, those with the highest carbohydrates consumption and the lowest lipids consumption, was found to be 20–200 kcal lower than the recommended intake.
      Age was significantly associated with the percentage of nutrients' intake in all the centres: mean carbohydrate consumption decreased with age (p < 0.001) by 1.1 to 2.5% per year, while mean lipid consumption increased (p < 0.001) 0.8 to 2.2% a year and protein 0.7–1.8%. There were no differences between PS and PI patients regarding nutrient or energy intake.

      3.3 Use of PERT

      The mean PERT dose (LU/g fat/meal) differed widely between meals and centres. Table 2 shows that the majority of patients in all centres either exceeded or did not reach the advised range: up to 82.7% of patients in one centre took more enzymes than recommended, while in other centres up to 75% of patients had a PERT dose lower than 2.000 LU/g fat/meal. The percentage of patients fulfilling the recommended dose ranged between 13.8 and 46.6%. Considering the dose of PERT as referred to kg of body weight, patients in one centre exceeded the maximum recommended limit of 10.000 LU/kg/day, with a mean (SD) intake of 16.641 (10.568) LU/kg/day. The doses for the centres below the recommendations spread from 3.200 (1.871) LU/kg/day to 8.715 (2.199) LU/kg/day.
      Table 2Doses of PERT in the study cohort.
      Lisbon

      (n = 30)
      Madrid

      (n = 33)
      Valencia

      (n = 36)
      Milan

      (n = 30)
      Leuven (n = 29)Rotterdam (n = 49)TOTAL

      (n = 207)
      Mean (SD) LU/kg/day3200 (1871)5795 (1313)3206 (2346)8715

      (2199)
      16,641 (10568)5523

      (3714)
      7144

      (6801)
      Mean (SD) LU/g fat/meal1562 (802)3616 (4974)1559 (1347)4362 (1477)7858 (5027)4209 (5482)3805 (4365)
      Mean (SD) LU/day94,081 (60313)189,750 (105476)86,364 (65386)236,375 (159745)394,655 (230324)135,306 (88090)182,200 (168533)
      Enzyme supplements preparation (LU)1.000
      Capsules prepared in the Pharmacy Unit of the hospital, especially for children <1–2years.
      1.000
      Capsules prepared in the Pharmacy Unit of the hospital, especially for children <1–2years.
      5.000
      Pancreatin granules (1 measuring scoop=5.000LU).
      5.000
      Pancreatin granules (1 measuring scoop=5.000LU).
      5.000
      Pancreatin granules (1 measuring scoop=5.000LU).
      5.000
      Pancreatin granules (1 measuring scoop=5.000LU).
      10.00010.00010.00010.00010.00010.000
      25.00025.00025.00025.00025.000
      40.000
      Patients with PERT dose (%)<2.000 LU/g of lipids7042.4753.33.52417.3
      2.000–4.000 LU/g of lipids3014.419.446.613.84216.8
      >4.000 LU/g of lipids015.25.65082.73465.9
      PERT pancreatic enzyme replacement therapy; SD standard deviation; LU lipase units.
      a Capsules prepared in the Pharmacy Unit of the hospital, especially for children <1–2 years.
      b Pancreatin granules (1 measuring scoop = 5.000 LU).
      Overall, when considering main meals (breakfast, lunch, dinner) as compared to snacks (Fig. 3A ), enzyme doses or E/S (LU/g lipids) had a similar pattern, i.e. doses at snacks were not higher than at main meals or vice-versa. Considering different meals individually, there was not a common trend or pattern in enzyme doses, neither among patients from the same centre, or when comparing different centres. However, for some meals, mainly snacks, no enzymes were taken even though the meal contained lipids (data not shown in Fig. 3A since minimum value represented is 250 LU/g of lipids). The upper outliers of E/S values were found at snack meals in all centres.
      Fig. 3
      Fig. 3Dose of PERT per meal type and centre. Expressed as mean (E/S in LU/g fat) in Fig. A and expressed as intra-patient variability (SD E/S) in Fig. B.
      B, breakfast; S1, snack 1; L, lunch; S2, snack 2; D, dinner; S3, snack 3. Horizontal lines indicate the recommended range for dose in terms of lipase units per gram of fat (2.000–4.000 LU/g fat) according to Turck et al. 2016.
      Age was not associated with PERT dosage at any centre except in Valencia, where the oldest children had the highest E/S values (p < 0.01) and in Rotterdam where, on the contrary, the oldest patients had the lowest E/S (p < 0.01).
      Large differences in E/S ratios among meals for the same patient (intra-patient variability) were obtained, ranging from mean values of 400 LU/g of fat in some meal types to 3.200 LU/g of fat in others (Fig. 3B). No concrete meal type was significantly associated with a higher or a lower intra-patient variability in E/S, but snacks meals were the only ones showing cases of 0 variability. Centres with lower E/S ratios had the lowest intra-patient variability. Finally, age was not associated with intra-patient variability in E/S (p > 0.05) in all the centres.

      4. Discussion

      Through the present study we have characterized nutritional status, energy and nutrients intake and meal-specific use of PERT of a European group of paediatric patients with CF compared to what is recommended by the new guidelines on nutrition in CF [
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ].
      Firstly, we have found a very wide range of intra-centre variability in terms of SD-scores for BMI, height and weight for age, with the majority of the results standing between 0 and -1SD. Severe malnutrition (values < −2SD [
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ]) indicators were, however, found only occasionally. Association between diagnosis by NBS and better outcomes of nutritional status, as previously reported in wider series [
      • Yen E.H.
      • Ms H.Q.
      • Borowitz D.
      Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis.
      ,
      • Woestenenk J.W.
      • Van Der Ent C.K.
      • Houwen R.H.J.
      Pancreatic enzyme replacement therapy and coefficient cystic fibrosis.
      ], was not found in our study population with only 33% diagnosed by NBS.
      Secondly, the study has pictured centre-specific macronutrients distribution and energy intakes. In general terms, protein intake was lower than recommended in all centres, none of which achieved the daily intake objectives; this fact could possibly be explained by CF teams still applying the previous recommendations [
      • Sinaasappel M.
      • Stern M.
      • Littlewood J.
      • Wolfe S.
      • Steinkamp G.
      • Heijerman H.G.M.
      Nutrition in patients with cystic fibrosis: a European consensus.
      ], although not completely compliant with these neither.
      With regard to lipids, some centres more successfully accomplished recommendations than others, probably due to the higher amounts of oil and fats consumed related to the local nutritional habits. Of note, centres with the highest carbohydrate intake had the lowest lipids and energy intake and vice-versa. Our results are comparable to those of a previous multicentre study conducted in the US in infants and toddlers with CF, that showed an intake of 33.8% of energy from fat, 55.8% from carbohydrates and 12.4% from protein, and only 50% achieving the minimum energy recommendation [
      • Powers S.W.
      • Patton S.R.
      • Byars K.C.
      • Mitchell M.J.
      • Jelalian E.
      • Mulvihill M.M.
      • et al.
      Caloric intake and eating behavior in infants and toddlers with cystic fibrosis.
      ]. However, the mean energy intake of the whole group was slightly above the 110% limit, evidencing that despite almost half of the patients not complying with it, they were very close to the recommendation. This is clearly reflected in Fig. 2D: there is one single centre contributing to the low overall value, while the mean energy intake in four centres is higher than the mean of the group and than the minimum recommended. In another study carried out in the US, 86 subjects aged 6.0–8.9 years had around 37% of fat intake and the 120% energy goal was not reached by 61% of the children [
      • Schall J.I.
      • Bentley T.
      • Stallings V.
      Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis.
      ]. In addition, in a larger population of 234 Dutch children aged 0–18 years fat intake represented 34–36% of total energy, which in turn was 88 to 119% of recommendations for an healthy age-matched population [
      • Woestenenk J.W.
      • Castelijns S.J.A.M.
      • Van Der Ent C.K.
      • Houwen R.H.J.
      Dietary intake in children and adolescents with cystic fi brosis.
      ].
      Finally, our results have evidenced the lack of uniformity in PERT dosage among the centres, E/S ratios ranging from mean values of 1.520 up to 7.758 LU/g fat/meal with considerable differences among centres. In terms of maximum recommended daily dose, only in one centre patients exceeded the maximum recommended dose of 10.000 LU/kg/day whilst in others the mean value was far below. Despite this fact, no cases of fibrosing colonopathy were reported in any of the centres. This is in accordance to a previous study showing that 10.000 LU/kg/day should not be any longer a restriction [

      Woestenenk JW, Van Der Ent CK, Houwen RHJ. Pancreatic enzyme replacement therapy and coefficient cystic fibrosis. 2015;61(3):355–60. 10.1097/MPG.0000000000000784.

      ], although the new guidelines maintain this figure as the maximum recommended. We believe the outstripping result in one centre is related to the enzyme supplements preparation of 40.000 LU recently instituted. Likewise, the formulation of 1.000 LU available in the centres with the lowest PERT doses may be the reason for this finding. The mean value of the whole group (7.144 LU/kg/day) was, however, very similar to that reported in a Dutch population (7.627 LU/kg/day) [
      • Woestenenk J.W.
      • Van Der Ent C.K.
      • Houwen R.H.J.
      Pancreatic enzyme replacement therapy and coefficient cystic fibrosis.
      ].
      A comprehensive study in children 8–11 years assessing adherence to PERT concluded that 88% of the patients were within the previously recommended range of 500–4.000 LU/g fat and only 4% were below [
      • Schall J.I.
      • Bentley T.
      • Stallings V.
      Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis.
      ]. According to our results, in some centres very high percentage of patients were below the new recommended PERT dosage range (<2.000 LU/g), but if we take into account the 2002 guidelines (lower limit of 500 LU/g fat), we would find a similar percentage of patients under the lower limit as the previous study [
      • Schall J.I.
      • Bentley T.
      • Stallings V.
      Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis.
      ]. We highlight the fact that despite the very wide range of PERT intake (overdosing vs. underdosing) between centres, no differences were found in terms of nutritional status. There was no association either between PERT dose and energy intake. On the other hand, it is well known that there is an enormous variability in the response to PERT among patients; in a large retrospective study in children with CF no correlation was found between enzyme dose and the degree of fat malabsorption [

      Woestenenk JW, Van Der Ent CK, Houwen RHJ. Pancreatic enzyme replacement therapy and coefficient cystic fibrosis. 2015;61(3):355–60. 10.1097/MPG.0000000000000784.

      ]. It is also possible that differences would have been found when gastrointestinal complaints were taken into account.
      The discrepancies in PERT dosing criteria found in our study reinforces the absence at the present time, of a well-established and evidence-based adjustment method. The authors of the new guidelines acknowledge this insufficient evidence for the recommended PERT dosage, and some studies have highlighted the need of conducting research in order to improve PERT adjustment [
      • Hu M.
      • Li Y.
      • Decker E.A.
      • McClements D.J.
      Role of calcium and calcium-binding agents on the lipase digestibility of emulsified lipids using an in vitro digestion model.
      ,
      • Li Y.
      • Hu M.
      • McClements D.J.
      Factors affecting lipase digestibility of emulsified lipids using an in vitro digestion model: proposal for a standardised pH-stat method.
      ]. Other authors also highlight the need to investigate individual factors, such as gastric emptying time or intestinal transit time, and inherent-to-food factors, like physicochemical characteristics of the food matrix or the type of fat, as determinants on the efficiency of the pancreatic enzymes supplements [
      • Fieker A.
      • Philpott J.
      • Armand M.
      Enzyme replacement therapy for pancreatic insufficiency: present and future.
      ,
      • Borowitz D.
      • Gelfond D.
      • Maguiness K.
      • Heubi J.E.
      • Ramsey B.
      Maximal daily dose of pancreatic enzyme replacement therapy in infants with cystic fibrosis: a reconsideration.
      ,
      • Rovner A.J.
      • Schall J.I.
      • Mondick J.T.
      • Zhuang H.
      • Mascarenhas M.R.
      Delayed small bowel transit in children with cystic fibrosis and pancreatic insufficiency: commentary.
      ,
      • Farrel P.M.
      • Kosorok M.R.
      • Laxova A.
      • Guanghong G.
      • Koscik R.E.
      • Bruns W.T.
      • et al.
      Nutritional beneffits of neonatal screening for cystic fibrosis.
      ].
      Overall, the results of this study could have an impact on daily clinical practice in terms of nutritional advice and education to parents. We observed a change in macronutrients distribution with age in all centres. The younger the patient, the higher the carbohydrates intake (exceeding the daily recommendations), but as children got older, the percentage of energy intake from carbohydrates decreased in favour of an increase in that from protein and lipids. A similar tendency was previously reported in a cohort of Spanish patients by Calvo-Lerma et al. 2015 (PO-AHP-0006 ESPGHAN 48th meeting). Higher carbohydrates intake and lower protein as compared to the recommendations was also observed in another study with a population aged 7–35 months [
      • Powers S.W.
      • Patton S.R.
      • Byars K.C.
      • Mitchell M.J.
      • Jelalian E.
      • Mulvihill M.M.
      • et al.
      Caloric intake and eating behavior in infants and toddlers with cystic fibrosis.
      ]. Thus intervention to promote adequate dietary patterns should start at early age.
      Moreover, the high intra-patient variability for specific meals and regarding the enzyme to substrate dosage implicates that patients took a fixed enzyme dose for each particular meal independently of what they ate. For example, if the child takes a fixed amount of 2 enzyme capsules for breakfast each day, but the fat intake varies between 10 and 20 g of fat, the E/S ratio would be 2.000 LU/g of fat (inside the recommended range) – 1.000 LU/g (below the recommended amount). This would mean an intra-patient variability of 1.000 LU/g of fat between two days. These findings suggest that patients should be aware and take into account the content of fat in every meal in order to adjust the dose accordingly, with the target of reaching the optimal/recommended E/S ratio. For this purpose educational material and adequate tools should be available for patients at any time to help them to decide the dose of enzymes they should take for a particular meal.
      In this regard the results obtained, in the context of MyCyFAPP Project, may be very useful. The identification of the specific nutritional imbalances to be addressed and the goals established in the new guidelines will be considered as the project's premises to start building up the tailored educational resources and tools that eventually will be in the hand of the patient with the mobile APP.
      The major strength of the study is the use of robust methodology that makes it of scientific value, including specific and detailed food and enzyme information, reliable databases and tools to calculate the nutritional facts, the common consensus practice in explaining patients about how to fill in the record, expert dieticians participating in the study design and its implementation, and the nature of the statistical analyses performed (application of models rather than tests). Additionally this is the first time, to our knowledge, that a study has been conducted that specifically compares the current practice to the newly published experts' guidelines in a multicentre way in 5 different European countries.
      Our study has some limitations. Despite five European countries (6 different centres) from different areas were enrolled - two northern European cities (Leuven and Rotterdam) and four from the south (Lisbon, Madrid, Valencia and Milan) – the conclusions may not apply to all European countries. Indeed we have found that dietetic and therapeutic patterns vary from one region to another, thus future studies could consider the inclusion of other countries. Although the patients completed the dietary data in the food record form in detail, only a reduced number filled in the specific questions about gastrointestinal symptoms and stools frequency, so those data could not be used for the analyses. Besides, it cannot be ruled out that dietary data recorded was totally accurate, since filling in the food record might have supposed an extra burden to the patients. In the future, MyCyFAPP will provide a guided and user-friendly food recording system on a mobile APP. This will improve reliability and precision on the collected data. Another limitation of the study could be the number of patients included; however, from the descriptive analysis' perspective, which was the primary objective, the sample size was adequate. Besides other studies in the field included a similar or smaller number of patients [
      • Schall J.I.
      • Bentley T.
      • Stallings V.
      Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis.
      ,
      • Powers S.W.
      • Patton S.R.
      • Byars K.C.
      • Mitchell M.J.
      • Jelalian E.
      • Mulvihill M.M.
      • et al.
      Caloric intake and eating behavior in infants and toddlers with cystic fibrosis.
      ,
      • Woestenenk J.W.
      • Castelijns S.J.A.M.
      • Van Der Ent C.K.
      • Houwen R.H.J.
      Dietary intake in children and adolescents with cystic fi brosis.
      ].
      We found no association between NBS diagnosis and better nutritional outcomes - as previously reported– probably due to the small sample of patients applying for such analysis, and to the random nature of the inclusion criteria, only 32.8% of patients having been diagnosed by NBS. Moreover, the mean interval between NBS until the present time was short (only 4 years), and similarly mean age was low, while generally benefits from very early diagnosis and intervention is more evident with age increase [
      • Farrel P.M.
      • Kosorok M.R.
      • Laxova A.
      • Guanghong G.
      • Koscik R.E.
      • Bruns W.T.
      • et al.
      Nutritional beneffits of neonatal screening for cystic fibrosis.
      ]. Being pancreatic sufficient was also not associated with a better nutritional status, but this sample represented only 9% of the total study population. We did not study the association between nutritional status and FEV1 as it was scheduled with different periodicity in the different centres, and as this was a cross-sectional study, the data on FEV1 were insufficient to apply the comparative analysis.
      Our project is further studying the dietary origin of the nutrients in terms of foods sources in the different countries. This knowledge will allow for advising patients in a more practical way i.e. how to adjust the intake of certain products in order to correct the concrete nutritional imbalances, like a deficient intake of lipids. Additional information about type of lipids consumption in terms of degree of fatty acids' saturation could be relevant since variations in the type of fatty acids have been associated with different digestion fates [
      • Hunter E.J.
      Studies on effects of dietary fatty acids as related to their position on triglycerides.
      ]; this could affect PERT efficiency and thus dosing needs. Finally, results have reinforced the need to focus the research on an evidence-based method for PERT, which is being addressed in other areas of the project.
      To conclude, in a paediatric European CF population we have found discrepancies between the new guidelines on nutrition along with a wide spectrum of differences both in nutrient intake and PERT among the six centres. Furthermore, our results proof the lack of a general criterion to adjust PERT and the potential benefit of educational and self-managerial tools for patients' better adherence to therapies. The development of these tools is the target of the next steps of MyCyFAPP Project.

      Acknowledgements

      Authors of this paper, on behalf of MyCyFAPP consortium, acknowledge the European Union and the Horizon 2020 Research and Innovation Framework Programme for funding the project (ref. 643806).

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