Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20

Challenges with optimizing nutrition in cystic

fibrosis

Carla Colombo, Rita Maria Nobili & Gianfranco Alicandro

To cite this article: Carla Colombo, Rita Maria Nobili & Gianfranco Alicandro (2019) Challenges
with optimizing nutrition in cystic fibrosis, Expert Review of Respiratory Medicine, 13:6, 533-544,
DOI: 10.1080/17476348.2019.1614917

To link to this article: https://doi.org/10.1080/17476348.2019.1614917

Published online: 16 May 2019.

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EXPERT REVIEW OF RESPIRATORY MEDICINE
2019, VOL. 13, NO. 6, 533–544
https://doi.org/10.1080/17476348.2019.1614917

REVIEW

Challenges with optimizing nutrition in cystic fibrosis

Carla Colomboa,b, Rita Maria Nobilib and Gianfranco Alicandroc
a
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; bFondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Cystic Fibrosis Centre, Milan, Italy; cDepartment of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy

ABSTRACT ARTICLE HISTORY

Introduction. Optimizing nutrition remains the cornerstone of therapy for patients with cystic fibrosis Received 14 January 2019
(CF) since it is associated with better pulmonary function and survival. However, a significant proportion Accepted 1 May 2019
of patients still fail to achieve normal growth and nutritional status. KEYWORDS
Areas covered. This review describes the current challenges in providing effective nutritional therapy in Cystic fibrosis; nutrition; diet;
CF with a focus on the current issues related to energy imbalance, dietary composition, adherence to adherence; new therapies
nutritional recommendations, pancreatic enzyme replacement therapy, and the effects of modulators of
the CF transmembrane conductance regulator.
Expert opinion. CF is a multisystemic disease that requires a personalized nutritional approach with
accurate evaluation of energy balance. There is an urgent need for evidence-based recommendations
on the dietary composition, in consideration of the increasing prevalence of overweight, diabetes and
the potential effects of fatty acids on inflammation and immune response. More research into new
pancreatic enzyme formulations is also required.

Cystic Fibrosis (CF) is the most common life-threatening auto- were defined [10]. These recommendations were based on the
somal recessive disease in the Caucasian population. It is positive association between anthropometric indicators and the
a multisystemic disease affecting the lung, pancreas, liver, forced expiratory volume in one second (FEV1) which emerged
intestine, sweat glands, and reproductive tract [1]. Lung dis- among patients with CF and pancreatic insufficiency included in
ease is the main cause of morbidity and mortality. the 2005 CF Foundation Patient Registry data [10].
Over the last few decades, major advances have been made in By adopting the unrestrictive fat intake strategy, a progressive
our understanding of the disease, with discoveries of the under- improvement has been made in the nutritional status of both
lying chloride transport defect and the CF transmembrane con- pediatric and adult CF populations, with steady increases in
ductance regulator (CFTR) gene. These important achievements median BMI percentile in the 2- to 19-year-olds as well as average
have led to an improvement in median survival from less than BMI among adults. However, there is still room for improvement,
a few years when the disease was firstly described in 1938 to over and undernutrition still affects a significant proportion of
45 years more recently [2]. Several factors have likely contributed patients [11,12], with nutritional decline typically occurring in
to the improvement in survival, including therapeutic innova- late childhood and early adult life [13].
tions, aggressive treatment of infections from early life, care This review focuses on the major challenges in optimizing
delivered by multidisciplinary teams in specialized centers, and nutritional status in the modern era when standards of care
neonatal screening [3–6]. include aggressive treatment of pulmonary disease, more effi-
However, a key factor accredited as having added a further cient pancreatic enzyme replacement therapy (PERT) and also
10 years to the median survival has been improving and main- innovative pharmacological treatments targeting correction of
taining normal growth and nutrition [7]. the basic CF defect [14] (Table 1).
Between the 1960s and 1980s, in order to control abdominal
symptoms attributable to maldigestion and malabsorption, most
1. Correction of the energy imbalance
CF Centers used to administer a low-fat diet with the result that
most CF patients developed malnutrition and stunting due to Energy imbalance occurs when the energy content of food
insufficient energy intake. By contrast, the high-fat, high-energy eaten does not compensate for the energy expended to main-
diet prescribed to patients at the Toronto CF center resulted in tain physiological functions, to perform physical work and to
improved nutritional status with a significant survival advantage guarantee adequate growth in children.
over other CF centers in North America [8]. Energy imbalance is frequent in CF patients and results in
Since then, other studies have confirmed that maintaining undernutrition and growth failure. The pathophysiology of energy
a good nutritional status is critical to the long-term survival of CF imbalance in CF involves three interrelating factors (Figure 1): (1)
patients [9] and age-specific nutritional targets for CF patients reduced energy intake due to inadequate diet, reduced appetite,

CONTACT : Carla Colombo [email protected] Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre, Via della Commenda 9, 20122, Milan, Italy
© 2019 Informa UK Limited, trading as Taylor & Francis Group
534 C. COLOMBO ET AL.

Table 1. Factors involved and main challenges in achieving and maintaining Poor appetite and reduced energy intake increase the risk
a good nutritional status.
of nutritional deficiencies and weight loss, the latter being
1) Correction of energy imbalance:
- Reduced intake (reduced appetite, eating disorders)
difficult to reverse. Both are associated with more serious
- Increased energy loss (ineffective PERT) health outcomes as well as increased mortality. However, the
- Increased energy expenditure (need for quantification of REE and incidence of poor appetite in CF is poorly defined, because it is
physical activity)
2) Dietary macronutrient composition
subjective and experienced differently by each individual and
- Lipid intake no objective method or meaningful surrogate measures for its
- Protein intake assessment are currently available.
- Carbohydrate intake
- Free sugars
Research is needed to determine meaningful surrogate
3) Selective micronutrient deficiencies measures for appetite and to develop a disease-specific instru-
- Essential fatty acids ment for measuring poor appetite.
- Long-chain n-3 fatty acids
- Vitamin D
The etiology of poor appetite is multifactorial and involves
- Sodium factors directly related to CF disease, along with others that
- Zinc may be more prevalent in CF (Table 2).
4) Adherence to nutritional recommendations and PERT
5) Effects of CFTR modulators on nutrition
Information on appetite is generally inferred from the
results of food records and gained from investigation into
symptoms, negative emotions and food behavior; during ado-
abdominal symptoms, depression; (2) increased energy loss lescence, a voluntary control of appetite or avoidance of high
because of nutrient maldigestion/malabsorption; (3) increased energy foods, linked to the physical appearance, body satisfac-
energy expenditure as a consequence of advanced lung disease, tion, and desired body weight should be considered.
resulting in increased workload for respiratory muscles and oxy- Particular attention should be paid to psychological issues, as
gen cost of breathing. living with a chronic disease is associated with high stress levels.
From very early age, CF patients have a perception of their body’s
response to food that is not always consistent with that of healthy
2. Reduced energy intake
people. Since body and mind are inseparably bound and the mind
A good nutritional status is dependent on adequate energy shapes the perception of self through bodily experiences, before
intake which, in turn, is dependent on complex interrelated labeling a patient as having a ‘behavioral disorder,’ the history of
factors including physical hunger, appetite, food-related beha- symptoms and personal and family relationships should be care-
viors, emotion, knowledge, and beliefs. fully investigated. Attitudes and family habits are also very impor-
Food intake is also mediated by several peptide hor- tant in determining the reaction of a patient to food and
mones through their action on hypothalamic pathways. consequently his/her eating behavior.
Leptin, ghrelin and insulin are the main hormones A review of studies exploring body image among adults and
involved in the regulation of appetite, but data on their adolescents with CF suggested that females have a better body
plasma levels in CF are scarce and inconsistent and it is image compared to males, but this may negatively influence
still unclear whether a dysregulation in their secretion disease outcome, given their preference for a low body weight
exists and contributes to decreased appetite and weight [17]. Males may be more motivated to adhere to nutritional
loss [15,16]. advice because they favor a larger body shape. The topic of

Figure 1. Pathogenesis of energy imbalance in cystic fibrosis.

 EXPERT REVIEW OF RESPIRATORY MEDICINE 535

Table 2. Factors contributing to poor appetite and poor food intake in cystic z score) and appetite, with no difference between the two drugs;
fibrosis (CF).
side effects were insufficiently reported to fully establish safety
Factors related directly to CF
- Pulmonary exacerbations
[21]. All studies were small in size and offered only a moderate
- Chronic inflammation (anorectic effect of proinflammatory cytokines amount of evidence, making it impossible to provide evidence-
(IL-1, IL-6, and TNF-alpha) based recommendations on the use of appetite stimulants for CF
- Nasal polyposis
- Distal intestinal obstruction and constipation
patients. Lastly, the beneficial effects of CFTR modulators on
- Gastroesophageal reflux and/or poor gastric emptying nutritional status have been related to several factors including
- Abdominal pain, bloating, and other symptoms of malabsorption. improved appetite and food intake [22] (Figure 2)
- Avoidance of high-energy foods erroneously considered to be harmful
for CF (carbohydrates for diabetes, fats to control symptoms of
pancreatic insufficiency).
Factors that are more prevalent in CF
3. Increased energy losses due to pancreatic
- Depression, anxiety, stress insufficiency
- Eating disorders
Pancreatic insufficiency is present in 70–85% of CF patients
- Drugs and burden of treatment. and, if not adequately corrected, results in maldigestion and
malabsorption.
PERT is the cornerstone of the nutritional management of
body image should be tackled with the patient to ensure it CF and should be started as soon as the diagnosis of pancrea-
does not have a negative impact on self-management [17]. tic insufficiency is made, in order to prevent undernutrition
We have also to consider that self-esteem, and consequently and failure to thrive. Exocrine pancreatic function declines in
body image are connected with parental attitudes toward the most of the patients from the first months of life [23,24] with
child and his/her body. The potentially traumatic grief associated a faster rate in those carrying two severe mutations (Class I, II,
with diagnosis can affect caregiving behaviors, child attachment, and III), which are associated with no CFTR protein activity in
and parent perception of child vulnerability. Given the critical the apical membrane of epithelial cells [25].
role of nutrition in disease outcome, mealtimes can induce Pancreatic enzymes have been used in CF since the 1930s
negative interactions between parent and child [18]. Therefore, and different preparations have been tested to improve their
careful consideration of family functioning, parental mental effectiveness. In the late 1980s, pancreatic enzyme supplements
health and the way to manage a ‘normal’ function like feeding were reformulated as enteric-coated microspheres (ECM), to
could prevent destructive behaviors in the child and adolescent. prevent inactivation by gastric acidity and to make enzymes
In fact, parent/child attachment is probably the most protective quickly available in the duodenum in a more uniform mixture
quality in order to prevent psychological suffering and to sustain with chyme [26]. Adequate neutralization of gastric acidity is
successful adaptation to life regardless of health status. crucial for nutrient absorption and for timely release of pancrea-
Several strategies to improve appetite and adequacy of diet tic enzymes [27]. However, a study assessing concurrent gastric
have become part of common practice (e.g. enhancing the flavor emptying of labelled oil in an ordinary meal and labelled
of food with herbs, spices and sauces, serving smaller portions of spheres from enterically coated microspheres has provided evi-
enriched foods, eating in the company of others) and encoura- dence of a mismatch in their duodenal deliveries, with pancrea-
ging an increase in the level of physical activity, if appropriate, tin lagging behind the emptying of dietary fat [28].
may also help. When food consumption does not guarantee an At present, the main preparations in use are immediate-
adequate energy intake, supplements may help fill the gap release ECM and mini-microspheres, enteric-coated microtab-
between increased needs and reduced food intake, although lets, and ECM with a bicarbonate buffer [27]. ECM were shown
there are concerns that they may reduce the amount of food to be better in improving gastrointestinal symptoms than
eaten. The European Cystic Fibrosis Society (ECFS) and the Cystic other preparations; however, there is limited evidence of the
Fibrosis Foundation (CFF) guidelines recommend the use of superiority of any preparation with regard to long-term nutri-
nutritional supplements in addition to usual dietary recommen- tional and respiratory outcomes [29].
dations for children with growth deficits and adults with low The adequacy of PERT is considered one of the most impor-
weight [10,19]. However, a Cochrane review concluded that tant factors in preventing energy imbalance, with a positive
energy supplements are not essential in the dietary manage- impact on nutritional status.
ment of CF patients and do not confer additional benefits with Dosage should be tailored according to the fat content of
respect to dietary advice alone [20]. However, the included each meal and to the degree of fat malabsorption.
studies were focused on children with moderate malnutrition, Current nutritional guidelines [10,19] recommend 500–2500
so further studies are required to assess the benefits of energy IU lipase per kg of body weight per meal or 2000 to 4000 IU lipase
supplements in adult patients with more severe malnutrition. As per gram of dietary fat, and advise against exceeding 10,000 IU
energy supplements are expensive, cost-effectiveness must be lipase per kg of body weight to prevent the risk of fibrosing
assessed to reach conclusions with regard to their utility. colonopathy, a iatrogenic complication found to be associated
The use of appetite stimulants is still controversial because of with prolonged use of very high doses of enzymes [30].
doubts concerning their efficacy and also due to possible side As pancreatic bicarbonate secretion is also impaired in CF,
effects. A recent meta-analysis examined the efficacy and safety even larger doses of enzymes may be ineffective in achieving
of megestrol acetate and of cyproheptadine hydrochloride in full correction of malabsorption and steatorrhea; intestinal pH
a total of 47 patients [21]. In the short term (six months) in adults is often acidic and suboptimal for enzyme release, due to the
and children, appetite stimulants improved weight (or weight deficient buffering capacity required to neutralize gastric acid
536 C. COLOMBO ET AL.

Figure 2. Multisystemic effects of modulators of the cystic fibrosis transmembrane regulator (CFTR).

in the proximal small bowel [26,31]. Consequently, gastric acid Current guidelines suggest energy intake from 110 to 200%
reducing agents are often used as an adjunct to pancreatic of the energy requirements of healthy people [10,19]. Such
enzymes, but there is limited evidence that they are asso- a wide range reflects the fact that energy needs vary greatly
ciated with improvement in gastro-intestinal symptoms and among patients, depending on the degree of malabsorption,
fat absorption [32]. Further studies are needed to assess lung function, level of chronic inflammation and presence of
adverse effects associated with their long-term use, including acute respiratory exacerbations. This has led recent ESPEN-
an increased risk of pulmonary exacerbations [33]. ESPGHAN-ECFS guidelines [19] to recommend a personalized
The response to PERT is highly variable among patients and approach, adapting energy intake to achieve the individual
no correlation was found between enzyme dosage and the nutritional target.
degree of fat malabsorption [19,34] A few studies [38–43] found that resting energy expen-
The proper dosage to be used is another important ongoing diture (REE), the energy required to maintain vital body
question. Extensive variability was detected in the dose pre- processes at rest, is increased on average by 10% and can
scribed by different centers, suggesting a lack of evidence- be even higher during episodes of pulmonary exacerba-
based and reliable criteria to adjust PERT [35]. tions or in case of end-stage of CF lung disease [39,44,45].
Another significant problem is adherence to PERT. However, the increase in REE during these circumstances is
A prospective study [36] measured adherence to PERT for three offset by a decrease in physical activity, avoiding
months, with electronic pill-caps, and reported an average adher- a substantial increase in energy requirements. Indirect
ence of 49%, which was lower at home than at school, in toddlers calorimetry can reliably measure REE, however it is rarely
than in school-aged children and, in children with parents report- used other than for research purpose. This technique
ing depressive symptoms. In addition, adherence to PERT was is based on respiratory gas exchanges. It takes 30 min
positively related to three-month weight outcomes, suggesting and must be performed by trained operators, but has the
that poor adherence to PERT and dietary recommendations could advantage of being relatively inexpensive, portable and
be the main reasons why patients fail to achieve adequate nutri- suitable for use in outpatients and hospital settings.
tional status. Given that REE accounts for 60–70% of total
The potential benefit of education and self-management energy expenditure, a 10% increment in REE could be
using mHealth tools to ensure optimal PERT in relation to a reason for suboptimal growth or nutritional status in
individual meals is currently being assessed within the CF patients who do not fill the gap by increasing energy
Horizon 2020 MyCyFAPP project (see section 11.0) [37]. intake. Consequently, in patients who fail to achieve the
recommended nutritional goals, the information provided
4. Increased energy needs by indirect calorimetry, along with measures of daily phy-
Patients with CF need a higher energy intake than the general sical activity, should be used to customize the dietary
population in order to achieve normal growth in childhood intervention to the patient’s real energy requirements
and adequate nutritional status in adults. [38–45].
 EXPERT REVIEW OF RESPIRATORY MEDICINE 537

5. Dietary macronutrient recommendations with CF are limited, but there is increasing awareness of the
importance of muscle maintenance and optimal protein intake
In CF patients, increased energy requirements are usually met
in CF [54]. A study, based on 15 pediatric CF patients showed
by increasing fat intake up to 40% of total energy and this
that the intake of a mixture of essential amino acids with a high
strategy has resulted in a significant improvement in nutri-
leucine content stimulated protein anabolism to a greater
tional status and survival in recent decades.
extent than a standard balanced mixture of all essential and
Although total plasma cholesterol and low-density lipopro-
nonessential amino acids [58]. Further studies are needed to
tein (LDL) concentrations are usually lower than in the general
determine protein requirements in CF and to assess the role of
population, CF patients, especially if pancreatic sufficient, may
specific amino acids in improving protein synthesis and avoid
have an abnormal lipid profile with high triglycerides and LDL
loss of muscle mass.
and low high-density lipoprotein (HDL) concentrations [46,47]. In
the long term, the high saturated fat content of the CF diet [48]
may have a negative impact on cardio metabolic risk also in 6. Selective micronutrient deficiencies
patients with CF, who are now expected to reach middle age,
6.1. Dietary fatty acids
when cardiovascular disease may occur. In addition, a high satu-
rated fat intake may also promote chronic systemic low-grade Despite increased dietary fat intake, insufficient plasma level
inflammation and worse insulin activity [49], although this rela- of the essential n-6 fatty acid linoleic acid, as well as reduced
tionship has never been investigated in CF. levels of n-3 long chain fatty acids, eicosapentaenoic (EPA) and
Overweight and obesity are becoming a cause for concern, docosahesaenoic acids (DHA) are common in CF patients,
especially in patients with pancreatic sufficiency [50,51]. In 2017, while n-6 long chain arachidonic acid (AA) is normal or
an alarming prevalence of overweight (30%) and obesity (21%) in increased [59,60].
patients carrying mild CFTR mutations (IV–V class) was reported The imbalance between n-6 and n-3 long chain fatty acids
by the CFF Patient Registry [2]. A cohort study [51], based on 909 reflects abnormalities in fatty acid metabolism and has been
individuals monitored at the Adult CF Clinic in Toronto from 1985 thought to be involved in many pathological pathways in CF,
to 2011, found a weaker association between BMI and FEV1 at including inflammation, immune-response and hepatic dysfunc-
BMI values above 25 kg/m2, suggesting that benefits to pulmon- tion [61]. The theoretical basis behind the potential proinflam-
ary function for BMI values within the overweight and obese matory action of the CF fatty acid profile relies on the enhanced
range are small and need to be balanced against the known synthesis of proinflammatory eicosanoids derived from AA and
health risks of overweight [51]. An adjustment in fat and energy on the reduced anti-inflammatory effects of the long chain n-3
intake is therefore recommended individually to achieve normal fatty acids. DHA and EPA are the precursors of a series of anti-
growth and nutritional status, avoiding obesity. More precise inflammatory molecules, including resolvins, docosatrienes and
indications for carbohydrate and protein intakes should be also protectins. Therefore, supplementation with n-3 polyunsatu-
provided [19]. rated fatty acids may result in downregulation of the produc-
Given the high amount of dietary fats, carbohydrate intake as tion of AA-derived proinflammatory mediators with beneficial
a percentage of total energy is generally reduced (below 50%). effects on pulmonary inflammation and disease outcome.
Current guidelines provide neither recommendations on In animal models, diets enriched in n-3 polyunsaturated fatty
sugar intake nor any indications on the type of carbohydrates acids improved host resistance to Pseudomonas aeruginosa
to prefer, and this is also the case for patients with CF-related infection [62,63] and reduced CF-related lung damage [64].
diabetes (CFRD) [52]. Carbohydrate-containing foods with low In CF patients, plasma levels of these fatty acids are influ-
glycemic index are characterized by slower glucose release in the enced by dietary intake [65] and fatty acid deficiency can be
intestine, minimizing the postprandial peak in blood glucose and reversed by oral supplementation [66]. However, molar concen-
insulin levels, and may be beneficial in patients with impaired tration and n-3 membrane content are critical factors in deter-
glucose tolerance with the potential to delay insulin therapy, mining the extent of n-3-mediated inflammatory and immune
which represents an additional treatment burden in CF [52]. responses. DHA membrane enrichment in immune cells after
However, the effects of such dietary intervention have not DHA exposure is less efficient in humans than in mice and this
been adequately tested in these patients and it is not suggested probably explains why n-3 supplementation has shown remark-
in guidelines for CF management [53] because these foods have able effects in mice, whereas in human clinical trials, it failed or
a lower energy density and could enhance satiety with the risk of yielded modest effects. These considerations suggest that very
reducing energy intake and promoting weight loss, a condition high doses may be necessary to observe anti-inflammatory
that should be avoided in patients with CF. effects in humans (if any) [67]. Doses of more than 2 g/day
Recent studies suggest recommendations are also needed have been suggested in non-CF subjects [67], although CF
for increasing protein intake in order to maintain lean body patients may require even higher doses.
mass and improve long-term outcomes [54]. A growing body of evidence suggests that dietary fats are
Lean body mass is frequently reduced in CF, as a probable linked to inflammation by promoting translocation of microbial
consequence of increased protein breakdown induced by products (lipopolysaccharide, endotoxin) from the gut to the
chronic inflammation and frequent pulmonary exacerbations blood and by modulating the proinflammatory activity of lipopo-
[55]; however this abnormality is often unrevealed by BMI lysaccharide [67]. Indeed, saturated fatty acids have been shown
both in children and adult patients [54,56,57]. Studies examin- to activate lipopolysaccharide-mediated signaling through TLR4,
ing the effects of dietary proteins and amino acids in patients which in turn would activate NF-kB, a transcription factor that
538 C. COLOMBO ET AL.

regulates the expression of several proinflammatory cytokines, 400–500 IU/day of vitamin D3 from birth to 12 months,
whereas this was not the case for monounsaturated and polyun- 800–1000 IU/day up to 10 years and 800–2000 IU/day above
saturated fatty acids. These mechanisms have not been studied in 10 years, with increasing dosage for those not achieving the
CF, but deserve more attention to better define the role of the optimal serum concentration.
high-saturated fatty acid diet in CF-related inflammation. These recommendations are based on consensus opinions
Despite promising results in the reduction of some inflam- with a high degree of uncertainty. In fact, there is a gap in
matory markers [68–71], there is currently insufficient evi- knowledge of the appropriate dosing regimen, bioavailability
dence to recommend supplementation with n-3 fatty acids of different formulations and potential benefit of vitamin
or high doses of docosahexaenoic acid to improve nutritional D treatment in CF-related comorbidities, including lung infec-
status or pulmonary function [72] as studies carried out so far tion and CFRD.
have generally included a small number of patients and used
different dosages. Large-scale, long-term clinical trials consid-
ering significant clinical outcomes with dose-response evalua- 6.3. Antioxidants
tion are required to draw firm conclusions on the therapeutic
CF is characterized by dietary antioxidant deficiencies, which
utility of n-3 fatty acid supplementation in CF.
may contribute to excessive oxidative stress. High amounts
6.2. Fat-soluble vitamins of reactive oxygen species are released by inflammatory cells
during pulmonary exacerbations, thus administration of
CF patients are also at risk of fat-soluble vitamin (A, D, E, and K)
bioactive substances that can reduce oxidative stress may
deficiency as a result of fat malabsorption. With the aid of oral
be beneficial.
supplementation, intakes of vitamin A and E are generally ade-
Supplementation of multiple antioxidants has been pro-
quate or even higher than the dietary recommendations for CF,
posed by several administration routes, at different doses
raising some concerns about excessive intakes in patients taking
and with different timing, as well as in several combinations.
water-soluble formulations [73]. In contrast, vitamin D and
Most of the evidence comes from short-term clinical trials
K status are often suboptimal despite routine oral supplementa-
with a possible residual confounding effect of the intensive
tion with potential negative effects on bone health [73].
antibiotic treatment that patients with CF often receive [83].
Further research on optimal supplementation regimens of
However, a micronutrient mixture containing vitamins and
fat-soluble vitamins is required also considering the potential
other antioxidants did not prove effective in improving lung
benefits on nutritional status, bone mineralization, lung func-
function and nutritional status, despite better antioxidant
tion, and pulmonary exacerbations [74–77].
plasma levels [83,84]. Some promising effects of glutathione
Vitamin D has recently received special attention for a variety of
or N-acetylcysteine (a glutathione precursor) were observed
extra-skeletal effects that may extend beyond bone health, on
in small randomized short-term clinical trials that found
numerous organs and body functions, including inflammation,
improved growth [85] and FEV1 [86] after six months of
insulin secretion and sensitivity [78,79]. Vitamin D deficiency was
oral supplementation. Similarly, a small nonrandomized
recently found in up to 90% of patients with CF and was associated
pilot study [87] of 27 patients has shown that supplementa-
with more severe inflammation, colonization by P. aeruginosa,
tion with whey proteins, rich in sulfhydryl groups, can
number of pulmonary exacerbations and risk of diabetes [80].
increase levels of intracellular glutathione, the most abun-
However, a prospective study did not find any positive effect on
dant intracellular antioxidant, and may improve nutritional
nutritional status, pulmonary function and pulmonary exacerba-
status and reduce inflammation markers.
tions in 200 adults with CF after a supplementation protocol of
A recent clinical trial in 73 patients assessed the effects of an
1600 IU/daily or 10,000 IU/weekly during summer and 3200 IU/
oral antioxidant-enriched multivitamin supplement (β-carotene,
daily or 20,000 UI/weekly during winter [80].
coenzyme Q10, γ-tocopherol, and lutein) for 16 weeks on
The high prevalence of vitamin D deficiency and osteopenia
plasma antioxidant concentrations, inflammation markers/oxi-
in CF patients has promoted research to optimize vitamin D and
dative stress and clinical outcomes. The supplement was safe
calcium metabolism and detailed recommendations both for
and well tolerated and resulted in increased systemic concen-
screening and treatment of vitamin D deficiency have been
tration of antioxidants and modest reduction in systemic
reported [81,82].
inflammation after four weeks, and was also associated with
There is no consensus on the optimal serum concentration
a lower risk of pulmonary exacerbation [88].
of vitamin D, with the European guidelines recommending
Larger clinical trials, which should also assess timing and
a minimum serum 25(OH)D concentration of 20 ng/mL
effective dose, are needed before recommending any antiox-
(50 nmol/L) [82], while the US CFF recommends levels above
idant or other bioactive compound supplementation in CF.
30 ng/mL (75 nmol/L), in consideration of potential extra ske-
letal benefits [81]. However, the season at the time of testing
should be taken into account when interpreting vitamin
6.4 Sodium
D status and also for the treatment regimen, since serum con-
centrations are expected to be lower during the winter months. Excessive salt loss in sweat can result in inadequate levels of
European guidelines recommend an initial dose of 1000–2000 sodium in patients with CF of all ages. This may occur in hot
IU/day of vitamin D2 or D3 in infants and 1000 to 5000 IU/day environmental conditions, strenuous physical activity, and in
in children above one year of age and in adults [82]. Lower the presence of fever, rapid breathing, and fluid loss due to
dosages are recommended by the CFF [81]: an initial dose of diarrhea, vomiting, or stoma output.
 EXPERT REVIEW OF RESPIRATORY MEDICINE 539

Infants with CF, in whom sodium depletion can lead to The recommendation for fat intake is generally met, although
impaired growth, are particularly at risk. Indeed, the sodium studies using self-reported measures indicate higher adherence
content of breast milk and normal infant formula is relatively than those using objective measures [93].
low (<7 mmol/L in breast milk, and <15 mmol/L in formula) Psychological barriers to dietary adherence for children with
and most first baby foods also have a low sodium content. CF should be carefully considered. Feeding and eating occur
In a prospective multicenter study assessing nutritional sta- within the context of parent/child interaction and parental
tus in the first two years of life in children with CF diagnosed by mismanagement of the child’s eating behavior (parental coax-
neonatal screening, urinary sodium excretion was often low, ing, making a second meal, using threats, force feeding, getting
despite routine sodium supplementation. This may be related angry with their child, using physical prompts at mealtime) [94];
to the negative impact of essential fatty acid deficiency on also caregiver psychological status constitute significant bar-
sodium handling [89]. riers. When patients grow and reach adolescence, societal pres-
Recent European nutritional guidelines [19] recommend sure on girls and young women to remain thin and the
assessment of infant sodium supplementation requirements emphasis on a low-fat high-fiber regimen contrast the dietary
on an individual basis, taking climate and sodium losses into recommendations coming from CF centers [95]. Demands for
consideration. The individual need for sodium supplementa- patients to adhere to prescribed dietary regimens may cause
tion can be easily assessed by measuring fractional excretion young people to develop destructive attitudes toward food and
of sodium (FENa), to be maintained within a range of 0.5% and body weight and unhealthy eating habits too. Disordered eat-
1.5%. In clinical practice, the urinary sodium:creatinine ratio is ing practices include food avoidance, preoccupation with food,
proposed as a simple and non-invasive measure to monitor bodily function distortion with regard to gastrointestinal func-
sodium supplementation. tion and misuse of PERT [96].
In most cases, supplementation with 1–2 mmol/kg body Nutritional counseling integrated with behavioral interven-
weight/day of sodium should correct deficiency [90] although tions have proved to be more effective than dietary education
more may be required, with or without hot weather. Salt (sodium alone in improving adherence to dietary recommendations,
chloride) should be given in small portions throughout the day, weight gain and height [97–99].
diluted in water or formula. In a randomized clinical trial based on 79 children aged 4–
12 years, Stark et al. found that a behavioral and nutritional
education intervention was more effective than nutritional edu-
6.5 Zinc
cation alone at increasing dietary intake and weight over
Zinc status in patients with CF has been variously reported as 9 weeks of treatment. At 24 months follow-up, however, both
adequate or low, and this may be due to the fact that measur- intervention obtained similar outcomes [98] . In this trial, parents
ing plasma zinc levels, the method used in most studies, is not were taught child behavior management strategies, and chil-
a sensitive marker of zinc status and is highly variable under dren were encouraged to try new foods and meet their caloric
different conditions. Use of PERT can improve zinc absorption. goal with rewards.
Zinc deficiency can be associated with a variety of symptoms
in CF, including growth retardation, increased susceptibility to
8. Enteral tube feeding
infections, delayed sexual maturation, eye problems and anor-
exia, caused by reduced sense of taste (hypogeusia). When dietary counselling and oral supplements fail to prevent
Zinc supplementation in divided doses is recommended in undernutrition, enteral tube feeding should be attempted to
infants or children with CF with insufficient growth, and in prevent further clinical deterioration. There are differences
patients of any age who have vitamin A deficiency or persis- among CF centers in the adoption of this procedure because
tent steatorrhea [19]. of the possible negative effect on self-esteem and body image
and for the significant increase in therapeutic burden. However,
observational studies suggest that enteral tube feeding may
7. Adherence to nutritional recommendations
improve nutritional status and respiratory function, but these
Energy intake of patients with CF is higher compared to outcomes could not be assessed in randomized clinical trials
healthy peers, but it is generally below or in the lower range due to ethical considerations [100].
of recommendation (110–200% of the energy requirement for Another relevant clinical issue relates to the inability of CF
healthy people) [91]. patients with severe pancreatic insufficiency to absorb complex
The longitudinal relationship between energy intake and long-chain triglycerides provided by enteral formulas due to
growth was recently assessed in 191 children with CF: the insufficient pancreatic lipase. No specific PERT products for use
energy intake was higher than the lower limit of recommenda- in patients receiving enteral nutrition have been available so far
tion (>110%) in less than half of the 969 dietary records and administration of standard enzyme preparations through
obtained in this population and appeared to be insufficient to enteral feeding tube is often uncomfortable and associated
prevent suboptimal growth over eight-year of follow-up [92] with risks, such as feeding tube obstruction and inconsistent
Similarly, in a cross-sectional study [35] of pediatric patients enzyme concentrations. Therefore, pancreatic insufficient
with CF from six European centers, the percentage of children patients requiring enteral nutrition are at risk of inadequate
reaching the lower limit of energy intake recommendation was caloric intake and fatty acid deficiency and may complain
only 40% and mean nutrient intakes were 14% of total calorie a wide range of gastrointestinal symptoms. Recently, an innova-
intake for proteins, 51% for carbohydrates and 34% for lipids. tive in-line digestive cartridge, connected with enteral feeding
540 C. COLOMBO ET AL.

pumps, has been specifically designed to deliver PERT in patients All types of CFTR modulators have shown positive effects on
receiving enteral nutrition [101]. RELIZORB (immobilized lipase) nutritional status in clinical trials and in real life. Improvement in
has proved to be effective and well tolerated with more than nutritional parameters has been related to multiple mechan-
90% of fats within the enteral formulas hydrolyzed in absorbable isms, which are summarized in Figure 2 and include greater
fatty acids and monoglycerides. Moreover, this digestive car- effectiveness of digestive enzymes and correction of several
tridge increases n-3 fatty acid levels and reduces the severity of postlipolytic defects [22]. In a recent small-scale study of 23
gastrointestinal symptoms in CF patients on enteral feeding patients, mechanisms identified for ivacaftor-associated weight
[102,103]. RELIZORB represents a cost-effective solution in gain included decreased REE, gut inflammation and fat malab-
these patients as it allows the use of polymeric enteral formulas sorption [113].
that are less expensive than semi-elemental formulas. Most studies of CFTR modulators assessed some of the consid-
ered outcomes by means of the CF Questionnaire-Revised, which is
an age- and disease-specific, multidimensional instrument to
assess quality of life. Responses are provided on a four-point
9. Probiotics
Likert scale and rescaled within each domain to a score range
Gut dysbiosis is common in CF due to frequent exposure to from 0 to 100 with higher scores indicating better function. The
pathogens and antibiotics. Intensive antibiotic treatment alters domains that are interesting in terms of digestive aspects are:
intestinal and respiratory microbiota of CF patients. A potential Eating (perception of eating), Digestion (frequency of gas, diarrhea,
benefit of probiotics on intestinal inflammation, pulmonary abdominal pain and eating problems) and Body image (self-
exacerbations and weight gain has been reported by a few small perception of thinness and physical appearance).
controlled trials, however none of the clinical effects were con- Adolescent and adult versions also include the Weight
firmed by subsequent trials [104,105]. All these studies were het- domain, to explore difficulties related to gaining weight. In
erogeneous with regard to probiotic strain, dosage and duration of a large series of patients with the G551D mutation, significant
the intervention [106]. Further studies with a standardized inter- improvements (>4 points) were found in the perception of
vention, in terms of bacterial species and dosage, are necessary problems related to eating, body image and weight after
before recommending long-term use of probiotics in CF patients. treatment with Ivacaftor [22].

11. Summary
10. Effects of CFTR modulators on nutrition
A significant number of CF patients still fail to achieve optimal
CFTR modulators are a new class of drugs that address the growth and nutritional status, despite increasing awareness of
underlying basic defect of CF within a mutation-targeted per- its importance and the availability of effective therapeutic stra-
sonalized approach. This approach is quite different from tegies. The reasons why this happens include unmet energy
standard therapies that target the downstream effects of needs consequent to reduced appetite and poor adherence to
CFTR dysfunction to control symptoms. Ivacaftor was the first nutritional recommendations and PERT. A personalized and
potentiator of the CFTR protein to be developed for CF integrated approach is probably the most effective way to
patients with gating mutations, which affect the regulation guarantee optimal nutritional status to these patients and
of channel opening thus preventing sufficient ion transport tackle this unsolved clinical issue in CF care. This approach
across the membrane. Ivacaftor can increase the open prob- should start with the assessment of energy balance with accu-
ability of the CFTR channel and provides clinically relevant rate quantification of energy requirements and intake. This
benefits in terms of pulmonary function, weight gain, information should be the starting point to plan targeted diet-
decreased sweat chloride, reduced rate of respiratory exacer- ary and behavioral interventions for patients struggling to
bations, improved patient-reportedrespiratory symptoms and achieve their nutritional goals.
quality of life [107,108]. Moreover, in young children treated Recommendations for nutritional goals and therapy are
with Ivacaftor, a trend was noted toward an increase in fecal summarized in Table 3.
elastase, suggesting an improvement in the function of resi-
dual pancreatic tissue [109].
12. Expert opinion
By contrast, Ivacaftor monotherapy cannot work if there is
no CFTR on the cell surface, as is the case for F508del-CFTR, and Achieving optimal growth and nutritional status is among the
other drugs called correctors are also to be used to bring the greatest challenges in CF. Although, outstanding improve-
mutant CFTR to the cell membrane. Combining the two types ments have been seen over the last three to four decades
of drugs can increase CFTR level and function, and Ivacaftor has much more still has to be done for those failing to thrive and
been administered in combination with the correctors undernourished.
Lumacaftor [110] or Tezacaftor [111] to patients homozygous Investigating all the causes involved is essential and should
for F508del-CFTR. However, combined therapy was less effec- include the assessment of energy intake and energy require-
tive than Ivacaftor monotherapy for patients with gating muta- ments as well as the adequacy of PERT. Gastrointestinal symp-
tions and it has become clear that optimization of F508del-CFTR toms, appetite and psychological barriers to treatment
correction requires double or even triple combination therapy adherence should be also routinely screened to gain a full
for synergistic F508del-CFTR correction by other compounds at picture of the causes that prevent patients from meeting diet-
distinct conformational sites [112]. ary and PERT recommendations.
 EXPERT REVIEW OF RESPIRATORY MEDICINE 541

Table 3. Recommendations for nutritional goals and therapy in cystic fibrosis. composition and type of carbohydrate. The role of dietary
● Timely monitoring of nutritional status and adherence to PERT with visits fatty acids as modulators of immune response and inflamma-
scheduled every 1–2 weeks in infants, monthly in early childhood and at least
every 3 months in older children and adults. A closer monitoring may be tion should be clarified through well-designed clinical trials
required in patients with severe undernutrition poorly responsive to nutritional testing diets with different fat composition as well as supple-
intervention. mentations of long chain n-3 fatty acids at different dosages
● Energy expenditure should be assessed on individual basis by using indirect
calorimetry, accelerometers, physical activity diaries or questionnaires. to find the right dose able to supply clinical benefits (if any).
● Energy and nutrient intake should be evaluated trough food dairies to Moreover, diabetes is frequent among adult patients and
evaluate adherence to the nutritional recommendations.
● Nutritional interventions should be planned for patients not meeting the there are no specific dietary recommendations for these
nutritional goal, i.e., weight-for-length percentile≥50th for patients aged patients.
less than 2 years, BMI-for-age percentile≥50th for patients aged 2–19 years, Although BMI values have improved over the last decade,
BMI≥23 kg/m2 for adult males and BMI≥22 kg/m2 for adult females.
● In patients not meeting the nutritional goal, body composition analysis the prevalence of muscle mass depletion due to excess cata-
provides a more accurate picture of the nutritional status of the patient. bolism is still high in CF. The imbalance between anabolism
● Behavioral interventions, in combination with nutritional counseling should
be used in patients failing to achieve optimal growth and nutritional status. and catabolism caused by inadequate energy and nutrient
● Excess weight gain in people meeting the nutritional goal should be avoided. intake, and also mediated by chronic inflammation results in
● Energy needs and energy intake should be reassessed in children with BMI-
for-age≥2 standard deviation scores and in adults with BMI≥30 kg/m2 . cachexia, a complex metabolic syndrome characterized by
● Fat soluble supplementation should be prescribed to patients with protein degradation and loss of muscle mass with or without
pancreatic insufficiency with special attention to vitamin D status. loss of fat mass. Therefore, there is urgent need for nutritional
● Sodium supplementation should be administered on an individual basis.
therapies targeting muscle mass loss and new data to provide
patients with evidence-based recommendations on protein
Indirect calorimetry should be included in clinical practice and amino acid intake.
since it is the most accurate and feasible technique for The efficacy of PERT is still suboptimal in CF. New technol-
measuring the REE of the patients in clinical settings; other ogies should be developed to guarantee timely and effective
tools to quantify physical activity, including self-reported release of enzymes into the duodenum to allow normal diges-
questionnaires, activity dairies or movement sensors, such tion and absorption of nutrients.
as accelerometers should be also considered. All these data The enzyme preparations currently in use derive exclusively
should be collected along with food diaries and evaluation of from the porcine pancreas, with a potential risk of contamination
fat malabsorption (if possible) to determine the patient’s from porcine viruses and reduced bioavailability. Other sources
energy balance. of pancreatic enzymes may become available and offer advan-
Body composition analysis should be included among the tages in terms of purity, standardization of dose, activity and
diagnostic tools used to identify patients at risk of inade- safety. A new non-porcine and highly purified formulation
quate nutritional status as it has been recently suggested for (Liprotamase) had been designed which was well tolerated and
patients with chronic obstructive pulmonary disease [114]. associated with weight gain or weight maintenance in a 12-
Indeed, BMI alone does not allow detecting muscle mass month open-label phase III clinical trial [115]. Despite these
depletion [57] and is not a reliable marker of nutritional promising results, Lipromatase was not approved by the Food
status in a complex disease as CF characterized by chronic and Drug Administration since, in a phase III parallel-group,
inflammation, metabolic alterations and high risk of muscle double-blind placebo-controlled trial [116], the change in the
wasting. Thus, the importance of determining body composi- coefficient of fat absorption was lower than that planned for
tion in predicting the health outcomes of CF patients is the study (15%) and also lower than those achieved with other
becoming evident [55]. formulations [117,118]. A bacterial lipase was also designed to
The future approach to nutritional management should be as prevent inactivation of enzymes by gastric acidity. However, in
much personalized as possible in consideration of the fact that a phase II double-blind, randomized, placebo-controlled cross-
general recommendations can hardly apply to all patients with over study [119] the difference in the coefficient of fat malab-
CF. A high-calorie, high-fat diet is the standard of care in CF, sorption while on treatment with the new formulation as
however, given the increasing prevalence of overweight and compared to placebo was only modest (18%). No further devel-
obesity, the long-term effects of this dietetic approach should opment was planned for both formulations.
be carefully evaluated. This consideration is of particular impor- Improvement in PERT efficacy may be also achieved in the
tance for patients with mild mutations and those with a mild next future by means of mHealth tools specifically targeted to
form of the disease; for these patients the standard CF high- PERT adjustment and self-management.
energy, high-fat diet may even be damaging. A mobile application that integrates research in different
To achieve the best possible prognosis for each patient with areas of knowledge is under development within the Horizon
CF, it is important to provide evidence-based nutritional care. 2020 MyCyFAPP project, with the aim of providing an evi-
However, recent Cochrane reviews have highlighted a lack of dence-based method for PERT adjustment, and, through inter-
randomized controlled trials examining the effects of most of action between the patients and the clinical team, reaching
the current nutritional interventions in patients with CF nutritional goals and close nutritional follow-up.
[20,72,74–77,83]. These gaps in knowledge should be solved There are many open questions in CF (Table 4) that
over the next 5 years. require to be answered in the next future. More research
Certainly, the standard dietary approach in CF should be is expected to be carried out in these fields over the next
revised to ensure an adequate and healthy diet in an aging five years to ensure a better, personalized approach to
CF population, paying special attention to fatty acid nutritional care.
542 C. COLOMBO ET AL.

Table 4. Pending questions in the nutritional management of patients with cystic fibrosis (CF).
● How can we improve adherence to dietary recommendations and PERT?
● How many proteins does the patient need?
● Does free sugar intake matter?
● Should we advise patients with diabetes to prefer low glycemic index food?
● Should saturated fatty acid intake be reduced?
● Do patients need essential fatty acid and/or n-3 fatty acid supplement? If they do, which fatty acid or combination of fatty acid is best? What is the dosage to
achieve potential clinical benefits?
● Do patients need more antioxidants? If they do, what kind of antioxidant and what dosage?
● Should we extend enteral tube feeding in patients failing to achieve normal growth or nutritional status?
● Are probiotics of any therapeutic utility in CF?

Declaration of interest 16. Cohen RI, Tsang D, Koenig S, et al. Plasma ghrelin and leptin in
adult cystic fibrosis patients. J Cyst Fibros. 2008;7:398–402.
The authors have no relevant affiliations or financial involvement with any 17. Tierney S. Body image and cystic fibrosis: a critical review. Body
organization or entity with a financial interest in or financial conflict with Image. 2012;9:12–19.
the subject matter or materials discussed in the manuscript. This includes 18. Tluczek A, Clark R, McKechnie AC, et al. Factors affecting
employment, consultancies, honoraria, stock ownership or options, expert parent-child relationships one year after positive newborn screen-
testimony, grants or patents received or pending, or royalties. ing for cystic fibrosis or congenital hypothyroidism. J Dev Behav
Pediatr. 2015;36:24–34.
Reviewers Disclosure 19. Turck D, Braegger CP, Colombo C, et al. ESPEN-ESPGHAN-ECFS
Peer reviewers on this manuscript have no relevant financial relationships guidelines on nutrition care for infants, children, and adults with
or otherwise to disclose. cystic fibrosis. Clin Nutr. 2016;35:557–577.
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