ORIGINAL ARTICLE: PANCREATOLOGY

Highlights of the ESPEN-ESPGHAN-ECFS Guidelines on

Nutrition Care for Infants and Children With
Cystic Fibrosis

Michael Wilschanski, yChristian P. Braegger, zCarla Colombo, §Dimitri Declercq,
jj
Alison Morton, ôRuzha Pancheva, #Eddy Robberecht, Martin Stern, yyBirgitta Strandvik,
zz
Sue Wolfe, and §§Stephane M. Schneider

T he European Society for Clinical Nutrition and Metabolism

(ESPEN) launched a process of developing updated guide-
lines on nutrition care for infants, children, and adults with cystic
SCOPE OF THE PROBLEM
CF is a life-threatening autosomal recessive genetic disease,
caused by dysfunction of the cystic fibrosis transmembrane
fibrosis (CF). To that end, a group of experts systematically conductance regulator (CFTR) protein. The incidence in
reviewed the medical literature to summarize current knowledge Caucasians is 1 in 3500 births. Defective or absent CFTR function
on epidemiology and pathophysiology, prevention, and treatment of alters Naþ and Cl transport across excretory epithelia, which
CF-related undernutrition. The group included representatives from contributes to both the morbidity and mortality of the disease. CF
several European countries, physicians, dietitians, and educators, all prognosis is strongly associated with poor nutritional status.
experts in the field of CF, and the guidelines coordinator. The group Although the nutritional status of people with CF has improved
recommended evidence-based guidelines on nutrition care for markedly over the past 2 decades, adequate nutrition still remains a
infants, children, and adults with CF. The experts followed the major problem for some. Indeed, according to the most recent
GRADE method, which was based on determinations of grade of ECFS Patient Registry data, half of people with CF in Europe do
evidence and strength of recommendation. The European Society not achieve adequate nutritional status. People with CF who are
for Paediatric Gastroenterology, Hepatology and Nutrition (ESP- diagnosed early through newborn screening programs benefit
GHAN) and the European Society for Cystic Fibrosis (ECFS), who from earlier intervention. This gives the opportunity to minimize
are partners of these guidelines, reviewed the final manuscript, with nutritional deficits and is associated with positive nutritional out-
an external review for ESPGHAN. The reader of the Journal is comes. To achieve the best possible outcome for each person with
kindly invited to refer to the original article published in the June CF, it is important to provide care that includes attention to
2016 issue of Clinical Nutrition (1). nutrition.
This summary will outline some of the recommendations on
nutrition care for infants and children with CF.
CAUSES OF UNDERNUTRITION IN CYSTIC
FIBROSIS
Undernutrition in CF results from a combination of con-
From the Department of Pediatric Gastroenterology, Hadassah-Hebrew
University Medical Center, Jerusalem, Israel, the yDivision of Gastro- ditions—energy losses, high-energy needs, and inadequate nutrient
enterology and Nutrition and Children’s Research Center, University intake. The primary cause of energy loss is malabsorption, often
Children’s Hospital Zurich, Zurich, Switzerland, the zFondazione IRCC resulting from maldigestion due to insufficient release of pancreatic
Ca’ Granda, Ospedale Maggiore Policlinico (IRSS), Universita degli enzymes into the intestinal lumen (exocrine pancreatic insuffi-
Studi di Milano, Milan, Italy, the §Department of Pediatrics, CF Center, ciency). Energy losses are further worsened when digestive
Ghent University Hospital, Ghent, Belgium, the jjRegional Adult CF abnormalities are associated with metabolic changes, for example,
Unit, St James’ University Hospital, Leeds, UK, the ôDepartment of intestinal inflammation, small intestinal bacterial overgrowth, low
Hygiene, Faculty of Public Health, Prof Dr Paraskev Stoyanov Medical bicarbonate output, impaired insulin secretion with a variable
University of Varna, Varna, Bulgaria, the #Department of Pediatric
degree of insulin resistance (CF-related diabetes), and impaired
Gastroenterology, Hepatology and Nutrition, University of Ghent, CF
Center, Princess Elizabeth Pediatric Hospital, Ghent, Belgium, the liver function (CF-related liver disease).
University Children’s Hospital, University of Tubingen, Tubingen, Furthermore, energy needs are higher in people with CF and
Germany, the yyDepartment of Bioscience and Nutrition, Karolinska pancreatic insufficiency in comparison with needs of healthy
Institute, Novum, Stockholm, Sweden, the zzRegional Pediatric CF Unit, individuals, an observation supported by measurement of high
The Leeds Children’s Hospital, Leeds, UK, and the §§Gastroenterology resting energy expenditure in people with CF. Such high-energy
and Clinical Nutrition, Archet University Hospital and University of expenditure correlates strongly with pancreatic insufficiency,
Nice Sophia-Antipolis, Nice, France. although the mechanism remains unclear. Furthermore, high-
Address correspondence and reprint requests to Michael Wilschanski, energy requirements have also been attributed to persistent lung
MBBS, Department of Pediatric Gastroenterology, Hadassah-Hebrew
inflammation and infections associated with CF.
University Medical Center, PO Box 24035, Jerusalem, Israel
(e-mail: michaelwil@hadassah.org.il). People with CF may be unable to consume sufficient energy
The authors have no conflicts of interest. to overcome shortfalls due to inefficient energy use and increased
Copyright # 2016 by European Society for Pediatric Gastroenterology, energy needs. Psychosocial issues, such as stress and treatment
Hepatology, and Nutrition and North American Society for Pediatric noncompliance, may contribute to energy shortfalls. Pulmonary
Gastroenterology, Hepatology, and Nutrition inflammation, discomforts related to associated gastrointestinal
DOI: 10.1097/MPG.0000000000001349 problems (gastroesophageal reflux, constipation, distal intestinal

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Selected Summaries JPGN  Volume 63, Number 6, December 2016

obstructive syndrome, bacterial overgrowth), and the adverse TABLE 1. Criteria indicating adequate nutritional status
effects of medications can also decrease appetite and interfere with
intake goals. Infants and children 2 years: 0 SD (50th percentile) of weight and length
for a healthy same-age population.
Children 2–18 years: 0 SD (50th percentile) of BMI for a healthy, same-age
CONSEQUENCES OF UNDERNUTRITION IN population. Change in height percentile/SD score should be considered, as
CYSTIC FIBROSIS stunted children can have a normal BMI. Any height measurement should
Undernutrition affects respiratory muscle function, decreases be interpreted taking parental height into consideration.
exercise tolerance, and leads to immunological impairment. Lean body mass and bone mineral content are more sensitive indicators of
Although CF pathophysiology is directly linked to a deficit of nutritional deficit than low BMI; low values predict impaired lung
energy intake relative to needs, CF also affects multiple body function in children with CF.
systems in ways that further worsen pulmonary status, impair
growth, lower quality of life, and shorten life expectancy. BMI ¼ body mass index; CF ¼ cystic fibrosis; SD ¼ standard deviation.
In infants and young children with CF, poor nutritional status
results in stunted growth, as detected by low weight- and height-for- screening, attention to nutrition is key to maintaining normal
age percentiles. If untreated, such CF-related undernutrition in growth—even before signs of the CF phenotype become evident.
infancy or early childhood can lead to the serious consequence Criteria indicating adequate nutritional status are described
of impaired cognitive function. In cases of severe undernutrition in in Table 1; recommendations for nutritional assessment and follow-
infants and children, lung function worsens markedly, and survival up, and for energy requirements are shown in Tables 2 and
is poor. 3, respectively.
As CF progresses in older children, a wide range of metabolic
complications cause nutritional deficits, which further compromise PANCREATIC ENZYME REPLACEMENT
quality of life and increase mortality risk. For example, CF-related
diabetes—insulin deficiency and/or insulin resistance—causes and
THERAPY
worsens malnutrition by lowering insulin’s anabolic effects. Sim- Pancreatic enzyme replacement therapy (PERT) is vital to
ilarly, CF-related liver disease and hepatic steatosis are associated maintain adequate nutritional status in people with CF with
with selective nutritional deficiencies, for example, fat-soluble exocrine pancreatic insufficiency; the efficacy of this treatment
vitamins, essential fatty acids, and calcium, this in turn worsening is well established. Recommendations for PERT are described in
malnutrition and contributing to problems such as reduced bone Table 4.
mineral density.
Taken together, such adverse consequences of nutrient def- FEEDING INFANTS AND CHILDREN WITH
icits in infants and children with CF are a rationale for early and CYSTIC FIBROSIS
aggressive nutrition intervention, beginning in the first years of life Exclusive breast-feeding is recommended for newly diag-
and continuing over the lifespan of the patient. nosed infants with CF, and the use of a regular infant formula if
breastfeeding is not possible (grade of evidence: low).
Dietary counseling is essential throughout early childhood
A SYSTEMATIC APPROACH TO NUTRITIONAL when long-term feeding habits are being established. Advice from a
ASSESSMENT AND MONITORING IN CYSTIC CF dietitian should be tailored to the individuals’ age and evolving
FIBROSIS independence, clinical status, and support the goal of self-care.
At all ages, individuals with CF are at nutritional risk; Nutrition education and behavioral counseling are recom-
therefore, routine and complete nutritional assessments are essential mended for all families of infants and children with CF (grade of
to improve outcomes. For infants who are diagnosed by newborn evidence: high).

TABLE 2. Recommendations for nutritional assessment and follow-up

For pancreatic-sufficient infants and children, it is suggested that an annual assessment of pancreatic function by fecal pancreatic elastase-1 determination, with
the test repeated when inadequate growth and/or nutritional status occur(s).
For children and adolescents, it is recommend assessing for pancreatic enzyme replacement therapy (PERT) need or adequacy of treatment by monitoring
growth, nutritional status, and gastrointestinal symptoms; monitoring is suggested every month for children, and every 3 months for adolescents (grade of
evidence: low).
For children, care managers are suggested to consider annual nutritional review with blood tests (blood count, iron status, plasma fat-soluble vitamin levels,
serum liver function tests, and electrolyte measurements). Plasma phospholipids or red blood cell fatty acids can be monitored if the assay is available (grade
of evidence: low).
Annual screening of all people with CF at 10 years of age is recommended for glucose tolerance (grade of evidence: low).
It is recommended that children and adolescents undergo dietary review at least every 3 mo, including questions about adherence to dietary advice (grade of
evidence: low).
It is recommended to assess calcium intake at least annually (grade of evidence: low).
It is recommended to assess bone mineral density using dual-energy x-ray absorptiometry (DXA) in all people with CF from 8 to 10 years of age and then every
1 year to 5 years, depending on the age of the patient, value of the previous scan, and presence of risk factors (eg, physical inactivity, glucocorticoid therapy).
For patients younger than 20 years of age whose height is more than 1 standard deviation below age- and sex-matched healthy controls bone mineral density z
score should be adjusted for height or statural age to avoid overestimating deficits in bone mineral density in people with short stature.

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JPGN  Volume 63, Number 6, December 2016 Selected Summaries

TABLE 3. Recommendations for energy requirements role in intestinal calcium absorption, and deficiency of this vitamin
is one of several factors that can contribute to reduced bone mineral
Age Energy target Detail density in people with CF. The major source of vitamin D, exposure
of skin to sunlight, can vary widely between individuals and
Infants and children 2 110%–200% of Energy intake should available sunlight, which in turn depends on geographical latitude.
years or younger energy be adapted to The best indicator of vitamin D status is serum 25-hydroxy vitamin
requirements for achieve normal D (25[OH]D).
same-age healthy weight- and length- Vitamin D deficiency is common and has been reported in
infants and children for-age percentiles 22% of infants with CF at newborn screening; and > 90% of older
Children 2–18 years 110%–200% of Energy intake should children and young adults with CF were found to have suboptimal
energy be adapted to levels of 25(OH)D in 1 study. Table 5 shows the recommendations
requirements for achieve target BMI for fat-soluble vitamin supplementation.
same-age healthy percentile tailored It is suggested to supplement children with CF with vitamin
children to 1-year age D to maintain serum 25(OH)D concentrations >20 ng/mL (50
intervals nmol/L). The supplemental dose should take into consideration
dietary intake and sunlight exposure of the individual patient.
Although there is some debate, vitamin D3 is preferred over D2
for supplementation in people with CF. Serum monitoring of
Fat-Soluble Vitamin Deficiency 25(OH)D is recommended annually, preferably at the end of dark
months, and 3 to 6 months after a dosage change.
Fat-soluble vitamin deficiency is common, occurring in 10%
to 35% of children with pancreatic insufficiency. It is unusual, Electrolytes, Minerals, and Trace Elements
however, for people with CF to show clinical signs of overt
deficiency. Instead, the goal of evaluation and treatment is to People with CF may have higher than normal requirements
correct suboptimal levels and achieve optimal biochemical values for salt, calcium, iron, zinc, and selenium as a consequence of the
of these vitamins. increased sweating, intestinal malabsorption, and chronic inflam-
For pancreatic insufficient patients, it is recommended to mation that are common in CF.
evaluate plasma levels of fat-soluble vitamins after initiation of Excessive salt loss in sweat can result in inadequate levels of
enzyme and vitamin supplementation; 3 to 6 months after initiation sodium in people with CF of all ages, and may lead to impaired
or change in vitamin therapy; and annually thereafter. Vitamin growth in infants. Zinc status in people with CF has been variously
supplements should be taken together with high-fat food and reported as adequate and low. Zinc deficiency can be associated
pancreatic enzyme supplements to improve absorption. When with a broad range of symptoms in CF, including growth retar-
biochemical deficiency is detected despite adequate vitamin supple- dation, increased susceptibility to infections, delayed sexual matu-
mentation, poor adherence or poor absorption of supplements must ration, eye problems, and anorexia caused by reduced sense of
be ruled out before adjusting the dosage. For pancreatic sufficient taste (hypogeusia). Recommendations for sodium (as sodium
patients, it is recommended to assess vitamin sufficiency annually chloride) and zinc supplementation are described in Tables 6 and
using plasma levels. 7, respectively.
In recent years the adequacy of vitamin D supplementation in
CF has received considerable attention. Vitamin D plays a major
NUTRITION INTERVENTION
It is recommended to base nutrition intervention on a full
review of nutrition status, including a detailed review of PERT, and
TABLE 4. Recommendations for pancreatic enzyme replacement correction of any underlying medical conditions (grade of evidence:
therapy high).
It is recommended to use age-appropriate body mass index–
Age Suggested supplementation related thresholds for deciding when to advance nutrition interven-
tion (grade of evidence: high).
Infants (up to 12 2000–4000 U lipase/120 mL formula or
A progressive approach to intensification of nutrition inter-
months) estimated breast milk intake and
ventions as needs increase is recommended: preventive nutritional
approximately 2000 U lipase/gram dietary
counseling, dietary modification and/or oral nutrition supplements,
fat in food
and enteral tube feeding (grade of evidence: low).
Children 1–4 years 2000–4000 U lipase/gram dietary fat,
Clinicians are recommended to consider the use of oral
increasing dose upward as needed
nutritional supplements for treating children and adults who fail
(maximum dose 10,000 U lipase/kg per
to achieve optimal growth rates and nutritional status with oral
day)
dietary intake and pancreatic enzyme replacement therapy (PERT)
Children >4 years and Consider starting at 500 U lipase/kg per meal,
alone (grade of evidence: low).
adults titrating upward to a maximal dose of:
Recommendations for sodium (as sodium chloride) and zinc
1000–2500 U lipase/kg per meal, or
supplementation are status with oral dietary intake and PERT alone
10,000 U lipase/kg per day, or
(grade of evidence: low).
2000–4000 U lipase/gram dietary fat taken
Clinicians are recommended to consider the use of polymeric
with all fat-containing meals, snacks, and
enteral tube feeding when oral interventions have failed to achieve
drinks
acceptable rates of growth and nutritional status (grade of evidence:
Seventy-two-hour fecal fat measurement and the calculation of the high).
coefficient of fat absorption may be used in patients whose nutritional Although additional research trials will strengthen the evi-
status is questionable. dence base for many recommendations, there is a specific need for

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TABLE 5. Fat-soluble vitamin guidelines for pancreatic insufficient patients with cystic fibrosis ¼ consensus guidelines

Vitamin Supplementation Serum reference values and monitoring frequency

Fat-soluble vitamins
Vitamin A Amounts dependent on serum values, and Normal reference range provided by the laboratory
supplement form: processing the sample
Retinol (preformed):
Start low Monitor annually and 3–6 mo after a dosage change.
Also test when pregnancy is considered.
Adapt rapidly to target normal serum reference
range
Beta-carotene (provitamin A):
Prescribe 1 mg  kg1  day1 (maximum 50 mg/
day) for 12 wk
Follow with maintenance dose (maximum 10 mg/
day)
Vitamin D Dependent on serum values, which vary with Serum-25 (OH) D minimum 20 ng/mL (50 nmol/L)
dietary intake and sun exposure:
Starting dose of D3 (cholecalciferol) Monitor annually, and check 3–6 months after a
dosage change
Infants 400 IU/day (advance to upper limit of 1000
IU/day)
All others 800 IU/day (advance to upper limit of
2000 for children 1–10 years, and 4000 IU/day for
older)
Maintenance dose: adapt to annual serum values,
preferably measured at the end of dark months
Vitamin E a-Tocopherol dosing: 100–400 IU/day 50 IU/day for Plasma a-tocopherol:cholesterol ratio >5.4 mg/g;
(tocopherols) infants <12 mo (1 mg ¼ 1.49 IU) monitor annually, and check 3–6 mo after a
dosage change
Vitamin K Vitamin K1 Routine biochemical measurement not widely
available
Infants: 0.3–1.0 mg/day
Older children and adults: 1–10 mg/day
Water-soluble vitamins
Folic acid Women planning to become pregnant, and during first trimester of pregnancy: 400 mg/day
Vitamin B12 May need supplementation after extensive ileal resection.
When deficient: 100 mg/mo, intramuscular injection
Vitamin C Supplement only when nutritional intake is insufficient

25(OH)D ¼ 25-hydroxyvitamin D.

TABLE 6. Recommendations for sodium supplementation (as sodium chloride) in children with cystic fibrosis (grade of evidence: moderate)

Age Sodium supplementation Detail

1 1
Breast-fed infants 0–6 months 1–2 mmol  kg  day For infants at risk of sodium deficiency give salt in small portions
throughout the day, diluted in water or fruit juice.
For infants with special Up to 4 mmol/kg/day Increase intake for infants living in hot ambient temperatures; or for those
considerations (see detail, right) with increased fluid loss due to vomiting, fever, diarrhea, or tachypnea; or
infants with ostomies.
Older children and adolescents Salty foods or sodium chloride Supplement in stress situations when excessive sweating is expected (ie,
capsules or vials fever, exercise/sports, hot weather).

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TABLE 7. Recommendations for zinc supplementation in children with cystic fibrosis

Age Recommended supplementation Recommended dosing period, mo

1 1
Infants and children younger than 2 year and at risk of zinc insufficiency 1 mg  kg  day (max 15 mg/day) 6
Children 2–18 years and at risk of zinc insufficiency 15 mg/day 6

studies on new treatments for nutritional complications of specific children, and adolescents is a major goal of multidisciplinary
fatty acids, antiosteoporotic agents, anti-inflammatory agents, ana- CF centers.
bolic therapies, and probiotics.
REFERENCE
CONCLUSIONS 1. Turck D, Braegger C, Colombo C, et al. ESPEN-ESPGHAN-ECFS
Nutritional care and support should be an integral part of guidelines on nutrition care for infants, children and adults with cystic
management of CF. Obtaining a normal growth pattern in infants, fibrosis. Clin Nutr 2016;35:557–77.

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