Received: 31 May 2019 | Accepted: 19 August 2019

DOI: 10.1002/ppul.24521

REVIEW

The Remaining Barriers to Normalcy in Cystic Fibrosis V

Nutrition in cystic fibrosis: From the past to the present and

into the future

Kimberly Altman MS1 | Catherine M. McDonald PhD2 | Suzanne H. Michel MPH3 |

4
Karen Maguiness MS

1
Gunnar Esiason Adult Cystic Fibrosis and Lung
Center, New York Presbyterian/Columbia Abstract
University Medical Center, New York, New York, Nutritional management is an integral part of multidisciplinary care for persons with
United States
2 cystic fibrosis. This review will look at how nutrition care has evolved over time. In
Primary Children’s Hospital, Salt Lake City,
Utah addition, we will look at how some newer therapies impact nutrition care.
3
Department of Medicine, Medical University
of South Carolina, Charleston, South Carolina, KEYWORDS
United States
cystic fibrosis, modulators, nutrition, pancreatic enzymes, SIBO, vitamins
4
Section of Pediatric Pulmonology, Allergy,
and Sleep Medicine, Riley Hospital for
Children at Indiana University Health,
Indianapolis, Indiana, United States

Correspondence
Kimberly Altman, New York‐Presbyterian,
Columbia University Medical Center, Room
859, 622 W, 168th Street, PH‐8, New York,
NY 10032.
Email: kia9007@nyp.org

1 | INTRODUCTION 2 | H IS T O R I CAL P E RS P E CTI V E S O N

Cystic fibrosis (CF) is the most common life‐shortening autosomal
recessive disease. 1-3 It is caused by mutations in the cystic
fibrosis transmembrane regulator (CFTR) protein leading to
absent or decreased function of the CFTR protein at the cell
surface.1,4 In addition to pulmonary manifestations, malnutrition,
and poor growth are common in patients with CF.5 Because of
this, nutritional management is an integral part of the multi-
6
disciplinary care of those with CF at all ages. Over time,
advances in both the pulmonary and nutrition management of CF
have helped to improve the nutritional status of patients with
7
CF. The goal of nutritional management is to reach and maintain
6,7
optimal nutritional status. Newborn screening, which was first
introduced in 1982, and gradually expanded to include all 50
states by 2010, has had a profound impact on nutrition
8
outcomes. This article will look at the changes in nutrition
management over time, as well as look at some newer therapies
and their impact on nutrition care.
N U T RI T I O N A L M A N A G E M E N T O F CF
Recommended nutritional management has changed considerably in the
eight decades since CF was recognized as a distinct entity. Andersen9
published the earliest comprehensive description of CF of the pancreas in
1938 and was the first to recommend dietary intervention for this
progressive disease. Although pancreatic enzyme replacement therapy
(PERT) reduced steatorrhea in CF, the effects were variable and not
completely satisfactory. Dietary intervention for CF was largely relegated
to reactive management of steatorrhea and gastrointestinal (GI)
symptoms. Andersen9-11 proposed a diet low in fat, high in protein with
a liberal allowance of fruit and vegetables, a moderate restriction of
starch, and supplementation with fat‐soluble vitamins to manage residual
malabsorption symptoms.
Kessler and Andersen12 also observed that children with CF were
more prone than other children to experience heat prostration with
dehydration, vasomotor collapse, and hypochloremia when exposed
to extremely hot weather. On the basis of these observations, Di

S56 | © 2019 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/ppul Pediatric Pulmonology. 2019;54:S56–S73.

ALTMAN ET AL.
Sant’agnese et al13 investigated the amount and electrolyte
composition of the sweat of individuals with CF. The sodium and
chloride levels in the sweat of children with CF were found to be two
to four times normal levels. The authors recommended vigorous and
prompt measures to restore depleted water and electrolyte stores.
Empiric and currently utilized recommendations for salt supplemen-
tation were derived from these observations.14
A pragmatic approach was recommended for dietary intervention
for infants diagnosed with CF. A series of case studies published in
the 1950s and 60s described hypoproteinemia and edema with
significant mortality in infants and children with CF. These reports
implicated human milk or soybean milk feedings and suspected
15-18
protein malabsorption as causing the hypoproteinemia.
edema resolved with the institution of a high protein, skim milk
formula with pancreatic enzymes. Dire warnings were published
against the use of breast milk or soy‐based formulas for infants with
CF.16 With advances in early diagnosis of CF and enteric‐coated (EC)
pancreatic enzymes, current infant feeding recommendations have
19
reversed the stance on breast milk for infants with CF.
The addition of medium‐chain triglyceride (MCT) oil to low‐fat
feedings was proposed to control steatorrhea in CF.17 A crossover
study of 14 pancreatic insufficient (PI) infants and children receiving
almost all dietary fat like MCT oil showed significantly decreased stool
fat content, increased daily caloric intake, and mildly to moderately
improved weight gain. Administration of PERT was not noted.
Prolonged MCT feeding trials, ranging from 6 weeks to 9 months,
resulted in proportional decreases of the originally low polyunsaturated
(linoleic C18: 2 and arachidonic C20: 4) fatty acids in these children.
Along with treating the primary pulmonary lesions and secondary
pulmonary infections, management of the pancreatic exocrine deficiency
and nutritional aspects was identified as a priority in CF therapy.
Although nutrition was classified as a pillar of CF management, mid‐ 20th
century CF research and clinical treatments focused on controlling the
obstructive pulmonary disease and infections.21 Significant associations
were identified between severe or chronic malnutrition, worsened
21
pulmonary function, and decreased survival in CF. Many CF clinicians
considered malnutrition to be the consequence of pulmonary disease
rather than a factor contributing to it.
The American Thoracic Society (ATS) issued Consensus Guide-
lines on Cystic Fibrosis in 1968, a comprehensive management
22
treatise by preeminent clinicians and leaders in CF. These guide-
lines stated, “Because most of the morbidity and 90 per cent of the
mortality associated with this disease is a result of the pulmonary
lesion, intensive treatment aimed at preventing or controlling this
lesion is essential … (The) control of pulmonary infection is of primary
importance in maintaining good nutrition.”22
The 1968 ATS Guidelines continued, “Patients without chronic
pulmonary infection usually have voracious appetites. This permits them
to gain weight and grow normally despite poor digestion and excessive
fecal losses.”22 The assertion that children with CF would gain weight and
grow normally was disproven with observational studies.23
23
In 1969, Weihofen and Pringle used 24‐hour dietary recalls to
estimate the caloric value and protein and iron contents of 36
| S57
children and young adults with CF. Eighty‐eight percent of the
individuals with CF consumed more calories, ninety‐eight percent ate
more protein, and thirty‐six percent received more iron than the
1964 Recommended Dietary Allowances (RDAs) for age. About half
of the mothers reported receiving instructions to restrict the fat
intake of the child. However, the majority (72%) of children with CF
who consumed more than 150% of the RDA for calories were more
than one standard deviation below normal for weight.23
The degree of underweight in children with CF was correlated
inversely with survival by Kraemer et al.24 Because of the prognostic
value, these authors recommended relative underweight be mon-
itored at periodic clinical visits.24 No early studies were conducted to
The determine the impact of nutritional intervention on long‐term
survival in individuals with CF.
In 1988, Corey et al25 published a comparison of survival,
pulmonary function, and growth in patients with CF in Toronto and
Boston. The median age of survival for the individuals with CF in
Toronto was 30 years vs a median age of survival in Boston of 21
years. The Canadians with CF weighed more and were taller than
their American counterparts. These differences were attributed to a
more liberalized dosing of PERT and higher intakes of dietary fats in
Canada. The authors stated, “Although the progressive pulmonary
disease is the major cause of mortality in CF, the differences in
growth and survival in these two patient groups, with very similar
age‐specific pulmonary function, suggest further examination of
nutritional guidance and intervention in CF, especially regarding the
traditional restriction of dietary fat.”25
17
High energy, high fat intake, often referred to as the “CF diet,”
became a cornerstone of CF dietary management throughout the
world over the next decades. However, recommendations for higher
20
caloric and fat intakes for individuals with CF have raised questions
about the nutrient profiles of such intakes and potential long‐term
impacts on future health. Since 1969, few studies have examined
dietary intakes in children or adults with CF and those studies
assessed only energy and fat intakes.26
However, two recent reports, one of food frequency question-
naires for Australian children with CF aged 2 to 18 years and the
other of detailed 4‐day food records for 2 to 17‐year‐old children at
six European CF centers provided insight into current pediatric CF
dietary habits.27,28 Both studies reported high intakes of sugar,
sweets, sweetened drinks, processed foods, and saturated fats or
energy‐dense, nutrient‐poor foods. In addition, both studies found
low intakes of nutrient‐dense foods such as fish, legumes, fruit,
vegetables, and nuts.27,28
3 | N UT R I T IO N A ND P UL M O NAR Y
FUNCTION
Poor nutrition status has been associated with undesirable outcomes
in CF such as an increased decline in lung function, impaired
pulmonary muscle function, and decreased exercise tolerance.29 This
was demonstrated by the comparison of survival, growth, and
S58 | ALTMAN
pulmonary function in patients with CF in Boston and Toronto.25 As
previously mentioned, this study compared the patient populations at
two large CF centers of similar size, age distribution, and sex
distribution for the years 1977 to 1981.25 The study found that
Toronto males were significantly taller and weighed more than the
Boston males.25 The Toronto females were taller as well.25 In
addition, the median age of survival in Toronto was significantly
higher at 30 vs 21 years in Boston, despite no significant difference in
mean forced expiratory volume in 1 second (FEV1).25 Nutritional
status has long been associated with survival and improvement or
stabilization of pulmonary function has been seen in malnourished
30 30
patients when their nutrition status improves. Zemel et al
the Cystic Fibrosis Foundation (CFF) National CF Patient Registry to
evaluate the effect of growth and nutrition on the progression of lung
disease on a larger scale. This study found that initial height for age z‐
score and weight for age z‐score and percent of height appropriate
body weight were positively and significantly associated with FEV1%
predicted.30 FEV1% predicted was negatively associated with annual
30
number of hospitalizations. A similar study using the CFQA—a CF
patient registry for the 97 CF outpatient clinics in Germany—was
31
done that included 3298 patients >2 years of age. They found that
malnutrition was associated with a significant decrease in FEV1,
approximately 20% predicted between the ages of 12 to 18 years of
31
age regardless of bacterial status. In comparison, adolescents at
normal weight maintained FEV1 values above 80% predicted.
addition, malnourished adolescents who had a decrease in weight for
height ≥5% over 1‐year simultaneous loss in FEV1 of 16.5%
31
predicted over the year. Patients who had a relative weight gain
over the year had an increase in FEV1 of 2.5% predicted.31 These
changes were statistically significant.31
The Epidemiological Study of Cystic Fibrosis, a prospective encoun-
ter‐based study including patients from the United States and Canada,
also evaluated the correlation between nutrition status and lung
function.32 They included patients who reached 3 years of age between
1994 and 1996 and were followed until the age of 6—a total of 931
32
patients. They found a strong association between nutrition status at
age 3 and pulmonary function at age 6.32 Patients with growth and
nutrition indexes at age 3 had a lower predicted pulmonary function at
age 6. This was most noticeable in weight for age, where the difference in
predicted pulmonary function was approximately 15 points between the
lowest and highest weight for age values, however, the trend was also
seen in height for age.32 Yen et al33 evaluated this further. They found
that weight for age percentile at 4 years predicts a higher rate of survival
33
into adulthood. They also found that patients with a weight for age
percentile >50% at age 4 typically spent fewer days in the hospital at age
18 than patients with weight for age percentile <50%.33 At 18 years of
age, patient with weight for age percentile was also less likely to have
33
impaired glucose tolerance. In this study, patients with a weight for age
percentile <10% had much lower lung function, never reaching 80%
predicted FEV1.33
Evidence‐based practice recommendations for nutrition‐related
management of children and adults with CF and pancreatic
insufficiency were published in 2008. On the basis of the available
ET AL.
research, the subcommittee recommended the maintenance of
normal ranges of weight and stature for age in children because
normal growth status was associated with improved FEV1 and
survival.34 They also recommended a normal weight for height in
adults for the same reason.34 In addition, based on registry data
information, the CFF recommended that children and adolescents
aged 2 to 20 years maintain a body mass index (BMI) at or above the
50th percentile since this was associated with FEV1 at approximately
80% predicted.34 Similarly, in adults, a BMI ≥22 for women and ≥23
for men was recommended. These values were associated with an
FEV1 ≥60% predicted.34
used Knowing that improved weight and BMI is correlated to lung function
may not provide a complete picture.35 A study done by King et al35 found
that BMI was not a good indicator of fat‐free mass (FFM) depletion or
FFM index. Their results suggest that using a BMI <18.5 kg/m2 to define
malnutrition would not identify 58% of patients with CF and FFM
depletion.35 A study was done by Sheikh et al36 also looked at body
composition rather than just BMI in comparison to pulmonary function.
They found that lean BMI was more strongly associated with pulmonary
function than BMI, especially in males.36 They also found that fat mass
index was not associated with pulmonary function.36 This reinforces the
hypothesis that the association between better nutritional status and
pulmonary function is an effect of lean body mass.36 This was also seen in
a study done by Calella et al.29 They found that FEV1 was significantly
31
In associated with total, truncal and appendicular lean body mass and it was
not associated with total and truncal fat mass.29 Compared with lean
body mass, BMI had a weaker, but still significant correlation to FEV1.29
Another important factor in nutrition status and pulmonary
function is the addition of newborn screening, done in all 50 states
since 2010.37 The Wisconsin Cystic Fibrosis Neonatal Screening
Project assessed the benefits, risks, and costs associated with CF
neonatal screening.38 They found that anthropometric indexes of
nutrition were significantly better in the screened group compared
with the control group both at diagnosis and up to age 16 years.38
Given all of the strong data stated above, the ability to improve or
maintain nutrition status early is a predictor of nutrition status later
as well as a pulmonary function later.
The graphs in Figures 1-6 are from the 2017 Annual Data Report.
They include data from patients with CF under care at CFF
accredited care center, who consented to have their data entered.
Figures 1 and 2 focus on the improvement in growth parameters over
the past 20 years. Figures 3-6 demonstrate the improvement of both
BMI and pulmonary function over the past 30 years and their
correlation, as well as current averages of BMI and FEV1.39
4 | MICRONUTRIE NTS
Persons who have CF are at risk for vitamin and mineral deficiencies.
A review of the literature identified a paper published as early as
1947 describing vitamin deficiency in CF.40 Many papers followed in
which the authors reported vitamin deficiency in patients with CF or
patients diagnosed with CF based upon presentation with symptoms
ALTMAN ET AL.
F I G U R E 1 Improvement in nutrition outcomes—pediatrics.
Source: Cystic fibrosis patients under care at Cystic Fibrosis
Foundation‐accredited care centers in the United States, who
consented to have their data entered39
F I G U R E 2 Improvement in nutrition outcomes—adults. Source:
Cystic fibrosis patients under care at Cystic Fibrosis Foundation‐
accredited care centers in the United States, who consented to have
their data entered39
of vitamin deficiency. Malabsorption of minerals, including zinc, was
also reported. Before the availability of enteric‐coated PERT,
improving fat‐soluble vitamin and mineral absorption was challen-
ging. Over the counter, multivitamins were used along with single
nutrient fat‐soluble vitamins.
Enteric‐coated enzymes became available in 1979 and with them
better nutrient digestion and absorption including vitamins and
minerals. Research describing vitamin status and dosing became and
| S59
continues to be active. As awareness of and research for supple-
mentation grew, work specific to newborn screening started and the
first paper linking fat‐soluble vitamin status in the newborn was
published in 1989.41 Researchers found vitamin and zinc deficiency
was present at birth, which in the majority of patients is corrected by
use of PERT and CF‐specific multivitamins with zinc.42,43 The
importance of early vitamin supplementation was best described in
work demonstrating better cognitive scores in children and adoles-
cents with CF who had optimal vitamin E levels starting after
newborn diagnosis.44
Although CF can now be identified in the newborn period there
are some infants who may be missed. There continues to be the
occasional report of an infant for which zinc deficiency was the
defining symptom leading to the diagnosis of CF.45 In addition, one
can find papers in which the author reports a diagnosis of CF in an
adult based upon overt symptoms of vitamin deficiency.46
The first US CFF Nutrition Consensus Report was published in
1992. Ramsey et al47 noted that maldigestion/malabsorption of fat
and fat‐soluble vitamins affect nutrition and although the use of
PERT will improve these symptoms some residual malabsorption of
vitamins continues. On the basis of available evidence the Consensus
Report noted deficiencies of vitamins A and E were common in the
CF population, vitamin K deficiency is more frequently seen in infants
or patients with cholestatic liver disease, and vitamin D to occur
rarely and in patients getting inadequate sunlight or with cholestatic
liver disease. Recommended assessments included complete blood
count, serum retinol, and alpha‐tocopherol. Annual assessment of
vitamins K and D were not considered necessary. Routine vitamin‐
dosing recommendations were based on readily available over‐the‐
counter multivitamins not specifically designed for CF. The recom-
mended dose was double of that prescribed for persons without CF.
Supplementing with single nutrient water‐soluble vitamin A and/or E
was suggested when serum levels were not within normal limits.47
The second US CFF Nutrition Consensus Guidelines (2002)
contained more details describing vitamin and mineral needs in CF.
Annual assessment recommendations include vitamins A, D, E and
PIVKA if hemoptysis or hematemesis is present and in patients with
liver disease. Assessment of calcium, iron, zinc, and sodium was
recommended based on specific patient needs. The paper provided a
limited review of fat‐soluble vitamins and minerals. A table of dosing
for fat‐soluble vitamins was included and, with the exception of
vitamin D, continues to be referred to Borowitz et al48 (see Table 1).
Later in 2002 Nutrition in Patients with Cystic Fibrosis: a
European Consensus was published.49 In terms of vitamins it differs
in its recommendations for children and adults and recommended
higher daily vitamin E and vitamin K. Nutrition Guidelines for Cystic
Fibrosis in Australia and New Zealand, published in 2017, is the most
recent nutrition guideline report and includes vitamin and mineral
recommendations.50
The US CFF published a number of guidelines directed toward
specific topics: Infant Care19; Preschool Care51; Vitamin D52; and
Adult Care.53 With the exception of the vitamin D guidelines, all refer
to the 2002 vitamin recommendations.
S60 | ALTMAN ET AL.

F I G U R E 3 Source: Cystic fibrosis patients under care at Cystic Fibrosis Foundation‐accredited care centers in the United States, who
consented to have their data entered39

F I G U R E 4 Source: Cystic fibrosis patients under care at Cystic Fibrosis Foundation‐accredited care centers in the United States, who
consented to have their data entered39

The Infant Guidelines refer the reader to the vitamin recommenda-
tions in the US CFF 2002 guidelines and addresses zinc, sodium, and
fluoride needs. Sodium intake during infancy is critical in CF and despite a
paucity of research describing sodium needs the Guidelines Committee
recommended 12.5 mEq (1/8 teaspoon) not to exceed 4 mEq/kg daily up
6 months of age at which time the daily dose is increased to ¼ teaspoon
daily.19 The Preschool Guidelines recommend use of CF‐specific vitamins
and, if needed, single nutrient supplements. The document also provides
sodium recommendations of a high salt diet and for those who may not
consume high salt foods, supplementation with ¼ teaspoon daily.51 The
Adult Care Guidelines suggested that clinicians be aware of clinically
important vitamin deficiency states. Daily dosing recommendations were
provided with reference to the 2002 Borowitz et al48 guidelines. In 2012
the US CFF published the vitamin D evidence‐based guidelines, which
provide a comprehensive review of vitamin D and CF. The paper has
succinct dosing recommendations52 (see Table 2).
Other than vitamin D, recommendations for vitamin supplementation
have not been updated and the 2002 recommendations do not reflect
the significant number of subsequent research papers which have
described optimal dosing of the fat‐soluble vitamins. In 1991, the first CF‐
specific vitamin with zinc was made available. In the following years, a
number of CF‐specific vitamin products were launched, most reflect
ALTMAN ET AL.
F I G U R E 5 Source: Cystic fibrosis patients under care at Cystic
Fibrosis Foundation‐accredited care centers in the United States,
who consented to have their data entered39
F I G U R E 6 Source: Cystic fibrosis patients under care at Cystic
Fibrosis Foundation‐accredited care centers in the United States,
who consented to have their data entered39
| S61
T A B L E 1 Individual vitamin daily supplementation
Individual vitamin daily supplementation
Vitamin A, Vitamin E, Vitamin D, Vitamin K,
Age IU IU IU mg
0‐12 mo 1500 40‐50 400 0.3‐0.5
1‐3 y 5000 80‐150 400‐800 0.3‐0.5
4‐8 y 5000‐10 000 200‐400 400‐800 0.3‐0.5
>8 y 10 000 200‐400 400‐800 0.3‐0.5
Source: Borowitz et al.48
vitamin‐dosing evidence available at the time the product was developed
including vitamin D recommendations.54-56 The products contain vitamin
A in the form of retinol and beta‐carotene and a greater amount of
vitamins K and D. For a comprehensive review of vitamin and mineral
research in CF the reader is referred to the vitamin and mineral chapter
in the book, Nutrition in Cystic Fibrosis.57
In summary, it is widely known that persons with CF malabsorb
fat‐soluble vitamins. Research has documented the need for
supplementation and dosing guidance; however, it remains a
challenge to provide optimal vitamin nutrition. At this time, with
continued research and available CF‐specific vitamins, meeting the
needs of those with CF has become easier for clinicians and patients.
As research continues to expect modification to CF‐specific multi-
vitamin formulations to reflect new findings (see Figure 7).
5 | PERT IN CF OVER THE YEARS
5.1 | Purpose
The purpose of PERT is to replace lacking digestive enzymes due to a
partially or nonfunctioning pancreas. Persons with CF may be classified as
PI or pancreatic sufficient (PS). It has commonly been stated that PI
occurs in approximately 85% of patients diagnosed with CF.58 This
estimate was recently verified by the 2018 CF Patient Registry Report,
which confirms a median of 85.9% of pediatric patients and 84.6% of
adult patients who take PERT.59 The goal of PERT is to mimic digestion
and absorption as would occur with a well‐functioning pancreas so that
nutrients are well‐absorbed; optimal growth and nutritional status are
realized, and adverse GI symptoms are negligible.
5.2 | History
PERT has been available in the US for more than 80 years.60 The
Food, Drug, and Cosmetic Act of 1938 was passed in response to a
legally marketed toxic elixir that killed more than 100 people.60 This
Act required evidence of safety for new drugs. Before that, drugs
only needed to meet standards of strength and purity, as established
in the 1906 Pure Food and Drugs Act.61
Drugs that were deemed effective before 1938, were “grandfathered
in” and did not require additional testing. More than 40 different drugs,
including PERT, were on this list.62 In 1962, the U.S. Kefauver Harris
Amendment required proving safety and efficacy before approval.63 In
S62 | ALTMAN ET AL.

T A B L E 2 Vitamin D intakes and treatment recommendations of vitamin D deficiency in children and adults with CF
Vitamin D intakes and treatment recommendations of Vitamin D deficiency in children and adults with CF
Age Routine dosing with CF‐specific vitamins, IU Step 1: Dose increases, IU Step 2: Dose titration maximum, IU Step 3
Birth to 12 mo 400‐500 800‐1000 Not more than 2000 Refer
>12 mo to 10 y 800‐1000 1600‐3000 Not more than 4000 Refer
>10 to 18 y 800‐2000 1600‐6000 Not more than 10 000 Refer
>18 y 800‐2000 1600‐6000 Not more than 10 000 Refer
52
Source: Tangpricha et al.
Abbreviation: CF, cystic fibrosis.

1982, the Hatch‐Waxman Amendment established the pathway for
generic drugs, requiring proof of bioequivalence.64
5.3 | Early preparations and studies
Similar to current enzyme preparations, early preparations of PERT
came from pig or hog pancreas. These were non‐EC and proved to be
65
of limited effectiveness due to inactivation by stomach acid.
weight gain and malnutrition used to be quite common in persons
with CF. In an attempt to counteract the adverse effects of stomach
acid, EC capsules containing non‐EC powder were developed, but
these, too, were only partially effective.66
Some of the first testings of PERT was done in 1955 when Harris
et al67 performed metabolic balance studies demonstrating improved
fat and nitrogen absorption on individuals with PI receiving non‐EC
pancreatic enzymes. In 1977, Regan et al68 studied the effects of
antacids and H2 blockers used in conjunction with non‐EC enzymes
Poor
and found H2 blockers to be a useful adjunct in some patients who

F I G U R E 7 Comparison chart of currently available CF‐specific vitamin preparations. 1The content of this table was confirmed as of August
2019. 2Created by Suzanne H. Michel, MPH, RD, LDN 2019MVWNutritionals, Inc. All rights reserved 8‐26‐19. 3Also contains mixed
tocopherols. 4Tangpricha et al.52 5NP = No Equivalent Product. 6AquADEKs is a registered trademark of Allergan, Inc., DEKAs are manufactured
by Callion Pharma, MVW Complete Formulation is a registered trademark of MVW Nutritionals, Inc. 7Form of vitamin E not confirmed.
Calculation for conversion for vitamin E from IU to mg based on the natural form of vitamin E. *Products also contain water‐soluble vitamins
and zinc. CF, cystic fibrosis
ALTMAN ET AL.
failed to respond to pancreatic enzymes alone. Graham69 compared
non‐EC tablets with EC capsules containing non‐EC powder and
demonstrated that to reduce steatorrhea, relatively large amounts of
lipase were required. He also showed that the EC preparations of
non‐EC enzymes were less effective than non‐EC enzymes alone.69
Until the late 1970s, Viokase (A.H. Robins) was one of the more
widely used non‐EC PERT and was available in tablet and powdered
form. The powdered form tended to cause irritation and in some
cases bleeding of the oral mucosa in infants. Improved recommenda-
tions for meticulous mouth care for infants who continue to receive
non‐EC enzymes has since been developed.70
5.4 | EC microspheres
PERT was revolutionized in 1979 when the first encapsulated EC
microspheres (Pancrease, Johnson & Johnson) were introduced.
These microspheres (often referred to as “beads”) were developed to
withstand the known adverse factors faced by non‐EC PERT.
Microspheres activate at a pH of approximately 5.5, thus allowing
the beads to endure and traverse the high acidity of the stomach and
subsequently be present where needed, in the duodenum. Graham71
demonstrated a significant reduction in fecal fat and nitrogen
excretion in subjects who received these new microspheres.
The product label stated original Pancrease contained 4000 USP
units lipase, 20 000 USP units amylase, and 25 000 USP units
protease per capsule. For nearly 10 years, Pancrease was the sole EC
PERT microsphere available. In 1988, a new product, Creon micro-
spheres, was introduced by Reid‐Rowell.72 Creon, as it was then
formulated, was described as a “High Lipase Pancreatin” containing
twice the lipase as Pancrease.72 Because Creon was “twice as strong”,
many providers changed patients to this “higher strength” enzyme.
5.5 | High‐strength pancreatic enzyme
replacements and microtablets
In 1988, microtablet (MT) enzymes were introduced. MTs are also EC
beads but manufactured by compressing (as opposed to “rolling”
heterogeneous sized microsphere) beads into compact uniform sizes.
Individual beads of MTs are larger and fewer than the microsphere
beads contained within similar strength capsules.
Pancrease MT was the first MT introduced in 1988, and initially
included strengths of MT 4, MT 10, and MT 16. This was later
followed by the introduction of Pancrease MT 25 in 1992 and MT 32
73
in 1993.
Over the next few years, other “high strength” enzymes were
introduced. In 1992, Creon (then owned by Solvay) introduced a
25 000 lipase unit microsphere, advertising a smaller sized capsule
and lower cost compared to Pancrease MT 25. 74
Also in 1992, a third
company, Scandipharm, entered the market and introduced Ultrase
MT. Ultrase microtablets were available in 6 different strengths (MT
6, MT 12, MT 18, MT 20, MT 24, and MT 30). 75
| S63
5.6 | Fibrosing colonopathy and enzyme dosing
guidelines
Coinciding with the introduction of high‐strength enzymes, a condition
that would later be termed fibrosing colonopathy (FC) was identified. On
22 December 1993, the CFF issued a letter to all CF Center Directors,
apprising of a situation in Europe, with reports of seven cases of children
with CF who developed fibrotic strictures of the ascending colon, six of
whom required surgical resection. Affected patients were described as
ranging in age from 2 ½ to 13 years, and treated from 7 to 15 months
with high doses of high‐strength PERT.76
These findings were published the following month by Smyth.77
The single common finding among patients who developed FC was a
change from lower strength EC enzymes to high‐strength PERT, 6 to
96 months (mean of 32 months) before presentation.77 Following
Smyth’s report, cases of FC were soon identified in the US. In
February 1994, McNeil, Solvay, and Scandipharm voluntarily with-
drew all enzyme preparations >20 000 lipase units until more could
be determined regarding the association between strictures and
high‐strength enzymes.78
In a swift and targeted response, the CFF convened the “CF and
Stricture Study Group”. This team was comprised of expert physicians
from around the country. Data analysis revealed patients who developed
FC tended to be younger (compared with the average age of patients in
the CFF registry) likely because they were easier to “overdose” on a per
kilogram basis. Average dosing for patients who developed FC ranged
from 6700 to 29 100 lipase units kg−1 meal−1. To confirm, these doses
were lipase unit kg−1 meal−1, not lipase units kg−1 day−1.79,80
Affected persons tended to have a history of meconium ileus (MI)
or perinatal surgery at a higher than average rate. Initial presentation
typically included diarrhea (often bloody), abdominal pain, distention,
and symptoms consistent with bowel obstruction that failed to
respond to usual medical intervention. Diagnosis of FC was usually
made following a barium enema with or without upper and lower GI
studies. Gross appearance of the colonic wall was similar, with
diffusely thickened rigid bowel walls and luminal narrowing at the
stricture site. The mucosal wall was often described as having a
“cobblestone” like appearance. Treatment was surgical excision of
the strictured segment of the large intestine.81,82
These findings culminated in a vigilant effort to determine safe
and appropriate dosing of PERT for persons with CF. In March 1995,
the CFF convened a meeting with representatives from the CFF,
FDA, pharmaceutical industry, statisticians, and other medical
experts including physicians and dietitians. All available dosing data
on patients who developed FC were presented to determine an
unquestionably safe dosing level such that FC would never be
expected to ever occur again. These recommendations were
published in November 1995 and continue to be in use today.81
The primary recommendation was to dose EC PERT at <2500
lipase units kg−1 meal−1 (10 000 lipase units per kg/day when
extrapolated to three meals and two snacks/day) or less than 4000
lipase units per gram of fat.79,83,84 In these findings, it was stated that
it was unknown if doses between 2500 and 6000 lipase units kg−1
S64 | ALTMAN ET AL.

meal−1 were safe, but that doses greater than 6000 lipase units kg−1 lipase, amylase and protease product was developed and tested. This
−1
meal were clearly associated with colonic strictures in children less product underwent a variety of manufacturers as well as name
than 12 years of age. It was agreed that a dose higher than 2500 changes (TheraCLEC‐Total, ALTU‐135, Trizytek, and Liprotamase).
lipase units kg−1 meal−1 could be “used with caution” if there was While the product was innovative, appeared promising, and deemed
documented improvement in fat absorption. safe, it never became commercially available; the coefficient of fat
Other recommendations were patients should not self‐increase absorption was at or slightly below 70% in all iterations.90-93
their enzyme dose (as this is how some achieved such high doses),
and that other causative factors should be considered for sympto-
matic individuals not responding to enzyme dose increases.83 Despite 5.10 | Pancreatic elastase testing/genetics
manufacturers removing PERT >20 000 lipase units from the market, of PS and PI
it was acknowledged that lower strength PERT would not guarantee
In the early 2000s, the CF community was introduced to the fecal
against FC, as it would still be possible to achieve a high lipase
elastase‐1 test for determining PI vs PS. This test, requiring a single stool
unit kg−1 meal−1 dose, should enough capsules be consumed.78
specimen, continues to be valuable in assessing the need for PERT and is
Lipase unit per capsule simply happened to be the measure to define
used with knowledge of specific CFTR mutations.94-96 Before this, PERT
the level at which damage occurred and was not intended to imply any
was often initiated solely on the diagnosis of CF, thus some were
sort of culpability to lipase.81 The exact offending agent that caused FC,
prescribed PERT and encouraged to take it unnecessarily. CFTR
whether the digestive enzymes or some other component contained
mutations as related to pancreatic status97 (see Table 3).
within the enzyme coating or capsule, was never clearly identified.
Fecal elastase‐1 is a proteolytic pancreatic enzyme, not subject to
degradation, and excreted in the stool.98 The test may be obtained while
5.7 | Overfill taking PERT or not. A pancreatic elastase value of <100 mcg/g of stool
indicates PI, and a negative test (>100 mcg/g of stool) has a 99%
To complicate dosing recommendations, a practice is known as
predictive value for PS.96,99 Pancreatic elastase tests results should not
“overfill” was common by enzyme manufacturers since PERT was not
yet regulated by the FDA.81,85 This meant the actual content of PERT T A B L E 3 Main CFTR mutations as related to pancreatic status
often exceeded what was stated on the label (it was common for
Main CFTR mutations as related to pancreatic status
overfill to be 25%‐50% above stated label claims, and in some cases
Usual PI associated mutations Usual PS associated mutations
nearly 90% above). This practice of overfilling allowed for natural
F508 del Y122X R117H
degradation of enzymes to occur and extend shelf life. While the
G542 1898+5G>T R347Pa
average dose of those who developed FC was documented as 6700
G551D 3120+1G>A 3849+10kbC>T
to 29 100 lipase units kg−1 meal−1, their actual dose of PERT, due to
overfill, will never be known.81 N1303K E822X 455E
W1282X 2751+2T>A A334Wa
R553X 296+1G>C G178R
5.8 | Bicarbonate containing enzyme
621+1G>T R1070Q‐S466Xb R352Q
In 1997, a new pancreatic enzyme was introduced to the market 1717‐1G>A R1158X R117C
named Pancrecarb (Digestive Care, Inc).86 Pancrecarb distinguished R1162X W496X 3272‐26A>G
itself from other EC preparations by its “bicarbonate buffer.” The b
1507del 2789+5G>A 711+3A>G
bicarbonate was incorporated into the enzyme preparation to
394 del1TT 2184insA D110H
optimize lipase activity in the upper intestine by increasing pH,
G85E 1811+1.6kbA>G D565G
making conditions more favorable toward enzyme dissolution.
R560T 1898+1G>A G576A
Pancrecarb was initially available in an 8000 lipase unit strength. In
1078delT 2143delT D1152H
1999, Pancrecarb MS‐4 was introduced, followed by Pancrecarb MS‐
16 in 2003.87 Efficacy studies were completed, one study showing 3659delC 1811+1.6kbA>G L206W

improvement in fat absorption compared with a standard EC enzyme, 1898+1G>T R1066C V232D
while the other study showed equivalency of fat absorption, though 711+1G>T Q890X D1270N
on a slightly lower dose of the buffered enzyme.88,89 Of interest, the 2183AA>G 2869insG
scientist who developed Pancrecarb participated in the development 3905insT K710X
of the original EC microsphere, Pancrease, 20 years earlier. S594N 1609delCA
2184delA
5.9 | Biotechnology‐produced enzyme Abbreviations: CTFR, cystic fibrosis transmembrane regulator;
PI, pancreatic insufficient; PS, pancreatic sufficient.
Between 2006 and 2011, a novel nonporcine, microbially‐derived, a
May also be associated with PI.
b
highly purified biotechnology‐produced, crystalline formulation of May also be associated with PS.
ALTMAN ET AL.
be performed on stool that is of liquid preponderance such as diarrhea or
66
an ileostomy, as false‐negative results may occur. Infants with CF have
been shown to exhibit variable fecal elastase‐1 values during the first
year of life, thus it is recommended that PERT be started in all infants
who have results of <200 mcg/g of stool, with remeasurement of fecal
100
elastase value by age one. Utilization of the CFTR2 Website
(coproduced by Johns Hopkins and the CFF) is an excellent resource
101
for patient‐specific information on PS vs PI.
5.11 | FDA Approval/New Drug Applications
The FDA issued a mandate in 2004 that all manufacturers of existing
PERT would need to submit New Drug Applications (NDA’s), with a
deadline of 28 April 2010, to remain in the market.60 NDA’s required
demonstration of PERT safety and efficacy in addition to zero‐overfill of
lipase, protease, and amylase as claimed on the label. Most enzymes
underwent slight name changes as well as label modification of stated
contents. Creon was the first to be approved on 1 May 2009, followed by
Zenpep on 1 September 2009, Pancreaze (formerly Pancrease) on 15
April 2010, Viokace (formerly Viokase) on 1 March 2012, Ultresa
(formerly Ultrase) on 2 March 2012 and which is no longer available, and
lastly Pertzye (formerly Pancrecarb) on 7 May 2012.102-107
5.12 | Infant dosing guidelines
In 2013, reconsideration of enzyme dosing in infants to not be limited
−1 −1
to 10 000 lipase units kg day was proposed. 108
Even the original
1995 publication from the consensus committee on enzyme dosing
suggested differentially dosing enzymes for infants, providing
enzyme dosing recommendations in lipase units per feeding, rather
than total lipase units kg−1 day−1.83
In 2009, evidence‐based guidelines for infant care were pub-
lished. These guidelines stated, “For infants with CF under two years of
age, the CF Foundation recommends that PERT be initiated at a dose of
2000‐50005000 [actual] lipase units at each feeding, adjusted up to a
dose of no greater than 2500 lipase units/kg/feeding …” 19
Using a 5 kg male infant as an example (this would be equivalent to a
6‐week‐old infant at the 50th percentile on both the CDC and WHO
growth charts), taking in 120 mL q every 3 hours eight times per day of
−1 −1
20‐24 calorie per ounce human milk or formula (192 mL kg day
129‐154 kcal kg−1 day−1), dosed at 2500 lipase units kg−1 feeding−1, would
be equivalent to 20 000 lipase units kg−1 day−1.
This infant guidelines statement ended with the phrase “…with a
maximum daily dose of 10,000 lipase units/kg”. It is understandable
why “10 000 lipase units kg−1 day−1” was tagged on, as the writing of
the infant guidelines coincided with the timeframe the FDA was
requiring safety and efficacy for all PERT. By this time, the “10 000
lipase units kg−1 day−1” dose was ingrained in most CF care providers.
It later became clear, that when this ending “10 000 lipase
units kg−1 day−1” is allowed to supersede the maximum lipase units
per kilogram per feeding recommendation, it equates to just 4
−1 −1
feedings/day (if dosed at 2500 lipase units kg feeding ), incon-
sistent with the feeding pattern of most infants. In addition, this
| S65
would equal only 65 to 77 kcal kg−1 day−1, clearly suboptimal for any
6‐week‐old infant, but especially one with CF.
Of note, some of the 2013 authors proposing this request were
also integral members of the 1995 enzyme Consensus committee and
the Infant guidelines committee. Thus, they were knowledgeable on
the dangers of high levels of enzyme doses and would not have made
revision recommendations without careful scrutiny.19,83,108
A 2018 study looked at initial dosing of PERT, and weight for age
and weight for length z‐scores at age two.109 Infants who receive
higher initial PERT doses (>1500 lipase units kg−1 feeding−1) have
more favorable weight for age z‐scores and weight for length
percentiles at 2 years of age. At the time of this writing, a large and
comprehensive multicenter infant feeding study (FIRST) for patients
with CF is in progress, that will include data on lipase unit kg−1 day−1
PERT dosing in infants.110
Finally, a CFF sponsored adjudication committee, is in year 6 of
10 in its follow up study of FC. This is a 10 year prospective,
observational, multicenter, cohort study, using data from the CFF
Registry. Data analyses from July 2012 to July 2016 revealed 26 025
patients with CF comprised the base study population and 96%
remain active (total time in study, 72 084 person‐years (PY) with 86%
receiving PERT. The mean daily dose was 8375 lipase units kg−1
day−1. Among patients receiving PERT, the incidence of confirmed FC
was 0.53/10 000 PY (95% confidence interval [CI], 0.11‐1.54), and
the incidence of not confirmed or indeterminate FC was 1.05/10 000
PY (95% CI, 0.39‐2.29), demonstrating a very low incidence of any
subsequent cases of FC.111
5.13 | Phthalates
Phthalates are synthetic chemicals with a wide spectrum of uses and
are found in many products. Multiple classes of phthalates exist.
Hypromellose phthalate (HPMCP) is a modified derivative of
cellulose, used in pharmaceuticals since 1971. In some PERT, HPMCP
is used in the tablet coatings. HPMCP is considered safe, and is
believed to be mostly unabsorbed.112
In August 2008, concern arose in the CF community regarding
phthalates and PERT. Some other classes of phthalates are: di‐ethylhexyl
phthalate (DEHP), di‐N‐butyl phthalate (DBP), and di‐isononyl phthalate
and (DINP) found in nonconsumable products such as vinyl flooring, toys,
adhesives, and inks. DEHP, DBP, and DINP have been associated with a
wide range of adverse effects in experimental animals including cancer
and reproductive abnormalities. At one time, DBP and DEHP were used
in the enteric coating of enzymes, but are no longer used. HPMCP is
listed as “Generally recognizes as safe” by the FDA.112
5.14 | Gastrostomy tubes and dosing enzymes per
gram of fat
Until recently, one of the more challenging aspects of CF nutritional
care for overnight continuous drip gastrostomy tube (GT) feedings
has been ensuring adequate PERT coverage. Tactics used for enzyme
dosing with overnight continuous drip GT feedings have consisted of
S66 | ALTMAN ET AL.

varied and creative approaches (a) giving oral PERT at the beginning
(and sometimes at the midpoint and end) of the feeding; (b) crushing
non‐EC enzymes and adding to the tube feeding; (c) dissolving EC
PERT in sodium bicarbonate solution and adding to the tube feeding;
or (d) administering the enzyme beads directly into the GT in
applesauce or thickened liquid via syringe, this last method typically
113,114
for bolus fed patients unable to take enzymes by mouth. PERT
dosing for enteral feedings (as well as meals, snacks, and supple-
ments) may be done per gram of fat. Dosing guidelines range from
500‐4000 lipase units per gram of fat, with a common practice of
dosing at 2000 lipase units per gram of fat.115
Relizorb (Alcresta) was introduced in 2017 as a medical device
that is an enzyme delivery system for continuous drip feedings.116
Relizorb is a single‐use, digestive enzyme cartridge designed to
hydrolyze the fat in feedings of continuous drip enteral formulas.
Relizorb connects with the enteral feeding pump tubing, and formula
flows through the cartridge. These cartridges contain small beads
that are covalently bound with immobilized lipase that hydrolyzes fat
in the formula as it flows through the cartridge, and subsequently
infuses into the G‐tube. These treated beads are contained and
retained within the cartridge. Studies suggest Relizorb is safe and
effective demonstrating a twofold increase in omega‐3 index, a long‐
term measure of fat absorption. Self‐reports showed improved
appetite while using the device, and less reports of abdominal pain
and bloating.117,118 As Relizorb is classified as a “medical device,”
6 | CF GUT M IC ROBIOME AN D SMAL L
INTESTINE BACTERIAL OVERGROWTH
The CFTR protein in the GI tract regulates the flow of water and ions
into the intestinal lumen, as well as the pH of the intestinal
contents.121 Because CFTR is responsible for regulating the intestinal
pH, it facilitates the change in pH from the acidity of the stomach to
the alkaline environment of the proximal small intestine.121 In CF, the
alterations in CFTR function lead to thickened mucus throughout the
intestinal tract, gastroesophageal reflux, inflammation, bacterial
overgrowth, and dysbiosis.122 The thickened mucus, delayed GI
transit time, frequent antibiotic use, use of proton pump inhibitors
and malabsorption all contribute to the altered gut microbiome in
CF.123-125 Alterations in the gut microbiome and small intestine
bacterial overgrowth (SIBO) are emerging areas of interest, with the
majority of the research occurring in the last 5 to 10 years.
T A B L E 4 Current Food and Drug Administration approved
pancreatic enzyme replacement therapy in the United States
Product Lipase,
(manufacturer) Form/ USP Amylase, Protease, Sphere
strength units USP Units USP Units size, mm
Creon (AbbVie Inc)
Microspheres

insurance coverage, at the time of this writing, has been inconsistent. 3000 3000 15 000 9500 0.71‐1.6
6000 6000 30 000 19 000 0.71‐1.6
12 000 12 000 60 000 38 000 0.71‐1.6
5.15 | Currently available enzyme preparations in 24 000 24 000 120 000 76 000 0.71‐1.6
36 000 36 000 180 000 114 000 0.71‐1.6
the United States
Pancreaze (Vivus Inc)
Currently, five different brands of enzymes are available in the United Microtablets
2600 (MT 2) 2600 10 850 6200 2
States (Table 4). Generic enzymes are not recommended as lipase activity
4200 (MT 4) 4200 24 600 14 200 2
has been shown to be lower than stated label contents when tested in 10 500 (MT 10) 10 500 61 500 35 500 2
simulated gastric fluid.62 EC microsphere preparations include Creon (5 16 800 (MT 16) 16 800 98 400 56 800 2
21 000 (MT 20) 21 000 83 900 54 700 2
strengths) and Pertzye (4 strengths) and two MT preparations: Pancreaze
Pertzye (Chiesi)
(5 strengths) and Zenpep (7 strengths). One brand of the non‐EC enzyme Bicarbonate buffered microspheres
is Viokace (2 strengths). The ratio of USP units of lipase to amylase to 4000 4000 14 375 15 125 0.8‐1.4
protease varies between and within products. Sphere size of micro- 8000 8000 30 250 28 750 0.8‐2.2
spheres and MTs also vary between and within products. Meyer et al119 16 000 16 000 60 500 57 500 0.8‐2.2
24 000 24 000 90 750 86 250 0.8‐2.2
studied optimal sphere size for pancreatic enzymes in 1988. Data from
this study showed that spheres 1.4 + 0.3 mm in diameter emptied at the Viokace (Allergan, recently acquired by Abbvie)
119
Non‐enteric tablet
same rate as food. 10,440 10 440 39 150 39 150
(0.49 grams/round
tablet)
5.16 | Summary 20 880 20 880 78 300 78 300
(0.96 grams/oval tablet)
PERT has improved the quality of countless lives of PI persons with Zenpep (Allergan, recently acquired by Abbvie)
CF. Improved safety measures required by the FDA and accurate Microtablets

labeling of PERT allows more precision and confidence for those 3000 3000 14 000 10 000 1.8‐1.9
5000 5000 24 000 17 000 1.8‐1.9
prescribing. Optimal PERT dosing, although guidelines exist, requires
10 000 10 000 42 000 32 000 2.2‐2.5
discernment and individualization. Pancreatic elastase testing and 15 000 15 000 63 000 47 000 2.2‐2.5
knowledge of CFTR mutations provide guidance to identify PI vs PS. 20 000 20 000 84 000 63 000 2.2‐2.5
CFTR modulator therapies may also lead to improved digestion of 25 000 25 000 105 000 79 000 2.2‐2.5
nutrients.4,120 (see Figure 8). 40 000 40 000 168 000 126 000 2.2‐2.5
ALTMAN ET AL.
FIGURE 8 Enzyme picture
Children and adults with CF have decreased gut bacterial species
diversity compared to their non‐CF siblings, as well as a decrease in
Bifidobacterium in CF patients.123,126,127 This is important because
increased gut microbiome diversity in infants and young children is
associated with longer time to first CF exacerbation.2 Schippa et al128
found that patients with CF with F508del mutations and severe
disease had a different microbiome than those with mild disease.
They were more likely to have more E. coli and E. biforme and less
128
beneficial bacteria. Alterations in colonic colonization of Oxalo-
129
bacter formigenes can also be a problem for patients with CF. This
bacterium has an integral role in oxalate regulation.129 There is a
higher incidence on calcium‐oxalate urolithiasis in patients with CF
0% to 2% in the general population vs 3% to 5% in CF patients over a
12‐year time.129 A study done by Sidhu et al129 found that 71% of
healthy volunteers were colonized with O. formigenes vs 16% of CF
study participants. Oxalate excretion was the only urine factor
significantly different in patients with CF that were colonized and
129
those not colonized with O. formigenes. This study suggests that
use of specific antibiotics are detrimental to this bacteria and are
likely a contributing factor to the increase risk of nephrolithiasis in
people with CF.129
SIBO can be difficult to diagnose because the symptoms are
similar to the usual abdominal symptoms in CF—abdominal pain,
bloating, gassiness, steatorrhea, and/or diarrhea.121,130 SIBO occurs
in 30% to 50% of patients with CF.130,131 In CF mice, where bacterial
load can be measured directly, there is a 40‐fold increase in bacterial
load in the small intestine (SI) when compared with wild‐type (WT)
mice.130 This study published by De Lisle130 in 2007 examined two
potential causes of SIBO in the CF mouse—impaired Paneth cell
| S67
function or delayed GI transit time. They found that SIBO develops in
the CF mouse before differentiation of Paneth cells, therefore, they
are unlikely related to the development of SIBO.126 In contrast, SI
transit time in the CF, specifically, the proximal SI, was significantly
slower than in the WT mouse.130 Although the initial cause of the
bacterial overgrowth was unknown at the time, a possibility noted
was that the abnormal mucus in the SI provides a good environment
for bacterial colonization.130 SIBO can lead to malabsorption due to
certain bacteria affecting absorption.131 CF mice have demonstrated
weight gain after treating their SIBO with antibiotics, further
enforcing this idea.131
6.1 | Testing for SIBO
Direct measurement of the GI bacterial load is challenging and
invasive, requiring endoscopic aspiration, possibly intestinal biop-
sies.121 A breath hydrogen test (BHT) or a hydrogen/methane breath
test, provides a noninvasive, indirect way to measure bacterial
overgrowth.121 The test is approximately 4 hours long following an 8
to 12 hour fast, making it difficult to perform. If performing an BHT, it
is important to test for both hydrogen and methane, especially in
patients with CF more than non‐CF controls, as chronic antibiotic use
may lead to colonization with methane‐producing bacteria.121,126,132
A study done in 1998 using only the BHT showed a significantly
higher bacterial overgrowth in children with CF than non‐CF children
(32% vs 7%).125 Methane was not measured in this study. Delayed SI
motility as well as air trapping that occurs as lung disease progresses
in CF, may make the breath test more difficult to evaluate in patients
with CF.121
S68 | ALTMAN
6.2 | Treatment for SIBO
Because the breath test can be difficult to perform and evaluate in
CF, SIBO is often treated empirically.121 The treatment is a 10 to
14 day course of antibiotics targeting the harmful bacteria colonizing
the gut, including metronidazole or rifaximin.121 Furnari et al124
demonstrated that treatment of SIBO with rifaximin after a positive
glucose breath test resulted in a negative follow up breath test in 9
out of 10 patients in their treatment group. However, resolution of
the bacterial overgrowth did not resolve all of the GI symptoms that
participants were experiencing, suggesting that other factors may
also contribute to these symptoms.124 The one symptom statistically
significantly associated with SIBO is poor appetite, likely contributing
to its effect on nutritional status.124 Treatment can also include
dietary intervention, prebiotic therapy and probiotic therapy.127
Polyethylene glycol was also shown to be helpful in improving SIBO
by 90% in CF mice.121
Probiotics are being studied in CF, and have shown some positive
results such as decreased pulmonary infections, increased pulmonary
function, increased weight and decreased SI inflamma-
tion.3,121,123,127,133 However, many studies are small, and larger
randomized control trials are needed to support probiotic use.133 A
pilot study from the ESPGHAN working group on Pancreas/CF could
not support improvement from probiotics seen on inflammatory
markers, pulmonary function, pulmonary exacerbations and micro-
biome.3 Due to small sample size, different probiotics/intervention
used and variable outcomes measured, neither the ESPGHAN
working group nor the review by Anderson et al133 could
conclusively make a recommendation regarding probiotics.3 Further
research is needed with larger cohorts.3
7 | N U T RI T I O N AN D M O D U L A T O R
THERAPY
CFTR modulator therapies are mutation‐specific oral medications
designed to correct the malfunctioning protein made by the CFTR
gene.4,134 The CFTR protein regulates the flow of water and chloride
ions in and out of cells throughout the body—including the lungs,
4,134
sweat glands, pancreas, and GI tract. How long‐term nutritional
outcomes will be impacted is unknown, as the first medication was
initially studied only approximately 10 years ago, but remains an
emerging area of interest and speculation.
The first modulator therapy to be approved by the FDA was
ivacaftor (Kalydeco). Ivacaftor was approved in 2012 for use in
patients with CF >6 years of age having the G551D mutation,
135
accounting for 4% of the CF population in the US. Ivacaftor’s FDA
approval has since been expanded to include additional mutations
(38 total) and now starting at age 6 months. This represents
approximately 15% of the CF population.136,137 In 2015, the FDA
approved lumacaftor/ivacaftor (Orkambi) for people with CF 12
years of age and older who are homozygous for the F508del CFTR
mutation. Those with two copies of the F508del mutation represents
ET AL.
the largest group of people with CF.138 It has now been approved use
in people with CF homozygous for F508del 2 years of age and
older.139 The most recently approved CFTR modulator is tezacaftor/
ivacaftor (Symdeko). Tezacaftor/ivacaftor was initially approved for
people with CF 12 years of age and older who are homozygous for
F508del or heterozygous with one copy of a responsive mutation,
and at the time of this publication, includes patients 6 years and
older.140,141
Patients receiving ivacaftor in the phase 3 clinical trial demon-
strated increased weight gain compared with control.4 The cause of
weight gain was not studied, however, subjects receiving ivacaftor
had an improvement in CFTR function demonstrated by an
improvement in sweat chloride.4 It was thought that this improve-
ment in CFTR function would also occur in GI tract, helping to
improve absorption.4 Additional evaluation of weight gain improve-
ments seen in the phase 3 clinical trial showed that pediatric patients
had improvements in weight and BMI throughout the 144‐week
observational period of the study, while adults only had an initial
increase that did not continue throughout.142
A study done after the approval of ivacaftor continued to show
improvements in weight and BMI.120 In addition, seven participants
in this study had intestinal pH measurements before and after
initiating ivacaftor.120 These patients had a significantly higher pH
after starting ivacaftor, likely contributing to improved absorption
and enzyme function.120 Another study of 10 patients measuring
intestinal pH before and after ivacaftor showed a significant
improvement in SI pH after taking ivacaftor, as well as reaching a
higher pH more rapidly.143 Ivacaftor did not appear to improve the
delayed bowel transit time that patients with CF experience.1 In a
study done in young patients aged 2 to 5 years with at least 1 G551D
mutation, 26 of 27 patients had fecal elastase below 60 mcg/g.1 At
the end of the study, this level normalized to >200 mcg/g in 7
patients and increased to >100 mcg/g in 11 patients, putting them
above the threshold for severe pancreatic insufficiency.1
A study was done by Stallings et al144 to determine the
mechanism for weight gain in patients starting ivacaftor treatment.
In addition to weight gain, they found increases in both FFM and fat
mass (FM).144 Calorie intake increased, but not significantly.
However, fat intake did increase significantly.144 This is likely related
to the need to take ivacaftor with fat‐containing food. There was also
a significant decline in resting energy expenditure from 95%
predicted to 90%.144 This study did not demonstrate a significant
change in fecal elastase, and no PI patients became PS.144 They did
however, see an increase in coefficient of fat absorption, suggesting
that Ivacaftor may impact other intestinal factors to improve
absorption.144
A study published in 2018 looked at other GI improvements
associated with treatment with ivacaftor.145 Ooi et al145 demon-
strated an improvement in intestinal microbiome with a decrease in
Enterobacteriaceae and an increase in Anaerostipes and Akkermansia—
beneficial bacteria.145 After adjustment, only the increase in
Akkermansia was significant.145 These microbiome changes were also
associated with a decrease in inflammation, demonstrated by a
ALTMAN ET AL.
decrease in fecal calprotectin.145 However, this was a small study,
and validation studies need to be done.
Studies were also done to assess changes improvements in
patients started on combination therapy with lumacaftor/ivacaf-
tor. In a study of patients ≥12 years with homozygous F508del
mutations on combination therapy with lumacaftor/ivacaftor,
increases in weight and BMI were seen at 24 weeks and were
more pronounced at 144 weeks. 1 It is unknown if the weight gain
is related to improved absorption or improved appetite related to
decreased pulmonary exacerbations. 1 Li et al146 compared
continuous glucose monitoring (CGM) results before and after
initiation of lumacaftor/ivacaftor therapy. 146 They found a
minimal impact on CGM results with the initiation of combination
lumacaftor/ivacaftor therapy. 146 This study was limited by
sample size with only nine participants. 146
Much remains to be studied, with the recent approval of
tezacaftor/ivacaftor, as well as new drug approval on the horizon.
Triple combo therapy, that has been studied and shown positive
results in both CF patients with homozygous F508del and hetero-
zygous f508del and minimal function mutations, has been submitted
for FDA approval—leaving the CF community waiting with expectant
hope.147
8 | S UMMAR Y
As this review has shown—there has been a shift over time, from a
focus on the pulmonary components of CF care to an emphasis on
the diet and nutrition aspects of CF care. This is a change from
practice‐based care to evidence‐based care. Credit is due to both the
CF dietitians and digestive disease physicians who have helped make
nutrition care such an integral part of CF treatment. It is also
important to acknowledge the efforts of the CFF that consistently
supports improvements in practice and patient care, the implementa-
tion of care protocols and advancements in therapy. It is an exciting
era in CF care. There is still a lot between what we know and what is
to come.
OR CID
Kimberly Altman http://orcid.org/0000-0002-4387-1573
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