Nutrition 102 (2022) 111725

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Nutrition
journal homepage: www.nutritionjrnl.com

Review

Improving nutrition in cystic fibrosis: A systematic literature review

Monika Mielus a,b,*, Dorota Sands a,b, Marek Woynarowski b,c
a
Cystic Fibrosis Department, Institute of Mother and Child, Warsaw, Poland
b
w Le
sny, Poland
Cystic Fibrosis Centre, Pediatric Hospital, Dziekano
c
Collegium Medicum of Jan Kochanowski University, Kielce, Poland

A R T I C L E I N F O A B S T R A C T

Article History: With increasing life expectancy of patients with cystic fibrosis (CF), gastrointestinal manifestations of the dis-
Received 4 November 2021 ease have been increasingly brought into focus. This was a systematic review of the PubMed database and
Accepted 25 April 2022 ongoing phase III clinical trials that aimed to summarize recent (published after June 1 2016) studies report-
ing the effects of nutritional interventions on anthropometric measures (weight, height, and body mass
Keywords: index) in patients with CF. Two ongoing trials and 40 published studies (18 interventional and 22 observa-
Systematic literature review
tional) were identified. Key results supported the benefits of comprehensive, individualized nutritional plans,
Nutrition
high-fat, high-calorie diet including high-quality carbohydrates, and enteric tube feeding (albeit the latter
Diet
Supplementation
was derived from observational studies only). In contrast, the supplementation of probiotics, lipids, docosa-
Weight hexaenoic, glutathione, or antioxidant-enriched multivitamin appeared to have little effect on anthropomet-
Hight, Body mass index ric measures.
© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction
Pulmonary disease is the main cause of mortality and morbidity
in patients with cystic fibrosis (CF) [1]; yet, with increasing life
expectancy of these patients, gastrointestinal (GI) manifestations
of the disease have been increasingly brought into focus. Approxi-
mately 85% of patients with CF present with pancreatic insuffi-
ciency, usually starting shortly after birth [2]. Insufficient
pancreatic enzyme production results in malabsorption of
nutrients and fat-soluble vitamins, which may be exacerbated by
concomitant liver disease [3]. On the other hand, pulmonary infec-
tion can result in larger caloric need and reduced appetite [3]. Con-
sequently, poor nutrition in CF is common. Data from the Cystic
Fibrosis Foundation registry has shown that 47% of adults with CF
are not meeting the body mass index (BMI) goals of 23 kg/m2 for
The conduct and publication preparation of this review were supported by Mylan
Healthcare Sp.zo.o. The authors had full independence in the conduct of the study
and the drafting of the manuscript. M.M. reported personal fees from Nestle, Nutri-
cia, and Vertex Pharmaceuticals and serves an advisory board for Mylan outside the
submitted work. D.S. reports personal fees from Chiesi, Nutricia, Pfeizer, Roche, and
Vertex Pharmaceuticals and serves on advisory boards for Vertex and Mylan outside
the submitted work. MW reports personal fees from Nutricia and Vertex
Pharmaceuticals.
*Corresponding author.
E-mail address: monika.mielus@imid.med.pl (M. Mielus).
men and 22 kg/m2 for women, whereas 42% of children are not
meeting the BMI goal of
50 percentile [4].
There is a clear link between improved nutritional status and
better lung function and longer survival in patients with CF [5].
Cystic fibrosis transmembrane regulator (CFTR) modulation ther-
apy revolutionized the treatment of CF, but a recent comprehen-
sive systematic review reported mixed effects of CFTR modulators
on anthropometric measures [6]. In addition to treatment targeting
the disease mechanism of CF, a range of nutritional interventions,
from dietary advice, through supplements, to enteric tube feeding
may be employed to improve nutrition in patients with CF. Despite
the wide array of interventions available, an analysis of gaps in the
evidence for treatment decisions in CF identified as many as 20 evi-
dence gaps related to GI care of patients with CF [7], highlighting
the need for high-quality research in the area. Against this back-
drop, we conducted a systematic review of published literature
and ongoing clinical trials that aimed to summarize recent
research into nutrition and GI care in people with CF.
Review methodology
The protocol of the review (Supplementary Material) was developed in accor-
dance with Preferred Reporting Items for Systematic review and Meta-Analysis
Protocols (PRISMA-P) [8] criteria and the results of the review are reported herein
in accordance with the PRISMA 2009 Checklist [9].
The present review focused solely on nutritional interventions and gene ther-
apy; CFTR modulators were not captured as these had been recently described in a
comprehensive systematic review by Bailey et al. [6].

https://doi.org/10.1016/j.nut.2022.111725
0899-9007/© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
2 M. Mielus et al. / Nutrition 102 (2022) 111725

Table 1
Eligibility criteria for published studies describing nutritional interventions in cystic fibrosis.

Inclusion criteria Exclusion criteria

Population Individuals with CF Individuals without CF; Animal studies

Intervention and comparator Diet; nutrients; appetite stimulants; PN; ETF; PERT; supple- Intervention of interest not reported
ments; gene therapy
Outcomes Dosing of the intervention; efficacy of the intervention, Outcomes of interest not reported
including change in weight/weight z-score/weight percentile
(for pediatric patients) from baseline; change in BMI/ zBMI/
BMI percentile (for pediatric patients) from baseline; change
in height/height z-score/height percentile (for pediatric
patients) from baseline; change in the proportion of patients
who are underweight, from baseline
Study design Original research articles describing: clinical trials: RCTs; non- Case reports or case series; Reviews, editorials, letters, com-
randomized controlled trials; single-arm studies; observa- ments, notes; animal or in vitro studies; pharmacokinetic
tional studies: cohort studies; case control studies; cross- studies; cost-effectiveness studies
sectional studies; registry/database studies
Language restrictions Studies published in English or Polish Studies published in languages other than English or Polish
Publication date June 1, 2016 March 14, 2021 Studies published before June 1, 2016; Studies published after
April 22, 2020
BMI, body mass index; ETF, enteral tube feeding; PERT, pancreatic enzyme replacement therapy; PN, parenteral nutrition; RCT, randomized controlled trial; zBMI, BMI z-score

The present review comprised two independent components: a review of the
published literature and a review of ongoing clinical trials. The PubMed database
was initially searched to identify relevant studies published between June 1, 2016
and April 22, 2020. Ongoing clinical trials posted between those dates were
searched across the clinicaltrials.gov, EduraCT, and ISRCTN registers. These
searches were subsequently updated using the same search terms as in the origi-
nal review, except for the updated date restriction so that, overall, the date range
for the review was from June 1, 2016 to March 14, 2021.
Publication date was restricted to identify studies published from June 2016,
to update on an earlier comprehensive review performed to inform the develop-
ment of Australian and New Zealand guidelines on nutrition in CF [10].
Screening of titles and abstracts for published studies was performed in End-
Note X8 and EndNote20 to facilitate duplicate removal. Full texts of potentially eli-
gible studies were subsequently reviewed to determine eligibility based on the
Population, Intervention, Comparator, Outcomes, and Study Design (PICOS) crite-
ria provided in Table 1.
For ongoing trials, results from each registry search were exported into Micro-
soft Excel and duplicates were removed manually to enable identification of
unique studies. The review of ongoing clinical trials applied the eligibility criteria
outlined in Table 1 for population, intervention and comparator, and outcomes. In
terms of study design, however, only phase III trials were included.
Data extraction was performed by a single reviewer in a consistent manner
using two piloted forms in Microsoft Excel, one for published studies and one for
ongoing trials. Risk of bias in included studies was not assessed.
Outcomes of interest to the review focused solely on anthropometric meas-
ures of nutritional status (weight, height, and BMI), which are known to correlate
with lung function [11,12] and are easy to evaluate even in less developed health
systems, potentially expanding the geographical scope of the review.
Search results
Ongoing phase III trials
Clinicaltrials.gov (37 hits initial search, 7 hits update), EduraCT
(36 hits initial search, 15 hits update), and ISRCTN (0 hits at both
initial search and update) registers were searched, rendering 61
unique trials across the three registries. Of these trials, 58 were
excluded due to population (n. = 6) or intervention (n = 52) not fit-
ting the review’s PICOS criteria. Three trials were included.
The intervention assessed in two of these trials (EduraCT num-
bers 2017-000571-85 [Reliable, Emergent Solution Using Liprota-
mase Treatment (RESULT)] and 2016-002851-92 [Extended Access
to Sollpura over Years (EASY)]) was liprotamase, a pancreatic
enzyme replacement therapy (PERT) from non-animal sources, the
development of which has been discontinued due to a failure to
meet the primary end point in the phase III RESULT trial. Conse-
quently, both EASY and RESULT were listed as prematurely ended.
RESULT was a phase III, randomized, open-label, assessor-blind,
non-inferiority trial evaluating the efficacy and safety of
liprotamase compared with Pancreaze in patients with CF-related
exocrine pancreatic insufficiency (EPI). EASY was an open-label,
single-arm study to evaluate long-term safety of liprotamase in
patients with CF-related EPI.
The final trial, NCT04411901, was a single-arm trial that
assessed the effect of vitamin D3 on the severity of CF and non-CF
pediatric bronchiectasis. The primary end point of this trial was
reaching vitamin D levels of >30 ng/dL, while decreased number
of exacerbations and increased lung function were the secondary
end points. It was not clear from the records available if the trial
assessed anthropometric measures of interest. Although the trial
was recorded as completed, no results were available on Clinical-
trials.gov. A publication based on this trial was therefore identified
[13]. Although the improvement in vitamin D levels was signifi-
cantly higher in patients with CF than in the non-CF bronchiectasis
group, changes in anthropometric measures with vitamin D sup-
plementation were not reported in the publication [13].
Published reports
The initial search strategy defined in the review protocol ren-
dered 506 hits. An additional 150 hits were identified at the
update, resulting in 656 hits. We excluded 578 abstracts, and 77
full-text articles were screened for eligibility. Of these, 36 were
excluded; the vast majority (n = 33) because they did not report
outcomes of interest. Overall, 40 studies corresponding to 41
articles were included (one identified article [14] was a correction
to an included study [15]). Outcomes of the selection process are
documented in Figure 1.
Overview of published studies
Table 2 summarizes the characteristics of included studies.
Interventional studies
Of the 40 included studies, 18 were interventional. Of these, 11
were clinical trials, of which 7 were placebo-controlled [15 21],
and the remaining were active controlled (n = 3) [22 24] or sin-
gle-arm (n = 1) [25]. Six studies were prospective, interventional
cohort studies [26 31], including a patient access scheme [30].
The final publication reported on a small, prospective, cross-over
study [32].
 M. Mielus et al. / Nutrition 102 (2022) 111725 3

Fig. 1. Preferred Reporting Items for Systematic review and Meta-Analysis flow diagram of the PubMed review. *Forty studies corresponding to 41 articles as 1 identified arti-
cle was a correction to another included study. OrR, original review; U, update.

A wide range of pharmacologic, dietary, and other interventions Australasian Clinical Practice Guidelines for Nutrition in Cystic
was tested, including probiotic/symbiotic supplementation (n = 3) Fibrosis [51].
[17 19], dietary modification (n = 3) [22,28,31], patient education/
dietary management frameworks (n = 2) [25,29], vitamin supple-
Populations included
mentation (n = 2) [23,26], PERT (n = 1) [24], gene therapy (n = 1)
[16], choline (n = 1) [27], glutathione (Glu) [20], docosahexaenoic
Included studies varied substantially in cohort size (range:
acid (DHA) [21], a readily absorbable structured lipid (Encala) [15],
10 2304) and apparent methodological quality, although the latter
and supplemental foods (n = 1) [32]. Additionally, one study
was not formally assessed. Four studies included adults only
assessed a device, an immobilized lipase cartridge for extracorpo-
[27,35,38,39], 21 included solely pediatric patients
real digestion of enteral feedings (RELiZORB) [30].
[15,17 20,22,25,28,29,32,33,36,37,40,41,43,47,48,51,52,54], 8 did
not report the proportion of pediatric patients
Observational studies
[21,24,42,44 46,49,53], and the remaining 7 studies included a
mixed population of children and adults [16,23,26,30,31,34,50].
Twenty-two observational studies were included. Among these
22, four were prospective cohort studies [33 36] and 5 were retro-
spective studies [37 41]. Other study designs included cross-sec- Key results from identified published studies
tional studies (n = 8) [42 49], registry-based studies (n = 3)
[50 52], and case control studies (n = 2) [53,54]. Two Canadian Dietary management plans and frameworks
publications reported on the same cohort of 200 patients treated
at the Centre Hospitalier de l’Universite de Montreal [35,38]. No Four interventional studies examined holistic approaches to
overlap was detected between any of the remaining studies. nutritional care in the form of dietary plans, frameworks, or man-
Included studies assessed the relationships between nutrition- agement tools.
related outcomes and PERT (n = 3) [33,37,52] or pancreatic suffi- El-Koofy et al. enrolled 50 pediatric patients with CF in a pro-
ciency status (n = 1) [36], enteral feeding (n = 5) [34,39,50,53,54], spective, interventional cohort study of a comprehensive nutri-
vitamin intake (n = 8) [35,38,40 42,44 47], and calorie and/or tional plan with vitamin and mineral supplementation. The study
macronutrient intake (n = 3) [41,43,48]. One cross-sectional study was conducted in a single center in Egypt. Implementation of the
assessed the effects of oral nutritional supplements [49]. The final nutritional plan was associated with a significant improvement in
study reported on the effects of implementing the 2006 several nutritional indices, including weight z-score, after a period
 4
Table 2
Summary of the design of included studies.

Study name Country Study design Cohort size Intervention Comparator Treatment duration

Dietary management plans and frameworks

Boon 2020 [25] International (Portugal, Spain, 6-mo, open label, prospective, 171 Mobile MyCyFAPP app None 6 mo
Italy, Belgium, Netherlands) multicenter interventional clini-
cal trial
El-Koofy 2020 [28] Egypt Prospective, interventional 50 Nutritional plan plus vitamin None 3 mo
cohort study and mineral supplementation
Revert 2018 [29] France Prospective, interventional Open cohort: 34 patients at Individually adapted therapeutic None 3y
cohort study study start and 44 at study end patient education
Van Biervliet 2021 Belgium Prospective pre post-interven- 34 Residential rehabilitation pro- None 3 wk
tion study gram combining nutritional
optimization, therapy support,
and physical activity
General calorie and macronutrient intake and diet
Gorji 2020 [22] Iran Randomized, double-blinded, 44 (22 per arm) Low glycemic index/HFCD HFCD 3 mo
parallel-group, clinical trial
Neri 2019 [43] Brazil Cross-sectional study 101, including 9 infants (<2 y of None (reported nutritional out- None N/A
age), 23 preschoolers (2 5 y), 18 comes by macronutrient intake
students (5 10 y), and 51 ado- and age group)

M. Mielus et al. / Nutrition 102 (2022) 111725

lescents (10+ y)
Poulimeneas 2020 [48] Greece Cross-sectional study 76 None (non-interventional study None N/A
that assessed nutritional intake
in general)
Ruseckaite 2018 [51] Australia Australian Cystic Fibrosis Data 2304 Implementation of the 2006 None N/A
Registry-based study Australasian Clinical Practice
Guidelines for Nutrition in Cystic
Fibrosis
Woestenenk 2019 [41] Netherlands Retrospective cohort study 191 None (reported on the relation- None N/A (mean § SD follow-up
ship between calorie intake and period was 4.7 § 2.3 y)
nutritional outcomes)
Supplemental foods
Pitman 2019 [32] U.S. Crossover study 10 2 flavors of peanut-based ready- None 2 wk
to-use supplemental food
Victoria 2021 [49] Spain Cross-sectional observational 59, including 13 patients (22%) ONS None N/A
study receiving ONS
Probiotics
Bruzzese 2018 [17] Italy Prospective, multicenter, dou- 95, including 41 in the probiotic Lactobacillus GG probiotics Placebo 1y
ble-blind, randomized, placebo- group and 40 in the placebo
controlled, interventional trial group
De Freitas 2018 [18] Brazil Randomized, placebo-controlled, 58, including 17 non-CF controls, Symbiotic supplementation Placebo 90 d
double-blind trial 19 CF patients in the placebo
group, and 22 patients in the
symbiotic group
Van Biervliet 2018 [19] Belgium Randomized, double blind pla- 31 Probiotic Placebo 4 mo, separated by a wash-out of
cebo-controlled crossover-study 1 mo
Vitamin supplementation general
Sagel 2018 [23] US Randomised, multicenter, dou- 73 in the mITT population, Antioxidant-enriched Standard multivitamin 16 wk
ble-blind, controlled trial including 36 randomized to anti- multivitamin
oxidant multivitamin and 37 to
control multivitamin

(continued on next page)

Table 2 (Continued)
Study name Country Study design Cohort size Intervention Comparator Treatment duration

Tham 2020 [47] Australia Cross-sectional study 164 including 82 children with None (reported the intake of None N/A
CF and 82 age- and sex-matched several vitamins and micronu-
controls trients, and nutritional out-
comes, for CF patients vs
controls)
Vitamin D supplementation
Abu-Fraiha 2019 [26] Israel Prospective, interventional 90 Vitamin D supplementation None 12+ mo (median 16.28 mo)
cohort study
Coriati 2017 [38] Canada Retrospective study 200 Vitamin D3 supplementation NR mean § SD: 5 § 0.9 y
(reports on the same cohort as
Lehoux Dubois 2019)
Lehoux Dubois 2019 [35] Canada Prospective observational cohort 200 Vitamin D3 supplementation NR mean § SD: 5 § 0.9 y
study (reports on the same cohort as
Coriati 2017)
Ongaratto 2018 [44] Brazil Retrospective cross-sectional 37 None (reported nutritional out- None N/A
study comes by vitamin D deficiency
status)
Vitamin A supplementation
Sapiejka 2017 [45] Poland Cross-sectional study 196 None (reported nutritional out- None N/A
comes by vitamin A deficiency

M. Mielus et al. / Nutrition 102 (2022) 111725

status)
Woestenenk 2016 [40] Netherlands Retrospective, observational 221 None (reported nutritional out- None N/A
study comes by serum vitamin A
levels)
Supplementation of other vitamins
Krzyzanowska 2018 [42] Ukraine Cross-sectional study 79 None (reported nutritional out- None N/A
comes by vitamin K deficiency
status)
Sapiejka 2018 [46] Poland Cross-sectional study 211 None (reported nutritional out- None N/A
comes by vitamin E deficiency
status)
Pancreatic sufficiency status and PERT
Calvo-Lerma 2017 [37] Spain Retrospective observational 16 PERT None 1y
study
Gelfond 2018 [33] US Prospective, observational 231 including 205 with pancre- PERT None Up to 1 y
cohort study atic insufficiency who initiated
PERT, 6 with pancreatic insuffi-
ciency but no PERT use, and 20
with pancreatic sufficiency
Munck 2018 [36] France Prospective, longitudinal, obser- 105, including 86 with pancre- None (reported nutritional out- None N/A
vational, multicenter study atic insufficiency and 19 with comes by pancreatic sufficiency
pancreatic sufficiency at baseline status)
Schechter 2018 [52] US Retrospective cohort analysis 502 PERT None 2y
based on the Cystic Fibrosis
Foundation Registry, including a
nested case control component

(continued on next page)

3
of

5
 6
Table 2 (Continued)
Study name Country Study design Cohort size Intervention Comparator Treatment duration

Taylor 2016 [24] International: 34 sites in 7 Euro- Randomized, double-blind, 96 randomized (48 to Zenpep Kreon 28 d on each PERT
pean countries including Bel- active-controlled, crossover, Zenpep ! Kreon and 48 to
gium, Bulgaria, Germany, multinational, non-inferiority Kreon ! Zenpep)
Hungary, Italy, Poland, and the study 83 completers (41
UK Zenpep ! Kreon and 42
Kreon ! Zenpep)
Enteral tube feeding
Declercq 2020 [54] Belgium Retrospective case control 24 ETF None Median 4.7 y (IQR 2.8 5.7 y)
study
Hollander 2017 [39] Netherlands Retrospective observational 26 eTF, comprising at baseline: None 6 mo
study 57.7% nasogastric tube, 30.8%
PEG, 7.7% PRG, 3.8% nasoduode-
nal tube
Kedzior 2019 [34] Poland Prospective, observational 53 Enteral nutrition (PEG) None Range: 6 mo to 7 y
cohort study <1 y in 21%
1 2 y in 56%
2+ y in 23%
Khalaf 2019 [53] US Retrospective case control 60, including 20 patients who Enteral nutrition (PEG) No PEG NR
study received PEG and 40 controls

M. Mielus et al. / Nutrition 102 (2022) 111725

who did not
Libeert 2018 [50] Belgium Belgian Cystic Fibrosis Registry- 339, including 113 cases receiv- ETF No ETF Median (IQR): 2 (1 5) y
based, retrospective, longitudi- ing ETF and 226 controls not
nal study receiving ETF
Other interventions
Alton 2016 [16] UK Randomized, double-blind, pla- 136 (ITT) 60 in placebo arm and gGene therapy (CFTR gen- Placebo 1y
cebo-controlled phase IIb trial 76 in gene therapy arm e liposome complex pGM169/
116 (PP) 54 in placebo arm and GL67A)
62 in gene therapy arm
Bernhard 2019 [27] Germany Prospective, interventional 10 Choline None Median (IQR): 84 (84 91) d
cohort study
Bozic 2020 [20] United States Randomised, Double-blind, mul- 60 Reduced L-glutathione (GSH) Placebo 24 wk
ticenter, placebo-controlled
phase II trial

pez-Neyra 2020 [21]
Lo Spain Randomized, double-blind, par- 87 Docosahexaenoic acid Placebo 48 wk
allel-group, placebo-controlled
trial
Sathe 2021 [30] Not reported explicitly, most Patient access program 100 RELiZORB: immobilized lipase None 12 mo
likely United States cartridge for extracorporeal
digestion of enteral feedings
Stallings 2020 [15] United States Double-blind placebo-controlled 66 Readily absorbable structured Placebo 3 mo presented in the analysis
study lipid (Encala) (total study duration was 12 mo)
CF, cystic fibrosis; ETF, enteral feeding tube; GSH, glutathione; HFCD, high-fat, high-calorie diet; IQR, interquartile range; ITT, intention-to-treat; mITT, modified intention-to-treat; N/A, not applicable; NR, not reported; ONS, oral
nutritional supplement; PEG, percutaneous endoscopic gastrostomy; PERT, pancreatic enzyme replacement therapy; PP, per-protocol; PRG, percutaneous radiologic gastrostomy;
 M. Mielus et al. / Nutrition 102 (2022) 111725
mo; however, it should be noted that the study population was
substantially malnourished at baseline [28].
Revert et al. reported on a quality-of-care improvement pro-
gram at a specialist CF center in France, aiming to improve the
nutritional status of children with CF. Initial cohort size was 34
children, increasing to 44 by the end of the study. The program
was multistep, and involved, among other steps taken, effective
follow-up of each patient’s nutritional status, individualized
weight gain goals, and intensified follow-up for more difficult
cases. Implementation of the program over a 3-y period led to a
numerical improvement in mean BMI z-score (zBMI; P-value not
reported) in addition to achieving a high level of patient and parent
satisfaction [29].
The study by Boon et al. [25], was a single-arm, open-label, pro-
spective, multicenter, international, interventional clinical trial
investigating the effect on MyCyFAPP mobile app on GI-related
quality of life (QoL) in 171 pediatric patients with CF. The app
allowed recording of meals to be eaten (returning recommended
PERT dose in real-time) and GI symptoms, contained educational
materials, and enabled contact with a health care professional.
Although usage of the tool over 6 mo improved patient QoL, there
were contradictory effects on anthropometric parameters (signifi-
cant increases in height z-score, but statistically significant
decreases in weight z-score and zBMI), making it difficult to draw
any conclusions.
Finally, an interventional pre post study conducted in Belgium
by Van Biervliet et al. described a 3-wk residential rehabilitation
program combining nutritional optimization, therapy support, and
physical activity. In a cohort of 34 patients (mixed pediatric and
adult), the program resulted in significant increases in weight and
zBMI, as well as a reduction in the proportion of patients who
could be considered malnourished [31].
Calorie and macronutrient intake and diet
Four observational studies examined calorie and macronutrient
intake, strongly suggesting that nutritional intake [41] and growth
parameters [43,48] remain suboptimal in some children with CF;
however, implementation of nutritional guidelines may improve
these parameters [51].
Neri et al. performed a cross-sectional study of 101 children and
adolescents with CF attending a single center in Brazil and reported
adequate calorie and macronutrient consumption and adequate
nutritional status in most patients [43]. However, lower zBMIs
were observed in children 5 to <10 y of age and adolescents
10 y
of age, with 35.3% and 33.3%, respectively, classed as underweight
based on a zBMI below 1 [43]. Similarly, in a cross-sectional study
enrolling 76 children with CF in Greece, 9% of boys and 5% of girls
were underweight (BMI-for-age z-score [BAZ] < 2) and 19% of
boys and 18% of girls experienced nutritional failure (BAZ < 1.04),
despite all patients meeting or exceeding the recommended total
energy intake [48]. Carbohydrate and fiber intake was generally
inadequate, suggesting there remains room for improvement in
terms of diet quality [48].
In contrast to the results from Brazil [43] and Greece [48], a ret-
rospective, single-center cohort study of 191 Dutch children with CF
(2 10 y of age) reported that dietary intake exceeded 110% of the
estimated average requirement in only 47% of dietary measure-
ments, and therefore did not fully achieve the recommended high
energy levels [41]. Energy intake in relation to estimated require-
ments decreased with increasing age [41]. In a cross-sectional analy-
sis, higher calorie intake was associated with significantly higher
weight-for-age z-score (WAZ), height-for-age-adjusted-for-target-
height, and zBMI in boys, but only with significantly higher WAZ in
7
girls [41]. A longitudinal analysis over a mean follow-up of 4.7 y
revealed that increased calorie intake was associated with signifi-
cant increases in WAZ in both sexes and a significant ZBMI increase
in boys only [41]. There was no association between calorie intake
and height-for-age adjusted-for-target-height z-score [41]. The die-
tary contribution of protein, fat, and carbohydrates was not associ-
ated with any of the three nutritional and growth parameters [41].
The Australian Cystic Fibrosis Data Registry (ACFDR)-based
study by Ruseckaite et al. reported on the effects of implementing
the 2006 Australasian Clinical Practice Guidelines for Nutrition in
Cystic Fibrosis [51]. Nutritional data from two independent pediat-
ric-age cohorts (2 5 y and 6 11 y) were collected longitudinally
between 1998 and 2014 (8 y before and after the publication of the
guidelines) [51]. After adjusting for cofounders, there was a signifi-
cant increase in weight and height z-scores and zBMI in both age
cohorts following the implementation of the nutritional guidelines
in 2006, suggesting that implementing these guidelines in clinical
practice had a positive effect on nutritional status of patients with
CF [51].
Glycemic index of consumed carbohydrates also appears to affect
nutritional outcomes. In a randomized controlled, double-blind, par-
allel-group, single-center trial conducted in Iran, Gorji et al. com-
pared low-glycemic index, high-fat, high-calorie diet (HFCD;
macronutrient percentage as per the HFCD group, with carbohy-
drate source restricted to glycemic index <50) with HFCD diet (40%
fat, 20% protein, and 40% carbohydrate of any source regardless of
glycemic index). Forty-four pediatric patients (22 in each arm) were
included in the analysis. Both diets resulted in significant increases
in body weight over a 3-mo period; however, this was significantly
higher in the low-glycemic index, HFCD group [22].
Supplemental foods
In a crossover, U.S.-based, single-center study by Pitman et al.,
two types of ready-to-use, high-energy supplemental foods
resulted in small but statistically significant increases in zBMI and
weight [32]. However, this study was both small (N = 10) and
short-term (2 wk), so that no conclusions on the effects of supple-
mental foods could be drawn based on it.
A cross-sectional study in Spain identified oral nutritional sup-
plement (ONS) use in 13 (22%) of 59 included patients [49].
Patients using ONS had significantly lower BMI, although the pro-
portion of malnourished participants (fat-free mass index <17 kg/
m2 in males and <15 kg/m2 in females) was not significantly differ-
ent between users and non-users of ONS [49].
Probiotics
Probiotic/symbiotic supplementation was assessed in three pla-
cebo-controlled randomized controlled trials (RCTs) enrolling 31
to 95 pediatric patients with CF [17 19]. Two of the RCTs followed
a parallel-group design, one for 3 mo [18] and the other for 1 y
[17]. The final RCT was a crossover study, with probiotic and pla-
cebo administered for 4 mo each, separated by a washout period of
1 mo [19]. None of the three probiotic supplements improved
growth parameters. In the multicenter Italian study by Bruzzese
et al., BMI did not significantly differ between the study groups
after 12 mo of supplementation with Lactobacillus rhamnosus GG
or placebo [17]. Similarly, the single-center Brazilian study by de
Freitas et al. reported that 90 d of supplementations with Lactofos
(containing L. paracasei, L. rhamnosus, L. acidophilus, and Bifidobac-
terium lactis) did not result in improvements in WAZ, BAZ, or
height-for-age z-score (HAZ) relative to presupplementation base-
line, and the effect of probiotic supplementation on these
8 M. Mielus et al. / Nutrition 102 (2022) 111725
parameters was not statistically different from placebo [18].
Finally, the Belgian-based multicenter study by van Biervliet et al.
reported no significant differences in zBMI, weight or height z-
scores after 4 mo of supplementation with probiotics (containing L.
rhamnosus and B. animalis) or placebo [19].
Vitamin supplementation
The intake of various vitamins was assessed in two interven-
tional studies and eight observational studies.
Dietary intake of micronutrients, including vitamins, in patients
with CF was assessed in a cross-sectional study by Tham et al., who
reported on micronutrient intake in a pediatric CF population
treated at a single center in Australia [47]. Absolute intakes of all
assessed micronutrients apart from vitamin C and folate were sig-
nificantly higher in patients with CF than in non-CF controls [47].
Furthermore, for most micronutrients, the proportion of children
not meeting adequate intake was lower in patients with CF than in
controls [47].
Vitamin D intake was assessed by four studies, including three
observational studies [35,38,44] and an interventional study [26].
Two of the observational studies (one retrospective and one pro-
spective) [35,38] reported on the same cohort of 200 adults with
CF from a single center in Canada. The remaining observational
study, a retrospective cross-sectional study based in a single center
in Brazil, was small (N = 37) [44]. Vitamin D levels did not appear
to significantly associate with differences in BMI in any of the three
studies [35,38,44]. Similarly, in a prospective, interventional cohort
study conducted by Abu-Fraiha et al. in a single center in Israel,
vitamin D supplementation according to the CF Foundation guide-
lines resulted in only a very modest numerical increase in BMI
(from mean [SD] 19.40 [3.87] to mean [SD] 19.74 [3.83]) over a
median supplementation period of 16.28 mo; no P-values for the
change in BMI were reported [26].
Two studies assessed the effect of vitamin A intake on nutri-
tional status, identifying no clear associations [40,45]. A retrospec-
tive, single-center, observational study of 221 pediatric Dutch
patients with CF reported that vitamin A deficiency was rare and
median serum retinol values were within the reference age across
all age groups [40]. This study also reported WAZ, HAZ, and
weight-for-height z-score (WHZ) for the different pediatric age
groups, with the two former measures consistently <0 [40]. In a
Polish cross-sectional study of 196 patients with CF, those with
vitamin A deficiency and normal vitamin A status did not differ sig-
nificantly in terms of weight or height z-scores [45].
The role of intake of vitamins K and E was assessed in one study
each. A cross-sectional study of 79 Ukrainian patients with CF
employed two different measures of assessing vitamin K defi-
ciency: prothrombin concentration induced by vitamin K absence
(PIVKA-II) and undercarboxylated osteocalcin percentage (u-OC)
[42]. Weight z-score, but not height z-score, was significantly
lower in patients with abnormal PIVKA-II level [42]. However,
when u-OC was used to determine vitamin K status, patients with
normal, insufficient, and deficient u-OC levels did not differ signifi-
cantly in terms of weight or height z-scores [42]. Therefore, the
relationship between vitamin K status and anthropometric param-
eters depended on definition of vitamin K status used. In terms of
vitamin E status, a cross-sectional study of 211 Polish patients with
CF found that those with and without vitamin E deficiency did not
differ significantly in terms of weight and height z-scores [46].
Finally, Sagel et al. reported on a comparison of two multivita-
min preparations, based on a double-blind RCT conducted across
multiple centers in the United States [23]. There were no differen-
ces between the two groups in weight or BMI after 16 wk of
supplementation with antioxidant-enriched or standard multivita-
min and weight z-score changed little over the course of the study
in both groups [23].
PERT
A prospective, longitudinal, observational, multicenter study
reported on the effects of pancreatic (in)sufficiency on nutritional
status and found longitudinal patterns of weight and length
z-scores in infants with pancreatic insufficiency to be significantly
lower compared with infants with pancreatic sufficiency [36].
PERT itself was assessed in three observational studies
[33,37,52] and one RCT [24].
Of the three observational studies, two were U.S.-based, includ-
ing a large prospective, observational cohort study by Gelfond
et al. using the BONUS (The Baby Observational and Nutrition
Study) cohort [33] and a retrospective cohort study based on the
Cystic Fibrosis Registry [52]. The registry-based study by Schechter
et al. reported greater improvements in WAZ in infants receiving
higher PERT doses [52]. Conversely, Gelfond et al. reported that
12-mo weight z-scores were numerically lower in infants receiving
higher PERT doses, although this relationship did not reach statisti-
cal significance [33]. The authors concluded these results likely
represented indication bias, due to clinicians increasing PERT dos-
ing in patients with failing growth and not increasing it in those
growing well [33]. The final study on PERT was a small, retrospec-
tive, observational study, conducted at a single center in Spain that
reported stable BMI in a cohort of 16 children receiving individual-
ized PERT doses over a 12-mo period [37].
The relevant RCT was a double-blind, active-controlled, cross-
over, multinational, non-inferiority trial comparing two PERT prep-
arations, Zenpep and Kreon. Although non-inferiority and
equivalence of Zenpep to Kreon were demonstrated in this trial,
both PERT preparations resulted in a similar, modest increase in
body weight (least squares mean of 0.5 kg) over a 28-d period that
did not differ significantly between trial arms. P-values for change
from baseline were not reported [24].
Enteral tube feeding
Enteral tube feeding (ETF) was investigated in four observa-
tional studies, the largest of which was a Belgian Cystic Fibrosis
Registry-based, retrospective, longitudinal study enrolling 339
patients with CF (113 cases receiving ETF for a median of 2 y and
226 controls not receiving ETF; »70% of patients were pediatric)
[50]. Patients who progressed to receiving ETF had significantly
worse nutritional status than controls; this difference was evident
both at ETF initiation and earlier at first entry in the registry [50]. It
was also maintained at 3 y from ETF initiation [50]. Although zBMI
improved significantly after 3 y, there was no effect on height in
children [50].
The remaining four studies were smaller and included a pro-
spective, observational cohort study of 53 patients in Poland
receiving ETF [34], a retrospective observational study of 26
patients receiving ETF in a single center in the Netherlands [39],
and two retrospective case control studies: a U.S.-based, single-
center study including 20 patients who received ETF and 40 con-
trols who did not [53] and a Belgian study of 24 patients receiving
ETF and 18 age, sex, and pancreatic status-matched controls not
receiving ETF [54]. All four studies reported numerical increases in
body weight and/or BMI with ETF, although statistical significance
of these findings varied between the studies [34,39,53,54].
 M. Mielus et al. / Nutrition 102 (2022) 111725
Other supplements
Four interventional studies assessed various types of supple-
ments: choline [27], Glu [20], a readily absorbable structured lipid
[15], and DHA [21]. The study by Bernhard et al. was a small, inter-
ventional cohort study conducted in a single center in Germany
that investigated the effects of choline supplementation in adult
men with CF for a median of 84 d [27]. Weight and BMI were
within the normal range at the beginning of the study and did not
change during its course; however, statistical significance of these
findings was not reported [27]. Glu [20] and DHA [21] displayed no
difference versus placebo in terms of BMI or weight in double-
blind RCTs enrolling 60 and 87 patients, respectively. Similarly, the
change in weight, height, and BMI z-scores over 3 mo with the
readily absorbable lipid (Encala) was no different from the results
of the placebo group [15]. However, the identified study only
reported 3-mo data despite the total study duration being specified
as 12 mo [15]. Inspection of the original report from this trial [55]
also did not permit assessment of Encala effects on anthropometric
parameters over the full 12-mo study duration.
Other interventions
Two additional studies assessing unique types of interventions
were also identified. The first was a patient access scheme for an
immobilized lipase cartridge for extracorporeal digestion of enteral
feedings (RELiZORB), which aims to improve digestibility of enteral
feeds in patients with pancreatic insufficiency [30]. Significant
increases in weight, height,and weight z-score were reported
among 100 (mostly pediatric) included patients over 1 y of using
the device [30].
The final study was a double-blind, placebo-controlled, multi-
center, UK-based phase IIb RCT assessing nebulized gene therapy
over a period of 1 y [16]. Efficacy assessments focused primarily on
respiratory function, whereas weight and BMI were only included
as safety assessments [16]. No treatment-related differences in
weight or BMI were observed [16].
Discussion
This systematic review of available literature collects and sum-
marized recent evidence on nutrition in CF. The 40 identified stud-
ies provided evidence on specific nutritional interventions,
nutritional status, and holistic approaches to nutritional manage-
ment in CF.
European Society for Clinical Nutrition and Metabolism
(ESPEN); European Society for Paediatric Gastroenterology, Hepa-
tology, and Nutrition (ESPGHAN); and European Cystic Fibrosis
Society (ECFS) guidelines [5] and Australian and New Zealand
guidelines [10] on nutrition in CF both recommend regular assess-
ment of anthropometric parameters and nutritional markers, and
highlight the importance of patient or parent education about
nutrition. Similarly, the 2020 guidelines from the Academy of
Nutrition and Dietetics recommend that nutritional assessment
findings are translated into individualized patient education and
counseling, to obtain a personalized nutrition care plan [56].
Implementation of comprehensive individual nutritional plans
resulted in improvement of anthropometric parameters in three
studies [28,29,31] identified in our review. Technology such as
mobile apps could be employed to facilitate implementation of the
nutritional plan by the patient. Although the evidence identified in
this review did not conclusively support a positive effect linked to
using an app for CF nutritional management on anthropometric
parameters, there was an improvement in QoL [25].
9
A recent systematic review was not able to identify and associa-
tion between macronutrient distribution and BMI in adults [57]
and a similar lack of association between anthropometric parame-
ters and dietary contribution of protein, fat, and carbohydrates
was observed in a pediatric study [41] identified in this review.
However, evidence from a small RCT conducted by Gorji et al. sug-
gests that deriving the carbohydrate contribution from low glyce-
mic index sources enhances weight gain [22]. It would be of
interest to attempt to replicate these results in a larger, interna-
tional study enrolling a more diverse population to ascertain the
relative roles of glycemic index and carbohydrate quality in dietary
management.
Many studies identified in the review investigated probiotics
[17 19], vitamin supplementation [23,26,35,38,40,42,44 47], or
other supplements, including choline [27], Glu [20], a readily absorb-
able structured lipid [15], and DHA [21]. In general, none of these sup-
plements were associated with improvements in anthropometric
measures. This result is not surprising given that the primary aim of
probiotic supplementation is to restore normal intestinal microbiota
and thus potentially reduce inflammation within the gut, while vita-
min supplementation aims primarily to prevent and correct deficien-
cies. With regard to lipid and fatty acid supplements, CF is associated
with a dysregulation of fatty acid metabolism [58], so interventions
aiming to correct this may not necessarily readily translate into
improvements in anthropometric measures. However, outcomes per-
taining to vitamin deficiency status, gut function and lipid metabo-
lism were not assessed in this review.
A single study assessed the effects of gene therapy [16] and,
although the trial was not specifically focused on anthropometric
measures, no treatment-related differences in weight or BMI were
observed [16]. This is in stark contrast with CFTR modulators, for
which some positive effects on anthropometric measures were
noted in a recent systematic review, although these varied depend-
ing on the CFTR mutation present and the type of modulation ther-
apy used [6].
Identified evidence suggests that pancreatic insufficiency in
infants with CF is associated with hampered growth [36]. Replen-
ishment of pancreatic enzymes through PERT is the mainstay of
nutritional management in patients with CF and pancreatic insuffi-
ciency [5,10] and plays a key role in maintaining an adequate
nutritional status through facilitating the digestion and absorption
of nutrients. Best practices pertaining to PERT use have been
described in recent clinical guidelines on nutrition in CF [5;10].
The non-inferiority RTC by Taylor et al. identified in this review
compared two porcine PERT preparations formulated as enteric-
coated microspheres (Kreon and Zenpep) and determined their
equivalence [24]. The benefits of enteric-coated microsphere PERT
compared with enteric-coated tablets are well known [7]. A recent
Cochrane review reported beneficial bowel-related outcomes with
enteric coated microspheres when compared with enteric-coated
tablets (and non enteric coated pancreatic enzyme prepara-
tions); however, limitations to the evidence included small
study size and risk of bias [59]. Another Cochrane review is
planned to assess the effects of different PERT regimens
(including dose and administration timing) on clinical out-
comes in patients with CF [60] and its publication may help to
further optimize PERT use. Another avenue of research on PERT
is the identification of non-porcine enzyme sources, which may
be preferred in patients with allergies or those abstaining from
pork-derived products for religious reasons. Both ongoing trials
identified in this review assessed liprotamase, a non-porcine
biotechnology-derived PERT. The development of this product
was, however, discontinued as its phase III trial failed to meet
its primary end point.
10 M. Mielus et al. / Nutrition 102 (2022) 111725
Another notable intervention examined in the identified
studies was ETF. ETF is recommended in patients who remain
persistently undernourished despite less invasive nutritional
interventions [5]. All studies examining ETF that were identi-
fied in this review were observational; the largest reported a
sustained increase in BMI in Belgian Cystic Fibrosis Registry
patients receiving ETF [50]. Indeed, a recent Cochrane review
identified no RCTs of ETF, likely due to the ethical challenges of
withholding this intervention in patients who need it [61].
Despite this limitation of available evidence, comprehensive
guidelines on ETF are available from the Cystic Fibrosis Founda-
tion [62].
Limitations of the current review include a lack of formal
assessment risk of bias in included studies, involvement of a
single reviewer, and limiting the searches to the PubMed data-
base. The outcomes of interest were restricted to include only
anthropometric measures, which are readily measurable and
routinely used across different health systems. Although body
composition (fat versus muscle mass) would also be of interest
to the review, as fat-free mass has been reported to correlate
with respiratory function in patients with CF [63], there is no
standardized way to measure body composition, limiting com-
parisons across studies and making the data potentially difficult
to interpret. Therefore, we refrained from collecting data on
body composition. The evidence collected in this systematic
review varied substantially in terms of study design and appar-
ent quality as well as geographic location, resulting in different
populations and health systems being captured, which should
be considered when making any comparisons between the dif-
ferent studies identified. In general, few RCTs were identified,
and those captured were often small. Although ethical consid-
erations may prohibit the conduct of RCTs assessing ETF, there
is a need for comprehensive, high-quality evidence on a num-
ber of other common nutritional interventions in CF, such as
optimizing PERT and the role of supplemental foods in ensuring
adequate nutrition. Another important consideration, particu-
larly when interpreting the real-world, observational studies
identified, is the potential for confounding. Nutrition is a com-
plex area and nutritional status may be affected by several fac-
tors that are difficult to adjust for. Examples include poor
adherence to therapeutic recommendations where there is high
treatment burden and low socioeconomic status, which are
known risk factors for poor clinical outcomes in CF [64]. Fur-
thermore, CF affects multiple organ systems, and its manifesta-
tions may vary between individuals, making it difficult to
firmly establish relationships between specific nutritional inter-
ventions and nutritional status. Currently available guidelines
offer direction in establishing appropriate nutritional care for
patients with CF, and implementation of guidelines is associ-
ated with long-term improvements in nutritional status of
these patients [51]. However, nutritional care and its goals
should be individualized and regularly reviewed, to ensure
they continue to optimally fit the patient’s needs.
Conclusion
This systematic review of recent studies assessing nutritional
interventions in patients with CF confirmed the benefits of com-
prehensive, individualized nutritional plans, HFCD diet including
high-quality carbohydrates, and ETF. No evidence has been identi-
fied to support a significant positive effect on anthropometric
measures of the supplementation of probiotics, lipids, DHA, Glu, or
antioxidant-enriched multivitamin.
Acknowledgments
The authors acknowledge Karolina Badora of Proper Medical
Writing sp. z o. o. for editorial assistance in the preparation of this
manuscript.
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