RESEARCH ARTICLE

Abdominal symptoms in cystic fibrosis and

their relation to genotype, history, clinical and
laboratory findings
Harold Tabori1, Christin Arnold1☯, Anke Jaudszus1, Hans-Joachim Mentzel2, Diane
M. Renz2, Steffen Reinsch3, Michael Lorenz1, Ruth Michl1, Andrea Gerber1,
Thomas Lehmann4, Jochen G. Mainz1☯*
1 Jena University Hospital, Cystic Fibrosis Center, Jena, Germany, 2 Jena University Hospital, Pediatric
Radiology, Jena, Germany, 3 Jena University Hospital, Pediatric Gastroenterology, Jena, Germany, 4 Jena
a1111111111 University Hospital, Institute of Medical Statistics, Jena, Germany
a1111111111
a1111111111 ☯ These authors contributed equally to this work.
* [email protected]
a1111111111
a1111111111

Abstract

OPEN ACCESS
Background & aims
Citation: Tabori H, Arnold C, Jaudszus A, Mentzel
H-J, Renz DM, Reinsch S, et al. (2017) Abdominal Abdominal symptoms (AS) are a hallmark of the multiorgan-disease cystic fibrosis (CF).
symptoms in cystic fibrosis and their relation to However, the abdominal involvement in CF is insufficiently understood and, compared to
genotype, history, clinical and laboratory findings. the pulmonary manifestation, still receives little scientific attention. Aims were to assess and
PLoS ONE 12(5): e0174463. https://doi.org/
quantify AS and to relate them to laboratory parameters, clinical findings, and medical
10.1371/journal.pone.0174463
history.
Editor: Philipp Latzin, University Children’s Hospital
Bern, SWITZERLAND

Received: August 16, 2016 Methods

Accepted: March 9, 2017 A total of 131 patients with CF of all ages were assessed with a new CF-specific question-
naire (JenAbdomen-CF score 1.0) on abdominal pain and non-pain symptoms, disorders of
Published: May 4, 2017
appetite, eating, and bowel movements as well as symptom-related quality of life. Results
Copyright: © 2017 Tabori et al. This is an open
were metrically dimensioned and related to abdominal manifestations, history of surgery,
access article distributed under the terms of the
Creative Commons Attribution License, which P. aeruginosa and S. aureus colonization, genotype, liver enzymes, antibiotic therapy, lung
permits unrestricted use, distribution, and function, and nutritional status.
reproduction in any medium, provided the original
author and source are credited.

Data Availability Statement: All relevant data are Results

within the paper and its Supporting Information AS during the preceding 3 months were reported by all of our patients. Most common were
files.
lack of appetite (130/131) and loss of taste (119/131) followed by abdominal pain (104/131),
Funding: This research was supported by the flatulence (102/131), and distention (83/131). Significantly increased AS were found in
German Academic Exchange Service (DAAD,
patients with history of rectal prolapse (p = 0.013), distal intestinal obstruction syndrome
Grant: 57130097) to HT. The funder had no role in
study design, data collection and analysis, decision (p = 0.013), laparotomy (p = 0.022), meconium ileus (p = 0.037), pancreas insufficiency
to publish, or preparation of the manuscript. (p = 0.042), or small bowel resection (p = 0.048) as well as in patients who have been intermit-
Competing interests: The authors have declared tently colonized with P. aeruginosa (p = 0.006) compared to patients without history of these
that no competing interests exist. events. In contrast, no statistically significant associations were found to CF-associated liver

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Abbreviations: CFTR, cystic fibrosis disease, chronic pathogen colonization, lung function, CF-related diabetes, and nutritional
transmembrane (conductance) regulator; CF, status.
cystic fibrosis; GI, gastrointestinal; PI, pancreatic
insufficiency; PS, pancreatic sufficiency; DIOS,
distal intestinal obstruction syndrome; MI, Conclusion
meconium ileus; CFLD, CF-associated liver disease; As the complex abdominal involvement in CF is still not fully understood, the assessment of
CFRD, CF-related diabetes; RP, rectal prolapse;
the common AS is of major interest. In this regard, symptom questionnaires like the herein
PIP, pancreatic insufficiency prevalence; SA,
Staphylococcus aureus; PsA, Pseudomonas presented are meaningful and practical tools facilitating a wider understanding of the
aeruginosa; Wtp, weight percentile; Htp, height abdominal symptoms in CF. Furthermore, they render to evaluate possible abdominal
percentile; BMIp, body mass index percentile; LFT,
effects of novel modulators of the underlying cystic fibrosis transmembrane (conductance)
liver function test; ALT, alanine aminotransferase;
AST, aspartate aminotransferase; GGT, gamma regulator (CFTR) defect.
glutamyl transferase; VAS, visual analogue scale;
HRQoL, health related quality of life; ULN, Upper
limit of normal.

Introduction
Cystic fibrosis (CF) is the most common life threatening autosomal recessive disorder caused
by mutations in the cystic fibrosis transmembrane (conductance) regulator (CFTR) gene. The
CFTR protein, which is essential in the regulation of chloride and sodium transport in epithe-
lial cells [1], is highly expressed on the apical surface of intestinal epithelial cells, pancreatic
ductal cells, and cholangiocytes in bile ducts which in the healthy transport ions, bicarbonate
and fluid to the organs’ lumen [2]. Thus, CFTR dysfunction results in viscous luminal secre-
tions obstructing the bile and pancreatic ducts as well as the intestine [3]. The resulting gastro-
intestinal (GI) manifestations include pancreatic insufficiency (PI), meconium ileus (MI),
distal intestinal obstruction syndrome (DIOS), and biliary tract complications which can lead
to cirrhosis and hepatic failure [4]. Typical resulting GI symptoms are frequent and volumi-
nous greasy stools, flatulence, abdominal bloating, constipation, abdominal pain, an impaired
nutritional status, as well as failure to thrive. Even though GI symptoms are a hallmark of CF
[5–7], often leading to diagnosis of the inherited disease, they are still insufficiently understood
for why deeper investigations into the abdominal involvement in CF are needed [2]. Moreover,
with enhanced survival due to improved therapeutic options and patient management, comor-
bidities of the GI, hepatobiliary, and pancreatic tract are of increasing clinical and scientific
interest. However, because of the complex interaction of a variety of dysfunctioning organs,
medicinal effects, and even psychosocial factors (Fig 1), the differentiation of the multitude of
abdominal symptoms constitutes a major challenge.
Interestingly, previous studies assessing the general symptom of pain in CF indicate that its
most common location was the abdomen [8–11]. Nevertheless, most of these studies did not
differentiate abdominal pain e.g. regarding frequency, intensity and location, and thus failed
to specify the origin of GI symptomatology and its clinical associations. In a recent systematic
review, 16 studies investigating pain in CF were evaluated [12]. Eight of them reported occur-
rences of abdominal pain in CF, with a high variance ranging between 21% and 60% of the
assessed CF patients, while only few studies measured pain intensity. This mostly was not spe-
cific for the abdominal region and based on single items scales (e.g. a numerical rating scale).
It has been recognized that abdominal symptoms relevantly impair health related quality of
life (HRQoL) by affecting CF patients’ daily activities as well as their emotional, social and
physical functioning [13]. Yet, only one study focused on reporting prevalence of recurrent
abdominal pain in CF [14].
Recent developments of small molecules that potentiate or correct defective CFTR protein
function entail a need to assess changes in abdominal involvement by the new systemic

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Fig 1. Multifactorial causes of abdominal symptoms in CF. CFLD–CF-associated liver disease, CFRD–CF-related diabetes, DIOS–distal intestinal
obstruction syndrome, GERD–gastroesophageal reflux disease, MI–meconium ileus, PI–pancreatic insufficiency.
https://doi.org/10.1371/journal.pone.0174463.g001

treatment. Most interestingly, in some mutations (e.g. G551D) CFTR modulators even allow
restoration of pancreatic function in some patients [15,16] and they procured a trend towards
normalization of sweat tests [17,18]. Besides outcome measures acquired by laboratory, radio-
logical and electrophysiological methods, the Food and Drug Administration (FDA) encour-
ages the usage of patient reported outcome measures (PROM) such as symptom
questionnaires as supportive tools or even endpoint measures in clinical trials and offers guid-
ance for their development [19].
Aim of the present study was to obtain structured and detailed information on GI involve-
ment and symptoms with a new pilot score specifically designed for assessment of abdominal
involvement in CF patients (JenAbdomen-CF Score 1.0) and relate results to clinical and labo-
ratory findings, history, and CFTR genotype.

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Materials and methods

Ethical statement
This study has been conducted in strict accordance with the ethical guidelines in the Declara-
tion of Helsinki and it was approved by the Jena University ethics committee (registration
number 4458-06/15). All patients aged 18 y and parents of minors provided written
informed consent.

Patients
The prospective study was performed including CF patients of all ages at the Jena University
Hospital CF Center. Inclusion criteria were: (1) a diagnosis of CF determined by a sweat chlo-
ride of >60 mEq/L and/or (2) detection of 2 disease causing CFTR mutations with evidence of
organ involvement.

Evaluation of the score

The novel JenAbdomen-CF Score 1.0 was designed considering the recommendations given
by the FDA for development of a PROM [19] including in-depth interviews with patients, lit-
erature reviews, and physician expert opinions. During routine presentation in our outpatient
clinic, patients and/or the guardians completed a questionnaire consisting of 17 items (Fig 2,
S1 Table) to measure the GI symptoms during the previous three months grouped into the fol-
lowing four domains:
1. abdominal pain,
2. non-pain symptoms,
3. subjective evaluation of the feces’ frequency, form and color, and
4. disorders of eating and appetite.

1. The abdominal pain domain consists of three items which assess frequency, intensity, and
duration of abdominal pain. In addition, one item regarding the intensity of pain during
bowel movements was evaluated. Pain frequency was measured using a Likert-type scale
[20], with six response options ranging from ‘never´ (0pts) to ‘daily´ (5pts). Pain intensity
was assessed using a well-validated Visual Analogue Scale (VAS) [21], which consists of an
11-point scale ranging from 0 to 10 with a series of six emotion expressing faces anchored
at either end by ‘no pain´ (0pts) to ‘worst pain ever´ (5pts; 2 VAS steps each). The duration
of experienced abdominal pain was assessed by offering six options ranging from ‘0 min-
utes´ (0pts) to ‘more than 360 minutes´ (5pts). In addition, we asked for the location, aggra-
vating and alleviating factors, coping strategies, radiation, onset and quality of abdominal
pain. Location of the abdominal pain was marked on a well-validated body outline adapted
from Savedra et al. [22] displaying an anterior and posterior view of the abdomen. Coding
of body location was conducted using the nine quadrants of abdomen including: hypo-
chondriac (right and left); epigastric; lumbar (right and left); umbilical; iliac (right and left)
and hypogastric regions. Cut-off points for mild (VAS <3), moderate (VAS 3–5) and severe
(VAS 5) abdominal pain was given according to Kainzwaldner et al. [23].
2. The non-pain symptoms consist of 8 items which include flatulence, abdominal distention,
constipation, nausea, vomiting, heartburn, fatty stools, and reflux of stomach content. Each
symptom was measured with a 6-point rating scale anchored at either end by ‘not at all´

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Fig 2. Pain and non-pain symptoms of the JenAbdomen-CF Score 1.0. *to some extend additionally related to pain symptoms.
https://doi.org/10.1371/journal.pone.0174463.g002

(0pts) to ‘always´ (5pts) at the other end, except for fatty stools that was assessed by a binary
response: ‘no´ (0pts) and ‘yes´ (5pts).
3. The consistency of stool (one item) was evaluated using an adaptation of the well-validated
Bristol Stool Form Scale [24,25] classified into seven types (type 1–2 = hard; type 3–4 = formed;
type 5–7 = soft). Zero points were given for this item by a formed stool consistency; 1 point
for a hard stool consistency; 3 points for both hard and soft stool consistency and 5 points for
a soft stool consistency. The patient’s stool color (one item) was assessed using a modified
Stool Color Card for the screening of biliary atresia by addition of five from brown to black,
tarry stool colors adapted from Gu et al. [26] with 12 consecutive pictures ranging from pale

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

to tarry stools (1–3 = pale; 4–11 = normal; 12 = tarry). For this scoring, 0 points were given
for a normal color, 5 points for a pale color and 3 points for a tarry color.
4. Disorders of eating and appetite were assessed questioning the following three items: lack
of appetite, loss of taste, and need for a forced feeding (by the patient himself or by others).
The first two items were measured on a 6-point rating scale anchored at either end by ‘not
at all´ (0pts) to ‘always´ (5pts), respectively. The last item was evaluated by a binary
response: ‘no´ (0pts) and ‘yes´ (5pts). A total of 17 items were evaluated so that the sum of
obtained points could range from 0 to 85 points with higher rates for increasing severity of
GI symptoms. Abdomen scores were compared with each other and gastrointestinal CF
manifestations, history of surgery, the nutritional status, CFTR genotype, liver function test
(LFT) including alanine aminotransferase (ALT), aspartate aminotransferase (AST),
gamma-glutamyl transpeptidase (GGT), total bilirubin (BIL), and alkaline phosphatase
(ALP), adherence to pancreas enzyme intake (self-reported), antibiotic therapy, weight
(ΔWtP), height (ΔHtP) and BMI (ΔBMIP) percentiles changes in the previous 3, 12, and 24
months for patients <18 yrs and ΔBMI in the previous 3, 12, and 24 months in adults, lung
function including FEV1%, and airway colonization with P. aeruginosa (PsA) and/or S.
aureus (SA).

Classification of CFTR genotype

The recently established pancreatic insufficiency prevalence (PIP) scores [27] were used to
measure the severity of specific CFTR mutations in regard to pancreatic function. The PIP
score is calculated as the proportion of PI among all patients (PI and non-PI) carrying the
same CF-causing mutation in a homozygous or in a heterozygous state, in the latter case con-
sidering the lower PIP value for both alleles. The term ‘genotype´ therefore refers to the combi-
nation of CFTR mutations on both alleles, accounting for the milder of both alleles for
characterization of the PIP score [28]. According to the Canadian Consortium for CF Genetic
Studies (CCCFGS), CF mutations are classified as ‘mild´ regarding pancreatic involvement
when PIP is 0.25 and as ‘moderate-severe´ when PIP is >0.25. The patients carrying at least
one mutation not reported from Ooi that could not be attributed to a specific PIP score were
excluded from the genotype analysis (15/131 patients in the Jena CF center).

Measures of clinical data

Demographic, clinical, and laboratory data were obtained from the charts. Nutritional failure
was defined according to the 2002 Cystic Fibrosis Foundation (CFF) criteria [29]. Specifically,
weight-for-height percentile (WHp) <10th for ages 0–2 y, or body mass index percentile
(BMIp) <10th for ages 2–20 y were used to identify underweight. BMI was calculated as
[weight in kilograms/(height in meters)2]. Age- and gender-specific percentiles for BMI
(BMIp), weight (Wtp) and height (Htp) were classified according to the longitudinal local
anthropomorphic data from Jena obtained by Krohmeyer-Hauschild [30]. Changes in Wtp,
Htp and BMIp were calculated by subtracting baseline from values in the previous 3, 12, and
24 months, thus a negative value corresponded to a decrease in Wtp, Htp, and BMIp and a
positive value to an increase of those. A potentially clinically significant (PCS) LFT elevation
was defined as ALT/AST/GGT >3× upper limit of normal (ULN) or BIL/ALP >2× ULN. CF-
associated liver disease (CFLD) was defined according to recently published guidelines for the
diagnosis and management of CFLD [31]. Pulmonary disease severity was divided into three
groups accounting FEV1 70 percent of predicted (pp) as ‘mild´ disease, FEV1 40–69 pp as
‘moderate´ disease, and FEV1 39 pp as ‘severely advanced´ lung disease. This established

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

classification has been adopted internationally as a categorization of disease severity for CF

[32–34]. Status of PsA and SA colonization were defined according to Leeds criteria [35].

Data analysis
Statistical analyses were performed with SPSS, Version 23.0 (IBM Corp. 2015, Version 23.0.
Inc., Armonk, NY, USA). Normal distribution of the data was tested using the Kolmogorov-
Smirnov (K-S) test. Parametric tests were used to compare means between two independent
samples (two-tailed Student t-Test) or more than two groups (ANOVA), when the samples
were normally distributed. When criteria for normal distribution were not met, nonparametric
tests were chosen to detect statistical difference in means of two independent samples (Mann-
Whitney U test) or more than two groups (Kruskal-Wallis test). Nominal data were compared
with Chi-square test or Fisher’s exact tests, as appropriate. Correlations between variables were
examined using the Pearson’s correlation coefficient, the Spearman’s rank correlation coeffi-
cient and the mean square contingency coefficient, as appropriate. Data are given as
means ± SD. A p-value 0.05 indicated a significant difference or correlation.

Results
Baseline characteristics of the total study cohort
Between April 2015 and December 2015 a total of 131 CF patients attended in the Jena Univer-
sity CF center were included into the prospective study. The mean age was 19.1±14.2 years.
Mean FEV1 was 84%predicted and 31 patients (24%) had CF-related diabetes, of whom 14
(45%) were insulin dependent. CF diagnosis most frequently was established on the basis of
either predominant GI or respiratory symptoms, whereby 24% of the patients presented a
combination of symptoms. CFTR gene mutations were identified on both alleles in all patients.
The most common CFTR mutation in the German population, F508del, was detected in 117/
131 (89%) of the included CF patients, with 56 (43%) being homozygous for this CFTR defect.
G551D was detected in 17 patients (13%). Further characteristics of CF patients are presented
in Table 1 and in S1 Table.

JenAbdomen-CF Score 1.0

Abdominal symptoms. Abdominal symptoms during the previous three months were
reported from all CF patients. Most common were lack of appetite (99%) and loss of taste
(91%; Table 2) followed by abdominal pain (79%), flatulence (78%), and abdominal distention
(63%; Fig 3A, Table 2). Interestingly, children reported to have more abdominal pain than
adults (87% vs. 70%; p = 0.022), while adults more frequently reported abdominal distention
(79% vs. 51%; p = 0.001) and heartburn (61% vs. 22%; p<0.001; Fig 3B). 11% of patients admit-
ted they forgot to take pancreas enzyme at least once a week. These patients did not report sig-
nificantly more GI symptoms than patients who had good adherence to treatment (21.7 vs.
19.6 score points; p = 0.280).
Abdominal pain. The most frequent locations of abdominal pain were the umbilical
(83%) and epigastric regions (11%), and 8% of patients reported a radiation of pain to the dor-
sum (Fig 4). More than one pain location was reported by 28%. Pain intensity on the visual
analogue scale (VAS) resulted in a mean of 3.4 of maximally 10 points (SD: 2.3). Of these
patients, 7% had mild- (VAS: 1-3pts), 43% moderate- (VAS: 4-5pts), and 30% severe pain
(VAS: 5pts). Thereby, 34% reported a frequency of abdominal pain occurring ‘at least once a
week´ (Table 3). Most common quality of abdominal pain experienced were ‘pulling´ (42%),
‘colicky´ (41%) and ‘sharp´ (28%). 49% of patients described abdominal pain lasting ‘less than

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Table 1. Patient characteristics.

Variable Frequency (n = 131)
Gender
Male 58/131 (44.3%)
Female 73/131 (55.7%)
CFTR genotype
F508del/ F508del 56/131 (42.7%)
F508del/ other 61/131 (46.6%)
G551D/ other 17/131 (13.0%)
ther/ other 14/131 (10.7%)
Age (y)
0–5 23/131 (17.6%)
6–11 27/131 (20.6%)
12–17 24/131 (18.3%)
18 57/131 (43.5%)
Nutritional status (<18 yrs.)
Underweight 6/74 (8.1%)
Short stature 2/74 (2.7%)
P. aeruginosa (PsA): chronic 41/129 (31.3%)
P. aeruginosa (PsA): intermittent 16/129 (12.2%)
Antibiotic therapy
Intravenous therapy 27/131 (20.6%)
Oral therapy 85/131 (64.9%)
Inhaled therapy 55/131 (42.0%)
Abdominal surgeries
Laparotomy 17/131 (13.0%)
Small bowel resection 12/131 (9.2%)
Appendectomy 12/131 (9.2%)
Elevated liver function test (LFT) 90/129 (69.8%)
CF abdominal manifestations
Exocrine pancreatic insufficiency (PI) 121/131 (92.4%)
PIP score ‘mild´ 4/116 (3.4%)
PIP score ‘moderate-severe´ 112/116 (96.6%)
Meconium ileus (MI) 12/131 (9.2%)
Distal intestinal obstruction syndrom (DIOS) 11/131 (8.4%)
Rectal prolapse 14/131 (10.7%)
CF-associated liver disease (CFLD) 25/122 (20.5%)
CF-related diabetes (CFRD) 31/131 (23.7%)
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45 minutes´ and a small subgroup of patients (8%) lasting ‘five hours´ or ‘longer´. It appeared
more frequently ‘during meals´ (35%), ‘before bowel movements´ (34%), and ‘during stressful
events´ (12%). Interestingly, a small subgroup of patients (3%) reported that pain is relieved
‘after antibiotics administration´ and 10% reported amelioration by ‘bowel movements´.
The percentage of missing item responses on the abdomen score was 4.8%. Abdomen
scores were non-normally distributed (different sizes of subgroups, e.g., PI and PS) with a
mean/median (range) of 19.3/18.0 (3–46). Altogether, female patients revealed slightly higher
abdomen scores than males (20.4 vs. 18.0; p = 0.139). Moreover, no significant difference was
observed among age subgroups (<18 y: 19.7 vs. 18 y: 18.9; p = 0.385). In contrast, signifi-
cantly increased AS were found in patients with history of rectal prolapse (p = 0.013), distal

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Table 2. Frequency of abdominal symptoms in patients with CF.

Abdominal symptoms (Item) Responded Reported symptoma [n] Mean symptom scoreb (SEM)
[%]
Lack of appetite 99.2 130 2.1 (0.1)
Loss of taste 90.8 119 1.6 (0.1)
Abdominal pain 100 104 −− c
Flatulence 95.4 102 2.6 (0.1)
Abdominal distention 81.7 83 1.9 (0.1)
Pain during bowel movements 96.2 58 1.5 (0.1)
Fatty stools 97.0 57 −− d
Soft and hard stool consistency 98.5 54 −− e
Heartburn 92.4 51 1.9 (0.1)
Reflux of stomach content 94.7 49 1.6 (0.1)
Nausea 99.2 48 1.4 (0.1)
Constipation 95.4 40 1.7 (0.1)
Vomiting 99.2 32 1.3 (0.1)
Forced feeding 99.2 20 −− d
Soft stool consistency 98.5 12 −− e
Pale stool 98.5 6 −− f
Hard stool consistency 98.5 2 −− e
Tarry stool 98.5 2 −− f
a
Item scale ‘1–5´ (anything but ‘0´)
b
within the respective item (item scale ‘1–5´)
c
response type: Likert
d
binary response type
e
Bristol Stool Form Scale
f
Stool Card Color

https://doi.org/10.1371/journal.pone.0174463.t002

intestinal obstruction syndrome (p = 0.013), laparotomy (p = 0.022), meconium ileus

(p = 0.037), pancreatic insufficiency (p = 0.042), or small bowel resection (p = 0.048) as well as
in patients who have been intermittently colonized with PsA (p = 0.006) compared to patients
without history of these events (Fig 5). For appendectomy, a strong trend was seen (p = 0.053;
Fig 5).
CFTR genotype. Patients who carry mild genotypes (PIP score 0.25) had significantly
lower rates for GI symptoms compared to those with severe mutations (PIP score >0.25) (11.0
vs. 19.6; p = 0.042). In addition, patients with a G551D mutation on at least one allele had sig-
nificantly lower JenAbdomen-CF Scores 1.0 compared to patients without this mutation (15.6
vs. 19.9; p = 0.020). Of these patients, 59% (10/17) were treated with ivacaftor (Fig 6).
CF-associated liver disease (CFLD). A total of 122 (93%) patients were assessed for a
diagnosis of CFLD. Patients who underwent liver transplantation (n = 2) or had <2 consecu-
tive examinations spanning a 1-year period (n = 7) were excluded from the evaluation of a
liver disease. Twenty-five of 122 patients (21%) met the criteria for CFLD and seven of these
had liver cirrhosis (6% of all included patients). There were no significant differences between
CFLD patients and those without liver involvement concerning the JenAbdomen-CF Score 1.0
(18.3 vs. 19.8; p = 0.487). Interestingly, JenAbdomen-CF Score 1.0 did not differ significantly
between non-cirrhotic CFLD individuals and CF patients without liver involvement (17.9 vs.
19.8; p = 0.462). Even in cirrhotic CFLD individuals, JenAbdomen-CF Score 1.0 did not reveal

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Fig 3. Abdominal symptoms in patients with CF. Frequencies of abdominal symptoms in CF patients of all ages (Fig 3a) and in children compared with
adults (Fig 3b). N.d.–not determined (missing data).
https://doi.org/10.1371/journal.pone.0174463.g003

a significant difference when compared to patients without liver involvement (20.0 vs. 19.8;
p = 833).
Liver enzymes in serum. Of the 131 patients, 129 were tested for liver enzymes in the past
three months. A total of 90/129 participants (70%) had at least one elevation above the ULN
and 14% (18/129) presented elevations of LFT considered as PCS. There was no statistically
significant difference in mean JenAbdomen-CF Scores 1.0 between patients with and without
elevated LFT (19.6 vs. 18.9; p = 0.699). Similarly, there was no difference between LFT consid-
ered as PCS and those without PCS consideration (19.6 vs. 19.3; p = 0.897).
Nutritional status. No significant differences in JenAbdomen-CF Score 1.0 were
observed between CF patients with a reduced (nutritional failure) and stable nutritional status.

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Fig 4. Location of abdominal pain in patients with CF.

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Additionally, there were no significant differences in JenAbdomen-CF Score 1.0 between neg-
ative and positive changes in Wt, Ht and BMI in the previous 3, 12, and 24 months (data not
shown).
Lung function. Patients with ‘severe´ lung disease showed slightly decreased scores com-
pared to patients with ‘moderate´ lung disease (17.2 vs. 19.7; p = 0.360) and ‘mild´ lung disease
(17.2 vs. 19.5; p = 0.402).
Antibiotics. Of all included patients, 97 (75%) were treated with oral, intravenous, or
inhaled antibiotics during the past three months. Average JenAbdomen-CF Scores 1.0 were
slightly higher in children who received any antibiotics therapy compared with adults treated
with antibiotics (20.5 vs. 18.9; p = 0.175). Among all patients who received antibiotics, patients
treated with ciprofloxacin and/or meropenem tended to score higher than patients treated
with any other antibiotics (23.3 vs. 19.0; p = 0.085).

Discussion
Although GI involvement is a hallmark of CF, until now it received comparatively little clinical
and, even less, scientific attention. To our best knowledge, GI symptoms in CF as a multiorgan
manifestation have not yet been systematically quantified. Here, we present data of a new ques-
tionnaire assessing the complexity of GI symptoms from 131 CF patients of all ages; the ques-
tionnaire prospectively shall be elaborated to a standardized and validated abdominal CF
score, considering the FDA guidelines [19]. Additionally, quantified symptoms were related to
phenotypic characteristics and to laboratory findings. The JenAbdomen-CF Score 1.0

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Table 3. Abdominal pain characteristics.

Characteristic Total (n = 131) Children (n = 74) Adults (n = 57)
Intensity (VAS) 3.4 ± 2.3 3.7 ± 2.1 3.1 ± 2.5
Frequency
Never 27/131 (20.6%) 10/74 (13.5%) 17/57 (29.8%)
Ca. once a month 59/131 (45.0%) 29/74 (39.2%) 30/57 (52.6%)
Ca. once a week 25/131 (19.1%) 21/74 (28.4%) 4/57 (7.0%)
Each 2–4 days 9/131 (6.9%) 6/74 (8.1%) 3/57 (5.3%)
Almost daily 9/131 (6.9%) 6/74 (8.1%) 3/57 (5.3%)
Daily 2/131 (1.5%) 2/74 (2.7%) 0/57 (0.0%)
Location
Umbilical 77/93 (82.8%) 48/54 (88.9%) 29/39 (74.4%)
Right hypochondriac 2/93 (2.2%) 1/54 (1.9%) 1/39 (2.6%)
Epigastric 10/93 (10.8%) 6/54 (11.1%) 4/39 (10.3%)
Left hypochondriac 2/93 (2.2%) 1/54 (1.9%) 1/39 (2.6%)
Left lumbar 9/93 (9.7%) 4/54 (7.4%) 5/39 (12.8%)
Right lumbar 9/93 (9.7%) 1/54 (1.9%) 8/39 (20.5%)
Left iliac 3/93 (3.2%) 0/54 (0.0%) 3/39 (7.7%)
Hypogastric 9/93 (9.7%) 3/54 (5.6%) 6/39 (15.4%)
Right iliac 9/93 (9.7%) 2/54 (3.7%) 7/39 (17.9%)
Quality
Pulling 35/83 (42.2%) 19/44 (43.2%) 16/39 (41.0%)
Colicky 34/83 (41.0%) 17/44 (38.6%) 17/39 (43.6%)
Sharp 23/83 (27.7%) 11/44 (25.0%) 12/39 (30.8%)
Burning 4/83 (4.8%) 1/44 (2.3%) 3/39 (7.7%)
Pressing 3/83 (3.6%) 2/44 (4.5%) 1/39 (2.6%)
Crampy 2/83 (2.4%) 1/44 (2.3%) 1/39 (2.6%)
Duration (min)
0 26/108 (24.1%) 10/58 (17.2%) 16/50 (32.0%)
<45 53/108 (49.1%) 37/58 (63.8%) 16/50 (32.0%)
45–90 6/108 (5.6%) 4/58 (6.9%) 2/50 (4.0%)
91–180 11/108 (10.2%) 2/58 (3.4%) 9/50 (18.0%)
181–360 3/108 (2.8%) 2/58 (3.4%) 1/50 (2.0%)
>360 9/108 (8.3%) 3/58 (5.2%) 6/50 (12.0%)
Onset
Suddenly 50/81 (61.7%) 27/44 (61.4%) 23/37 (62.2%)
Progressively 31/81 (38.3%) 17/44 (38.6%) 14/37 (37.8%)
Radiation to dorsum 7/90 (7.7%) 5/52 (9.6%) 2/38 (5.3%)

VAS: visual analogue scale

https://doi.org/10.1371/journal.pone.0174463.t003

questionnaire is a simple but meaningful two-page instrument capable to detect differences

between several CF phenotypic characteristics, as shown within this publication. For purposes
of monitoring, it can quickly and therefore routinely filled-in at on-site visits. In clinical trials,
it can be implemented as an additional easy and inexpensive tool of, however, high relevance.
First of all, our study showed that all included CF patients presented at least one abdominal
symptom within the preceding three months. A high prevalence rate of GI symptoms in 60%
of 70 CF patients has also been reported in a recent survey by Fraquelli et al. [36]. This study,
however, considered a lower number of items for the evaluation of the GI symptoms (7 items,

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Fig 5. JenAbdomen-CF Score 1.0 of patients presenting indicated abdominal manifestations and complications of surgery in comparison with
patients without history of these events (Ø). Int PsA–intermittently colonized with P. aeruginosa, chr PsA–chronically colonized with P. aeruginosa.
Means ± SEM.
https://doi.org/10.1371/journal.pone.0174463.g005

compared to 17 items in the JenAbdomen-CF Score 1.0) what might explain the difference in
the prevalence rates. Nevertheless, high prevalence rates of GI symptoms are known to be rep-
resentative in CF. For reasons of comparison, clear distinction, and specification, age-matched
healthy controls should be included in future research on CF-related GI symptoms using the
questionnaire.
In our study, around one-third (34%) of CF patients experienced at least one episode of
abdominal pain per week with a small subgroup suffering ‘almost always´ (7%) and ‘always´
(2%) from the relevant symptom. By comparison, Munck et al. [14] reported a very low preva-
lence of recurrent abdominal pain (RAP) of 6%, yet using the more strict Apley’s criteria (at
least three bouts of pain, severe enough to affect one´s activities, over a period of not less than
three months, with attacks continuing in the year preceding the examination) [37]. In our
study, the mean abdominal pain intensity was indicated as moderate (3 VAS pts; median = 4/
max = 10) and of relatively short duration (<45 min), which is in the range of previous reports
[8,10]. The majority of studies on abdominal pain in CF, however, did not specify the localiza-
tion of pain [8,10,38,39].
In the 85% of patients with exocrine PI, enzyme substitution may relieve many but not all
GI symptoms. Thereby, low treatment adherence is considered a major cause of increased
symptomatology. That adherence to pancreatic enzyme intake was self-reported may consti-
tute a limitation of our study, as maladherence might be under-reported. Of all included PI
patients, 76% stated to have taken their enzymes regularly (never or less than once a month
missed a dose). Furthermore, 3% stated to have forgotten them several times a week, 7% about
once a week, and 14% several times a month. This self-reported rate of adherence regarding
enzyme intake is comparatively high. For instance, Modi et al. only estimated an adherence
rate at 50% or below [40]. Compared to objective measures, self-reports in general involve

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

Fig 6. JenAbdomen-CF Score 1.0 in relation to genotype. Left: Scores obtained from ‘mild´ (PIP0.25)
compared to ‘moderate-severe´ (PIP>0.25) genotypes. Right: Scores of patients carrying the G551D mutation
compared to those without this mutation. Of note, the fact that 10/17 of the patients with G551D mutation
received ivacaftor may have influenced the result.
https://doi.org/10.1371/journal.pone.0174463.g006

some uncertainty and may be biased for several reasons. In consecutive studies it would be
most interesting to use objective methods to measure adherence to enzyme intake and its cor-
relation to symptoms but possibilities to effectively and objectively control intake of tablets
within daily life are markedly limited.
Altogether, in our study, female subjects revealed slightly higher JenAbdomen-CF Score 1.0
values than males. To some extent, this may be explained by an overlap with some symptoms
associated with the menstruation cycle. In accordance, significantly more abdominal pain has
been described both in CF and in healthy pubescent girls [14,41]. Of note, our study revealed
no differences in the overall abdomen scores between the age groups. This accords well to a
recent systematic review showing that prevalence and intensity of nonspecific pain was not
linked to age in CF [12].
Our results showed slightly higher abdomen scores in patients with mild lung symptom-
atology (FEV1 70 pp; 19.5 score points) compared to patients with severe lung disease (FEV1
39 pp; 17.2 score points). In line with this, it has recently been noticed that mild lung disease
in CF is associated with more severe extrapulmonary manifestations [42].
In general, CFLD reveals a slow progression over years and even decades and often is
asymptomatic until most advanced stages [31,43,44]. In accordance, we did not see differences
in abdomen scores among non-CFLD, non-cirrhotic CFLD, and cirrhotic CFLD groups. Fur-
thermore, six of the seven cirrhotic CFLD individuals included in our study were classified
with Child-Pugh score A indicating compensated liver cirrhosis without signs of portal
hypertension.
In our study, CF patients with nutritional failure (reduced nutritional state) did not report
higher rates of GI symptoms. This finding can be explained by the retrospective and cross

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

sectional character of our questionnaire. In a prospective study, Shoff et al. [45] reported that a
better nutritional status was associated with increased HRQoL scores. This questionnaire,
however, included only one item on ‘digestive symptoms´. Thus, further prospective studies
using meaningful questionnaires are warranted to evaluate the impact of GI symptoms on the
nutritional status of CF patients. In this respect, additional factors that contribute to growth
failure such as intestinal inflammation [46–49] and dysbiosis [50,51] should be considered.
A main finding of our study was that the majority of patients who underwent laparotomy
scored higher than those without such surgery. This might be attributed to a more severe
course of gastrointestinal disease, causing volvulus, intestinal atresia, intussusception, MI, and
DIOS in these patients. Interestingly, in 15 of these 17 patients, PIP scores were 0.96 that
accords to PI in almost all of these patients.
Among children and adolescents, those who received several antibiotic i.v. courses tended
to suffer from more pronounced GI symptoms than patients without antibiotic treatments.
Especially early in life, antibiotic treatment may affect the intestinal microbiota with putative
long-term health consequences [52]. The usage of broad-spectrum antibiotics has been sus-
pected to increase the risk of abdominal pain on the one hand [52]. On the other hand, it has
been associated with a reduction in physiological anaerobic species and enterobacteria in the
intestinal flora [53,54]. Some studies have shown that ciprofloxacin particularly suppresses
gram-negative rods such as Enterobacteriaceae and Bacteroides species [55,56], thus promoting
dysbiosis in CF [50]. In accordance, we observed higher symptom scores in patients with inter-
mittent P. aeruginosa colonization, who often receive longer courses of ciprofloxacin.
Altogether, the 17 CF patients of our cohort carrying at least one G551D-CFTR mutation
showed lower scores than non-G551D-CFTR patients (13.6 vs. 17.0; p = 0.029). As 59% of
these patients (10/17) received ivacaftor at the time of questioning, we cannot distinguish
whether this outcome was due to therapy or because of the general milder clinical phenotype
compared to F508del, as previously suggested [57,58]. In addition, patients treated with ivacaf-
tor (IVA) reported significantly lower scores in comparison with non-G551D-CFTR patients
(11.7 vs. 17.0; p = 0.032). In line with this, we herein propose the usage of our questionnaire
with special emphasis on its value for future clinical studies. As CFTR modulators such as IVA
act systemically, the assessment of changes in abdominal symptoms is of outstanding interest,
especially, since first CFTR modulators for frequent mutations like F508del are now available
[59], and many studies with novel modulating substances are on the way. Thereby, a deeper
understanding of the complex abdominal involvement is needed and assessment of changes of
abdominal symptoms during CFTR modulation is of high interest. In light of this, the comple-
menting usage of PROMs such as symptom questionnaires like the herein presented is
promising.
As mentioned above, one limitation of our study is its retrospective character. Furthermore,
missing values in the questionnaire were replaced by zero what might have introduced biased
estimates interfering with the final score. However, the percentage of missing data was only
4.8%, what can be considered as low, according to Monte Carlo [60].
Finally, from our data we can conclude that patients with a severe course of the disease or
with genotypes causing a moderate to severe abdominal involvement (what at the same time
more frequently is associated with history of DIOS, MI, PI and rectal prolapses) are more likely
to have higher rates for GI symptoms. Concurrently, GI symptomatology was not associated
with CFLD or elevated LFTs.
Meanwhile, we have elaborated a revised and improved version of our questionnaire and
the deduced JenAbdomen-CF Score, which now will undergo the following steps:

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

• Evaluation of reliability of the questionnaire by examining internal consistency and con-

struct validity,
• Evaluation of reproducibility of the questionnaire by re-testing of patients,
• Assessment of cross-generational applicability of the questionnaire by subscoring of age
groups,
• Evaluation of the responsiveness of the score by comparison with age-matched healthy
controls,
• Evaluation of the power of the questionnaire by comparison with the Cystic Fibrosis Ques-
tionnaire Revised (CFQ-R) which inquires mainly QoL items,
• Assessment of applicability of the questionnaire in other CF centers,
• Assessment of putative relationships of abdominal symptoms with faecal inflammatory
markers.
Prospectively, we aim at disseminating and applying our JenAbdomen-CF Score to a larger
patient cohort not only in Germany but also in other countries in order to assess practicability
of the questionnaire and provide proof of principle for the significance of the thus calculated
score on GI involvement in CF.

Supporting information
S1 Table.
(XLSX)

Acknowledgments
The authors especially thank the patients who participated in this study.

Author Contributions
Conceptualization: HT JGM CA.
Data curation: HT CA TL.
Formal analysis: HT TL.
Funding acquisition: HT JGM.
Investigation: HT ML RM AG CA JGM.
Methodology: HT CA JGM SR HJM DR.
Project administration: CA JGM.
Resources: ML RM AG JGM.
Supervision: CA TL AJ JGM.
Validation: HT CA TL JGM.
Visualization: HT CA TL AJ JGM.
Writing – original draft: HT CA JGM.
Writing – review & editing: HT CA JGM.

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 First results obtained with the JenAbdomen-CF Score 1.0, a new CF-specific patient reported outcome measure

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