World J Gastroenterol 2015 January 7; 21(1): 318-325
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
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DOI: 10.3748/wjg.v21.i1.318
© 2015 Baishideng Publishing Group Inc. All rights reserved.
ORIGINAL ARTICLE
Observational Study
Long-term follow-up of distal intestinal obstruction
syndrome in cystic fibrosis
Moran Lavie, Tzipora Manovitz, Daphna Vilozni, Sarina Levy-Mendelovich, Ifat Sarouk, Ilana Weintraubv,
David Shoseyov, Malena Cohen-Cymberknoh, Joseph Rivlin, Ori Efrati
Moran Lavie, Tzipora Manovitz, Daphna Vilozni, Sarina
Levy-Mendelovich, Ifat Sarouk, Ilana Weintraubv, Ori Efrati,
Pediatric Pulmonary Unit and the National Center for Cystic
Fibrosis, Edmond and Lily Safra Children’s Hospital, Sheba
Medical Center, Tel Hashomer 52621, Israel
David Shoseyov, Malena Cohen-Cymberknoh, Cystic
Fibrosis Center and Pediatric Pulmonary Unit, Hadassah Hebrew
University Medical Center, Jerusalem 91120, Israel
Joseph Rivlin, Cystic Fibrosis Center, Carmel Medical Center,
Haifa 34362, Israel
Author contributions: Lavie M, Vilozni D and Efrati O designed
the study, analyzed the data and wrote the manuscript; Manovitz
T, Levy-Mendelovich S and Sarouk I collected the medical data
and performed the statistical analysis; Weintraubv I, Shoseyov
D, Cohen-Cymberknoh M and Rivlin J provided the medical
data, analyzed the data and were also involved in the writing and
editing of the manuscript.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Correspondence to: Dr. Moran Lavie, Pediatric Pulmonary
Unit and the National Center for Cystic Fibrosis, Edmond and
Lily Safra Children’s Hospital, Sheba Medical Center, Derech
Sheba 2, Tel Hashomer 52621,
Israel. moran.lavie@sheba.health.gov.il
Telephone: +972-3-530-2884
Fax: +972-3-534-5914
Received: June 16, 2014
Peer-review started: June 20, 2014
First decision: July 21, 2014
Revised: August 27, 2014
Accepted: September 29, 2014
Article in press: September 30, 2014
Published online: January 7, 2015
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Abstract
AIM: To investigate the long-term follow-up of distal
intestinal obstruction syndrome (DIOS) in Israeli cystic
fibrosis (CF) patients.
METHODS: This is a multi-center, comparative,
retrospective study in which we reviewed the medical
records of all CF patients from three major CF centers
in Israel who were treated in the period from 1980 to
2012. Patients diagnosed with DIOS were defined as
the study group. The patients were diagnosed with
DIOS based on their clinical presentation and typical
findings on either abdominal X-ray or computerized
tomography scan. For the control group, CF patients
with no DIOS were matched to the patients in the study
group for age, sex, and cystic fibrosis transmembrane
conductance regulator (CFTR) mutations. For both
groups, the collected data included age, sex, CFTR
genotype, weight, height, and body mass index. Clinical
data included respiratory function tests in the last
five years prior to the study, respiratory function test
immediately before and after the DIOS event, number
of hospitalizations, sputum culture results, and CFrelated conditions diagnosed according to the CF clinical
practice guidelines. In the study group, data on the
DIOS treatment and tendency for DIOS recurrence were
also analyzed.
RESULTS: The medical charts for a total of 350 CF
patients were reviewed. Of the 350 CF patients, 26
(7.4%) were diagnosed with DIOS. The control group
included 31 CF patients with no DIOS diagnosis. The
mean follow-up period was 21.6 ± 8.2 years. The total
of DIOS episodes in the follow-up period was 60. The
distribution of DIOS episodes was as follows: 6/26
(23.1%) study patients had one episode of DIOS in
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January 7, 2015|Volume 21|Issue 1|
Lavie M et al . DIOS in CF patients
to an increase in the average age of CF patients[3]. The
two gastrointestinal manifestations in CF that lead to
intestinal obstruction are meconium ileus (MI) and
distal intestinal obstruction syndrome (DIOS). MI is a
condition specific to infants, who in most cases are also
diagnosed with CF, strongly suggesting that MI may be
the first clinical marker of the disease. The MI appears
in 10%-21% of CF patients[4-6]. The meconium in the MI
neonates is viscous, dry and thick, consequently causing
intestinal obstruction. DIOS, a similar phenomenon
of intestinal obstruction, occurs later in life. DIOS is
characterized by the accumulation of viscous intestinal
contents within the bowel lumen involving the terminal
ileum, cecum and ascending colon, potentially causing
complete or partial intestinal obstruction[7]. The DIOS
incidence rate ranges from 2.3% to 41.3%[8]. A recent
study in European children showed complete obstruction
incidence rate ranging 5-12 episodes per 1000 CF patients
per year[9].
Some of the indications of the presence of acute
complete obstruction are bilious vomiting, a mass in the
ileocecal area, abdominal pain and distention, and airfluid level in the small intestine on abdominal X-ray.
The incomplete fecal obstruction is characterized
by abdominal pain and a mass in the ileocecal area[9].
Although the pathogenesis of DIOS is unknown, the
underlying assumption is that DIOS is a combination of
a few factors, including pancreatic insufficiency (PI) with
abnormal secretion of pancreatic enzymes and abnormal
digestion, insufficient secretion of bicarbonate, viscous
and mucoid secretions of the intestinal mucosa, and
impaired intestinal motility[9]. Various DIOS treatment
options are available[3,9]. In most cases, patients with
incomplete DIOS respond well to oral rehydration
combined with stool softeners or laxatives. When
DIOS presents with more severe intestinal obstruction
characterized by bilious vomiting or when washout
therapy has failed, hospitalization is recommended,
and intravenous rehydration and nasogastric aspiration
should be commenced. With early aggressive medical
management, surgery is seldom required; laparotomy
with washout via enterostomy should supersede resection
of the ileocecum.
There is a lack of consensus in the literature on the
different aspects of DIOS in CF patients. Correlation
between DIOS and the pulmonary and nutritional status
was found to be either non-significant[7] or positive[3]. On
the other hand, DIOS patients suffered from a lower
forced expired volume in 1 s (FEV1) and had more severe
morbidity than patients without DIOS[9,10]. The correlation
between pancreatic enzyme replacement therapy (PERT)
and DIOS is still not fully understood. Some reports
suggest a positive correlation between PERT and an
increased risk of obstruction[9,11]. Others found that the
pancreatic failure and uncontrolled steatorrhea led to an
increase in intestinal obstruction frequency that did not
improve even after the introduction of a more efficient
pancreatic enzyme treatment [3,10,12-14]. The correlation
between DIOS and MI also remains inconclusive, ranging
their lifetime, 7/26 (26.9%) had two episodes, 7/26
(26.9%) had three episodes, and 6/26 (23.1%) had
four or more episodes. Compared to the control group,
DIOS patients had a significantly higher incidence of
meconium ileus in the past (65.4% vs 0%, respectively,
P < 0.02), more Aspergillus spp. colonization (34.6%
vs 3.2%, respectively, P < 0.02), and a higher number
of hospitalizations due to respiratory exacerbations (8.6
vs 6.2 mean total hospitalizations per follow-up period,
respectively, P < 0.02). No other significant differences
were found between the control and study groups. The
conservative treatment of DIOS, which mainly includes
hydration and stool softeners, was successful in 82%
of the episodes. The survival rate was similar for both
groups.
CONCLUSION: CF patients with DIOS suffer from
recurrent hospitalizations and airway pathogen
acquisition. Although recurrence of DIOS is common,
conservative treatment is successful in most patients.
Key words: Distal intestinal obstruction syndrome;
Cystic fibrosis; Meconium ileus; Treatment; Recurrence
© The Author(s) 2015. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Distal intestinal obstruction syndrome (DIOS)
is a gastrointestinal complication of cystic fibrosis
(CF). This study reviews the long-term follow-up of
DIOS across two decades in Israeli CF patients. The
DIOS patients were more prone to meconium ileus,
Aspergillus spp. airway colonization and frequent
hospitalizations then the DIOS-negative CF patients.
DIOS recurrence was observed in 77% of patients.
Conservative treatment was successful in 82% of the
episodes, which makes it the treatment of choice for
DIOS management. The survival rate was similar to the
CF patients without DIOS.
Lavie M, Manovitz T, Vilozni D, Levy-Mendelovich S, Sarouk
I, Weintraubv I, Shoseyov D, Cohen-Cymberknoh M, Rivlin J,
Efrati O. Long-term follow-up of distal intestinal obstruction
syndrome in cystic fibrosis. World J Gastroenterol 2015;
21(1): 318-325 Available from: URL: http://www.wjgnet.
com/1007-9327/full/v21/i1/318.htm DOI: http://dx.doi.
org/10.3748/wjg.v21.i1.318
INTRODUCTION
Cystic fibrosis (CF) is an autosomal recessive disease
caused by mutation of the cystic fibrosis transmembrane
conductance regulator (CFTR) protein, which is a cell
membrane channel for transport of chloride ions[1]. The
systems usually affected by this disease are respiratory,
gastrointestinal, and reproductive[2]. The prevalence of
CF-related gastrointestinal complications has been on
the rise in recent years, a fact that can partly be attributed
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Lavie M et al . DIOS in CF patients
from positive[2,8,9] to non-significant[10]. Contradictory
evidence exists for the correlation between severity of the
CFTR mutation and the chance of developing DIOS, as
well[8-10]. Additional DIOS risk factors include dehydration,
CF-related diabetes, and organ transplantation[15].
The objective of the current study was to assess
clinical characteristics, risk factors, morbidity and mortality
among Israeli CF patients with and without DIOS during
a 20-year follow-up period. Furthermore, the treatments
used by the three CF centers for DIOS-positive CF
patients were also assessed. A more comprehensive
understanding of DIOS and a development of a clear
treatment strategy will help create an all-encompassing
management plan to be used by patients and doctors to
manage this complicated disease.
propensity for recurrence. The study was approved by the
Institutional Ethics Committees of all three institutions.
Diagnosis and management of DIOS
The diagnosis of DIOS was performed based on
the clinical manifestations, such as abdominal pain,
constipation, bilious vomiting, a mass in the ileocecal
area, and abdominal X-ray or computerized tomography
scan showing distention and air-fluid level in the small
intestine [15] . The treatment included (1) hydration
with intravenous or feeding tubes; (2) stool softeners
(polyethylene glycol) administered either per os or via a
feeding tube; (3) continuation of oral pancreatic enzymes;
or (4) surgical management[15]. The stool softeners used
were MerokenTM (Taro Pharmaceutical Industries Ltd.,
Haifa, Israel), mineral oil, lactulose, N-acetylcysteine or
Gastrografin® solution (sodium meglumine diatrizoate;
Bracco Diagnostics Inc., Monroe, NJ, United States).
For the treatment of adults, 100 mL of Gastrografin
was added to 400 mL of drinking water per dose; for
the treatment of children < 6-years-old, 50 mL of
Gastrografin was added to 200 mL of drinking water per
dose.
MATERIALS AND METHODS
Subjects
The subjects included in the study were patients from
three major CF centers in Israel: (1) Pediatric Pulmonary
Unit and the National Center for Cystic Fibrosis,
Edmond and Lily Safra Children’s Hospital, Sheba
Medical Center, Tel Hashomer, affiliated with Sackler
Medical School, Tel-Aviv University; (2) Cystic Fibrosis
Center and Pediatric Pulmonary Unit, Hebrew University
of Jerusalem Hadassah Medical Center, Jerusalem; and
(3) Cystic Fibrosis Center, Carmel Medical Center, Haifa,
affiliated with Technion Faculty of Medicine, Haifa.
The Cystic Fibrosis Foundation’s consensus statement
was used to diagnose CF in all of the patients based on
the clinical characteristics, identified CFTR alteration
mutation, and/or pathological sweat chloride test
(performed on two occasions)[16].
Statistical analysis
Data was analyzed using the IBM SPSS Statistics for
Windows software (version 21.0; IBM Corp., Armonk,
NY, United States). Categorical parameters were analyzed
using the Pearson’s chi-square and Fisher’s exact tests.
Continuous variables were analyzed using the paired t-test
and the Mann-Whitney U test. A P-value less than 0.05
were considered significant.
RESULTS
Study design
A retrospective review of the CF patients’ medical
records during 1980-2012 was performed. CF patients
were divided into either the study group (DIOS-positive)
or the control group (DIOS-negative). Patients in both
groups were matched based on age, sex, and CFTR
mutations. Data collected from medical files included
age, sex, CFTR genotype, weight, height, and body
mass index (BMI). The study group was composed of
26 CF patients and the control group was composed
of 31 CF patients, for a total of 57 patients. The
clinical data included respiratory function tests in the 5
years prior to data collection, respiratory function test
immediately prior to and following the DIOS episode,
number of hospitalizations, and sputum culture results.
CF-related conditions (diagnosed according to the
CF clinical practice guidelines[17]) were also collected,
and included rectal prolapse, gastritis, PI, CF-related
diabetes, portal hypertension, percutaneous endoscopic
gastrostomy, cholelithiasis, cholestasis, cholecystitis,
sinusitis, hemoptysis, nasal polyps, organ transplantation,
malignancy, and mortality. The study group data also
included information of the treatment for DIOS and
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The study encompassed 350 patients, accounting for
about 60% of all CF patients in Israel. Of the 350
patients, 26 (7.4%) were diagnosed with DIOS. The
average length of the follow-up period for the entire
cohort was 21.6 ± 8.2 years. Twenty (76.9%) DIOS
patients and 26 (83.8%) control patients underwent
follow-up for > 15 years, and 17 (65.3%) DIOS patients
and 19 (61.3%) control patients were followed for ≥ 20
years (Table 1). The average age for occurrence of the
first DIOS episode was 9.7 ± 8.5-years-old. Following
this first episode, 13 patients (50.0%) were followed for
at least 10 years and 6 (23.1%) patients were followed for
at least 15 years. The average follow-up period after the
first DIOS episode was 9.5 ± 7.7 years. Six (23.1%) study
patients had one episode of DIOS in their lifetime, 7
(26.9%) had two episodes, 7 (26.9%) had three episodes,
and 6 (23.1%) had four or more episodes. The control
group included 31 CF patients not diagnosed with DIOS
matched by age, sex, and CFTR genotype to the study
group. The clinical characteristics of the 57 patients
included in the study are presented in Table 2.
From the DIOS group, 13 (50.0%) patients were
homozygous and 8 patients (30.7%) were compound
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Table 1 Long-term follow-up of the cohort n (%)
Follow-up length in years
Table 2 Characteristics of the cohort n (%)
Study group
Control group
23 (88.4)
20 (76.9)
17 (65.3)
13 (50.0)
5 (19.2)
26
29 (93.5)
26 (83.8)
19 (61.3)
9 (35.4)
1 (3.2)
31
10
15
20
25
30
Total number of patients per group
Study group
Patients
Sex
Male
Female
Age, mean ± SD (years-old)
Genotype
Homozygote
Heterozygote
Unknown
DeltaF508
BMI, weight/height
PI
MI in the past
Lung colonization
Pseudomonas aeruginosa
Staphylococcus aureus
Burkholderia cepacia
MOTT
Aspergillus spp.
Study group: Cystic fibrosis patients diagnosed with distal intestinal
obstruction syndrome; Control group: Cystic fibrosis patients.
heterozygous for the CFTR gene. In the control group,
12 (38.7%) patients were homozygous and 9 (35.4%)
patients were compound heterozygous for CFTR gene.
The rest of the patients in both groups had unknown
mutations. The two prominent alleles were DeltaF508
and W1282X. DeltaF508 was found in 46.2% of the
DIOS patients and 58.1% of the control group patients.
W1282X was found only in 46.2% of the DIOS
group patients. Other mutations included: T360K,
3849+10KBC→T, G85E, D952H, R334W, 405+1G→
A, S549R, 5T, Q359K, N1303K, 3120del, e92x, and
I1234V. There was no statistical difference between the
DIOS and control group in the severity of mutations or
mutation class. In the DIOS group, the BMI was slightly
lower than that in the control group but the difference
was not significant (18.4 vs 19.3, respectively, P = 0.301).
The percentage of patients who received percutaneous
endoscopic gastrostomy tube insertion, to improve
nutritional status, was similar between the DIOS group
and the control group (7.7% vs 6.5%, respectively, P =
1.00). In the DIOS group, 18 patients had pancreatic
insufficiency and were treated with an enzyme
replacement therapy. There was no statistical difference
in PI between the DIOS group and the control group
[18 (69.2%) vs 27 (87.1%), respectively, P = 0.97]. The
incidence of MI in the medical history of DIOS group
patients compared to the control group was 65.4% vs
0.0%, respectively (P = 0.001).
The incidence rate and diversity of bacterial
colonization by Pseudomonas aeruginosa, Staphylococcus aureus,
Burkholderia cepacia, and nontuberculous Mycobacterium was
similar between the DIOS and control groups (84.6% vs
90.3%, P = 0.691; 53.8% vs 41.9%, P = 0.431; 7.7% vs 0%,
P = 0.204; and 7.7% vs 16.1%, P = 0.436, respectively). In
contrast, patients suffering from DIOS had significantly
more infections with Aspergillus spp. then the control
group (34.6% vs 3.2%, P = 0.003, respectively).
The patients who developed intestinal obstruction
did not suffer from an increase in the number of CFrelated complications (42.3% vs 58.1% in the controls, P
= 0.292). There was an upward trend in the number of
organ transplantations in the DIOS group (15.4% vs 3.2%,
respectively, P = 0.167) and an increase in rectal prolapse
in the control group (0.0% vs 6.5%, respectively, P =
0.0495).
In order to evaluate the severity of lung disease,
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Control group P -value
26
31
NS
19 (73.1)
7 (26.9)
9.7 ± 22.5
20 (64.5)
9 (35.5)
6.7 ± 20.9
NS
NS
NS
13 (50.0)
8 (30.8)
5 (19.2)
12 (46.2)
18.4
18 (69.2)
17 (65.4)
12 (38.7)
9 (35.5)
8 (25.8)
18 (58.1)
19.3
27 (87.1)
0 (0.0)
NS
NS
NS
NS
NS
NS
< 0.021
22 (84.6)
14 (53.8)
2 (7.7)
2 (7.7)
9 (34.6)
28 (90.3)
13 (41.9)
0 (0.0)
5 (16.1)
1 (3.2)
NS
NS
NS
NS
< 0.021
1
Statistically significant. Study group: Cystic fibrosis patients diagnosed
with distal intestinal obstruction syndrome; Control group: Cystic fibrosis
patients; n: Number of patients; SD: Standard deviation; BMI: Body mass
index; MI: Meconium ileus; MOTT: Mycobacteria other than tuberculosis;
PI: Pancreatic insufficiency; NS: Not significant.
pulmonary function tests (PFTs) performed during
the 5-year period prior to the study (2007 - 2011) were
reviewed. The average value of each PFT parameter
was calculated from all the yearly PFTs. There were no
significant differences between the DIOS and control
groups, as seen in Table 3. Further evaluation of the
effect of an intestinal obstruction episode on lung
disease included comparison of the PFTs of DIOS
patients collected up to 2 mo before, and PTFs collected
2 to 4 wk after an obstruction. There was no significant
difference between PFTs in the period prior to or
following the bowel obstruction. The average FEV1 was
68.6% before vs 70.2% after obstruction (P = 0.979), the
average forced vital capacity was 76.35% before vs 76.4%
after obstruction (P = 0.759), and the average forced
expiratory flow between 25% and 75% of forced vital
capacity was 54.9% before vs 50.0% after obstruction (P
= 0.418). The patients in the study group had significantly
more hospitalizations due to respiratory exacerbations
than those in the control group (8.6 vs 6.2 mean total
hospitalizations per follow-up period, respectively, P =
0.018). In order to exclude age bias, the average number
of hospitalizations per year for a 20-year follow-up period
was measured. Even with this correction, our results still
show a significantly higher number of hospitalizations in
the DIOS group compared to the control group (0.4 vs
0.3 mean total hospitalizations per year, respectively, P =
0.008).
Overall, the DIOS group included 26 patients who
suffered 60 episodes of intestinal obstruction during
the 20-year follow-up period. The treatment distribution
for the 60 episodes was as follows: 75.0% of episodes
were managed conservatively, 18.3% surgically, and
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Lavie M et al . DIOS in CF patients
Table 3 Forced expired volume in 1 s (% predicted) comparing study patients and controls in the 5-year period prior to the study
FEV1
Study group
1st yr
2nd yr
3rd yr
4th yr
5th yr
P -value
Control group
n
Mean % predicted ± SD
n
Mean % predicted ± SD
17
21
21
21
22
68.8 ± 19.5
66.6 ± 19.1
69.7 ± 21.0
67.7 ± 20.4
70.7 ± 20.1
22
29
25
29
17
70.0 ± 16.9
71.0 ± 16.3
69.9 ± 18.2
68.5 ± 18.6
68.5 ± 19.8
0.837
0.386
0.978
0.876
0.691
Study group: Cystic fibrosis patients diagnosed with distal intestinal obstruction syndrome; Control group: Cystic fibrosis patients; n: Number of patients;
SD: Standard deviation; FEV1: Forced expired volume after 1 s of blowing out; SD: Standard deviation. A P < 0.05 is considered statistically significant.
patients in the study group did have it (P = 0.001). The
intestinal obstruction in the neonate, which is frequently
managed surgically, leaves a diseased intestine, increasing
the possibility for future adhesions and subsequent
obstructions. MI may be the primary indication of
intestinal susceptibility that makes the intestine prone
to recurrent obstructions. Of the 26 DIOS patients,
20 (76.9%) had more than one episode of intestinal
obstruction in their lifetime, supporting these two
possible explanations. Several groups reported a
significant correlation between DIOS and a history of
MI[8]. O’Halloran et al[18] showed MI incidence of 28% in
patients with DIOS. Houwen et al[9] found an even higher
incidence of MI in DIOS patients (44%). A significant
positive correlation was also supported by the findings
from a study by Efrati et al[2] that used the same unique
CF population in Israel as our study. Since both MI
and DIOS probably share similar pathophysiology, this
association seems logical. However, Dray et al[10] found
no significant correlation between DIOS and a history
of MI. In our study, DIOS patients had a significantly
higher hospitalization rate mostly due to respiratory
exacerbations, although some of the hospitalizations
were due to intestinal obstructions.
Despite the increased number of hospitalizations, the
results of our study show that morbidity and mortality
rates of the DIOS patients were similar to those of the
control group. This finding is surprising since one would
expect every hospitalization to be related to the patient’s
baseline deteriorating. Similar results have been shown by
Koletzko et al[7] who found no correlation between DIOS
and severity of lung disease, with the respiratory function
of DIOS patients being similar to CF patients without
DIOS in terms of the severity spectrum. Khoshoo
et al [3] showed that DIOS is related to a less severe
pulmonary disease. It appears that the administration
of the immediate treatment to resolve the acute DIOS
event, as well as the long-term supportive care given
to these patients, contributed to these good results.
Treatments that demonstrated beneficial properties
in decreasing the damage and increasing recovery of
the patients to their pre-hospitalization state include
antibiotic treatment, Gastrografin, long-term laxative
treatment, stool softeners, fluids, nutritional support, and
chest physiotherapy. Still, other studies have found an
association between DIOS and higher morbidity[9,10].
Table 4 Management strategies for the intestinal obstruction
in the study group
Type of treatment
n (%)
Conservative
Gastrografin PO
Enema
Combination of Gastrografin PO + enema and/or
Gastrografin enema and/or N-acetylcysteine PO
Gastrografin enema
N-acetylcysteine enema
Surgical
Laparotomy with milking
Other
No intervention
Total
Supportive
Antibiotics
IV fluids
Feeding tube
Peglax
Laxatives
45 (75.0)
15 (33.3)
12 (26.6)
11 (24.4)
4 (8.8)
3 (6.6)
11 (18.3)
3 (27.2)
8 (72.7)
4 (6.6)
60 (100)
37 (61.6)
10 (27.0)
13 (35.1)
6 (16.2)
6 (16.2)
2 (5.4)
n: Number of treatments; PO: Per os; IV: Intravenous.
6.7% resolved without any intervention. The most often
used drug for the treatment of intestinal obstruction
was oral administration of Gastrografin, and the least
used drug was N-acetylcysteine (Table 4). As part of
supportive treatment, 61.6% of the DIOS patients
received antibiotics and fluids. There was one mortality
case in each group. In the study group, death was due
to complications related to liver transplantation, not
associated with DIOS; the patient in the control group
died due to the end-stage lung disease.
DISCUSSION
This study followed Israeli CF patients who suffered
from DIOS for an average follow-up period of 21.6 ±
8.2 years after the first bout of bowel obstruction. In the
60% of all Israeli CF patients, the DIOS incidence rate
was 7.4%. This rate most likely represents the actual rate
of the entire CF patient population in Israel, and it falls
within the wide range of DIOS incidence worldwide of
2.4%-41.3%[8]. This incidence can be due to mutations,
the hot climate, and/or food that are specific to Israel.
In our study, none of the patients in the control
group had a prior history of MI, while 65.4% of the
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Lavie M et al . DIOS in CF patients
et al[8] did not support this statement and the authors
argued that modifier genes do not contribute to DIOS, as
opposed to MI.
In our study, the two most-prominent mutations in
the patients suffering from DIOS were DeltaF508 and
W1282X. Among the study patients, 46.2% carried at
least one DeltaF508 allele, and 36.5% of the alleles of
the entire cohort carried this mutation. Prior studies
reported this mutation as the most-common within the
CF patient population worldwide, being found in 67%
of chromosomes[23]. In addition, the correlation between
DeltaF508 and pancreatic insufficiency has previously
been reported [23]. Indeed, 45 (78.9%) patients from
the entire cohort suffered from PI. The second mostprominent mutation in the study group was W1282X,
found in 46.2% of our DIOS patients in at least one
allele. This mutation is almost exclusively found in the
Jewish Ashkenazi population, which constitutes 1% of
CF patients in the world [27]. Although morbidity and
mortality of the W1282X mutation have not been studied
in depth, the mutation is considered to be a Class I stop
mutation. Our study found that the respiratory, nutritional
and morbidity status, as well as the mortality of the study
patients, were all similar to that of the control group. The
unique W1282X mutation, more prevalent in our patient
population, compared to the world CF population, may
be contributing to this fact. It is unlikely that this severe
mutation would have a protective effect on the patients.
Most likely, the W1281X mutation enables modifier genes
to affect the clinical presentation of DIOS, consequently
providing a protective effect. In light of our study results,
one can concede that modifier genes or the mutation
itself may indeed be a factor affecting the clinical
presentation of DIOS.
In this study we demonstrated the efficacy of
supportive and conservative management of intestinal
obstruction with rare need for surgical treatment. Oral
Gastrografin was the most commonly used treatment.
Indeed, of the 45 episodes managed in a conservative
manner, 15 (33.3%) were resolved solely by Gastrografin
and 9 (20%) were resolved by Gastrografin with an
additional oral agent or enema as part of a combined
therapy. Combined therapy was initiated either as the
first choice or when Gastrografin alone did not resolve
the obstruction. If the combined therapy was initiated
as a second line after the failure of Gastrografin to
resolve the obstruction, then the success rate of the
Gastrografin treatment was 57.7%. However, since
combined therapy was initiated as the first choice in some
cases, usually due to severe obstruction, then the actual
success rate of Gastrografin was even higher. In the past,
N-acetylcysteine treatment either orally or via enema,
was highly accepted[7,28-30]. However, some investigators
have shown that treatment with N-acetylcysteine either
has a high failure rate[7] or that a high dose increases the
risk of liver damage[7,31]. Furthermore, N-acetylcysteine
is cost-prohibitive and due to offensive taste patients
often fail to comply with the treatment[32]. In comparison,
The survival rate was similar for the two groups in
this study, suggesting that DIOS does not increase the
mortality rate of CF patients. In addition, as shown
previously, there are similarities between the DIOS
patients and the control regarding the respiratory function
tests and nutritional status. An interesting result is that the
study patients were not sicker in the long run and did not
deteriorate more than the control patients, despite their
need for more treatments and recurrent hospitalizations.
A potential explanation of this observation is that the
majority of DIOS patients suffered from MI as neonates
and were diagnosed early as CF patients, therefore
receiving close medical attention and aggressive treatment
very early in life. This early diagnosis gave them an
advantage by preventing or postponing irreversible lung
damage. Indeed, several studies have shown that an early
diagnosis of CF improves prognosis in the long run[2,19,20].
Moreover, Efrati et al[2] showed that patients with MI
showed no differences regarding PFTs in comparison
to patients who did not suffer from MI after a 25-year
follow-up.
CF patients suffer from recurrent respiratory tract
infections, in part due to dehydration of the airway surface
and decreased mucociliary clearance which may lead to
chronic lung infections[21]. As a result, various bacterial
pathogens such as Pseudomonas aeruginosa or Staphylococcus
aureus colonize the respiratory airways in all of the
CF patients regardless of DIOS diagnosis. However,
Aspergillus spp. colonization is seen more frequently in
patients who suffer from DIOS. We hypothesize that
frequent hospitalizations expose DIOS patients to a
higher number of antibiotic treatments, creating an
optimal microenvironment for fungal infections.
The majority of CF patients, who participated in our
study, suffered from pancreatic insufficiency and their
condition was managed with PERT. Furthermore, there
was no statistical difference in the PI prevalence and
use of PERT between the DIOS group and the control
group. These findings contradict previous studies that
showed a connection between the aggressive use of
PERT during the years and an increased risk of DIOS[9,22].
Others have shown an increase in intestinal obstruction
and the DIOS incidence due to pancreatic failure and
uncontrolled steatorrhea despite the introduction of
more efficient pancreatic enzyme treatment[3,10,13-15].
The current study was not able to establish a clear link
between CFTR mutations and DIOS as demonstrated in
prior studies. The Cystic Fibrosis Genotype-Phenotype
Consor tium [23] and others [24-26] showed a strong
association between severe mutations and pancreatic
insufficiency. DIOS is mainly seen in patients with severe
CFTR-related phenotypes[8,10]. Houwen et al[9] showed
that 82% of DIOS patients had severe CFTR mutations
vs 3% who had non-severe mutations. However, even
patients with a mild phenotype developed DIOS, which
suggests that not only CFTR but other modifier genes
may have an effect on the severity of the gastrointestinal
phenotype [9]. The results from a study by Blackman
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January 7, 2015|Volume 21|Issue 1|
Lavie M et al . DIOS in CF patients
believe that these results can be implemented for the entire
CF patient population worldwide.
In conclusion, CF patients, both pediatric and adult,
who suffer from recurrent intestinal obstruction either
in the form of MI or DIOS, have similar pulmonary and
nutritional status, survival rates and associated morbidities
compared to CF patients who do not. This finding is
encouraging considering that DIOS patients often suffer
from high rates of hospitalization and respiratory tract
infections. Conservative treatment, especially with oral
Gastrografin, is very successful in these patients. The
combination of early diagnosis, appropriate treatment,
and close follow-up all lead to successful results in CF
patients of older age. The more we expand the knowledge
regarding the treatment of DIOS in CF patients, the more
efficient the clinical management approach will become,
potentially significantly improving the life expectancy and
the quality of life for these patients.
Gastrografin, a hyperosmolar dye (1500-2000 mOsm/
kg), has a success rate of up to 81% with a single oral
dose, and patients prefer this treatment over other
available treatments [18]. However, the potential risks
associated with taking Gastrografin orally are vomiting
or coughing while drinking, resulting in aspiration
of the drug [7], causing pulmonary edema and acute
inflammation with alveolar damage and bleeding, due
to the high osmolality of the drug[6,7]. Houwen et al[9]
related the use of Gastrografin to enema. The group
emphasized the importance of the substance as both
a diagnostic and therapeutic tool (radiopaque and
hyperosmolar) followed with caution regarding the
danger of translocation of large quantities of water
from the circulation to the intestine. Their conclusion
was that this procedure should be administrated to older
children with appropriate monitoring[9]. Our study refutes
these concerns regarding Gastrografin. Indeed, being
the most-common treatment, the study patients did
not have lower respiratory function tests in comparison
to the control, the mentioned complications were not
observed during the treatment, and the treatment had
a high success rate for resolving the obstruction. In
contrast, the previously popular treatment involving
the use of enema with N-acetylcysteine was rarely
used. Surgical treatment, which was the only definitive
treatment in the past, is associated with high morbidity
and mortality and was rarely used and required in the
current study. The high morbidity and mortality rates
associated with surgical treatment are related to bleeding,
delayed healing of surgical wounds, and postoperative
infections[29]. Therefore, as of recently the application of
surgical treatment has been decreasing and in most cases
conservative treatment is the primary choice. However,
researchers like Speck et al[33] suggest that with an increase
in the incidence of DIOS in the adult CF population, the
need for surgical intervention will rise; but this did not
seem to be the case in our study population.
Our study has a few limitations. Primarily, the data
were taken from three different centers, each using
different follow-up and report systems. On the other hand,
these three centers are all located in Israel; therefore, the
treatment strategies were not significantly different in terms
of drug choice and treatment regimen. A prospective study
would be the best approach for determining the efficacy
of different treatment strategies in the management of
intestinal obstruction. However, our study is retrospective
and was based on a review of the treatments given through
the years to treat different episodes and could, therefore,
be affected by different habits or tendencies of centers
to offer one agent over another as a primary treatment
option. Nonetheless, oral Gastrografin was the mostcommon agent used by all three centers and showed very
high success rates in each. Because Gastrografin has few
side effects and forms of administration, we strongly
recommend this compound as the primary choice for
treating intestinal obstruction in CF patients diagnosed
with DIOS. Despite the above-mentioned limitations, we
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COMMENTS
COMMENTS
Background
Distal intestinal obstruction syndrome (DIOS) is a gastrointestinal complication
commonly associated with cystic fibrosis (CF). Long-term clinical implications
of DIOS regarding the morbidity and mortality of CF patients have not been
thoroughly investigated.
Research frontiers
Currently, no strong consensus exists in the literature regarding the different
aspects of CF patients’ medical history (morbidity, mortality, and DIOS
reoccurrence rate) and the most beneficial treatment for DIOS. The purpose of
the current study was to assess clinical characteristics, risk factors, morbidity
and mortality in Israeli CF patients with and without DIOS during a 20-year
follow-up period. In addition, the different DIOS treatments used were also
assessed.
Innovations and breakthroughs
Long-term follow-up of DIOS patients has shown DIOS patients having
more frequent airway colonization by Aspergillus spp., as well as more
hospitalizations due to respiratory exacerbations. The DIOS patients had
significantly higher incidence of meconium ileus in their medical history
compared to the control patients. Although recurrence of DIOS was common,
the administration of conservative treatment was successful in most of the
cases. The occurrence of DIOS did not alter the survival of these patients
compared to that of the control group.
Applications
The results imply that the conservative approach is the treatment of choice
with a good outcome. Meconium ileus may be a risk factor for the development
of DIOS as CF patients get older. Patients with a history of DIOS are prone to
recurrent intestinal obstruction.
Terminology
Distal intestinal obstruction syndrome is an intestinal obstruction caused by
an accumulation of viscous intestinal contents within the bowel lumen that
may cause complete or partial intestinal obstruction in cystic fibrosis patients.
Despite the lack of knowledge regarding the specifics of the pathogenic
mechanism of DIOS, the assumption is that the condition is a combination of
pancreatic insufficiency, insufficient bicarbonate secretion, viscous and mucoid
secretions of the intestinal mucosa, impaired intestinal motility, and chronic
inflammation. Different therapeutic options are available for use in the treatment
of DIOS, and they mainly include oral rehydration combined with stool softeners
or laxatives.
Peer review
This paper presents a very interesting multi-center, comparative, retrospective
study showing a promising prognosis for cystic fibrosis patients with a history of
DIOS using conservative treatment as the treatment of choice in management
of DIOS.
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Lavie M et al . DIOS in CF patients
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S- Editor: Qi Y L- Editor: A E- Editor: Wang CH
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