Keywords
bowel - Bristol - constipation - depression - diarrhea - gastroenteritis - infection
- PI-IBS - Rome - stool
Introduction
Irritable bowel syndrome (IBS) is a common condition diagnosed in the daily outpatient
department. It is characterized by abdominal pain and altered bowel habits, with no
detectable structural abnormalities and normal routine diagnostic tests.[1] IBS is a form of gut–brain interaction disorder as most intestinal functions are
found to be regulated by the brain. It affects approximately 8 to 9% of the world
population.[2]
Post-infection IBS (PI-IBS) is development of de novo IBS symptoms (by Rome criteria)
in an individual after he or she experiences an episode of acute gastroenteritis (AGE),
which includes two or more of the following: fever, vomiting, diarrhea, or a positive
stool culture.[3]
[4] This includes persistent abdominal discomfort, diarrhea, and bloating despite clearance
of the inciting pathogen. Since the first description of PI-IBS by Chaudhary and Truelove
in 1962, numerous studies have demonstrated relationship between AGE and development
of subsequent IBS.[5] Long-term studies have suggested that the risk for development of PI-IBS increases
up to sixfold after gastrointestinal infection.[6]
India has a high incidence of AGE, hence a lot of people are at risk of developing
PI-IBS. There is a lack of prospective studies showing incidence of PI-IBS as per
Rome IV criteria in India. Identification of risk factors leading to PI-IBS would
give us early interventional opportunities to ameliorate symptom development and to
educate the patients with AGE about the possibility of development of IBS in future.
Hence, this study has been performed to study the incidence of PI-IBS and to identify
the risk factors associated with the development of PI-IBS.
Methods
This study included patients aged 18 years or older who were diagnosed with AGE admitted
in the medical ward of Dr. Prabhakar Kore Hospital and Medical Research Center, Belagavi.
It was performed over a period of 1 year. AGE was defined as per the Rome Foundation Working Team report on PI-IBS (2019), i.e., presence of a positive stool culture in a symptomatic
individual or presence of two or more of: fever, vomiting, and diarrhea for a duration
of less than 2 weeks.[7] The patients who did not give consent to be a part of the study or those with a
history of chronic diarrhea or diagnosed cases of disorders that may cause chronic
diarrhea such as inflammatory bowel disease, tuberculosis, prior abdominal surgery,
radiation enterocolitis, hereditary polyposis, etc., were excluded from the study.
A written informed consent was obtained from all patients included in the study.
All included AGE patients were subjected to an IBS questionnaire (based on Rome IV)
that elaborately evaluated patient's symptoms along a timeline, along with questions
to exclude other functional gastrointestinal disorders (FGIDs) like functional dyspepsia
at the time of AGE episode and after 6 months. Those found to be having IBS already
were excluded from the study. Those not having IBS at the time of AGE episode were
assessed for various risk factors associated with the development of PI-IBS in a face-to-face
interview. These included age, gender, duration of episode, peak stool frequency per
day, abdominal cramping, bloody stools, fever, use of antibiotics, anemia, direct
contact with livestock, and psychological factors (anxiety and depression). The Hospital
Anxiety and Depression Scale (HADS) questionnaire was used to ascertain psychological
status. Stool samples were collected for microscopic study and culture. Follow-up
survey was done after 6 months of AGE episode either as a face-to-face interview or
telephonically to diagnose post-infection IBS.
The Rome IV criteria for IBS is as follows:
Recurrent abdominal pain, on an average, at least 1 day per week in the last 3 months,
with symptom onset at least 6 months before diagnosis, associated with ≥2 of the following:
Every patient was asked to identify the type of stool they were passing usually as
per the Bristol stool chart. The risk factors were compared in the groups that developed
PI-IBS and that did not. This study was approved by Institutional Ethics Committee
on Human Subjects Research of Jawaharlal Nehru Medical College, Belagavi (approval
MDC/DOME/38) on November 24, 2018 and was performed according to the ethical guidelines
of the 1975 Declaration of Helsinki and its amendments.
Statistical Analysis
All the data were analyzed using the Statistical Package for Social Sciences (SPSS)
software (SPSS for Windows, version 20, SPSS Inc., Chicago, United States). The categorical
data were expressed in terms of rates, ratio, and percentage and the continuous data
were expressed in terms of mean ± standard deviation. The association between risk
factors and development of PI-IBS was tested using the Chi-square test. Odds ratio
was calculated for each risk factor. Multiple logistic regression analysis was used
to study the risk factors together and individually. Probability (p) value of ≤0.05 was considered statistically significant.
Results
A total of 100 patients with AGE who met the inclusion criteria were enrolled in the
present study. They were followed up after 6 months of the AGE episode and PI-IBS
was diagnosed based on Rome IV criteria. Twenty-five patients, i.e., one-fourth of
the total patients, developed PI-IBS in our study after 6 months of AGE ([Fig. 1]). Eighteen out of these 25 patients (72%) had diarrhea-predominant IBS (IBS-D) and
the remaining 7 (28%) had constipation-predominant IBS (IBS-C), as represented in
[Fig. 2]. Out of the 25 patients who developed PI-IBS, 28% patients were passing Bristol
type II stool, whereas 72% were passing Bristol type VI stool. Our study sample had
50% males and 50% females; however, 22% males and 28% females developed PI-IBS at
6 months. Sex was not statistically significant as a risk factor in our study (p-value: 0.4880). People of younger age developed PI-IBS more than those over 60 years
of age (30.56% of the patients with age ≤60 years vs. 10.71% of those >60 years; p-value = 0.040). Fever, vomiting, number of stools per day, use of antibiotics, and
contact with livestock were not significantly associated with development of PI-IBS.
However, 90.91% of patients with longer duration of AGE (>7 days) developed PI-IBS
as compared with only 16.85% in those with duration of AGE ≤7 days (p-value = 0.0001). Presence of abdominal cramps was also significantly associated with
development of PI-IBS (p-value = 0.0001). In our study, stool cultures of all patients were negative for enteropathogens;
however, significant pus cells were present in all stool samples. Psychological factors
did play some role in the development of PI-IBS. In total, 40.91% of those with depression
during the episode of AGE developed PI-IBS as compared with only 20.51% of those without
depression (p-value = 0.050). Anxiety was not a significant risk factor. Presence of occult blood
in stool and anemia were not found to be significant risk factors in this study. [Table 1] summarizes the various risk factors at the time of AGE episode among patients who
did and who did not develop PI-IBS and their individual significance (p-value). On multiple logistic regression analysis ([Table 2]), duration of AGE (>7 days) (adjusted OR [AOR]: 71.55; 95% confidence interval [CI]:
3.83–1,337.58; p-value = 0.0040) and presence of abdominal cramps (AOR: 5.07; 95% CI: 1.42–18.18;
p-value = 0.0130) were found to significantly influence the development of PI-IBS at
6 months, when compared with the other risk factors.
Fig. 1 Study flowchart. AGE, acute gastroenteritis; IBS, irritable bowel syndrome; PI-IBS,
post-infection irritable bowel syndrome.
Fig. 2 Incidence of PI-IBS and subtypes. IBS-C, irritable bowel syndrome-constipation predominant;
IBS-D, irritable bowel syndrome-diarrhea predominant; IBS-M, irritable bowel syndrome-mixed
type.
Table 1
Comparison of risk factors at the time of AGE between patients who did and did not
develop PI-IBS
|
Risk factor
|
Patients who developed PI-IBS, n = 25 (%)
|
Patients who did not develop PI-IBS, n = 75, (%)
|
p-Value
|
|
Fever
|
23 (92)
|
56 (74.66)
|
0.0650
|
|
Vomiting
|
24 (96)
|
66 (88)
|
0.2480
|
|
Stool occult blood
|
1 (4)
|
10 (13.33)
|
0.1960
|
|
Direct contact with livestock
|
2 (8)
|
8 (10.66)
|
0.7000
|
|
Antibiotics use
|
24 (96)
|
61 (81.33)
|
0.0750
|
|
Anxiety
|
9 (36)
|
14 (18.66)
|
0.0750
|
|
Depression
|
9 (36)
|
13 (17.33)
|
0.0500[a]
|
|
Duration of AGE
>7 days
|
10 (40)
|
1 (1.33)
|
0.0001[a]
|
|
Abdominal cramps
|
20 (80)
|
23 (30.66)
|
0.0001[a]
|
Abbreviations: AGE, acute gastroenteritis; PI-IBS, post-infection irritable bowel
syndrome.
a
p < 0.05.
Table 2
Multiple logistic regression analysis for incidence of PI-IBS
|
Independent factors
|
Unadjusted OR
|
95% CI for OR
|
p-Value
|
AOR
|
95% CI for OR
|
p-Value
|
|
Lower
|
Upper
|
Lower
|
Upper
|
|
Age groups (≤60 vs. >60 y)
|
0.12
|
0.04
|
0.40
|
0.0010[a]
|
0.33
|
0.07
|
1.57
|
0.1630
|
|
Sex (male vs. female)
|
0.39
|
0.21
|
0.72
|
0.0030[a]
|
1.11
|
0.32
|
3.91
|
0.8710
|
|
Fever (no vs. yes)
|
0.41
|
0.25
|
0.67
|
0.0001[a]
|
0.62
|
0.16
|
2.47
|
0.5010
|
|
Vomiting (no vs. yes)
|
0.36
|
0.23
|
0.58
|
0.0001[a]
|
0.28
|
0.06
|
1.32
|
0.1080
|
|
No. of stools per day (≤6 vs. >6)
|
0.37
|
0.22
|
0.63
|
0.0001[a]
|
0.45
|
0.12
|
1.74
|
0.2500
|
|
Antibiotics (not use vs. use)
|
0.39
|
0.25
|
0.63
|
0.0001[a]
|
0.89
|
0.14
|
5.72
|
0.9010
|
|
Duration of AGE (≤7 vs. >7))
|
10.00
|
1.28
|
78.12
|
0.0280[a]
|
71.55
|
3.83
|
1,337.58
|
0.0040[a]
|
|
Abdominal cramps (no vs. yes)
|
0.87
|
0.48
|
1.58
|
0.6480
|
5.07
|
1.42
|
18.18
|
0.0130[a]
|
|
Anxiety (no vs. yes)
|
0.64
|
0.28
|
1.49
|
0.3010
|
2.19
|
0.53
|
9.13
|
0.2820
|
|
Depression (no vs. yes)
|
0.69
|
0.30
|
1.62
|
0.3960
|
2.68
|
0.65
|
11.08
|
0.1730
|
|
Contact with livestock (no vs. yes)
|
0.25
|
0.05
|
1.18
|
0.0800
|
0.69
|
0.07
|
6.91
|
0.7520
|
|
Stool occult blood (no vs. yes)
|
0.10
|
0.01
|
0.78
|
0.0280[a]
|
0.17
|
0.02
|
1.88
|
0.1480
|
Abbreviations: AGE, acute gastroenteritis; AOP, adjusted odds ratio; CI, confidence
interval; OR, odds ratio; PI-IBS, post-infection irritable bowel syndrome.
a
p < 0.05.
Discussion
As IBS is a common diagnosis in the outpatient department, a prospective study helps
us better in establishing AGE as an etiology for developing IBS, minimizing recall
bias and enhancing the quality of follow-ups and hence the data regarding risk factors
obtained. Although AGE is very common in tropical countries with poor hygiene, information
on PI-IBS is very scarce from these countries. Gwee et al, in 1996, had studied a
group of 75 patients with AGE, 20 of which had PI-IBS at 6 months (26.6%).[8] We found the incidence of PI-IBS to be 25% by Rome IV criteria in our study. The
Walkerton Health Study had also reported approximately 30% incidence of PI-IBS in
subjects with AGE.[4] Recently, in a study with 136 patients of AGE in Orissa, the incidence of PI-IBS
was reported to be 25.7% at 6 months by Rome III criteria.[9] However, in a study in 2006, only 3.7% incidence of PI-IBS in community subjects
was noted.[10] This was diagnosed by Manning and Rome I criteria, which currently are obsolete.
In the present study, females developed PI-IBS more than males (14 vs. 11); however,
it was not statistically significant. Klem et al, in a systematic review and meta-analysis
in 2017, had reported that females are 2.2 times more likely to develop PI-IBS.[11] Ruigómez et al and Wensaas et al have also reported PI-IBS to be more prevalent
in females but, it may not be statistically significant.[12]
[13] McKendrick and Read found in their study that women were almost five times more
as compared with men among those who had persistent symptoms after AGE.[14] Age less than or equal to 60 years was found to be statistically significant in
our study for the development of PI-IBS. This is comparable to majority of the studies
conducted to study risk factors associated with the development of PI-IBS.[4]
[6]
[9] Ji et al, on the contrary, did not find any significant difference in ages between
patients who did and did not develop PI-IBS.[15]
In our study, duration of AGE of more than 7 days and presence of abdominal cramps
were two independently significant risk factors (p = 0.0001) associated with the development of PI-IBS. Singh et al, in an Indian study,
have validated the same with duration of AGE and abdominal cramps getting more points
in a PI-IBS risk score.[16] A study by Kowalcyk et al also described these two factors as statistically significant
for development of PI-IBS.[17] Paula et al had studied the relationship between antibiotic use and FGID.[18] We found that though a higher number of patients with history of antibiotic consumption
developed PI-IBS, it was not statistically significant. More elaborate studies with
details of antibiotics might be needed to study their role in the development of PI-IBS.
Psychological disorders like depression and anxiety have been long associated with
FGIDs. In our study, patients with depression, according to HADS questionnaire, were
found to have statistically significant risk of developing PI-IBS (p = 0.050). Anxiety, however, was not statistically significant. Wouters et al had
observed that both anxiety and depression led to increased risk of developing PI-IBS.[19] The HADS questionnaire has been validated for clinical use in the general population
and has been found to perform well in diagnosing anxiety and depression.[20] Sykes et al also found that anxiety predisposed to development of IBS.[21] In a review of clinical and epidemiological perspectives of IBS in India, Rahman
et al observed that majority of patients could not be classified as IBS-C or IBS-D
and were put into a mixed category (IBS-M) as most of them could not define their
symptoms in accordance with frequency of stool criteria for constipation or diarrhea.[22] However, the patients in our study who developed PI-IBS could be subtyped with 72%
patients falling under the IBS-D category.
Our study did not show any stool cultures with growth of enteropathogens, hence we
could not relate the type of organism causing AGE as a risk factor for the development
of PI-IBS. As most of our patients had consumed antibiotics prior to hospital admission,
it may have influenced the result of stool cultures. Salmonella and Campylobacter
causing AGE have been found to commonly predispose to PI-IBS.[23] Genetic testing also plays a significant role in determining genetic risk factors
that predispose an individual to PI-IBS, like mutations in toll-like receptors, interleukin-6,
and cadherin-1.[24] This could yield more informative results in future prospective studies.
The patients in our study were not evaluated for conditions like tropical sprue and
small intestinal bacterial overgrowth (SIBO) that have been reported in recent studies
in the Indian subcontinent.[25] The frequency of SIBO has been reported to vary from 4 to 78% in patients with IBS,
especially diarrhea-predominant.[26] The frequency of tropical sprue has not been determined in association with PI-IBS
due to lack of studies in this area. In one study from Bangladesh, 9% of the patients
with PI-IBS according to Rome III criteria had at least two abnormal mucosal absorption
tests indicating tropical sprue or post-infection malabsorption syndrome (PI-MAS).[27] Ghoshal and Rahman, in a recent publication, have also suggested the need of larger
studies with mucosal absorption tests to estimate the incidence of tropical sprue
and PI-MAS, which in the absence of overt malnutrition can mimic PI-IBS.[28] Invasive and expensive investigations like small intestinal biopsies and jejunal
aspirates needed to rule out these co-existing conditions were a limitation to our
study.
The symptoms of PI-IBS are often treated as new episodes of subsequent AGE, sometimes
due to the patients visiting multiple physicians with the same problems. Physicians
should keep a high suspicion for PI-IBS, in patients with predisposing risk factors.
It is suggested to study a larger cohort, with inclusion of genetic risk factors to
extrapolate the statistics to the general population. The molecular mechanisms possibly
involved in the pathogenesis of PI-IBS should be investigated for better understanding
of the disease, and to plan and strategize therapeutic options. Targeting the gut
microbiota and its alteration is currently a topic of focus, and is proving to be
promising in the management of PI-IBS.
