Challenges in the diagnosis of ulcerative colitis with concomitant bacterial infections and chronic infectious colitis
Challenges in the diagnosis of ulcerative colitis with concomitant bacterial infections and chronic infectious colitis
Wei-Chen Lin 1 2
Chen-Wang Chang 1 2
Ming-Jen Chen 1 2
Cheng-Hsin Chu 1 2
Shou- Chuan Shih 1 2
Tzu-Chi Hsu 0 2
Horng-Yang Wang 1 2
0 Division of Colon and Rectal Surgery, Mackay Memorial Hospital , Taipei , Taiwan
1 Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital , Taipei , Taiwan
2 Editor: John Green, University Hospital Llandough , UNITED KINGDOM
Ulcerative colitis (UC) is a chronic inflammation of the large bowel characterized by diarrhea and a negative stool culture. However, several enteropathogens have been implicated as causative agents in UC. The differentiation between chronic infectious colitis (IC) and UC with concurrent infection is difficult owing to their similar clinical presentations. The study aimed to explore the presentations and diagnostic clues that enable differentiation between UC with concomitant infections and chronic IC. The study included 17 UC patients with a bacterial infection and 46 with chronic IC. The UC patients (47 ± 19 years) were younger than the chronic IC patients (58 ± 20 years) (P = 0.022). Bloody diarrhea was more common in UC than in chronic IC (58.8% vs 10.9%, P < 0.001). Previous antibiotic usage was a risk factor for chronic IC (5.9% vs 32.6%, P = 0.031). Malignancy was a common comorbidity of chronic IC (5.9% vs 34.8%, P = 0.022). UC patients had lower antibiotic response rates than chronic IC patients (60.0% vs 87.2%, P = 0.026). Aeromonas species and Clostridium difficile were common in both groups. Histological features of cryptitis and crypt abscess were useful in the diagnosis of UC (P = 0.052 and P = 0.016, respectively). Bloody diarrhea in a young adult, decreased response to antibiotic treatment, and results of endoscopy with biopsy are important features in the diagnosis of UC with bacterial infection.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Ulcerative colitis (UC), an inflammatory bowel disease (IBD) involving the large bowel, is
characterized by the presence of diarrhea and bloody mucoid stool. Exclusion of infectious
etiology in the diagnosis of UC is important, as the symptoms of infectious colitis, as well as
the endoscopic and histological findings, overlap with UC.[
] The prevailing theory of the
pathogenesis of UC suggests that the intestinal immune system is inappropriately activated
due to a confluence of genetic and environmental factors that leads to inflammatory tissue
] Imbalances in the gut flora or specific bacterial strains play an role in the
inflammatory process of UC.[
A large epidemiological study showed that the hazard ratio of IBD was 2.4 (95% confidence
interval [CI], 1.7±3.3) in a gastroenteritis cohort compared to a control cohort without a
] A higher risk of UC was noted during the first year after the infective
episode (hazard ratio, 3.7; 95% CI, 1.8±7.5). In this study, the most commonly identified
bacteria causing the enteric infection was Campylobacter spp., followed by Salmonella spp. and
] Another study found concurrent enteral infections at the time of IBD diagnosis in
21% of cases.[
] Shigella, Salmonella, and Yersinia strains have been investigated as a possible
cause of UC, and Clostridium difficile toxin has been associated with disease exacerbation.[
The role of Aeromonas species in UC is controversial, but recent studies have suggested that it
can trigger UC relapse.[
Chronic diarrhea is a common but challenging clinical scenario due to the presence of sev
eral hundred differential diagnoses.[
] Despite the use of invasive colonoscopy in chronic
diarrhea, the majority of macroscopic findings are unremarkable.[
] The most common causes
include irritable bowel syndrome, IBD, microscopic colitis, and malabsorption syndromes.
] Infection is an uncommon cause of chronic diarrhea.[
] Bacteria are less likely and
parasites are most likely to cause chronic infectious colitis (IC) in immunocompetent patients.[
However, when diarrhea lasts more than 4 weeks, other differentiated diagnoses such as UC should be considered.
To date, a causative bacterial agent for UC has not been identified because of the complexity
of the colonic ecosystem.[
] Some commensal bacteria might become pathogenic under
certain circumstances, and most bacteria live within the lumen without entering the mucosa.[
The differential diagnoses of UC and IC may be complicated by their clinical, endoscopic, and
] especially in cases of undiagnosed UC complicated by infection.
Therefore, in the present study, we compared the manifestations and the diagnostic clues of chronic
IC versus UC with a concomitant bacterial infection.
Materials and methods
Patients with UC and chronic diarrhea and a concomitant bacterial infection at Mackay
Memorial Hospital, Taipei Medical Center between January 2014 and March 2017 were
enrolled. The diagnosis of UC was based on a clinical evaluation of the patient's medical
history, clinical evaluation and typical endoscopic and histological findings. Chronic diarrhea is
defined as an increased number of unformed stools (three or more times per day) compared
with the normal state lasting at least 4 weeks.[
] Chronic infectious colitis is characterized by
chronic diarrhea with a positive stool test (mucus, white blood cells, red blood cells, and
culture for bacterial pathogens), and/or mucosal inflammation on colonoscopy. This study was
approved by the Institutional Review Board of Mackay Memorial Hospital (reference number:
17MMHIS089), which waived the requirement for informed consent because of its
retrospective design. Patient information was anonymized and de-identified prior to the analysis.
The database included computerized medical records of demographic data including age, sex,
and underlying comorbidities. All stool samples were analyzed for parasites, neutral fat, occult
blood, and pus cells. Stool samples were sent to a laboratory for routine culture (Salmonella,
Shigella, Campylobacter, Vibrio, Aeromonas, Plesiomonas, and C. difficile). Due to the low
sensitivity of C. difficile culture, a combined qualitative enzyme immunoassay of both toxin A/B
and glutamate dehydrogenase was performed.
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Clinical presentations included bloody diarrhea, fever (>38.0ÊC), weight lost and
abdominal pain. Medical history included antibiotic, proton-pump inhibitor, nonsteroidal
anti-inflammatory drug, and immunosuppressant drug use within the previous 6 weeks.
Laboratory data included complete blood count, C-reactive protein (CRP), and albumin level. Histological features included cryptitis, crypt abscess, Paneth cell metaplasia, and plasma/lymphocyte infiltrates.
Descriptive statistics for continuous variables are reported as mean ± standard deviation (SD).
The categorical variables were described using frequency distributions and are reported as n
(%). P values were based on a t-test for continuous variables and the chi-square or Fisher's
exact test was used for the categorical variables. The statistical analysis was performed using
the STATA statistical package (version 12.0; Stata, College Station, TX, USA). Tests were
twotailed with a significance level of 0.05.
The demographic and disease characteristics of patients with UC and chronic IC are
summarized in Table 1. There were 17 UC patients with a concomitant bacterial infection and 46
patients with chronic IC. The mean age of the UC patients (46.5 ± 19.2 years) was lower than
that of the chronic IC patients (57.9 ± 19.9 years) (P = 0.022). The male-to-female ratio of UC
and chronic IC patients was 1.4:1 and 0.9:1, respectively (P = 0.438). Bloody diarrhea is more
common in UC than in chronic IC (58.8% vs 10.9%, P < 0.001). Minor differences were seen
in symptoms such as abdominal pain, fever, and weight loss.
In previous medical history, antibiotic use was a risk factor of chronic IC (5.9% vs 32.6%,
P = 0.031). There were no differences in previous proton pump inhibitor, nonsteroidal
antiinflammatory drug, or immunosuppressant drug use. Malignancies were less common in
UC than in chronic IC (5.9% vs 34.8%, P = 0.022). The mean platelet count (351.0 ± 179.5 vs
225.1 ± 118.4 109/L, P = 0.001) was higher among UC patients than among chronic IC
patients. The hemoglobin, leukocyte, albumin, and CRP levels were not significantly different.
In terms of clinical management, 5-aminosalicylic acid (88.2% vs 6.5%, P < 0.001) and steroid
(29.4% vs 6.5%, P = 0.015) were more commonly used in the UC group. Antibiotics were the
most common first-line agent in both groups (differences not statistically significant). UC
patients had a lower response rate to antibiotic treatment than chronic IC patients (60.0% vs
87.2%, P = 0.026).
Infection in UC
Seventeen UC patients with a concomitant bacterial infection were enrolled; of them, eight
were initially diagnosed (Table 2). Pancolitis was the most common disease site (52.9%),
followed by left-side colitis (29.4%) and proctitis (17.6%). Two patients did not undergo
colonoscopy due to the disease occurring during a UC flare-up. Among 11 of 15 (73.3%) patients with
histologic UC features, six were initial diagnosis. Patients 1 and 2 presented with diarrhea that
was refractory to antibiotic treatment and diagnosed 1 month after endoscopic follow-up.
Patients 3 and 4, who had no histologic features, were diagnosed by their endoscopic features
and good response to 5-aminosalicylic acid treatment. Aeromonas species (41.2%, 7/17) were
the most common pathogen in UC patients with a concurrent infection, followed by C. difficile
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Abbreviations: NSAID, nonsteroidal anti-inflammatory drugs; 5-ASA, 5-aminosalicylic acid
P value was determined using t-test§ or
UC (N = 17)
Biopsies were performed at the time of infection in 15 of 17 patients with UC and 27 of 46 patients with chronic IC (Table 3). Cryptitis (13.3% vs 0%, P = 0.052) and crypt abscess (20% vs 0%, P = 0.016) were commonly seen in UC patients. There were no differences in plasma/ lymphocyte infiltration (P = 0.344) or Paneth cell metaplasia (P = 0.174) in the two groups.
Pathogenicity of different species
Aeromonas species was the most common pathogen in 62.5% (5/8) patients with an initial UC
diagnosis and 47.8% (22/46) of patients with chronic IC (S1 Table). C. difficile was the most
common pathogen in 44.4% of UC patients with flare-ups and the second most common
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pathogen (30.4%, 14/46) in chronic IC patients. However, there was no statistically significant
difference in pathogens between UC and chronic IC.
Diarrhea was long thought to be caused by infectious agents such as bacteria. In 1875, Wilks
and Moxon first described UC as a separate entity from IC.[
] Thereafter, UC was suggested
to be a chronic remitting-relapsing disease of the large colon for which an infective cause
should be excluded. Increasing evidence shows that a persistent infection with a specific
pathogen was related to degradation of the luminal protective structures and led to UC.[
the present retrospective study, we observed 17 UC patients with a concomitant bacterial
infection and compared them to a control group of 46 patients with chronic IC. Aeromonas
species and Clostridium difficile were common causative pathogens in UC and chronic IC. UC
patients tended to be younger. Symptoms of bloody diarrhea, poor response to antibiotics
treatment and histological UC features are useful in the initial diagnosis of UC with a
Bloody diarrhea is the most common characteristic symptom of UC, but elderly patients
have a less typical presentation.[
] In a prospective study of cases of acute bloody diarrhea
(<7 days) treated in emergency rooms caused by infectious agents, Shigella species was the
UC (N = 15)
IC (N = 27)
most common pathogen (15.3%), followed by Campylobacter and Salmonella spp.[
] In our
study, Aeromonas species are the most common pathogens in UC and chronic IC, followed by
C. difficile, which are quite different from the pathogens in acute bloody diarrhea. In Taiwan,
the most common etiologic agent in infectious diarrhea seen in community clinics is
Campylobacter species, and C. difficile is the most common pathogen in children. There was no sex
difference in the distribution of enteric pathogens in both adults and children. [
The most common symptom of Aeromonas infection is acute self-limiting diarrhea, while
bloody diarrhea and chronic indolent diarrhea have also been reported.[
] Aeromonas can
be a trigger of flare-ups or the development of IBD and cause a more severe infection in IBD
patients than in non-IBD patients.[
] The incidence of C. difficile in IBD has doubled in recent
years, increasing significantly in UC patients.[
] C. difficile can induce or mimic a UC
flareup, and patients with a concomitant C. difficile infection experience increased morbidity and
A previous study showed that thrombocytosis is associated with surrogate markers for UC
because the platelets are potent proinflammatory cells and inflammatory amplifiers in chronic
] The platelet count is markedly increased during the active stage
of UC (defined as platelet count >450×109/L), making it a rational marker for therapeutic
] In this study, the mean platelet count was higher in the UC group, but
remained within the upper limit of normal. This finding may be associated with chronicity
in our patients, making the platelet count less useful for differential diagnosis. CRP levels
increased with disease extent at UC diagnosis and could be used as a predictor of the need for
] The levels of nearly 70% UC patients were within the normal range;[
it was less useful as a marker for UC than for Crohn's disease.
Histological features of chronicity such as a distorted crypt architecture, Paneth cell meta
plasia, and increased plasma cell/lymphocyte infiltrates can help with the diagnosis of UC.[
In this study, 73.3% (11/15) of UC patients have typical histology and crypt abscess was the
strongest histological predictor of UC. The presence of plasma/lymphocyte infiltrates was not
a useful marker since 25.9% (7/27) of chronic IC patients also had such features. A previous
study showed that basal plasmacytosis was the most useful feature that differentiated UC from
IC; however, 81% of those IC patients had acute-onset disease and did not show any histologi
cal UC features.[
] Another study revealed that chronic IC may produce a histological pattern
of chronic active colitis that mimics UC.[
] The histological features are often not present
during the initial phase of UC.[
] Crypt distortion and basal plasmacytosis first appear 2
weeks after infection and subsequently increase in frequency.[
] Therefore, the most suitable
time to obtain a biopsy was 4±6 weeks after the first UC attack.
First, because bacterial infection is rarely a cause of chronic diarrhea and UC, the small sample
size and retrospective design of this study might have led to patient selection bias. A
prospective, large-scale study is needed to determine the role of enteric pathogens in UC. Second,
41.3% (19/46) of the clinical responses of chronic IC patients to antibiotic treatment were
not confirmed with follow-up endoscopy, indicating that the possibility of UC could not be
completely excluded. A short course of antibiotic therapy proved effective in patients with any
stage of UC.[
] Third, it is very difficult to determine whether UC is caused by bacterial
colonization or a new infection in a newly diagnosed patient. We cannot exclude the possibility
that other agents are responsible for UC owing to the complexity of the colonic ecosystem.
Most bacteria live within the lumen and do not enter the mucosa, so microbiological investigations of rectal biopsy samples may provide more solid evidence.
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Making the initial diagnosis of UC in patients with concomitant bacterial infections and dif
fuse continued mucosal inflammation in the colonoscopy is challenging. The combination of
bloody diarrhea in a young adult and poor response to antibiotic treatment is an important
clue to the possibility of undiagnosed UC. Follow-up colonoscopy with a biopsy wound help
provide solid evidence for UC diagnosis.
S1 Table. Pathogens identified in cases of initially diagnosed UC, UC flare-up, and chronic
The authors would like to thank all gastroenterology faculty of MacKay Memorial Hospital for excellent clinical assistance and care.
Conceptualization: Wei-Chen Lin, Horng-Yang Wang.
Data curation: Wei-Chen Lin, Tzu-Chi Hsu.
Formal analysis: Wei-Chen Lin, Ming-Jen Chen.
Funding acquisition: Shou-Chuan Shih.
Methodology: Chen-Wang Chang, Tzu-Chi Hsu.
Project administration: Cheng-Hsin Chu.
Resources: Cheng-Hsin Chu, Shou-Chuan Shih.
Software: Chen-Wang Chang.
Validation: Ming-Jen Chen.
Writing ± original draft: Wei-Chen Lin.
Writing ± review & editing: Horng-Yang Wang.
Supervision: Chen-Wang Chang, Cheng-Hsin Chu, Horng-Yang Wang.
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