The Turkish Journal of Gastroenterology
Volume 17, No 1, Page(s) 53-57
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|Dense eosinophilic infiltration of the mucosa preceding
ulcerative colitis and mimicking eosinophilic colitis:
Report of two cases
|Hülya UZUNİSMAİL1, İbrahim HATEMİ1, Gülen DOĞUSOY2, Onat AKIN3
|Departments of 1Gastroenterology, 2Pathology İstanbul University Cerrahpaşa Medical Faculty, 3Patomed, İstanbul
|Keywords: Ulcerative colitis, eosinophils, eosinophilic colitis.
There is increasing evidence about the involvement of eosinophils
in the pathogenesis of inflammatory bowel disease. We report
here two patients with ulcerative colitis who were initially
diagnosed as eosinophilic colitis based on histopathological
examination during their first attacks. They had symptomatic
improvement with ketotifen and metronidazole during their
first attacks. However, subsequent attacks which were histopathologically
diagnosed as ulcerative colitis did not resolve with
the above-mentioned treatment and necessitated a treatment
with 5-ASA agents plus corticosteroids. Azathioprine also had
to be added in the treatment of the second patient. Dense eosinophilic
infiltration in these cases may suggest a role of eosinophils
in the initiation of attacks in some ulcerative colitis patients.
Eosinophils are present in healthy gut mucosa
and their presence is considered to be protective
against bacteria and more so against helminthic
parasites. Eosinophils can cause tissue damage by
releasing cytotoxic granule proteins. Activated eosinophils
also produce cytokines, chemokines and
lipid mediators which modulate immune response
and amplify the immune cascade (1). Increased
knowledge about the diverse function of eosinophils
has provoked curiosity about their potential
role in the physiopathology of different diseases,
represented by an increased tissue eosinophil count.
The role of eosinophilic granules in the pathogenesis
of gut inflammation is well known in eosinophilic
gastroenteritis in which tissue injury was found
to be correlated with degranulated eosinophil
count, eosinophilic cationic protein (2) and major
basic protein levels (3). Increased count and activation
of eosinophils are also detected in celiac disease
(3, 4) and collagenous colitis (5), as well as in
the active phase of ulcerative colitis (UC) and
Crohn’s disease (CD) (6-9). Different methods such
as electron microscopy (7), determination of eosinophil
granule protein levels (8) and immunohistological
examination of tissue samples (9) were
utilized to show that tissue eosinophils in inflammatory
bowel disease (IBD) are active rather than
resting cells. Increased levels of eosinophil granule
proteins were detected in perfusion fluids in UC
(10) and in stool (11-13 ) and gut lavage fluids (14,
15) in both UC and CD. All these findings suggest
that eosinophils contribute to tissue damage and intestinal inflammation in IBD. Activated eosinophils
play an important role in ongoing disease
due to granule proteins, eosinophil derivated cytokines
and lipid mediators, but it is not known
whether eosinophils initiate the attacks in these
We report here two cases presenting as eosinophilic
colitis in their first attacks of colitis who were
diagnosed as UC based on histological and clinical
findings in later attacks.
An 18-year-old female patient was admitted with
bloody diarrhea. Her medical history was unremarkable;
her sister had UC. Stool culture was negative,
no parasites or ova were detected by microscopic
examination. Colonoscopy showed that
rectum and sigmoid colon mucosa was hyperemic
and edematous with increased exudation. In histopathological
examination, dominant eosinophilic
infiltration of lamina propria without crypt destruction
suggested eosinophilic colitis. The mean
eosinophil count was 34 per high-power field
Her complaints regressed with 2 mg of ketotifen
and 500 mg metronidazole, b.i.d, and elimination
diet. Two years later she was hospitalized again
because of bloody diarrhea, weight loss and abdominal
pain. Her erythrocyte sedimentation rate
(ESR) was 40 mm/hour, C-reactive protein (CRP)
7 mg/L (normal range 0-5), hemoglobin 9 g/dl, hematocrit
26%, and WBC count 7300/ml with no eosinophils
on peripheral smear. Her IgE level was 355.7 IU/ml (normal range 0-100) and serum albumin
level 3.65 mg/dl. Stool culture was negative,
no parasites were found, and toxin A and B assays
for Clostridium difficile were negative. Endoscopy
showed left-sided colitis with diffuse edema, hyperemia,
fine granular appearance, fragility and increased
exudation. In histopathological examination,
fibropurulent exudation on surface epithelium,
distortion and inflammation of crypts, and dense
infiltration of lymphoplasmocytes and neutrophils
on lamina propria were noted. Histological diagnosis
was active phase of UC (Figure 2).
Clinical activity was moderate according to the
Mitsuru Seo index (16). Because of the past diagnosis
of eosinophilic colitis, the same therapy was
started but her symptoms did not improve.
Methylprednisolone 32 mg/day, sulfasalazine 3
g/day and mesalamine enemas were started.
Symptomatic, clinical, and histological remission
was achieved. For maintenance therapy, sulfasalazine
2 gr/day was recommended.
A 52-year-old female patient was admitted with
bloody diarrhea and abdominal pain. The patient
had been in good health until one week previously.
Her daughter was being treated for severe UC
(past five years). Her stool culture was negative,
no parasites or ova were detected, and Clostridium
difficile toxins A and B assays were negative.
Eosinophil count was 420/mm3 with 7% of total leucocytes. IgE level was 28.3 IU/L. ESR was 18
mm/hour. Colonoscopy showed left-sided colitis
with hyperemia, edema and increased exudation.
Histopathological examination showed focal distortion
of crypts and dense eosinophilic infiltration
of lamina propria, and the diagnosis was eosinophilic
colitis. The mean eosinophil count was 30
per high-power field (Figure 3). Ketotifen (2 mg)
and 500 mg of metronidazole, b.i.d., and elimination
diet were started. Symptomatic relief was obtained
but she refused colonoscopic control.
Six months later she had another attack of bloody
diarrhea. Her stool examination showed no parasites
or ova, there were no Clostridium difficile toxins,
and stool culture was negative. Her eosinophil
count was 630 with WBC 10500/ml. Her ESR
was 27 mm/hour, hemoglobin level 12.4 g/dl, CRP
10 U/L, and albumin 4.1 g/dl. Colonoscopy showed
hyperemia, edema, petechial hemorrhage areas
and increased exudation beginning from rectum
and continuing as far as the mid transverse colon.
Ulcerations with a diameter of 1-2 mm were also
detected in this region. Clinical activity was mild
according to the Mitsuru Seo index. Histopathological
diagnosis was active phase of UC. Ulceration
on surface epithelium, decreased number of crypts
and goblet cells, distortion of crypts, neutrophilic
infiltration of lamina propria and crypts, and infiltration
of lymphoplasmocytes on lamina propria
were noted (Figure 4).
As symptomatic relief had been achieved with the
first treatment when the diagnosis was eosinophilic
colitis, the same regimen was started, but no
symptomatic improvement could be obtained. The
patient’s symptoms improved with methylprednisolone
36 mg/day, mesalamine tablets 3 g/day and
mesalamine enemas, but the symptoms recurred
after methylprednisolone was tapered 4 mg/per
week to a dose of 28 mg/day. The patient was considered
to be steroid-dependent after a second
high-dose therapeutic attempt, in regular descending
dose manner, demonstrated no positive result;
hence, azathioprine was necessary to obtain
Figure 1. Eosinophilic infiltration of lamina propria suggesting
Figure 2. Histopathologic findings suggesting active phase UC:
distortion and inflammation of crypts, and dense infiltration of
lymphoplasmocytes and neutrophils on lamina propria
Figure 3. Eosinophilic colitis: focal distortion of crypts and
dense eosinophilic infiltration of lamina propria
Figure 4. Ulcerative colitis: regeneration of surface epithelium,
and decreased number of crypts and goblets cells
The findings of our patients suggest that in some
UC patients eosinophilic infiltration may precede
UC. Eosinophil infiltration can be expected in UC.
The classical knowledge of the cytokine pattern of
UC is that it is a Th-2 disease with increased IL-5
release (17). Matsuzaki et al. (18) have shown that
Th-2 responses mainly occur in colonic mucosa
with mild inflammation, while Th1 responses significantly
occur with severe inflammation in UC
patients. IL-5 and eotaxin, which is an eosinophilspecific
chemoattractant, play an important role
in eosinophil recruitment (19). High levels of serum
eotaxin are found during active disease in UC
and CD (20), but Mir et al. (21) reported that high
levels may be detected in both active and inactive
We may have detected the inflammatory cell infiltration,
which was mainly eosinophilic, in the
early lesions of UC. This finding could suggest
that eosinophilic infiltration is the initiating event
for UC in some patients. We could not detect the
exact duration between the onset of symptoms and histopatholological examination in our first patient,
but it was eight days in the second patient.
The histopathological findings of this patient may
be an example of the very early stage of a first UC
Generally, IBD is a disease of younger ages. The
majority of patients with UC seek medical assistance
from internists or local general practitioners
for their first attacks with bloody diarrhea. Diagnostic
tools such as stool examinations (e.g., parasites,
culture) are requested and an empiric antibiotic
treatment is usually prescribed even in case
of negative results. In fact, endoscopic and histopathologic
examinations in patients with bloody
diarrhea are done afterwards. Thus, all initial
steps have taken some time.
Seegert et al. (22) detected significantly increased
IL-16 mRNA and IL-16 protein in the inflamed colonic
mucosa of patients with IBD compared to
controls. They also detected that most of IL-16
protein was predominantly expressed in eosinophils.
IL-16 has strong chemoattractant activity on
CD4+ T cells and stimulates the expression and
production of pro-inflammatory cytokines by human
monocytes (23). The study of Seegert (22) led
us to consider whether eosinophils not only modulate,
but also initiate, the inflammation in IBD.
There is no data about the early lesion of UC yet,
but in early recurrence of CD, a higher expression
of IL-5 mRNA was found in involved areas compared
to endoscopically normal ones (24). In another
study by Desreumaux et al. (25), eosinophil count
per area was found to be increased in both chronic
and early lesions and was significantly higher
than in controls. However, according to the inflammation
score, increase in the number of eosinophils
was statistically significant in the early lesions.
Although cytokine profile tends to be predominantly Th-1 type with increased levels of IFN-α
in CD (17, 26), Desreumaux et al. (25) showed that
while chronic intestinal lesions of CD are compatible
with a Th-1 type pattern, early lesions are associated
with a Th-2 type pattern with significant
increase of IL-4 mRNA and decrease of IFN-α m-
RNA. The authors suggested that there were divergent
cytokine patterns during different clinical
stages and noticed that the shift from type 2 to
type 1 pattern was also detected in atopic dermatitis,
as suggested by Thepen et al. (27). The relation
of Th-2 cytokine pattern with colitis was also
determined in animal models, such as the T cell
receptor α chain-deficient mice model, in which
the colitis develops spontaneously within three
months of age (28), and the oxazolone colitis murine
model, which is more characteristic of UC (29).
The Th-2 type cytokine pattern is seen in allergic
disorders, and eosinophils are closely associated
with Th-2 immune response (19, 30). Another finding
of our patients was the positive family history
of their first-degree relatives. Positive family
history is an important finding not only in IBD but
also in allergic disorders.
These two cases may be an example of a subgroup
of UC patients with massive eosinophilic infiltration
as Heatley et al. (31) has suggested. The authors
have pointed out that the large numbers of
eosinophils in rectal mucosa during active disease
might predict a benign course in some patients
who have responded to disodium chromoglycate.
Recently, this theory was also supported by successful
response to ketotifen therapy for UC in
children who were observed to have high tissue eosinophilia
These two cases may be an example of the event in
which eosinophils can initiate the attacks of ulcerative
colitis at least in a minority of patients.
1. Wardlaw AJ, Barry Kay A. Eosinophils and their disorders.
In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligshon
U, eds. William’s Haematology. Sixth ed. New York:
McGraw Hill, 2001; 785-99.
2. Keshavarzian A, Saverymuttu SH, Tai PC, et al. Activated
eosinophils in familial eosinophilic gastroenteritis. Gastroenterology
1985; 88: 1041-9.
3. Talley NJ, Kephart GM, McGovern TW, et al. Deposition of
eosinophil granule major basic protein in eosinophilic gastroenteritis
and celiac disease. Gastroenterology 1992; 103:
4. Colombel JF, Torpier G, Janin A, et al. Activated eosinophils
in adult coeliac disease: evidence for a local release of
major basic protein. Gut 1992; 33: 1190-4.
5. Levy AM, Yamazaki K, Van Keulen VP, et al. Increased eosinophil
infiltration and degranulation in colonic tissue
from patients with collagenous colitis. Am J Gastroenterol
2001; 96: 1522-8.
6. Bischoff SC, Wedemeyer J, Herrmann A, et al. Quantitative
assessment of intestinal eosinophils and mast cells in
inflammatory bowel disease. Histopathology 1996; 28: 1-
7. Dvorak AM. Ultrastructural evidence for release of major
basic protein -containing crystalline cores of eosinophil granules
in vivo: cytotoxic potential in Crohn’s disease. J Immunol
1980; 125: 460-2.
8. Raab Y, Fredens K, Gerdin B, Hallgren R. Eosinophil activation
in ulcerative colitis: studies on mucosal release and
localization of eosinophil granule constituents. Dig Dis Sci
1998; 43: 1061-70.
9. Bischoff SC, Mayer J, Nguyen QT, Stolte M. Immunohistological
assessment of intestinal eosinophil activation in patients
with eosinophilic gastroenteritis and inflammatory
bowel disease. Am J Gastroenterol 1999; 94: 3521-9.
10. Carlson M, Raab Y, Peterson C, et al. Increased intraluminal
release of eosinophil granule proteins EPO, ECP, EPX,
and cytokines in ulcerative colitis and proctitis in segmental
perfusion. Am J Gastroneterol 1999; 94: 1876-83.
11. Berstad A, Borkje B, Riedel B, et al. Increased fecal eosinophil
cationic protein in inflammatory bowel disease. Hepatogastroenterology
1993; 40: 276-8.
12. Bischoff SC, Grabowsky J, Manns MP. Quantification of
inflammatory mediators in stool samples of patients with
inflammatory bowel disorders and controls. Dig Dis Sci
1997; 42: 394-403.
13. Saitoh O, Kojima K, Sugi K, et al. Fecal eosinophil granule
derived proteins reflect disease activity in inflammatory
bowel disease. Am J Gastroenterol 1999; 94: 3513-20.
14. Levy AM, Gleich GJ, Sandborn WJ, et al. Increased eosinophil
granule proteins in gut lavage fluid from patients
with inflammatory bowel disease. Mayo Clin Proc 1997; 72:
15. Troncone R, Caputo N, Esposito V, et al. Increased concentrations
of eosinophilic cationic protein in whole gut lavage
fluid from children with inflammatory bowel disease. J Pediatr
Gastroenterol Nutr 1999; 28: 164-8.
16. Seo M, Okada M, Tsuneyashi Y, et al. An index of disease
activity in patients with ulcerative colitis. Am J Gastroenterol
1992; 87: 971-6.
17. Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina
propria (LP) lymphokine secretion profiles in inflammatory
bowel disease. Crohn's disease LP cells manifest
increased secretion of IFN-gamma, whereas ulcerative colitis
LP cells manifest increased secretion of IL-5. J Immunol
1996; 157(3): 1261-70.
18. Matsuzaki K, Hokari R, Kato S, et al. Differential expression
of CCR5 and CRTH2 on infiltrated cells in colonic mucosa
of patients with ulcerative colitis. J Gastroenterol Hepatol
2003; 18: 1081-8.
19. Rankin SM, Conroy DM, Williams TJ. Eotaxin and eosinophil
recruitment: implications for human disease. Mol
Med Today 2000; 6: 20-7.
20. Chen W, Paulus B, Shu D, et al. Increased serum levels of
eotaxin in patients with inflammatory bowel disease.
Scand J Gastroenterol 2001; 36: 515-20.
21. Mir A, Minguez M, Tatay J, et al. Elevated serum eotaxin
levels in patients with inflammatory bowel disease. Am J
Gastroenterol 2002; 97: 1452-7.
22. Seegert D, Rosentiel P, Pfahler H, et al. Increased expression
of IL-16 in inflammatory bowel disease. Gut 2001; 48:
23. Mathy NL, Scheuer W, Lanzendorfer M, et al. Interleukin
–16 stimulates the expression and production of proinflammatory
cytokines by human monocytes. Immunology 2000;
24. Dubucquoi S, Janin A, Klein O, et al. Activated eosinophils
and interleukin 5 expression in early recurrence of Crohn’s
disease. Gut 1995; 37: 242-6.
25. Desreumaux P, Brandt E, Gambiez L, et al. Distinct cytokine
patterns in early and chronic ileal lesions of Crohn’s
disease. Gastroenterology 1997; 113: 118-26.
26. Niessner M, Volk BA. Altered Th1/Th2 cytokine profiles in
the intestinal mucosa of patients with inflammatory bowel
disease as assessed by quantitative reversed transcribed
polymerase chain reaction (RT-PCR). Clin Exp Immunol
1995; 1001: 428-35.
27. Thepen T, Langeveld-Wildschut EG, Bihari IC, et al. Biphasic
response against aeroallergen in atopic dermatitis
showing a switch from an initial Th2 response to a Th1 response.
J Allergy Clin Immunol 1996; 97: 828-37.
28. Iijima H, Takahashi I, Kishi D, et al. Alteration of interleukin
4 production results in the inhibition of T helper type
2 cell-dominated inflammatory bowel disease in T cell receptor
alpha chain-deficient mice. J Exp Med 1999; 190:
29. Boirivant M, Fuss I, Chu A, Strober W. Oxazolone colitis: a
murine model of T helper type 2 colitis treatable with antibodies
to interleukin-4. J Exp Med 1998; 16: 1929-39.
30. Bischoff SC, Mayer JH, Manns M. Allergy and the gut. Int
Arch Allergy Immunol 2000; 121: 270-83.
31. Heatley RV, James PD. Eosinophils in the rectal mucosa. A
simple method of predicting the outcome of ulcerative proctocolitis.
Gut 1978; 20: 787-91.
32. Jones NL, Roifman CM, Griffiths AM, Sherman P. Ketotifen
therapy for acute ulcerative colitis in children: a pilot
study. Dig Dis Sci 1998; 43: 609-15.
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