Eosinophilic Colitis and Colonic Eosinophilia
Eosinophilic Colitis and Colonic Eosinophilia
CURRENT
OPINION Eosinophilic colitis and colonic eosinophilia
Marjorie M. Walker, Michael D. Potter, and Nicholas J. Talley
Purpose of review
Eosinophilic colitis is a rare condition, with a prevalence rate in the USA of 2–3/100 000 persons
(0.003%), but diagnosed in 0.1% of biopsies in those colonoscoped for diarrhoea. Secondary colonic
eosinophilia is more common and associated with systemic, colonic and infectious diseases. In this review,
the latest advances in diagnosis, treatment and prognosis are summarized and discussed.
Recent findings
What constitutes a ‘normal’ count of eosinophils is poorly documented but there are recent studies that
establish normal colonic eosinophil ranges as well as distinguishing histological and clinical findings in
primary eosinophilic colitis and secondary colonic eosinophilia in children and adults. Primary eosinophilic
colitis is rare, relatively straightforward to diagnose, but may be difficult to treat. Colonic eosinophilia may
be overt in parasite infection and connective tissue disease. More subtle, secondary colonic eosinophilia is
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a useful biomarker for gastrointestinal diseases, such as inflammatory bowel disease, colonic spirochaetosis
and collagenous colitis, but the eosinophilia may more often be overlooked. A limited number of drugs are
also known to cause left sided colonic eosinophilia such as clopidogrel, ibuprofen and oestroprogestinic
agents.
Summary
Advances in our understanding of primary eosinophilic colitis and secondary colonic eosinophilia is
progressing and if present, colonic eosinophilia should point the clinician and pathologist to a list of
differential diagnoses worth considering to direct optimal management.
Keywords
colitis, colon, eosinophils
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colon biopsies in busy routine histopathology depart- estimates from patients with no obvious mucosal
ments to establish the clinical background. disease are shown in Table 1 (pediatric biopsies) and
It is difficult to obtain true normal estimates of Table 2 (adult biopsies). Whilst both show a marked
eosinophils in colonic biopsies; however, recent best variation in mean, uniformly the highest number
Turner et al. USA-statewide 159 Normal colonoscopy/ Right colon 55.7 23.4
[22], 2017 discrete polyps/histologically
normal
Transverse colon 41.0 18.6
Left colon 28.6 17.2
Matsushita Japan 25 Normal colonoscopy/ Caecum/ascending/ 36.59 15.50
et al. [23] 2015 histologically normal transverse colon
Descending/sigmoid 8.53 7.83
colon/rectum
Polydorides Worcester, Ascending colon 35.2 (SD 4.4)
et al. [30] 2008 Massachusetts, USA
Descending colon 11.3 (SD 4.2)
are present in the caecum/right colon with a tail off made, which showed little difference in geographi-
to the rectosigmoid. In a clinical setting, however, cal region [23]. A study from Colorado specifically of
there have been studies that attempt to address this paediatric patients with colonic eosinophilia con-
issue. In the proximal colon, eosinophils may even cluded this was present in three main groups, those
occasionally infiltrate crypt epithelium, compared with eosinophilic colitis, or inflammatory bowel
&
with the distal colon where this finding is seen in disease (IBD) or no significant colonic disease [24 ].
less than 5% of biopsies [9]. In a study evaluating Turner et al. [22] suggest a diagnostic algorithm
yield of biopsy for diagnosis of diarrhoea, the biopsy that relies on the eosinophil numbers derived from
diagnosis of eosinophilic colitis can be made from these patients without full clinical data. The idea is
all sites from left to right colon; 0.1% had symptoms sensible, but perhaps the cut offs should be viewed
of diarrhoea as an indication for colonoscopy [17]. with caution in light of pediatric and adult data that
&
Kiss et al. [18 ] is to be commended for tackling clearly shows functional may be pathological in
the difficulties of defining normal counts in chil- terms of eosinophil numbers. It is likely that ‘nor-
dren and also highlighting that eosinophil counts mal’ is a spectrum and we should not be too wedded
should be expressed per square millimeters for com- to absolute numbers. In the presence of innumera-
parability between studies. This meta-analysis also ble eosinophils with crypt abscesses, eosinophil
points out that previous studies have shown eosin- degranulation, abnormal location of eosinophils
ophilia to be present in functional bowel disorders, and lack of acute inflammation the diagnosis of
for example, in duodenal biopsies in functional eosinophilic colitis should be easily made, whereas
dyspepsia in both adults [19] and children [20] in if numerous, but not excess, colonic eosinophilia is
the absence of endoscopic or other routine present one should seek a cause for this diagnosis
histological findings. [25]. Reasonable cut-offs for diagnosis of eosino-
Indeed, one study that looked at mild, moderate philic colitis [25] and colonic eosinophilia [22] are
or marked eosinophilia in colonic biopsies found no presented in Table 3.
relationship with single symptoms, and as func-
tional and other diseases are usually characterized
by a constellation of symptoms [21], this underlines HYPEREOSINOPHILIC SYNDROME
the importance of clinicopathological correlation. Currently defined as blood eosinophilia of greater
There are very few studies that have truly normal than 1500 cells/ml for more than 1 month in the
pediatric controls and as such there is no robust data absence of other causes for eosinophilia (infections,
as yet for normal cut offs of eosinophil density in the parasitic or viral, allergic disease, drugs, chemicals,
&
small intestine and the colon [18 ]. In adults, similar hypoadrenalism, and cancer), HES is rare but impor-
&
caveats should be applied. The largest study is of tant to recognize [10 ]. The syndrome occurs pre-
biopsies from 159 patients biopsies with a normal dominately in men, 20–50 years of age, with
colonoscopy or discrete polyps only and a normal endocardial disease with risk of embolization, eosin-
histology diagnosis [22]. In a Japanese study, com- ophilic gastrointestinal disease and high levels of
&
parisons for patients from Japan and Hawaii were mast cell tryptase in serum [31 ].
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Table 3. Suggested guideline for counts/HPF for case reports of colonic eosinophilia with docu-
eosinophilic colitis and colonic eosinophilia mented biopsy confirmation and resolution of symp-
toms on withdrawal of the drug include rifampicin
Eosinophilic colitis More than 100 eosinophils per HPF
Collins [25], 2014 in the right colon [38], carbamazepine [39], gold and also three cases of
(children and adults) eosinophilic colitis in liver transplant recipients on
More than 84 eosinophils per HPF in tacrolimus in association with food allergy [40].
the transverse or descending colon
More than 64 eosinophils per HPF in
the rectosigmoid colon Inflammatory bowel disease: Crohn’s disease
Colonic eosinophilia More than 50 eosinophils per HPF in and ulcerative colitis
Turner et al. [22], the right colon The role of the eosinophil in inflammatory bowel
2017 (adults)
disease (IBD), ulcerative colitis and Crohn’s disease
More than 35 eosinophils per HPF in
is debated, but it is now apparent that colonic
the transverse colon
eosinophilia may contribute to disease and have
More than 25 eosinophils per HPF in
the left colon
prognostic significance in both. In Geboes’ scoring
system for ulcerative colitis [41] and that of Naini
HPF, high power field. and Cortina [42], eosinophils are specifically scored,
although not all histology systems include this
parameter [43]. However, recent work shows the
COLONIC EOSINOPHILIA value of assessing colonic eosinophilia in predicting
outcome in IBD. Histology compared with endos-
Allergic colitis and proctitis copy is a better indicator of mucosal healing [44].
In children, the most common cause of rectal bleed- The presence of eosinophils in the lamina propria in
ing in those under the age of 2 years is allergic Crohn’s disease is a significant indication of
proctocolitis, a food protein-induced allergy to usu- impending flare-up of disease when examined in
ally cow’s milk protein, either alone or in combina- biopsies at 6, 12, and 24 months [45]. In paediatric
tion with soy protein and if breast fed, sensitized Crohn’s disease, ileal stricturing is associated with
because of maternal ingestion of proteins [9,32]. Of eosinophilia with epithelial interleukin (IL)-33
note, rectal biopsies show minimal epithelial dam- expression inducing intestinal fibroblast production
age but greater than 60 eosinophils/10 high power of pro-inflammatory cytokines [46]. In ulcerative
fields (HPFs) in the lamina propria, which may spill colitis in children, mucosal and blood eosinophilia
into the muscularis mucosa [33]. is correlated with clinical severity of disease at diag-
nosis and predict a need for short-term step-up of
therapy [26].
Drugs inducing colonic eosinophilia/colitis In the PROTECT study of ulcerative colitis, an
Colonic eosinophilia (not amounting to eosino- assigned eosinophil infiltrate of less than 32/HPF in
philic colitis ) may be considered as a general feature rectal biopsies was deemed low [47] – this was based
of drug pathology and is associated with a range of on the study of ‘normal’ patients by DeBrosse et al.
medications but few studies that back this up [34]. It [29] from a study of rectal biopsies in 13 paediatric
should be remembered that temporal clinicopatho- patients with functional bowel disorders, mean
logical correlation is needed, and ideally, improve- score 8.36 5.9, maximum count 32. In the PRO-
ment on withdrawal and rechallenge provoking TECT study, 42% of patients (155/369) had grade 1
symptoms as evidence, but this is rarely feasible eosinophilia, that is, none or 32 or less eosinophils/
for the pathologist. HPF and 56% (206/369) grade 2, with a peak eosin-
In a study of drug related colitis adopting strict ophil count greater than 32/HPF. It is conceivable
cause-effect with temporal criteria between the use that further divisions of this eosinophil count may
of a single drug (or two similar), Casella et al. [35] have shed more prognostic light in this study.
established a common pattern of left sided colitis In ulcerative colitis with primary sclerosing
with eosinophilia in relation to antiplatelet drugs cholangitis (PSC), caecal biopsies eosinophil num-
(clopidogrel, aspirin and ticlodipine), ibuprofen and bers were increased in both active ulcerative colitis
oestroprogestinic agents. and ulcerative colitis-PSC, but with different pro-
Most other reports are only single case studies. inflammatory cytokine profiles in colonic mucosa;
Nonsteroidal anti-inflammatory drugs (NSAIDs), thus the eosinophil activation phenotype may dis-
including naproxen, have been described to induce criminate between ulcerative colitis and PSC-ulcer-
colonic eosinophilia on biopsy [36] and also colonic ative colitis [48]. In a meta-analysis of 15 studies on
eosinophilia with solitary caecal ulcer [37]. Other histological disease activity in ulcerative colitis,
absence of eosinophils (and neutrophils) were asso- Table 4. Known drug triggers of colonic eosinophilia
ciated with a lower probability of relapse or exacer-
Antiplatelet drugs, clopidogrel, aspirin and ticlopidine
bation [49].
Nonsteroidal anti-inflammatory drugs (NSAIDs) – ibuprofen,
In a study that compared ulcerative colitis and
naproxen
Crohn’s disease, colonic eosinophils were increased
Oestroprogestinic agents
in the active phase of both diseases compared with
Rifampicin
controls, however, in quiescent disease, eosinophil
numbers were lower in Crohn’s disease but in ulcer- Carbamazepine
ative colitis, on a par with active disease [50]. This Gold
study suggested that eosinophil activation in Tacrolimus
Crohn’s disease and ulcerative colitis is a result of
a different host T-helper profile in the two diseases, a
TH-1 profile in Crohn’s disease and TH-2 in ulcera- collagenous [56] colitis. Useful markers of activity
tive colitis [50]. Subsequent work shows that eosin- are elevated faecal levels of eosinophil granule pro-
ophils and GM-CSF derived from TH17 cells teins [57].
contributes to relapse and chronicity of IBD [14,51].
TREATMENT
Infections: parasitic and nonparasitic, colonic Careful evaluation for secondary causes of colonic
spirochaetosis eosinophilia (Table 4) will allow for targeted treat-
Tissue and peripheral eosinophilia is seen in infec- ment or removal of culprit medications. Colonic
tion with Enterobius vermicularis (pinworms), Ancy- spirochaetosis has been effectively treated with met-
lostoma caninum (hookworms), Ascaris spp., Anisakis ronidazole, although randomized controlled trials
spp., Eustoma rotundatum, Trichuris spp., and Schis- are lacking [53].
tosoma spp. [5]. To diagnose parasitic infection, a The treatment for eosinophilic colitis is based
travel history, laboratory evaluation of stool for ova upon case series and expert opinion, and often
and parasites, serology and sometimes histologic considered with or extrapolated from the manage-
& &
examination of endoscopic biopsies is necessary. ment of eosinophilic gastroenteritis [10 ,58 ]. Ele-
Diagnostic paracentesis should be performed in mental and elimination diets such as the four or six
patients presenting with suspected eosinophilic food elimination diets, which remove the common-
ascites [5]. est antigenic triggers (milk, wheat, eggs, soy, seafood
Recently colonic spirochaetosis has been associ- and nuts), and used with much success in eosino-
ated with irritable bowel syndrome with diarrhea, philic oesophagitis [59], have been shown to be
and in the histology, colonic mucosa (rectal and effective in the treatment of eosinophilic colitis,
particularly sigmoid biopsies) show characteristic and may be a reasonable first line nonpharmaco-
&
clusters of subepithelial eosinophils [52 ,53]. logical option in motivated patients [60]. Cortico-
steroid therapy, at doses 0.5–1 mg/kg are considered
&
first line pharmacological treatment [58 ,61]. This
Connective tissue disease and vasculitis can be tapered over 2–4 weeks, although some
Whilst 20 cases of connective tissue disease (CTD) – patients may require prolonged treatment (see
& &
systemic lupus erythematosus, rheumatoid arthritis, ‘Prognosis’ below) [10 ,58 ].
systemic sclerosis, dermato/polymyositis and Sjög- Budesonide, a poorly absorbed corticosteroid
ren’s syndrome – associated with eosinophilic gas- may be a useful alternative in those in who require
trointestinal disease have been published, only prolonged treatment in order to avoid the systemic
rheumatoid arthritis is associated with eosinophilic side effects of corticosteroids [62,63]. Other steroid-
colitis [54]. In vasculitis, polyarteritis and eosino- sparing agents, which have been used successfully in
philic granulomatosis with polyangiitis may present the treatment of eosinophilic colitis include 5-ami-
in the colon with small vessel eosinophilic inflam- nosalicylic acid [64], azathioprine [64,65], antitu-
mation, peripheral eosinophilia and autoantibodies mor necrosis factor agents such as infliximab and
&
are also present [31 ]. adalimumab [66], mast cell stabilizers such as keto-
tifen [67], and faecal microbiota transplantation
[68]. Surgery may be required for presentations with
Microscopic colitis: lymphocytic colitis/ acute abdomen [69], although some have described
collagenous colitis conservative management of severe presentations
Of note, studies highlight an eosinophil infiltrate [65]. An approach to treatment is outlined below
in microscopic colitis, both lymphocytic [55] and (Fig. 1).
0267-1379 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-gastroenterology.com 47
Acknowledgements
CONCLUSION None.
Eosinophilic colitis is a rare disorder characterized
by abnormal eosinophilic infiltration of the colon. Financial support and sponsorship
Clinical presentation is varied, but symptoms None.
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