A Practical Approach in Differentiating IBD From Other Causes of Enterocolitis.

IBD is a chronic inflammatory condition of the GI tract which is generally categorized into CD and UC. Both conditions are characterized by chronic inflammation, but they affect different parts of the GI tract and have distinct features. UC usually affects only the colon and rectum and typically always involves the rectum with varying degrees of proximal involvement. The inflammation is usually continuous and predominantly affects the mucosa. Symptoms are usually bloody chronic diarrhea, urgency, and tenesmus. Arthralgia is common in both UC and CD as well as other extraintestinal manifestations. Typical histological features include a diffuse increase in mucosal chronic inflammatory cells, accompanied by varying degrees of basal plasmacytosis, mucosal architectural distortion, Paneth cell metaplasia, as well as neutrophil infiltrate in active disease. CD can affect any part of the GI tract, from the mouth to the anus, with the most common location being the ileum and the colon, with perianal involvement in a third of cases. All layers of the bowel wall are involved in a transmural fashion, and inflammation can occur in patches known as skip lesions. Strictures are commonly seen in advanced disease. Common symptoms are abdominal pain, diarrhea, weight loss, fever, and mouth ulcers. Unlike with UC, signs of malnutrition are common, and in ileocaecal disease, a right iliac fossa mass can sometimes be palpable, although this is more common in ITB. Histologically, there is chronic inflammation, mucosal architectural distortion, and the activity is discontinuous or patchy and of variable intensity, affecting any of the bowel segments; which, unlike in UC, mucosal changes may be mild or subtle. Granulomas, if present, are typically fewer in number per biopsied area, small (or micro), poorly formed, in superficial mucosa, non‐caseating, and non‐coalesced. These granulomas may also be seen in endoscopically non‐inflamed or normal‐looking areas. Even when the diagnosis of IBD is made, differentiation between the two conditions may be difficult, although one could argue that IBD is probably more of a spectrum of phenotypes rather than strictly two separate conditions. For example, cecal patch, rectal sparing, upper GI involvement, and perianal fistulas are also well recognized in UC [ 35 , 36 ]. When it is not possible to differentiate between the two, the diagnosis should be labeled as IBD‐unclassified (IBD‐U) rather than the previous misleading term “indeterminate colitis.” The management of the two conditions is generally the same but there are differences in terms of efficacy of various drugs as well as surgical outcomes. ITB is the great mimicker of IBD. ITB and CD share similarities, in that they are both chronic granulomatous diseases with similar symptoms, radiological, and endoscopic findings [ 37 ]. The usual clinical presentation of ITB consists of weight loss, night sweats, lethargy, chronic diarrhea, abdominal pain, and pulmonary symptoms [ 37 ]. TB can also manifest with extraintestinal manifestations such as reactive arthritis, erythema nodosum, erythema induratum, and uveitis, all of which can confound the diagnosis of CD [ 38 , 39 ]. Clinical examination usually discloses generalized abdominal pain and a mass localized to the right iliac fossa, lymphadenopathy, hepatomegaly due to involvement of the liver, and ascites [ 37 ]. ITB should always be considered as a differential in areas endemic for tuberculosis, and the Asian Organization for Crohn's and Colitis (AOCC) states that ITB should be excluded prior to IBD diagnosis [ 40 ]. There is currently no single test for the diagnosis of ITB, and the diagnosis is made on a constellation of endoscopic, radiological, histopathologic, and microbiological findings [ 40 ]. Endoscopically, patients with ITB usually have a patulous ileocecal valve with the presence of circumferential or transverse ulcers. Classical radiological findings of ITB include the presence of necrotic lymph nodes, a patulous ileocecal valve, the presence of short strictures, asymmetrical mural thickening, ascites or peritoneal and/or omental involvement, and pulmonary lesions. Histologically, ITB presents with large, confluent, and caseating granulomas with ulcers lined by histiocytes [ 41 ]. Microbiologically, AFB or PCR are taken as the gold standard for the diagnosis of ITB. However, it is worth noting that AFB positivity in the intestinal tissue has a very low sensitivity for the diagnosis of ITB [ 41 ]. Mycobacterium tuberculosis (MTB)‐PCR also has similar limitations with a pooled sensitivity of 47% [ 42 ]. As such, despite multiple modalities, distinguishing ITB from IBD remains a challenge. The Asia Pacific guidelines recommend an 8–12‐week therapeutic trial of ATT with close clinical monitoring for response to ATT, while repeat colonoscopy and biopsy are indicated if there is a lack of response to ATT [ 25 ]. An algorithm based on a prospective study in our center showed a high accuracy of 89.6% in distinguishing between ITB and CD [ 43 ]. Bacterial enterocolitis due to pathogens such as Shigella, Campylobacter, and Salmonella exerts its virulence via marauding the mucosa of the intestines or results in inflammation of the mucosa without invasion (e.g., Shiga toxin producing E. coli ) [ 44 ]. These bacterial pathogens usually result in an acute self‐limiting colitis. However, they may also result in persistent infection resulting in the histologic appearance of chronic colitis [ 44 ]. Yersinia enterocolitica and Yersinia pseudotuberculosis usually infect the terminal ileum, causing intestinal edema and ulceration, which can result in small bowel obstruction or a right iliac fossa mass [ 44 ]. The diagnosis of infectious diarrhea can be made by stool culture and microscopy, while appropriate anti‐microbial should be administered promptly once the diagnosis is made. Clostridium difficile infection (CDI) can mimic IBD, as the symptoms overlap significantly, which include diarrhea with or without blood, fever, fatigue, and weight loss. In CDI, diarrhea is typically caused by the toxins produced by C. difficile , leading to colitis. Stool testing for toxins encompasses Enzyme Immunoassay (EIA) for Toxins A and B, Glutamate dehydrogenase (GDH) antigen test, and NAATs. EIA for Toxins A and B is a rapid test used to detect C. difficile toxins A and B in stool samples. However, it is not the most sensitive test and may miss cases of CDI (false negatives). The GDH antigen test detects the presence of C. difficile bacteria through its metabolic enzyme (GDH). It is sensitive but not specific because it cannot distinguish between toxigenic and non‐toxigenic strains of C. difficile . As such, this test is often used in combination with toxin testing. NAATs utilize PCR to detect the genes responsible for toxin production (e.g., tcdB gene) and are highly sensitive and specific. However, they may detect colonization (presence of the bacteria without active disease). Given the limitations of the tests, a two‐step algorithm has therefore been proposed by The Infectious Disease Society of America (IDSA) whereby an initial GDH test is followed by toxin EIA or PCR if the GDH test is positive [ 45 ]. Patients with IBD are at higher risk for CDI; hence, it needs to be actively ruled out in patients presenting with an IBD flare. Treponema pallidum (Syphillis) and Lymphogranuloma venereum, L1, L2, L3 ( Chlamydia ) proctitis is common among patients with HIV infection and usually present with rectal bleeding and pain. Rectal ulcerations are commonly seen in this group of patients. The diagnosis can be made based on positive serology and PCR [ 44 ]. Histology usually reveals a dense infiltration of lymphohistiocytic cells with plasma cells and lymphoid aggregates with scant basal plasmacytosis and crypt distortion. Findings of a marked submucosal plasmacytic infiltrate without architectural distortion, eosinophilia, and acute crypt‐centric damage is consistent with infection [ 44 ]. Entamoeba hiatolytica , which causes amoebic colitis, is another IBD mimicker that can cause bloody diarrhea. Endoscopic findings include skip lesions and multifocal ulceration, which is more common on the right side of the colon and can mimic CD. Microbiologically, the diagnosis of amoebiasis can be made by stool microscopy and periodic‐acid Schiff (PAS) positive trophozoites on biopsy [ 45 ]. Histologically, there are flask‐shaped ulcers with florid necroinflammatory exudate [ 46 ], erythrophagocytosis, cryptitis, lamina propria‐containing chronic inflammatory infiltrates, surface epithelial damage, and PAS stains highlight the organisms [ 44 ]. In contrast to IBD, the mucosa adjacent to the amoebic ulcers is normal, with an absence of granuloma [ 46 ]. Of note, chronic amoebic infection can lead to crypt distortion and fibrosis, which could mimic IBD [ 47 ]. Strongyloides infection can sometimes mimic IBD, both in terms of symptoms and clinical presentation. Strongyloides infection presents with chronic or intermittent diarrhea, abdominal pain, weight loss, and malabsorption caused by the larvae migrating through the intestinal lining. Strongyloides infection often leads to peripheral eosinophilia, but may not be present in the early stages. Diagnosis can be made by full blood count looking for peripheral eosinophilia, stool examination for Strongyloides larvae, and Strongyloides serology [ 48 ]. It is important to distinguish Strongyloides infection from IBD as steroids or other immunosuppressants can result in hyperinfection syndrome, a life‐threatening complication where the parasite disseminates into multiple organs [ 49 ]. Trichuris trichiura infection can present with symptoms that closely resemble UC. Patients who have a history of l iving in or traveling to endemic areas, who present with chronic diarrhea, should prompt investigation with a full blood count to detect peripheral eosinophilia, stool ova cyst, and parasite test for identifying the characteristic eggs in a stool sample, which are barrel‐shaped, yellow‐brown in color, and have bipolar plugs [ 50 ]. Other tests include Trichuris trichiura serology, colonoscopy for direct visualization of the worms, fecal antigen detection, and polymerase chain reaction of the stool samples [ 50 ]. CMV is a common infection and most acquire it asymptomatically during childhood. At least 70% of adult individuals have been exposed to CMV and have a latent CMV infection. CMV rarely causes any disease in immunocompetent patients, but in immunocompromised patients, it can cause severe disease affecting many organs. CMV colitis should strongly be suspected in patients who are on chemotherapy or with underlying HIV infection [ 51 ]. Endoscopically, features of CMV colitis include punched‐out, geographic, longitudinal, and irregular ulcers but may appear completely undisguisable from UC. Histological tests including Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining, and/or tissue PCR. H&E staining reveals the classical “owl's eye” feature; the nuclei of cytomegalic cells containing CMV inclusion bodies are surrounded by clear cytoplasm [ 52 ]. One of the main issues is that CMV is not uncommonly seen on colonic biopsies of IBD patients, approximately around 20%–40% in patients with steroid‐refractory UC and 6% in patients with severe CD [ 53 ]. Whether CMV colitis is a sequela or a contributing factor in steroid refractory UC has been widely debated, but several studies have shown the presence of co‐existing CMV in IBD colitis is associated with worse outcomes [ 54 , 55 , 56 ]. Therefore, current guidelines recommend rectal biopsies should be carried out during severe flares of IBD to rule out CMV [ 57 ]. Ischemic enterocolitis is more common in the elderly and associated with certain medications such as antibiotics, chemotherapeutic agents, and nonsteroidal anti‐inflammatory drugs and certain co‐morbidities such as atrial fibrillation, hypertension, diabetes mellitus, coronary artery disease, peripheral vascular disease, chronic renal disease, and hemodialysis. Only 10% of patients present with gangrenous colitis, whereas most other patients have transient colitis, reversible colopathy, chronic segmental colitis, or strictures or universal fulminant colitis [ 58 ]. Common symptoms are sudden onset of colicky abdominal pain, urgency, per rectal bleeding, and diarrhea. Endoscopic features include segmental erythema with sharp demarcation, hemorrhagic nodules, colon single stripe sign (a single line of longitudinal erythema with erosion or ulceration) and mucosal gangrene. Histologically, the mucosa may be entirely hemorrhagic and necrotic, or shows hyaline change of the lamina propria with associated reduced lamina propria lymphoplasmacytic cells. Erosion and superficial ulceration with viable/partially viable basal parts of the crypts (withered crypts) are typical, sometimes accompanied by secondary neutrophilic infiltrate. Mucosal chronicity changes, as in chronic IBD, may be seen in chronic ischemic enterocolitis. BD is a systemic autoimmune disorder characterized by oral and genital ulcers, recurrent iritis or chorioretinitis, and skin lesions. Although it generally involves at least one other feature of systemic BD, isolated intestinal BD has been described [ 59 ]. Common GI symptoms include abdominal pain, chronic diarrhea, and per rectal bleeding, which clinically can be very difficult to differentiate from IBD. Patients with BD are more likely to have oral and genital ulcers, as well as neurological manifestations, whereas strictures, fistulae, and abscesses are more common in CD. Endoscopic features include large(> 1 cm), discrete (often single), oval or volcano‐shaped ulcers commonly in the ileocecal region or proximal ascending colon. Mucosal findings of intestinal BD are generally non‐specific, and vasculitic lesions may be identified in the submucosa, typically affecting small veins in the submucosa (phlebitis) with or without arteritis. Immunoglobulin M (IgM) anti‐α‐enolase antibody can be seen in roughly two‐thirds of cases. The term “solitary rectal ulcer syndrome” is a misnomer because patients with SRUS do not necessarily have an ulcer and the lesions are not always confined to the rectum [ 60 ]. Common symptoms include per rectal bleeding, pain, tenesmus, per rectal mucus often on a background of chronic and severe constipation [ 61 ]. It is important to elicit a history of self‐induced trauma by rectal digitation as well as straining and in some cases, rectal prolapse [ 62 , 63 ]. Endoscopic findings include one or more ulcerations which may extend up to the sigmoid colon, cauliflower‐looking tumors or edema. Histologically, there is a mild degree of architectural distortion, with diamond‐shaped angulated crypts. The lamina propria is typically fibrous and contains prominent smooth muscle cells fibers (of muscularis mucosal origin). Surface erosion ulceration is accompanied by neutrophil infiltration and variable granulation tissue formation. Unlike in chronic IBD, lymphoplasmacytic infiltrate in SRUS is not increased. Drug‐induced enterocolitis is a result of a drug's direct toxic effect on the GI tract causing enteritis as well as colitis. Its underlying pathophysiology involves an allergic reaction, or an immune‐mediated response. The enteritis can mimic IBD with symptoms such as bloody diarrhea, crampy abdominal pain, fever, loss of appetite, and loss of weight. NSAIDS result in damage to the upper GI tract, the small and large intestines. NSAIDS associated colitis histologically is associated with a small amount of inflammatory infiltrate in the mucosa near the ulcers. IBD, on the other hand, demonstrates an acute inflammation that extends to the adjacent mucosa. Histology of NSAIDS‐associated enterocolitis typically demonstrates a normal cryptal architecture with normal inflammatory cells, in contrast to CD, where there are chronic features of crypt distortion and focal lamina propria inflammation [ 47 ]. ICIs have changed the landscape of cancer treatment. They harness the ability of the patients own immune system to attack cancer cells by targeting several receptors, that is, PD‐L1, PD‐1, and CTLA‐4. Certain undesirable side effects that arise from ICI administration are linked to the overstimulation of the immune system [ 64 ] develop weeks to months after ICI commencement, which can be divided into acute (during treatment) and chronic (persistence 12 weeks after cessation of ICI) [ 65 ]. Symptoms include abdominal pain, diarrhea, fever, fatigue, weight loss, and PR bleeding. Checkpoint inhibitor colitis develops in approximately 10% of patients who receive anti‐CTLA4 and in 15% of those receiving a combination of ICI [ 66 ]. Endoscopy is the gold standard for the diagnosis of ICI‐induced colitis and can vary from normal‐appearing mucosa to erythema, erosions, and ulcerations, which may mimic UC [ 67 ]. Histologically, ICI are divided into 5 types: acute active colitis, chronic active colitis, microscopic colitis‐like, graft‐versus‐host disease‐like, and other types [ 64 ]. The histological changes of patients with ICI colitis demonstrate structural and/or architectural changes in the glands, chronic inflammatory infiltrate, lamina propria neutrophil infiltrate, epithelial neutrophils, crypt abscesses, crypt destruction, and erosions/ulcerations [ 68 ]. SCADD is another mimicker of UC which presents with bloody diarrhea and abdominal pain in patients 60 years and older and almost exclusively in males. Fever and weight loss are usually absent. The endoscopic appearance of SCADD is segmental colitis confined to the left colon with the presence of diverticular disease. Histologically, Haboubi and Alqudah divided this disease into four pathological groups: (1) mucosal herniation polyploidal lesion type which usually appears as a polyp and may mimic neoplasia, (2) Crohn's like granulomatous process, (3) UC like process and uncommonly, (4) collagenous colitis like process [ 69 ]. It is crucial that the endoscopist provide the pathologist all the relevant clinical examination and endoscopic findings. Rectal involvement rules out SCADD and biopsies should be submitted separately. Radiation proctopathy/colopathy occurs after exposure to radiation therapy and can be divided into acute, which is after 2 weeks of radiation, and chronic, which is 5 months to more than 5 years post radiation. Patients who have received more than 50 Gy of radiation to the cervical, prostate, or pelvic region are at risk [ 70 ]. Clinical features include diarrhea, cramping, bloating, pain, incontinence, mucus discharge, bleeding, tenesmus, and urgency [ 71 ]. Endoscopic features include pallor, edema, and friability of the mucosa, along with spontaneous bleeding and telangiectasias [ 72 ]. Histology in the acute phase demonstrates epithelial meganucleosis, dense eosinophilic inflammatory infiltrate, and presence of eosinophilic microabscess, apoptosis and slough, and presence of crypt regenerative cellular atypia, which can masquerade as dysplasia [ 46 ]. Chronic radiation proctopathy demonstrates arteriolar intimal proliferation, lamina propria telangiectasia, and submucosal hyalization of the vessel [ 46 ]. Primary EoC is common in infants and children but can also present in adulthood [ 73 ]. Diarrhea is the most frequent symptom, present in more than 60% of cases, and rectal bleeding can also be seen in 20%. Other symptoms include abdominal pain, nausea, and mild weight loss. A personal or family history of atopy such as allergic rhinitis, eczema, and asthma can sometimes be elicited. Endoscopic appearance can be normal in up to 70%, but some cases very much resemble UC with erythema, with loss of vascular pattern, and in very rare cases, ulcerations. Histologically, the presence of over 40 eosinophils per high‐power field (×400) in at least two different colonic segments can be considered diagnostic for the condition. Blood eosinophilia further supports the diagnosis but is only seen in 27%–75% of patients with EoC [ 74 ]. Intestinal lymphoma can be part of extranodal involvement of non‐Hodgkin lymphoma (NHL), but may be primary and can be very challenging to diagnose. Most cases of GI lymphoma are NHL, and around 10%–15% of NHL is only confined to the GI tract, with the stomach as the commonest site, followed by the ileocaecal region [ 75 ]. The clinical presentation can be very similar to that of IBD, such as non‐specific abdominal pain, weight loss, diarrhea with or without per rectal bleeding, and an abdominal mass. In some cases, night sweats and fever also can be present. A study by Kim et al. categorized the endoscopic findings into (i) superficial/erosive, (ii) ulcerative, (iii) ulceroinfiltrative, and (iv) infiltrative [ 76 ]. Histologically, the diagnosis of intestinal lymphoma may be missed if there is inadequate tissue acquisition and immunohistochemical stains are not carried out. The common findings include atypical lymphoid cells which may be monomorphic or polymorphic, depending on the lymphoma subtypes. Crypt architecture is not significantly distorted but may appear to be “run over” and reduced in number. Specific histologic patterns may be seen with certain tumor subtypes (e.g., follicular arrangement in follicular lymphoma and lymphoepithelial lesions in MALT lymphoma) [ 77 ]. Imaging with CT or PET may reveal multiple enlarged lymph nodes and involvement of other organs, but these may be absent in primary intestinal lymphomas. Diversion colitis is characterized by inflammation of the mucosa in the defunctioned segment of the colon after colostomy or ileostomy. Although the diagnosis should be obvious in such patients, many clinicians are still unaware of this condition and mistake it for residual CD (which may impact their subsequent management) or de novo IBD. Most patients are asymptomatic, but some patients present with per rectal mucus discharge and bleeding, tenesmus, and abdominal discomfort [ 78 ]. Endoscopically, common findings include erythema, edema, and friability. As with many other cases of chronic colitis, the histological features are non‐specific such as lymphoid follicular hyperplasia, cryptitis, crypt abscess, crypt branching and distortion, regenerative hyperplasia, Paneth cell metaplasia, and thickening of muscularis mucosa. Features of ischemia such as coagulative necrosis and fibrosis have also been described [ 79 ].

The biggest challenge in making a positive diagnosis of IBD is that there are many causes of chronic inflammation of the bowel (Tables  1 , 2 , 3 ) [ 3 ]. In Asia, many physicians often assume that this is due to infection, but in reality, most infections tend to be acute and are easily recognized by severe diarrhea (without per rectum [PR] bleeding) which may or may not be related to a known food source lasting typically from 3 to 7 days. Acute self‐limited infective type colitis (previously known as “dysentery”) can usually be differentiated based on clinical and histological findings [ 4 ]. However, there are also chronic infectious mimics of IBD such as Cytomegalovirus (CMV), Clostridium difficile , Giardia lamblia , Cryptosporidium, and Yersinia enterocolitica . One of the biggest diagnostic challenges is differentiating Crohn's disease (CD) from intestinal tuberculosis (ITB). In terms of non‐infectious mimics of IBD, the causes listed are by no means exhaustive, and an experienced gastroenterologist will probably come across many of these mimics during their practice, underlying the importance of being aware of these conditions and a comprehensive approach in making the correct diagnosis. In the terminal ileum, one of the main differential diagnoses is tuberculosis, but lymphoma and even gynecological conditions such as tubo‐ovarian abscess and endometriosis should be considered. In terms of colitis, in addition to infection, vascular‐associated causes such as Behçet's disease and ischemia are not uncommon. In the rectum, one should bear in mind common diagnoses such as solitary rectal ulcer syndrome, radiation‐induced proctopathy, and sexually transmitted infections such as Neisseria gonorrhoeae and syphilis. Differential diagnosis of colitis (adapted from Sand et al. 2004). Tuberculosis CMV Salmonella Acute self‐limiting colitis (infectious) Clostridium difficile Ulcerative colitis Crohn's colitis Bechet's disease Ischemic colitis Eosinophilic colitis Amyloidosis Differential diagnosis of proctitis (adapted from Sand et al. 2004). Tuberculosis Herpes simplex type II Neisseria gonorrhoeae Syphilis Lymphogranuloma venereum Chlamydia trachomatis Ulcerative colitis Crohn's colitis Bechet's disease Ischemic colitis Differential diagnosis of ileitis (adapted from Sand et al. 2004). Yersinia Mycobacterium Salmonella Crohn's disease Backwash ulcerative colitis Appendicitis/Appendicular abscess Caecal diverticulitis Tubo‐ovarian abscess Pelvic inflammatory disease Ovarian cysts Endometriosis Ischemia Bechet's disease Eosinophilic ileitis Amyloidosis Lymphoma Small bowel adenocarcinoma The typical features associated with some of the common causes of noninfectious and infectious enterocolitis are summarized in Table  4 and Table  5 . Overview of inflammatory bowel disease and non‐infectious mimics. Tenesmus, urgency, passage of mucus and per rectal bleeding in distal colitis. In extensive colitis, symptoms of abdominal pain, chronic diarrhea, weight loss and fever more common. Patients also may present with extra intestinal manifestation such as erythema nodosum and arthralgia Symmetrical, circumferential, and continuous inflammation that begins in the rectum and extends proximally without the presence of skip lesions. Decreased/loss of normal vascular marking, mucosal erythema, and edema in mild/early disease Ulceration and spontaneous mucosal bleeding in severe disease Pseudopolyps, muscular hypertrophy, loss of normal haustral pattern and shortening of colon in long standing disease Back wash ileitis, cecal patch and rectal sparing well recognized entities Diffuse increase in mucosal chronic inflammatory cells, accompanied by varying degrees of basal plasmacytosis, mucosal architectural distortion, as well as neutrophil infiltrate (activity). Paneth cell metaplasia, which is also a feature of chronicity common. pANCA elevated in 20%–85% of patients with UC pANCA+/ASCA− 51% sensitive and 94% specific in differentiating UC from CD Multiple other serological markers (e.g., anti‐OmpC anti‐Cbir1 and antilaminaribioside carbohydrate IgG (ALCA)) also associated with IBD The routine use of serology not recommended by most guidelines to diagnose IBD Chronic diarrhea, abdominal pain, anorexia, and weight loss. In more advanced disease, patients may present with complications such as bowel obstruction, intra‐abdominal abscess, and fistulising disease. Patients also may present with extra intestinal manifestation such as erythema nodosum and arthralgia Early endoscopic features include aphthous ulcers, stellate and other discrete ulcers, submucosal edema and the presence of skip lesions. In later stage, cobblestone appearance, fistula and stricture may occur. Chronic inflammation, mucosal architectural distortion and activity are discontinuous/patchy and of variable intensity, affecting any of the bowel segments. Mucosal changes may be mild/subtle. Granulomas, if present, are typically few in number per biopsied area, small (micro), poorly formed, in superficial mucosa, non‐caseating and non‐coalesced. May also be seen in endoscopically non‐inflamed/normal‐looking areas. Paneth cell and pseudopyloric metaplasia (additional features of chronicity) may be present. CT features include wall thickening, mucosal or mural enhancement, mural stratification, comb sign and lymphadenopathy but typically less than 1 cm. MRI enterography as first line imaging useful in diagnosing isolated small bowel CD and MRI pelvis important to diagnose and subsequently assess perianal fistulizing disease ASCA antibodies most widely recognized as being associated with CD pANCA+/ASCA− 51% sensitive and 94% specific in differentiating UC from CD The routine use of serology not recommended by most guidelines to diagnose IBD Ischemic enterocolitis is more common in the elderly and associate with certain medications such as antibiotics, chemotherapeutic agents, and nonsteroidal anti‐inflammatory drugs and certain co‐morbidities such as atrial fibrillation. Common symptoms are sudden onset of crampy abdominal pain, urgency, per rectal bleeding and diarrhea. CT abdomen may show continuous segmental thickening of bowel wall and fat stranding. Arterial and venous vascular abnormalities are uncommon findings. Bechet's disease characterized by oral and genital ulcers, recurrent iritis or chorioretinitis and skin lesions. Common GI symptoms include abdominal pain, chronic diarrhea and per rectal bleeding. Ulcers in Behçet's disease contain nonspecific chronic inflammatory cells. Some ulcers are associated with lymphoid follicles/Peyer patches (aphthoid lesions). No granulomas and mucosa around the ulcers usually normal. Vasculitic lesions may be identified in submucosa, typically affecting small veins in submucosa (phlebitis) with or without arteritis. Vascular inflammation may be predominantly lymphocytic or neutrophilic. Ischemic changes may be observed if larger vessels are involved. Unless vasculitic and ischemic changes are seen, the histology is generally nonspecific. Image courtesy of Byong Duk‐Ye, Asan Medical Centre History of manual digital evacuation. Common symptoms are passage of mucus and per rectal bleeding. Some patients may complain of tenesmus, straining, altered bowel habits, and sensation of incomplete evacuation. Endoanal ultrasound typically shows absence of distinction between the mucosa and the muscularis propria, thickened muscularis propria, thickening of the internal anal sphincter and external sphincter, thickened submucosal layer. Defecating proctography may reveal anorectal prolapse, external prolapse of rectum and intussusception on‐relaxing puborectalis muscle. Dynamic MRI may be indicated which can assess the function of pelvic muscles, rectum and sphincter as well as to look for constipation. Drugs can induce wide range of enterocolitis such as microscopic colitis, ischemic colitis, and inflammatory type colitis. Common medications include NSAID, PPI, SSRI, chemotherapeutics agents and check point inhibitors. Symptoms vary according to the type of injury ranging from no symptoms to chronic diarrhea (microscopic colitis) or bloody diarrhea similar to UC in checkpoint inhibitor colitis. Can be divided into four types: (1) Mucosal herniation polyploidal lesion type, (2) Crohn's like granulomatous features, (3) UC like features, (4) Collagenous colitis like features Acute phase—epithelial meganucleosis, dense eosinophilic inflammatory infiltrate, eosimophilic microabscess, apoptosis and slough, crypt regenerative cellular atypia Chronic phase—arteriolar intimal proliferation, lamina propria telangiectasia, and submucosal hyalization of the vessel. Eosinophilic colitis (primary) 40 eosinophils per high‐power field (×400) in at least two different colonic segments is considered diagnostic It is important to note that increased eosinophils may be seen in other conditions such as parasitic infections, drug induced enterocolitis and IBD Blood eosinophilia may be seen (27%–75%) Other investigations to rule out secondary causes of eosinophilic colitis (e.g., stool microscopy for ova, cysts and parasites, specific serology such as for Trichuris or Strongyloides) Common clinical features are non‐specific abdominal pain, weight loss, diarrhea with or without per rectal bleeding and presence of abdominal mass. In some cases, night sweat, and fever also can be present. The dense cellular infiltrate in lymphoma consists of atypical lymphoid cells that may be monomorphic or polymorphic, depending on the lymphoma subtypes. Crypt architecture is not significantly distorted but rather, they may appear to be “run over” and reduced in number. Specific histologic patterns may be seen with certain tumor subtypes (e.g., follicular arrangement in follicular lymphoma and lymphoepithelial lesions in MALT lymphoma). CT abdomen may show symmetrical thickening of bowel wall, mucosal enhancement, and intra‐abdominal lymphadenopathy (see figure below) CT thorax will further support the diagnosis if there is presence of mediastinal and cervical lymphadenopathy PET scans may also have a role if there is a high index of suspicion Excision biopsy for histology and IHC Bone marrow biopsy Features include lymphoid follicular hyperplasia, crytptitis, crypt abscess, crypt branching and distortion, regenerative hyperplasia, Paneth cell metaplasia and thickening of muscularis mucosa. Features of ischemia such coagulative necrosis and fibrosis can sometimes also be seen. Overview of infectious colitis that mimics IBD. Intestinal tuberculosis (ITB) is a great mimic of CD and may be impossible to differentiate clinically in some cases. Common symptoms include non‐specific chronic abdominal pain, weight loss, fever, diarrhea, or constipation, and per rectal bleeding. Patients may have extra intestinal involvement such as pulmonary changes or presence of ascites. Granulomas typically large, multiple/many and coalesced, commonly with central caseating necrosis. Seen in deeper mucosa and submucosa in endoscopically inflamed areas. Mild mucosal architectural distortion and increase in lamina propria chronic inflammatory cells may be observed in inflamed areas. Acid fact bacilli seen in 25%–36% CT abdomen may show thickening of ileocecal valve, asymmetrical bowel wall thickening and large intra‐abdominal lymphadenopathy with central necrosis. May also detect pulmonary involvement (lung consolidation or cavitation) and peritoneal involvement(ascites). Common organisms include Shigella, Campylobacter and Salmonella Common symptoms include acute diarrhea (usually less than 2‐week duration), abdominal pain, passage of mucus or per rectal bleeding. Symptoms can be prolonged especially in immunocompromised patients. Colonoscopy is not recommended in acute infectious colitis and reserved for specific situations such as in an immunocompromised patient where initial investigation does not yield diagnosis. Endoscopic findings include mucosal erythema, edema, granularity, ulceration, and loss of normal vascular pattern and may mimic features of inflammatory bowel disease. Mucosal architecture preserved. Variable amount of neutrophil infiltration of the lamina propria with or without cryptitis and crypt abscesses. Lamina propria lymphoplasmacytic infiltrate is not increased (mild increase may be seen in prolonged/resolving phase of infection but basal plasmacytosis is not expected). Stool culture Stool sample for specific assays e.g., Campylobacter spp. and Escherichia coli 0157:H7 depending on availability and clinical suspicion Yersinia enterocolitica , Yersinia pseudotuberculosis 90% are foodborne Presents with self‐limiting diarrhea with or without blood, right lower quadrant pain but chronic symptoms due to chronic infection can also occur Typically affects the terminal ileum Endoscopic findings include edema and ulceration mainly of the terminal ileum Serology Stool cultures Stool PCR Image courtesy of Rupert Leong, Concord Hospital, University of Sydney and Macquarie University Risk factors include use of broad‐spectrum antibiotics, older age group and recent hospitalization. IBD is a risk factor for C diff colitis and conversely, co‐existing C diff colitis is a risk factor for IBD flares Typical presentation is diarrhea with or without blood, fever, fatigue and weight loss Fibropurulent exudate (pseudomembranes on the mucosal surface) Underlying mucosa is often edematous and hyperemic. Ulcers, which are mostly superficial and linear, may also occur. Fibrin, neutrophils, necrotic epithelium, and mucus (pseudomembrane) Crypts filled with mucopurulent exudate extending outwards, forming a “mushroom” or “volcano” shape. Dense infiltration of neutrophils, lymphocytes, plasma cells, and sometimes eosinophils in the lamina propria. Shu‐Chen Wei Image courtesy of Shu Chen Wei, National Taiwan University Treponema pallidum  (Syphillis) and Lymphogranuloma venereum, L1, L2, L3 ( Chlamydia ) proctitis is common among patients with HIV infection Usually presents with rectal pain, tenesmus and bleeding. Dense infiltration of lymphohistiocytic cells with plasma cells and lymphoid aggregates with minimal basal plasmacytosis and crypt distortion. Granulomas sometimes seen in Chlamydia Serology Rectal swabs for nucleic acid amplification tests (NAATs) Image courtesy of Wai‐Keung Leung, University of Hong Kong Protozoal colitis (e.g., Entamoeba hiatolytica ) Thickening of caecum and ascending colon Hypodense lesion(s) in the liver with rim of peripheral enhancement if co‐existing liver abscess Serology Stool microscopy (Trophozoites with ingested red blood cells) Stool PCR and antigen test Image courtesy of Alex Leow Hwong Ruey, Pantai Hospital Kuala Lumpur Helminth‐associated colitis (e.g., Strongyloides , Trichuris trichiura ) Risk factors include poor sanitation and hygiene, direct contact with contaminated soil Presents with diarrhea, abdominal pain, passage of worms on bowel opening Blood eosinophil count Serology stool microscopy for ova and parasite Cytomegalovirus (CMV) The classical “owl's eye” feature; the nuclei of cytomegalic cells containing CMV inclusion bodies surrounded by clear cytoplasm, CMV on IHC CMV DNA PCR (not diagnostic for CMV colitis but high levels more indicative of CMV disease) Stool for PCR Image courtesy of Shu‐Chen Wei, National Taiwan University

In view of the fact that there are many mimics of IBD and their therapeutic strategies largely differ, it is imperative for clinicians to clinch the precise diagnosis. This relies on a combination of typical clinical, endoscopic, radiological, and histological features and, in some cases, may require a therapeutic trial (shown in Figure  1 ). Approach to diagnosing IBD and other causes of enterocolitis. Differentiating IBD from infectious enterocolitis can be very difficult. A salient feature of IBD is its nature of chronicity. The hallmark of ulcerative colitis (UC) is diarrhea with blood, but in patients with proctitis, there is only PR bleeding with or without mucus [ 5 ]. However, infectious enterocolitis with bloody diarrhea, constipation, and tenesmus has also been described [ 6 ]. Abdominal pain, diarrhea, weight loss, and fever are the typical features of CD; PR bleeding is also a common symptom in colonic CD as well as perianal discharge and pain in those with co‐existing perianal fistulas. Right iliac fossa mass and evidence of malnutrition are also common in CD [ 7 ]. One should also enquire about the typical symptoms and signs associated with the common extra‐intestinal complications (arthropathy, skin manifestation, and anemia) as well as non‐steroidal anti‐inflammatory drug (NSAID) use, family history, diet, smoking, appendicectomy, and alcohol intake. A comprehensive history and examination are also important in terms of diagnosing or ruling out other causes of enterocolitis. Examples of potentially relevant history are atrial fibrillation or history of arteriopathy (ischemic colitis), ischemic heart disease, prostatic cancer with radiotherapy (radiation proctopathy), long‐term immunosuppressive therapy (CMV), drug history including over‐the‐counter non‐steroidal anti‐inflammatory drugs (NSAIDs), close contact with tuberculosis (TB), sexual history such as men who have sex with men (human immunodeficiency virus [HIV] associated enterocolitis). Examination findings which may be relevant would include orogenital ulcers (Bechet's, HIV), oral candidiasis, and large, palpable lymph nodes (lymphoma, TB). It is self‐evident that endoscopy plays a pivotal role in the workup of patients with enterocolitis. The most relevant is an ileocolonoscopy, but oesophagogastroduodenoscopy (OGD) and small bowel endoscopy (enteroscopy and capsule endoscopy) may be indicated for suspected isolated small pathology. In patients with suspected IBD, capsule endoscopy should not be carried out without a magnetic resonance enterography (MRE) or CT enterography (CTE) and ideally a patency capsule to avoid capsule retention. Endoscopic features which favor various causes of enterocolitis have been described, but often are also non‐specific, and differentiation from IBD can be challenging. Histology plays a very important role in making a diagnosis of IBD [ 5 , 8 ]. The typical features are the presence of chronic inflammatory cells, crypt architectural abnormalities, lymphoid aggregates, basal plasmacytosis, Paneth cell metaplasia, and villous surface. In Crohn's disease, one of the hallmarks is the presence of small non‐caseating granulomas [ 7 ]. The role of the clinicians is very important, that is, providing a complete history and differential diagnosis, accurate description of the endoscopic findings, adequate sampling from macroscopically abnormal and normal areas with precise labeling, and providing the pathologist with the working diagnosis or differential diagnosis so that specific immunohistochemistry (IHC) depending on clinical suspicion (acid‐fast bacilli [AFB], CMV, stains for lymphoma) can be carried out. Nevertheless, there are many pitfalls in making the diagnosis even on histology and again underlines the importance of a good clinical history and examination as well as other supporting investigations. For example, mucosal architectural distortion (e.g., crypt distortion), crypt abscesses, and lamina propria chronic inflammatory cells with basal plasmacytosis can be seen in almost all chronic enterocolitis such as ischemic and diverticular associated colitis [ 9 ]. Likewise, early UC may not show histological features of chronicity, making it difficult to initially distinguish from acute self‐limited infective type colitis [ 10 ]. In terms of differentiation between UC and CD, endoscopic and histological conundrums such as the above mentioned “cecal patch” [ 11 ], rectal sparing either as part of the initial phenotype (common in the pediatric group) [ 12 , 13 ] or due to topical therapy; gastroduodenal involvement and even granulomas in UC [ 14 ], have all been described and it is important to have an experienced pathologist to understand and recognize the pitfalls when making a positive diagnosis. As a standard investigation in someone with diarrhea, stool should be cultured for common pathogens including specific assays for Clostridium difficile toxin A and B, Campylobacter spp., and Escherichia coli 0157:H7; and stool microscopy (fresh, warm samples) should be carried out for amoebae or other parasites. However, one has to be aware of the false positives (coexisting infection) and false negatives (inappropriate stool collection, available assays, and partially treated, viral infection). Stool multiplex polymerase chain reaction (PCR) has the ability to detect multiple organisms with a very high sensitivity and specificity compared to conventional tests. However, it is limited by cost and availability, and any positive findings have to be interpreted in the correct clinical context [ 15 ]. They can also be used in confirmed cases of IBD during a flare to rule out co‐existing infection. Stool multiplex PCR assay versus conventional stool tests for detecting gastrointestinal (GI) infection as a cause for flare of inflammatory bowel disease [ 16 ]. Contrary to popular belief, stool calprotectin is not specific for IBD, as it is elevated in all inflammatory conditions of the GI tract including colorectal cancer [ 17 ]. Stool calprotectin has a role in differentiating organic pathology from irritable bowel syndrome or functional GI disorders and may be a useful first‐line investigation in suspected isolated small bowel Crohn's disease if OGD or ileocolonoscopy is normal [ 18 ]. Stool calprotectin has an important role in the assessment of disease activity and monitoring response to treatment and may be useful in IBD as well as its mimics including ITB. Imaging has an important role in the diagnosis of IBD. MRE is an important first‐line investigation in cases of isolated small bowel Crohn's disease. An index CT thorax, abdomen, and pelvis have an important role in supporting the diagnosis of IBD as well as diagnosing other pathology. Classical features of CD include wall thickening, mucosal or mural enhancement, mural stratification, comb sign, and reactive intraabdominal lymphadenopathy [ 19 ], whereas extra GI findings such as significantly enlarged lymph nodes/generalized lymphadenopathy, large volume ascites, and lung involvement will strongly point to another pathology such as tuberculosis and lymphoma. Ancillary tests for tuberculosis are essential in countries with a high prevalence of TB, such as Tuberculin skin test (TST) and Interferon gamma release assays (IGRA). However, one has to be aware of the false positives (latent TB, Bacillus Calmette‐Guérin [BCG] vaccination for TST) and false negatives (immunocompromised state). Tissue sampling for TB‐PCR is also important, but the limitations include cost, variable accuracy of assays, with an overall sensitivity of about 23% [ 20 ]. Antibodies in IBD patients are known to cross‐react with bacterial and fungal antigens due to abnormal immune interaction between the host and commensal enteric microorganisms [ 21 ]. Among the earliest recognized positive associations are between anti‐ Saccharomyces cerevisiae antibodies (ASCA) and CD; anti‐neutrophil cytoplasmic antibodies (ANCA) and UC [ 22 ]. Multiple other serological markers (e.g., anti‐OmpC, anti‐Cbir1 and antilaminaribioside carbohydrate IgG [ALCA]) are also associated with IBD. For now, they are still not recommended in most guidelines as a routine test in the diagnostic workup due to the overall low sensitivity and specificity [ 23 , 24 , 25 ]. Serology has been looked into for differentiating between CD and UC [ 26 ], as well as IBD and other GI disorders (including functional GI disease) but many overlaps remain, making interpretation difficult [ 27 ]. The role of ASCA in differentiating CD from ITB is controversial; studies in East Asia suggest there may be a role, in contrast to studies from India that failed to show a benefit [ 28 , 29 , 30 ]. There may be other relevant investigations depending on the clinical suspicion, such as urine or rectal samples for nucleic‐acid amplification (NAAT) or PCR for suspected sexually transmitted disease and lymph node excision biopsy for suspected lymphoma. In some cases, particularly in differentiating CD from ITB, a therapeutic trial is often necessary. A study from Mouli et al. showed that although a significant proportion of patients with CD treated with antitubercular therapy (ATT) had an initial response, repeat colonoscopy at 6 months of treatment showed mucosal healing in 100% patients with ITB, whereas < 5% of patients with CD had an endoscopic response [ 31 ]. However, delays in starting therapy in CD following a full course of ATT can result in an increased risk of fibro‐stenotic disease [ 32 , 33 ]. Therefore, reassessment including a repeat colonoscopy at 8–12 weeks should be carried out and CD therapy should then be initiated if there is a suboptimal response to ATT, although in cases of definite intestinal TB with rapid clinical and biochemical response, colonoscopy can be delayed till the completion on treatment at 6 months. Likewise, if the treatment for CD results in worsening or suboptimal symptoms, reassessment at 8–12 weeks to look for again for ITB should be carried out which may be inadvertently revealed following immunosuppressive therapy [ 31 , 34 ].

Despite all the advances in the therapeutic world of IBD, a positive diagnosis of IBD remains a challenge. In some cases, a therapeutic trial may be necessary, but close monitoring and periodic reassessment are essential.

Inflammatory bowel disease (IBD) is a chronic, inflammatory autoimmune condition mainly affecting the small and large bowel. The disease is emerging in Asia [ 1 , 2 ], but is still relatively rare, and even in populations where IBD is common, making the diagnosis can remain a challenge. There is no gold standard for the diagnosis of IBD, which is often made based on a combination of clinical, endoscopic, radiological, and histological features, none of which are specific for the condition.

Prof Ida Normiha Hilmi is the Associate Editor of JGH Open and a co‐author of this article. To minimize bias, she was excluded from all editorial decision making related to the acceptance of this article for publication. All other authors declare no conflicts of interest.