2026 APSPGHAN意见书：儿童炎症性肠病（PIBD）的诊断——对亚太地区的影响

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# Diagnosis of Pediatric Inflammatory Bowel Disease (PIBD)-Implications for the Asia-Pacific Region: A Position Paper from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition PIBD Working Group

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Received: Mar 9, 2025 Revised: Aug 31, 2025 Accepted: Oct 12, 2025 Published online: Jan 6, 2026

Correspondence to

Rohan Malik

Department of Pediatrics, Mother and Child Block, All India Institute of Medical Sciences, Room 803, Ansari Nagar, New Delhi 110029, India.

Email: dr.rohanmalik@gmail.com

Copyright © 2026 by The Korean Society of

Copyright © 2026 by The Korean Society of

Pediatric Gastroenterology, Hepatology and Nutrition

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ORCID iDs

Rohan Malik ID: https://orcid.org/0000-0003-3450-9668 Marion M Aw ID: https://orcid.org/0000-0002-6668-4623 Way Seah Lee ID: https://orcid.org/0000-0001-9163-2828 Andy Darma ID: https://orcid.org/0000-0001-5107-5895 Pornthep Tanpowpong ID: https://orcid.org/0000-0002-9374-8805

Rohan Malik ID,$^{1}$ Marion M Aw ID,$^{2}$ Way Seah Lee ID,$^{3}$ Andy Darma ID,$^{4}$ Pornthep Tanpowpong ID,$^{5}$ Nuthapong Ukarapol ID,$^{6}$ James Guoxian Huang ID,$^{7}$ Hong Ngoc Tran ID,$^{8}$ Yen Hsuan Ni ID,$^{9}$ and for Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) Pediatric Inflammatory Bowel Disease (PIBD) Working Group

$^{1}$Division of Pediatric Gastroenterology, Department of Pediatrics All India Institute of Medical Sciences, New Delhi, India

$^{2}$Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore $^{3}$Department of Pediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia

$^{4}$Department of Child Health, Dr. Soetomo General Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia

$^{6}$Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

$^{6}$Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand $^{7}$Division of Pediatric Gastroenterology, Nutrition, Hepatology and Liver Transplantation, Department of Pediatrics, National University Hospital, Singapore $^{8}$Department of Gastroenterology, Children's Hospital No. 1, Ho Chi Minh City, Vietnam

$^{9}$National Taiwan University College of Medicine, Taipei, Taiwan

ABSTRACT

A significant increase in the incidence of pediatric inflammatory bowel disease (PIBD) across the Asia Pacific region has been observed. Countries in the region have diverse economies, with both developed and resource limited economies being represented. Literature from the region also varies, from reports on detailed epidemiological data and nuanced therapeutic outcomes derived from PIBD registries to case series from several geographic areas that have previously not reported on the condition. Through this position paper, we aimed to provide a comprehensive review of the challenges faced with diagnosing PIBD in the Asia Pacific region and offer pragmatic recommendations based on region-specific literature.

Keywords: Child; Crohn's disease; Diagnosis; Inflammatory bowel disease; Pediatrics; Ulcerative colitis

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

Pediatric Gastroenterology, Hepatology & Nutrition

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Nuthapong Ukarapol ID https://orcid.org/0000-0001-6243-3395 James Guoxian Huang ID https://orcid.org/0000-0002-5869-4194 Hong Ngoc Tran ID https://orcid.org/0009-0002-0308-8231 Yen Hsuan Ni ID https://orcid.org/0000-0002-1158-5249

Funding

None.

Conflict of Interest

The authors have no financial conflicts of interest.

INTRODUCTION

In the last decade, we have seen a rise in the incidence of inflammatory bowel disease (IBD) in the Asia Pacific region, both in adults and children [1,2]. It has emerged as a significant cause of morbidity, with life-long implications and economic impact [3,4]. Approximately 20–25% of all IBDs begin in childhood. Considering a diagnosis of pediatric inflammatory bowel disease (PIBD) in Asia requires considering infectious disease as a possible differential diagnosis and navigating the best resources available.

The aim of this position paper was to bring together experts to produce a region-specific review of the specific challenges faced in making an accurate and timely diagnosis of PIBD in the Asia Pacific region, knowing that the predominant causes of chronic diarrhea, abdominal pain, and failure to thrive are continue to be caused by other diagnoses, such as infections.

EPIDEMIOLOGY OF IBD IN THE ASIA PACIFIC REGION

The highest annual incidence of pediatric inflammatory bowel disease (PIBD) was reported in Europe, reaching up to 23 per 100,000 person-years [1]. By contrast, PIBD has traditionally been considered relatively uncommon in Asia and, as such, national registries and prospective databases are limited [5]. However, recent data from selected countries indicate a rising trend.

Based on data from a provincial cohort, Choe et al. [6] reported a significant increase in the population-based annual incidence of PIBD in South Korea, from 7.24 per 100,000 in 2017 to 13.3 per 100,000 in 2020. Along with findings from other studies [7], this highlights a consistent upward trend in the incidence of PIBD in Korea. A multicenter registry study conducted in Japan reported that, among children diagnosed with IBD, 20.9% of cases of Crohn's disease (CD) and 21.9% of cases of ulcerative colitis (UC) occurred in children under the age of 10 [8]. This finding indicates a substantial burden of early-onset IBD. Furthermore, an analysis of national registry data collected from 2004 to 2013 revealed a 73.8% increase in the age-standardized prevalence of CD in children, increasing from 4.2 to 7.2 per 100,000; similarly, the prevalence of UC increased by 45%, from 11.0 to 15.0 per 100,000 [9]. These findings emphasize the growing burden of PIBD in Japan. In a systematic review and meta-analysis conducted by Forbes et al. [10], pooled rates of annual incidence and prevalence in the Oceania region were estimated. The pooled rates for the incidence of IBD per 100,000 population was 4.1 (3.4-4.8; I$^{2}$, 98.7), with most of the data gathered from Australia and New Zealand. Low rates were observed in Indigenous Australian, Maori, and New Zealand Pacific children; no studies from the Pacific Islands existed [10]. Although robust prevalence and incidence data remain scarce across much of the Asia Pacific region, emerging multicenter series—particularly from high-population, rapidly developing regions such as China and India—suggest an increasing incidence of PIBD in areas previously considered unaffected [11-16].

WHEN TO SUSPECT IBD

IBD is classified phenotypically as either CD, UC, or IBD unspecified when colonic disease that cannot be classified as either CD or UC is present [17]. Table 1 displays the phenotypes

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

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|Study|Country/Setting|Number (IBD)|% CD|% UC|% IBD-U|Phenotype|% Perianal CD|% Any EIM| |---|---|---|---|---|---|---|---|---| |Srivastava et al., 2020 [3]|India|325|65.2|26.2|8.6|CD L3 55.7% UC E4 57.8%|10.9|37.3| |Zhou and Huang, 2016 [14]|China|49|83.7|16.3|O|CD L3 58.5% UC E4 50%|22|34.7| |Choe et al., 2022 [6]|South Korea|304|71.4|28.6|NR|CD L3 74.3% UC E4 51.7%|44.8|NR| |Kang et al., 2020 [19]|Composite from 3 studies|CD 255||||UC E4 51.7%||| |Lim et al., 2024 [20]||UC 205||||||| |Tanpowpong et al., 2024 [21]|Thailand|72|48.6|50.0|1.4|CD L2 colonic 40% UC E4 88.9%|31.4|~26*| |Arai et al., 2020 [8]|Japan|243|37.4|60.1|2.5|CD L3 64.8% UC E4 76%|34.1|5| |Huang et al., 2022 [22]†|Multi-center (Singapore-led)|311|55.9|38.3|5.8|CD L3 41.3% UC E4 72.6%|34|NR| |Pipicella et al., 2025 [18]|Australia+New Zealand|114|68|30|2|NR|NR|NR|

CD: Crohn's disease, EIM: extraintestinal manifestation, IBD: inflammatory bowel disease, NR: not reported, UC: ulcerative colitis.

*~Denotes an approximate value where overlap of EIM types could not be excluded.

†Seven-center Asia-Pacific registry; Singapore contributed the largest share of cases.

of PIBD reported from the Asia Pacific region [3,6,8,14,18-22]. Across the Asia Pacific PIBD cohorts, CD exceeded UC in most settings, reaching 84% in Shanghai, 80% in South Korea, and 65% in India and Australasia. However, Japan (37%) and Thailand (49%) continued to lean toward UC. A regional division was observed in India, with the North having a higher proportion of UC (50%). Ileocolonic inflammation (Paris L3) dominated every series of CD in which location was reported (5-78%), whereas perianal disease ranged from 11% in India to 44.8% in Korea. Extraintestinal manifestations ranged from a proportion of 5% in Japan to one of 37% in India, confirming the systemic burden. Collectively, even though the studies revealed sizeable geographic heterogeneity, a clear regional shift toward CD-predominant, ileocolonic, and systemically active disease profiles was noted.

CD typically presents with growth failure, pubertal delay, abdominal pain, fever, weight loss, and anorexia [3,16,23,24]. Perianal disease, which is not observed in UC, may be present. Diarrhea may or may not be apparent and might not contain visible blood. For these reasons, other diagnoses, such as infections (e.g., tuberculosis or amebiasis) or an enteropathy (e.g., tropical sprue or celiac disease) are usually considered as the first diagnosis in children presenting with these symptoms. UC, on the other hand, presents with bloody diarrhea and rectal symptoms and sometimes with the dramatic syndrome of acute severe colitis. In its presentation, UC mimics infectious colitis due to infections, which are far more common in Asia. However, no clear data or recommendations from the region exist that offer guidance in distinguishing between the two.

Besides intestinal presentations, extraintestinal manifestations that should be searched for include arthralgia, erythema nodosum, pyoderma gangrenosum, immune liver disease, sclerosing cholangitis, uveitis, and ankylosing spondylitis. Approximately 87% of these presentations occur within the first year after the onset of IBD and are associated with increased disease severity [25]. These additional features, perianal disease, and extraintestinal manifestations may be clues that the chronic diarrhea or symptoms that the child may present with could be due to IBD rather than other causes.

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Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

![graph TD\n A1[Chronic gastrointestinal symptoms] --> A2[Bloody diarrhea lasting >2-4 wk despite optimal antibiotic treatment]\n A1 --> A3[Abdominal pain Weight loss Fever Poor growth Diarrhea with or without blood Perianal disease]\n A2 --> A4[Consider repeat stool cultures Molecular tests if available]\n A3 --> A5[Bowel USG]\n A4 --> A6[Bowel USG or abdominal CT depending on severity]\n A5 --> A7[Lower and upper GI endoscopy and biopsy CT or MR enterography Capsule endoscopy]\n A6 --> A8[Lower GI endoscopy and biopsy]\n A7 --> A9[Crohn disease Ulcerative colitis IBD-unclassified]\n A8 --> A10[Strongly consider ulcerative colitis]\n A11[Inflammatory markers Fecal calprotectin if available Stool cultures Stool molecular tests for pathogens] --> A5\n](1/parseimages/figure1770b031e4fd4052894e53bb5f01541f_0_3.png) Fig. 1. Approach to the diagnosis of pediatric inflammatory bowel disease in the Asia Pacific region. EIM: extraintestinal manifestations, TB: tuberculosis, CT: computed tomography, GI: gastrointestinal, MR: magnetic resonance, USG: ultrasound, IBD: inflammatory bowel disease.

Fig. 1 outlines the approach to diagnosis of PIBD in the Asia Pacific region.

DIFFERENTIAL DIAGNOSIS

From the Asian perspective, infections remain crucial when making the differential diagnoses. Table 2 lists important factors to consider in the differential diagnosis and suggestions for investigations that can be carried out to differentiate other diagnoses from IBD.

Multiplex polymerase chain reaction (PCR)–based stool panels and other molecular assays enable rapid, highly sensitive detection of pathogens from a single sample. A positive result pinpoints an infectious etiology—often within hours—allowing targeted antimicrobial or antiparasitic therapy and obviating the need for invasive endoscopy when symptoms mimic IBD. Conversely, the absence of detectable pathogens in a child with chronic diarrhea, blood in the stool, growth failure, or extraintestinal manifestations increases the pretest probability of IBD and supports proceeding to colonoscopy for definitive diagnosis. By integrating these molecular tests early in the diagnostic algorithm, clinicians can shorten the time taken to achieve accurate classification, avoid the unnecessary administration of antibiotics, and allocate limited endoscopic resources more efficiently.

For very young children (<6 years) and, especially, infants presenting with IBD-like symptoms, food allergies and more significantly genetic causes (so-called monogenic IBD) should be included in the differential diagnosis. These aspects are discussed in more detail in the subsequent sections.

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

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|Etiology|Clinical features|Investigations|Therapy| |---|---|---|---| |Intestinal tuberculosis|Fever|Mantoux test and interferon gamma release assay to screen for latent tuberculosis infection|When differentiation from TB is difficult, treatment with antitubercular therapy may be initiated with standard four drug regimens and patients monitored for a clinical response| |Intestinal tuberculosis|Abdominal pain|Imaging in the form of computed tomography or magnetic resonance enterography|| |Intestinal tuberculosis|Weight loss|Attempt should be made to obtain specimens for pathology and microbiology using colonoscopy|| |Intestinal tuberculosis|Diarrhea (usually not bloody), associated pulmonary symptoms or lymph node involvement|Definite diagnosis is possible in only 30% of cases|See Fig. 2| |Intestinal tuberculosis|Positive TB contact||| |Intestinal tuberculosis|History of TB or current TB||| |Entamoeba histolytica|Diarrhea may have blood and mucous, crampy abdominal pain, weight loss|Stool microscopy: Positive hematophagous trophozoites from a minimum of three stool samples collected over a period of 10 d Stool PCR/Multiplex PCR Colonoscopy: Friable colonic mucosa with discrete ulcer Abdominal imaging: Colonic inflammation and bowel wall thickening|Trial of anti-amoeba (metronidazole) therapy should be administered in endemic areas and when access to molecular diagnosis is limited| |Giardiasis|Watery diarrhea, weight loss, abdominal pain|Stool microscopy: Positive cyst and trophozoites from a minimum of three stool samples collected over a period of 10 d Stool PCR/Multiplex PCR|Tinidazole, metronidazole, or nitazoxanide as the drugs of choice| |Cryptosporidium|Watery diarrhea, crampy abdominal pain|Stool microscopy: Positive oocyst from a minimum of three stool samples collected over a period of 10 d Stool PCR/Multiplex PCR|Nitazoxanide is approved by the Food and Drug Administration of the United States to treat cryptosporidiosis in children without human immunodeficiency virus| |Clostridium difficile infection|Children ≥ 2 yr of age with prolonged or worsening diarrhea and risk factors (e.g., underlying IBD or immunocompromising conditions) or relevant exposures (e.g., contact with the healthcare system or recent antibiotic treatment)|Detection of toxigenic C. difficile in stool along with colonic histopathology showing pseudo membranes in a patient with clinical symptoms Stool PCR/Multiplex PCR|Metronidazole for early episodes of nonsevere C. difficile infection can only be recommended Oral vancomycin for severe disease| |Cytomegalovirus colitis|Patients with immunosuppression or those with acute steroid-resistant colitis|Histology with immunohistochemistry has the highest sensitivity and specificity for detecting intestinal cytomegalovirus colitis|Intravenous ganciclovir for 2-3 wk| |Campylobacter jejuni|Diarrhea may have blood and mucous, crampy abdominal pain, weight loss Nausea or vomiting|Stool microscopy or culture Stool PCR/Multiplex PCR|For severe symptoms, macrolide or fluoroquinolones may need to be administered| |Yersinia enterocolitica|Fever, abdominal pain that may be confused with appendicitis, diarrhea that may be bloody Suspect in countries with high pork consumption|Stool cultures require special media Stool PCR/Multiplex PCR Imaging may demonstrate mesenteric adenitis or terminal ileitis|Severe cases may need treatment with third-generation cephalosporins, trimethoprim-sulfamethoxazole, or fluoroquinolones| |Shigella and Salmonella|Diarrhea (may be bloody), fever, crampy pain|Stool culture or PCR|Ciprofloxacin, cephalosporins, and azithromycin for severe disease|

IBD: inflammatory bowel disease, PCR: polymerase chain reaction, TB: tuberculosis.

INITIAL SCREENING

Laboratory markers

Initial investigations for children with chronic gastrointestinal symptoms often comprise routine hematological tests and markers of inflammation, usually for the erythrocyte sedimentation rate and levels of hemoglobin, platelets, albumin, and C-reactive protein. In a landmark study conducted in Birmingham, the utility of blood tests was assessed in 153 children referred for suspected IBD: Both the sensitivity and specificity of thrombocytosis (>350×10$^{9}$/L) were 85%; an erythrocyte sedimentation rate of >10 mm/h had a sensitivity of 83% and specificity of 78%. C-reactive protein and albumin alone had poor sensitivities, yielding values below 60% for plausible thresholds. No single marker was sufficiently discriminative on its own, but using them in combination improved the yield—the study

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

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noted that the simple at least one of the two dual test rule i.e. anemia or thrombocytosis achieved a 91% sensitivity with 80% specificity [26].

Fecal calprotectin (FC) is a cytosolic neutrophilic protein that can be measured in stools; it has been validated as a good marker for noninvasive diagnosis or screening of inflammatory bowel disease. Levels below 50 µg/g are considered to suggest that the presence of IBD is unlikely, levels of 100–200 µg/g fall in the grey zone, and levels of >200 µg/g are strongly suggestive of the presence of IBD (levels above 212 µg/g have yielded a sensitivity of 90% and specificity of 87%) and warrant endoscopic evaluation. Children younger than 4 years and those on nonsteroidal anti-inflammatory drugs and proton pump inhibitors have higher levels, and the level of FC is also raised when enteric infections are present. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2021 position paper recommends FC levels as the first line of noninvasive screening when PIBD is suspected [27]. A 2017 individual-patient meta-analysis of 1,120 children with symptoms showed that by adding FC to this basic blood panel, approximately 40% of otherwise unnecessary endoscopies could be avoided [28].

Taken together, pairing at least one abnormal blood marker (most usefully low hemoglobin or high platelet levels) with an elevated FC level offers a cost-effective, relatively sensitive triage strategy that can be followed before committing a child to invasive diagnostics.

Children in Asia may have low hemoglobin levels as well as raised erythrocyte sedimentation rates and platelet levels due to nutritional iron deficiency or parasitic infections. The sensitivity of the FC level may also be lower in this region due to the prevalence of enteric infections. Hence, the early ruling out of infection in the presence of a raised FC level through reflex testing for pathogens using sensitive molecular tests such as PCR is important. Levels of FC in ileocecal tuberculosis (TB) have been reported to be similar to those in CD at diagnosis [29].

Antibody markers in PIBD

Antibody markers have minimal value in the diagnosis of IBD. Whilst anti-Saccharomyces cerevisiae antibodies have been shown to be positive in as many as 60% of patients with CD and in 10% of patients with UC, it is also positive in as many as 50% of patients with intestinal TB and 5% of the normal population. Thus, no recommendations to use anti-Saccharomyces cerevisiae or other auto-antibodies in the screening or diagnosis of IBD have been made [30-32].

IMAGING

In PIBD, imaging is used to diagnose; map the extent of disease; identify complications such as abscesses, fistula and strictures; and monitor disease activity and progression. Several imaging modalities may be used in a complementary manner. Traditionally, computed tomography (CT) and magnetic resonance imaging have been used as techniques for cross sectional imaging of the small bowel and colon intestinal ultrasound (IUS) is a recent addition to these options. In magnetic resonance enterography (MRE) and CT enterography, contrast or water is utilized to distend the small bowel while magnetic or ionizing radiation is utilized for imaging. All children with suspected IBD should undergo a small bowel examination [33] with MRE, the current imaging modality of choice [34]. A meta-analysis showed that MRE had a sensitivity of 87% and specificity of 81% in IBD [35]. However, because CT is more widely available and faster to obtain, it is the modality used in many centers. Enterography techniques may be

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

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impractical to use in younger children (<6 years old): Ingesting the large quantity of contrast and or water is difficult for children and jejunal tubes as well as anesthesia are often required to deliver these agents. In such cases, non-enterography MRI or CT may be utilized.

IUS is a relatively new modality used in the diagnosis and care of patients with IBD. Its role in adults is well established and the modality is now gaining acceptance for use in pediatric patients as well. IUS does not require fasting, anesthesia, or contrast and is often performed by a trained gastroenterologist in the setting of a clinic rather than that of a radiology suite; here, it can be used to guide further therapy and decision-making while avoiding the need for further appointments. The primary measure of disease activity includes thickness of the small bowel and hyperemia of the bowel wall using the Doppler signal. Meta-analyses show its overall sensitivity and or specificity for complications is on a par with those of CT enterography and MRE [36]. Although IUS has multiple clinical roles in management and monitoring, similar to the FC level it can be used as a screening tool in appropriate clinical settings. An IUS with a significant finding may enable expedited ileocolonoscopy or cross-sectional imaging. Compared to CT and magnetic resonance imaging, however, it has limitations in evaluating the proximal and mid small bowel and in performing rectal evaluations. Recently, a Japanese study involving children demonstrated that transperineal ultrasonography is as accurate as colonoscopy in evaluating rectal inflammation in ulcerative colitis [37]. Thus, IUS should be viewed as a complementary strategy for diagnosing and treating PIBD. Because IUS is relatively inexpensive and widely available in the Asia Pacific region, this modality has the potential to be widely utilized in pediatrics.

ENDOSCOPIC EXAMINATION

Upper gastrointestinal endoscopy and ileocolonoscopy with mucosal biopsies are the most valuable tools for evaluating a child with suspected IBD. Through these investigations, lesions can be phenotypically classified, and histopathologic and microbiological samples can be obtained. An attempt should always be made to intubate the terminal ileum during colonoscopy because doing so often helps differentiate CD from UC and infections such as TB. However, even after endoscopy and biopsies have been performed, differentiating IBD from infections prevalent in Asian regions may not be possible.

DIFFERENTIATION BETWEEN CD AND INTESTINAL TB

In clinical settings in Asia, a fundamental principle in the diagnostic evaluation of suspected PIBD is the rigorous exclusion of infectious etiologies, particularly intestinal tuberculosis (ITB). Studies have reported rates of misdiagnosis between IBD and ITB of as high as 50%, highlighting the diagnostic complexity and need for region-specific protocols [38,39]. Clinically, both conditions may present with chronic diarrhea, abdominal pain, weight loss, fever, and endoscopic ulcers, particularly in the ileocecal region. The 2023 Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition guideline on PIBD [40] explicitly mandates that clinicians exclude ITB through microbiological tests, imaging, histology, and—when necessary—a therapeutic trial before confirming a diagnosis of IBD.

Several studies involving adults have examined the discriminatory factors between CD and ITB [38,41-44]. Most agree that a longer duration of symptoms, chronic diarrhea, blood in

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

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stools, presence of perianal disease, and extraintestinal manifestations are significantly more common in CD, whereas subacute intestinal obstruction and ascites are usually observed in TB [38,44-46]. In the only pediatric study in which CD and ITB were compared [47], blood in stools and left-sided colitis were the two clinical features which were significant on multivariate analysis in predicting a diagnosis of CD.

The tuberculin skin test and interferon gamma release assay (IGRA) are tests for latent TB. A positive tuberculin skin test has been reported in 50-100% of patients with ITB [48]. Several meta-analyses have been conducted on the role of the IGRA, and the reports noted a pooled sensitivity and specificity of approximately 80% in differentiating ITB from CD [49]. Both the IGRA and tuberculin skin test are predictive of latent rather than active TB; hence, a positive or negative IGRA will neither rule in nor rule out a diagnosis of ITB.

On imaging, large (>1 cm) lymph nodes with central necrosis are highly suggestive of TB. Long segment involvement and isolated ileocecal disease are more common in TB, but deep ulcers, and multi-segment and left-sided involvement were more common in CD. The endoscopic features of ITB and CD are similar: Both may have aphous or deep ulcerations, pseudopolyps, cobblestoning, nodularity, skip lesions, luminal narrowing, and strictures [38,50,51].

HISTOLOGY

Endoscopic biopsy samples from lesions may be used for acid fast staining or PCR. However, they are able to confirm a diagnosis in only 30–40% of cases [47,52] due to the paucibacillary nature of the disease. The granulomas in patients with ITB are significantly larger and tend to be more confluent than in those with CD. In ITB, a higher number of granulomas per section is present and granulomas are more frequently located in the submucosa or in granulation tissue. Caseation is considered pathognomonic for TB. Features that favor a diagnosis of CD on mucosal biopsies include infrequent, small granulomas that are poorly organized and discrete or isolated. A meta-analysis in which the histological features for diagnosis of TB were compared showed that confluent granulomas and ulcers lined by epithelioid cells had a sensitivity and specificity of 38% and 94% and 41% and 94%, respectively, compared to caseation; caseation had a sensitivity and specificity of 21% and 100%, respectively [53].

THERAPEUTIC TRIAL OF ANTITUBERCULAR THERAPY

Despite optimal evaluation, sometimes making a definite differentiation between CD and ITB is not possible. In such clinical scenarios, a therapeutic trial of anti-tubercular therapy (ATT) may be warranted. After initiating ATT, almost all cases with TB would show a clinical improvement. Interestingly, CD may also show an apparent clinical response to ATT in up to 38% of cases [54]. Therefore, a clinical response to ATT should never be the gold standard for diagnosing TB after a therapeutic trial of ATT. Mucosal healing with administration of ATT, on the other hand, is very specific for ITB, with 74% of cases at 3 months and 100% at 6 months showing mucosal healing [55]. Kedia et al. [50] suggested that patients be reassessed over a period of 2–3 months. If no clinical response is observed, a colonoscopy examination should be repeated. The reason for nonresponse may be the presence of a fibrotic stricture due to inactive and or treated TB or active disease, which is CD. If a clinical response is observed, a repeat colonoscopy examination may be performed at 6 months. Mucosal healing

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Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

![graph TD\n A1[Diagnostic dilemma CD and intestinal TB] --> A2[Start ATT]\n A2 --> A3[Clinical improvement 2-3 months]\n A3 --> A4[Assess clinical & endoscopic response at 6 months]\n A3 --> A5[Clinical worsening or no change]\n A4 --> A6[Clinical and endoscopic improvement]\n A4 --> A7[Active disease on endoscopy]\n A5 --> A8[Repeat endoscopy & radiology]\n A6 -->|TB| A9[Inactive disease? Fibrotic structure]\n A7 -->|CD| A8\n A8 --> A9\n A8 --> A10[Active disease]\n A9 -->|TB| A8\n A10 -->|CD| A8\n](1/parseimages/figurec6fa422a05624c8e8ce6193a09215767_0_3.png) Fig. 2. Therapeutic trial for the differentiation of Crohn's disease from intestinal tuberculosis. ATT: antitubercular therapy, CD: Crohn's disease, TB: tuberculosis.

at this time indicates that the diagnosis of TB was correct, whereas active mucosal disease with or without clinical symptoms indicates CD.

Fig. 2 discusses therapeutic trial of ATT for differentiating CD from ITB.

MONOGENIC IBD AND WHEN TO CONSIDER GENETIC TESTING

Monogenic IBD refers to an IBD-like phenotype resulting from mutations in a single gene. Monogenic disorders account for a striking proportion of the youngest patients with PIBD: Sequencing studies of infantile-onset disease (<2 years) consistently detect pathogenic variants in approximately 20–30% of patients, emphasizing the importance of conducting a genetic work-up at this age. Among children diagnosed between 2 and 6 years, the yield falls to 15–20%, but still far exceeds that observed in later childhood. When onset occurs after the sixth birthday, large cohorts show that only 3–5% of patients harbor a monogenic defect, illustrating the steep age-related gradient in genetic causality. However, patients of any age may have a monogenic cause for their symptoms. Longitudinal reviews of these cohorts indicate that these proportions have remained essentially unchanged over the past decade, with the apparent rise in reported cases driven by wider access to next-generation sequencing rather than a true increase in incidence [56–58]. Uhlig originally described 40 monogenic IBD genes in 2013 [59]. The consensus diagnostic panel of Uhlig et al. [60] expanded this to 75 genes in 2021. Current reviews by the same research group acknowledge more than 100 confirmed monogenic IBD genes as of mid-2024 [61,62].

An example of these genes would be the two most common monogenic mutations that cause IBD. Loss-of-function mutations in IL10RA eliminate interleukin-10 signaling, unleashing macrophage and Th17-cell activation that drives fulminant infant-onset colitis with recurrent sepsis, fistulizing perianal disease, and steroid-refractory inflammation; curative outcomes are achievable with allogeneic hematopoietic stem-cell transplantation. By contrast, XIAP deficiency—an X-linked disorder that disrupts NOD2 and Toll-like-receptor pathways and dysregulates the inflammasome—typically affects male infants or young boys, presenting as stricturing or penetrating Crohn-like ileocolitis accompanied by recurrent fevers,

Diagnosis of PIBD in Asia Pacific: APPSPGHAN Working Group Position Paper

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cytopenias, and a high risk of hemophagocytic lymphohistiocytosis. Treatment using early hematopoietic stem-cell transplantation is recommended before severe hemophagocytic lymphohistiocytosis episodes develop.

Certain entities that may mimic CD have been predominantly reported in Asian countries; these deserve special mention. Chronic enteropathy associated with SLCO2A1 disease has been widely reported in Korea, Japan, China [63,64], and now also India (authors own data, unpublished). The phenotype is one of multiple circumferential small bowel stenosing ulcers of nonspecific histology with normal upper and lower endoscopies presenting with anemia and hypoproteinemia caused by homozygous mutations in the SLCO2A1 gene. Treatment pathways are not clearly established, although treatment with etoricoxib and immunosuppression, similar to that used for IBD, has been attempted with variable response.

Immediate next-generation sequencing, ideally trio whole-exome sequencing, should be pursued in any child with colitis or enterocolitis that begins before the second birthday; with disproportionately severe perianal disease such as fistulae, abscesses, or strictures; or with an inadequate or paradoxical response when treated with standard induction therapy. Similarly, testing is warranted in the presence of a red flag in the personal or family history, primary immunodeficiency, recurrent or atypical infections, hemophagocytic-like episodes, autoimmune cytopenias, parental consanguinity, or unexplained sibling deaths. Where next-generation sequencing is not yet locally available, patients should be referred to regional or research sequencing centers.

Early molecular diagnosis enables curative hematopoietic stem-cell transplantation for IL1ORA, XIAP and several other monogenic disorders, guides gene-specific medical therapy, and informs genetic counselling. Therefore, national societies should work toward centralized funding and referral pathways to overcome current financial and technical barriers that limit routine next-generation sequencing access across parts of Asia.

CONCLUSION

The PIBD milieu of the Asia Pacific region is changing. Areas are now emerging with rapidly increasing incidences and prevalences of disease. PIBD in Asia has some unique clinical characteristics that may be distinct from those in PIBD in North America and Europe. At the same time, infections—especially TB—remain endemic in many parts of this region and may closely mirror the symptomatology of IBD. Clinicians must include IBD in their differential diagnosis when evaluating children with chronic gastrointestinal symptoms. Diagnostic algorithms may have to be modified to consider the unique differentials, available resources, and expertise.

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