challenges in the diagnosis of pibd in the asian countries

Challenges in the diagnosis of PIBD in the Asian Countries

Suporn Treepongkaruna, MD.Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital

Mahidol University, Bangkok, Thailandhttps://appspghan.org

Disclaimer

• I have no conflict of interest to declare

https://appspghan.org

Outline

• Challenges in the diagnosis of PIBD in Asia • Diagnostic modalities• Assessment at diagnosis• Differential diagnosis and infectious diseases mimicking PIBD


Increasing prevalence of PIBD in Asia(Asian PIBD Network)


Cumulative IBD cases at Ramathibodi Hospital (2000 to 2018)

0

5

10

15

20

25

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Number of cumulative cases

Crohn’s disease

Ulcerative colitis

IBD-Uhttps://appspghan.org

PIBD at Ramathibodi Hospital (N= 42)

IBD subtype Crohn’s disease Ulcerative

colitis

IBD-U

N 23 15 4

Age at onset: median (IQR) – year 8.0 (2.6, 11.9) 5.1 (4.4, 7.6) 2.3 (1.1, 10.6)

Age at diagnosis: median (IQR) – year 8.6 (3.1, 13) 8.1 (5.7, 9.8) 2.6 (1.6, 11.2)

Duration between onset and diagnosis:

median (IQR) – month

6 (1.9, 18.3) 10.8 (3.7, 30.6) 6 (4, 7.6)


Duration between onset and diagnosis of early-onset IBD (EOIBD) at Ramathibodi Hospital (N = 42)

72

60

48

36

24

12

0

P = 0.02

2.9

10.6

Duration(months)

EOIBDNon-EOIBDhttps://appspghan.org

Challenges in diagnosis of PIBD in Asia

Early diagnosis and management is crucial

0102

03

Common infectious diseases (eg. TB) mimic IBD

05

There are no surrogate biomarkers for diagnosis of PIBD

06

Less experience due to lower incidence

Inadequate facilities in some countries

04


Diagnosis of PIBD

History and physical examination

Laboratory studies & stool tests

Ileocolonoscopy & esophagogastroduodenoscopy (EGD)

Histopathology

Small bowel evaluation

Diagnosis

Levine A, et al. J Pediatr Gastroenterol Nutr. 2014; 58: 795-806.https://appspghan.org

When to suspect PIBD?CD UC

Abdominal pain +++ ++Chronic diarrhea +++ +++Weight loss/growth impairment +++ ++Bloody stool ++ ++++Anemia +++ +++Fever ++ +Loss of appetite/anorexia ++ +Fatigue ++ +Perianal lesions +++ -Extraintestinal manifestations ++ ++

Classic triads (25%of CD)


Extra-intestinal manifestations

Arthritis, sacroiliitis, ankylosing-spondylitis, enthesitis

Uveitis, iritis, episcleritis

Erythema nodosum.pyoderma gangrenosum

Primary sclerosing cholangitis,

autoimmune hepatitischolelithiasis Thromboembolic disease

MyocarditisPleuritis

Oral ulcer

Nephrolithiasis


Initial investigationsTests Abnormalities seen in IBD

Complete blood count Leukocytosis, microcytic anemia, thrombocytosis

ESR Elevated marker of inflammation

CRP Elevated marker of inflammation

Liver function tests Hypoalbuminemia, elevated transaminases, GGT

Stool exam White blood cells, red blood cells, rule out parasite, protozoa

Stool culture Rule out bacterial enteriits

Stool C. difficile toxin Rule out C. difficile

Rapid giardia and cryptosporidium antigen Rule out giardia and cryptosporidium

Stool calprotectin Elevated marker of intestinal inflammation

• Normal blood tests do not exclude PIBD!• Identification of pathogen does not necessarily exclude IBD

• First episode or flare of IBD may be triggered by enteric infectionhttps://appspghan.org

Fecal calprotectin

• Mainly expressed by nutrophils and released during intestinal inflammation

• Values depend on the patients’ age• The most frequent cut-off point suggesting the

presence of intestinal inflammation is >50 µg/g• Meta-analysis (8 studies) showed the

sensitivity for the screening test for PIBD of 98% and speciifcity of 68%

• Stability is better in samples storage at 4℃

Lezyk-Ciemniak E, et al. Med Princ Pract 2020Handerson P, et al. Am J Gastroenterol 2014;109:637-45

1-3 m 3-6 m 3-9 m 9-12 m 12-24 m 4-36 m

1200

1000

800

600

400

200

0

Level (ug/g)


Non-invasive tests for diagnosis of PIBD: A meta-analysis

Holtman GA, et al. Pediatrics 2016;137:e20152126

19 studies (N=2,806)Test No. of study

N Prevalence of IBD (%)

Sensitivity (%)

Specificity (%) LR positive

LR negative

CRP 9 1146 49 63 88 5.1 0.42

ESR 11 1434 55 66 84 4.2 0.41

Platelet count 8 732 58 55 88 4.7 0.51

Hemoglobin 9 1454 50 37 90 3.7 0.70

Albumin 6 527 53 48 94 8.3 0.55

Fecal calprotectin 10 867 53 99 65 2.8 0.01

Negative fecal calprotectin Low risk for IBDPositive for albumin or CRP High risk for IBDhttps://appspghan.org

Endoscopy in PIBD (Porto IBD Group of the ESPGHAN)

• Combination of esophagogastroduodenoscopy (EGD) and ileocolonoscopy (IC) should be performed in children suspected of IBD

• During endoscopy multiple (>= 2) biopsies should be obtained from each segment even in the absence of macroscopic lesions

• EGD helps to establish the final diagnosis in 10% of children with IBD

Oliva S, et al. J Pediatr Gastroenterol Nutr 2018Kovac M, rt al. J Crohn Colitis 2012


Typical UC: Endoscopy findings• Continuous mucosal inflammation of the colon, starting distally from

the rectum• Involve parts of colon or the whole colon (pancolitis) • No small bowel involvement other than backwash ileitis (in pancolitis)

Normal terminal ileumPancolitis https://appspghan.org

Deep ulcers with skip area

Cobblestone Linear or serpentine ulcers

Fistula

CD: Endoscopic findings

Aphthous ulcer


Esophagogastroduodenoscopy in CD

Aphthous ulcershttps://appspghan.org

Typical CD: Macroscopic findings(ESPGHAN Revised Porto Criteria)

Endoscopic findings:üMucosal aphthous ulcersü Linear or serpentine ulcerationsü Cobblestoningü Skip lesions

Levine A, et al. J Pediatr Gastroenterol Nutr. 2014; 58: 795-806.

ü Small bowel wall thickening with luminal narrowing (imaging, surgical specimen)

ü Stenosis/stricturing of bowel with prestenotic dilatationü Jejunal or ileal ulcersü Perianal lesions (fistula, abscess, large skin tags,

anal stenosis, anal canal ulcer)https://appspghan.org

Histology of IBD

Chronicity – Crypt architectural distortion (shape, size, space)

Crypt atrophy/shortening(More prevalent in UC)


Muscularis

mucosae

Basal plasmacytosis (lymphoplasmatosis) Paneth cell metaplasia in the left side colon

Histology of IBD (UC)

Feakins RM. Histopathology 2014;64:317Levine A, et al. J Pediatr Gastroenterol Nutr. 2014; 58: 795-806.


Histology of IBD

o Cryptitis o Crypt abscess o Ulcer or erosion in severe cases

(UC- wide-based ulcer, CD- fissuring ulcer)

o Diffused cryptitis and crypt abscessses are features of UC

o UC: Inflammation most severe distally

Active inflammation

Feakins RM. Histopathology 2014;64:317Levine A, et al. J Pediatr Gastroenterol Nutr. 2014; 58: 795-806.https://appspghan.org

Noncaseating granuloma

Histology: CD

Histological hallmark: Noncaseatinggranuloma-must be remote from the ruptured crypt (found in 60% of surgical specimens, 20-40% of mucosal biopsies)

Other typical histological findingso Focal/patchy chronic

inflammationo Transmural inflammationo Submucosal fibrosis

Levine A, et al. J Pediatr Gastroenterol Nutr. 2014; 58: 795-806.https://appspghan.org

Atypical UC (ESPGHAN Revised Porto Criteria)

1 Macroscopic rectal sparing (5%)

2 HistologyLack of architectural distortion (34%) particularly in children aged < 10 years and short duration of disease

3 Cecal patch Cecal inflammation in patients with

left-sided colitis (2%)

4 UGI involvement Erosions and small ulcers (4%)

5 Acute severe colitis

Rectal sparing

Transmural inflammation and deep ulcers Levine A, et al. J Pediatr Gastroenterol Nutr. 2014; 58: 795-806.


IBD Unclassified (IBD-U)(ESPGHAN Revised Porto Criteria)

• Clinical and endoscopic signs of chronic colitis without speciifc features of UC or CDLikelihood of occuring in UC

Feature Diagnostic apprach

Class 2: Rare with UC • Rectal sparing and other feature are consisitent with UC• Significant growth delay• Transmural inflammation without acute severe colitis• Duodenal ulcer/esophageal ulcer• Multiple gastric aphthous ulcers• Positive ASCA and negative pANCA• Proximal inflammation > distal

IBD-U if at least 1 feature

Class 3: Uncommon • Severe scalloping of stomach and duodenum• Focal chronic duodenitis on multiple biopsies/marked scalloping

of duodenum• Focal active colitis > 1 biopsy from macroscopically inflammed site• Non-bloody diarrhea• Aphthous ulcerations in colon or UGI tract

IBD-U if at least 2-3 features



Small bowel imaging

CT scan

Magnetic resonance enterography (MRE)

Small-bowel follow through§ Low cost, widespread availability§ Low sensitivity and accuracy

Ultrasonography§ Low cost, widespread availability§ Operator dependence

§ Imaging modality of choice§ Require sedation in young children§ Not widely available

CT scan§ Radiation exposure


Small-bowel follow through in CD

stenosis Fistulahttps://appspghan.org

Capsule endoscopy (CE)(Porto IBD Group of the ESPGHAN)

• CE is complementary to MRE for evaluating small bowel inflammation

• In suspected CD, either CE or MRE are recommended

• If CD is highly suspicious, CE should be considered even after a negative MRE

• Before performing CE, intestinal stenosis must be excluded

Oliva S, et al. J Pediatr Gastroenterol Nutr 2018https://appspghan.org


Ileocolonoscopy & EGD

Strong suspicion of IBD

MRE/CE

Tests unhelpful or isolated extraintestinal symptoms

Test fecal markers, if elevated

MRE/CEMRE/CE

Typical UC

IBDUNormalClear CD

Atypical UC

Consider MRE Suggest CDSuggest UC Suggest CDNegative Negative

UC

Consider CE if MRE negative

NegativePositive

CD No IBD

IBD-U

CDhttps://appspghan.org

Assessment at the time of diagnosis

Evaluation for primary immunodeficiency in infantile IBD and VEO-IBD

Growth and nutritional status

1.

2.

3.

4.

Disease severity (PCDAI and PUCAI score)

Paris classification for CD and UC


Alarm signs and symptoms for primary immunodeficiency

• Infantile IBD (< 2 years)• Family history of primary immunodeficiency • Consanguineous parents or > 2 family members with early-onset IBD • Severe, refractory IBD (particularly with perianal/rectovaginal diseases)• Recurrent infections in the absence of immunosuppressive drugs• Neutropenia, thrombocytopenia, abnormal immune status in the

absence of immunosuppressive drugs• Nail dystrophy, hair abnormalities (trichorrhexis nodosa)• Skin abnormalities (congenital eczema, albino)



Disease severity

Pediatric Crohn’s disease activity index (PCDAI) • Score < 10: Remission• Score 10-30: Mild• Score > 30: Moderate to severe

Pediatric ulcerative colitis activity index (PUCAI)• Score < 10: Remission• Score 10-34: Mild• Score 35-64: Moderate• Score >65: Severe Hyams JS, et al. J Pediatr Gastroenterol Nutr 1991;12:439-47

Turner D, et al. Gastroenterology 2007;133:423-32https://appspghan.org

Paris classification for CD

Levine A, et al. Inflamm Bowel Dis 2011;17:1314-21

Age at diagnosis

Location Behavior

A1a: 0-<10 yA1b: 10-<17 yA2: 17-40 yA3: >40 y

I

A

B

L

G

Growth

B1: Nonstricturing nonpenetratingB2: StricturingB3: PenetratingB2B3: Both penetrating and and stricturingP: Perianal disease modifier

G0: No growth delayG1: Growth delay

L1: Distal 1/3 ileum ± limited cecumL2: ColonicL3: IleocolonicL4a: Upper disease proximal to Ligament of TreitzL4b: Upper disease distal to ligament of Treitz and proximal to distal 1/3 ileumhttps://appspghan.org

Paris classification for CD


Location

Behavior

A1a: 0-<10 yA1b: 10-<17 yA2: 17-40 yA3: >40 y

I

A

L

G

Growth

G0: No growth delayG1: Growth delay

L1: Distal 1/3 ileum ± limited cecumL2: ColonicL3: IleocolonicL4a: Upper disease proximal to Ligament of TreitzL4b: Upper disease distal to ligament of Treitz and proximal to distal 1/3 ileum

L1 L2 L3 L4

Location


Paris classification for UC

Extent Severity

I

SE S0: Never severeS1: Ever severe

E1: Ulcerative proctitisE2: Left-sided UCE3: Extensive (hepatic flexure distally)E4: Pancolitis (proximal to hepatic flexure)


E1 E2 E3 E4https://appspghan.org

Differential diagnosis of PIBDInfection Inflammation Malabsorption Allergy/immunology

Bacteriao C. difficileo Salmonellao Shigellao Campylobactero Yersiniao TuberculosisProtozoao Giardiao Cryptosporidiumo E.histolyticaViruso CMVOther bacteria, virus, parasites

o Celiac diseaseo Appendicitiso Microscopic colitis

o Henoch-Schonlein- purpurao Behcet syndromeo Systemic lupus

erythematosiso Sarcoidosis

o Lactose intoleranceo Fructose intoleranceo Small bowel bacterial

overgrowth

o Lymphomao Sarcomao Neuroblastomao Polyp

o Food allergyo Eosinophilic GI disorderso Autoimmune

enteropathyo Primary/secondary immunodeficiency

o Irritable bowel syndromeo Laxative abuseo Radiation enteritiso NSAID induced

gastroenteropathy

MiscellaneousTumorVasculitis


Tuberculosis (TB)• Tuberculosis (TB) is a progressive granulomatous infectious

disease caused by Mycobacterium tuberculosis• 10 million TB cases and 1.1 million in children (11%) (WHO 2018)• South East Asia region account for 39% of global burden • Thailand 2016: total 120,000 cases and 6,000 cases of children

Khan MK, et al. Mymensingh Med J 2019;28:259; Debi U, et al. World J Gastroenterol 2014; 20:14831

• Most common site of intestinal tuberculosis (ITB) is ileocecum (75%), followed by jejunum and colon

• Esophagus, stomach and duodenum are rarely involved• Symptoms: Fever, anorexia, weight loss, night sweating, abdominal

pain, partial bowel obstructionhttps://appspghan.org

Diagnostic differentiation between CD and ITB

Clinical features

Radiology (Chest film and other imagings)

Tuberculin skin test and/or blood test for interferon-gamma releasing assays (IGRAs)

Microbiologic studies (fluid/sputum/gastric aspirate/tissue for acid-fast smear and culture)

Endoscopy and tissue for histology and microbiologic study


Differentiation between ITB and CD in childrenITB (n=20) CD (n=23) P

Age at presentation, y 14 (3-17) 11 (1-17) 0.1

Male 8 (40%) 5 (65%) 0.09

Duration of symptoms, m 8 (1-36) 9 (1-48) 0.3

Growth failure 12 (60%) 11 (47%) 0.4

Fever 9 (45%) 12 (53%) 0.6

Anorexia 10 (50%) 7 (30%) 0.1

Weight loss 12 (60%) 9 (39%) 0.1

Abdominal pain 12 (60%) 9 (39%) 0.1

Chronic diarrhea 8 (40%) 19 (82%) 0.006

Blood in stool 2 (10%) 17 (74%) <0.001

Extraintestinal manifestation 0 5 (21%) 0.02

Subacute intestinal obstruction 4 (20%) 0 0.04

Ascites 6 (30%) 0 0.005

Singh SK, et al. J Pediatr Gastroenterol Nutr 2018;66:e6-11


A 2-year-old girl with prolonged fever and weight loss

CT scan:Extensively enlarged intraabdominal lymph nodes with central low attenuation and calcification

Thickening and enhancement of IC valvehttps://appspghan.org

Miliary nodules in both lungs

A 2-year-old girl with prolonged fever and weight loss


Endoscopic features in children with ITB and CD

ITB (n=20) CD (n=23) P

Endoscopy-site of involvementRectumSigmoidDescending colonLeft colonTransverse colonAscending colonCecumIC valveIsolated ileocecal area

6 (30%)7 (35%)7 (35%)8 (40%)

8/19 (42%)7/18 (39%)

10/18 (55.6%)11/18 (60%)

8 (4%)

16 (70%)18 (78.3%)

16/22 (72.7%)20 (87%)

13/21 (62%)12/19 (68.47%)11/18 (61.1%)6/18 (33.3%)

2 (8.7%)

0.010.0030.01

0.0030.20.10.7

0.090.03

Endoscopy-nature of involvementDeep ulcersLongitudinal ulcers

6 (30%)3 (15%)

14 (61%)11 (47.8)

0.040.02

Singh SK, et al. J Pediatr Gastroenterol Nutr 2018;66:e6-11


Differentiation between CD and ITB

CD TB

Longitudinal ulcersCobblestoningRectal involvementLeft side colonLuminal strictureFistula

Endoscopic findings

Transverse ulcersPatulous IC valveCecal involvement

Limsrivilai J, et al. Am J Gastroenterol 2017:112:415-27Singh SK, et al. J Pediatr Gastroenterol Nutr 2018;66:e6-11


Intestinal TB: Endoscopic findings

Ascending colon

Cecum

Platulous IC valve

Terminal ileum

Figures courtesy of Prof. Thawee Ratanashuek


Intestinal TB: Histology

Large granuloma (> 200 m)Confluent granuloma (>5-10/HPF)Caseation necrosisMultinucleated giant cells Absence of transmural crack and fissures (CD feature)

Figures courtesy of Prof. Nathaong Akarapol


TB (H&E x200) CD (H&E x400)

Histology: Intestinal TB vs CD


Microbiologic tests

Test Sensitivity (%)

Acid-fast stain 3-27

Culture 19-70

PCR 44(specificity 95%)

Gene-Xpert MTB/RIF

8 (specificity 100%)

Acid-fast stain (Ziehl-Neelsen, 400x) Kedia S, et al. World J Gastroenterol 2019;25:418-32

Tissue should be sent for microbiologic studies


A 15-year old boy presented with fever, abdominal pain and weight loss; previoulsy diagnosed with ITB. Anti-TB drugs were

given without clinical response.

Histology of biopsies at right colon: Ulcers with acute inflammation with crypt abscess. Prominent

lymphoplasmacytic inflammation and presence of non-caseating granulomaEndoscopic biopsies for PCR for TB and AFB stain: negative

Colonoscopy: Large ulcers at cecum and ascending colon

Diagnosis: Crohn’s diseasehttps://appspghan.org

Approach to dilemma ITB vs CD

ATT, anti-TB drug therapyKedia S, et al. World J Gastroenterol 2019;25:418-32


Amoebic colitis

Entamoeba histolytica with RBC ingestion

Discreate areas of ulcerations covered by exudate with normal intervening mucosaMost common site is cecum followed by ascending colon

Cooper CJ, et al. South Med 2015;108:676-81 Figures courtersy of Prof. Seksit Osatakul


Amoebic colitis• Approximately 50 million people develop colitis and extraintestinal manifestations

(eg. liver abscess) • Symptoms: subacute onset >1-3 weeks

- Mild diarrhea - Severe dysentery (abdominal pain, diarrhea and bloody stools)- Fulminant colitis- Weight loss (50%)- Fever (38%)

• Investigation: Stool microscopy- Stool antigen, PCR- Serology

Cooper CJ, et al. South Med 2015;108:676-81https://appspghan.org

CMV enterocolitis

CMV infected cells (intranuclear and intracytoplasmic inclusions) with positive in situ hybridization study


How to improve the diagnosis of PIBD in Asia?

MC SP

Multidisciplinary team

StandardizationResearch collaboration

Promote knowledge https://appspghan.org

challenges in the diagnosis of pibd in the asian countries

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