Calprotectin Less Accurate for Isolated Ileal Crohn’s Disease

G D’Arcangelo et al. JPGN 2021; 73: 242-246. Is Fecal Calprotectin a Useful Marker for Small Bowel Crohn Disease?

In this retrospective study with 98 patients, the authors examined the sensitivity and specificity of fecal calprotectin (FC) at a cutoff of 150 mcg/g in comparison to findings of ileocolonoscopy and MRE in those with isolated ileal CD (L1, n=14), colonic CD (L2, n=10) and ilecolonic CD (L3, n=74) . Note: the abstract erroneously states the cutoff as 50 mcg/g.

Key findings:

  • The sensitivity and specificity of FC for L1 CD were 36% and 91%, respectively, compared to 93% and 75% for L2 and 70% and 95% for L3.
  • An FC of 95 mg/kg was identified as the best cut off for identification of active isolated ileal disease, with a sensitivity of 77% and a specificity of 56%

My take: Though this study had only 14 patients with isolated ileal disease, it is likely that a calprotectin level is less reliable as a biomarker in these patients.

Related article: Jukic A, Bakiri L, Wagner EF, et al Calprotectin: from biomarker to biological functionGut Published Online First: 18 June 2021. doi: 10.1136/gutjnl-2021-324855. Thanks to KT Park for this reference. Open Access- Full text: Calprotectin: from biomarker to biological function

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Clinical Remission: Trust But Verify

A recent study reminded me of the slogan ‘trust but verify.’ This slogan was popularized by Ronald Reagan in nuclear disarmament talks with the U.S.S.R. In contrast, C Sarbagili-Shabat et al (JPGN 2021; 72: 569-573. Moderate-to-severe Endoscopic Inflammation is Frequent After Clinical Remission in Pediatric Ulcerative Colitis) discuss the issue of clinical remission in ulcerative colitis.

This study  prospectively assessed for mucosal healing by endoscopy 3 to 5 months after clinical remission, PUCAI <10, was documented. Key findings:

  • 28 children in continuous clinical remission at time of sigmoidoscopy were included. Mayo 0 was present in 12/28 (43%), Mayo 1 in 2/28 (7%) and Mayo 2 to 3 in 14/28 (50%) endoscopies.
  • Among 23 patients with follow-up through 18 months, remission was sustained in 6/12 (50%) with Mayo score 0 to 1 versus 2/11 (18%) of patients with Mayo 2 and 3
  • 16 (57%) of the patients were receiving 5-ASA treatment

It would have been helpful to have calprotectin values as well. In their discussion, the authors note that “a normal calprotectin is quite convincing with regard to endoscopic remission” and ECCO ESPGHAN guidelines “provide guidance that a colonoscopy should only be performed if fecal calprotectin” is >250 mcg/g.

My take: Clinical remission in ulcerative colitis should be verified. It is reasonable to start with a fecal calprotectin and if elevated to proceed with endoscopic evaluation (colonoscopy or sigmoidoscopy).

Also: new therapy for Crohn’s disease with favorable phase III study. From Pharmacy Times: Risankizumab (Skyrizi) Demonstrates Significant Improvements In Patients with Crohn Disease Two studies, ADVANCE and MOTIVATE showed similar results for Crohn’s disease. In the ADVANCE study: “40% of patients receiving 600 mg, and 32% of patients receiving 1200 mg achieved endoscopic response at week 12, compared to 12% in the placebo group.” In the MOTIVATE study, “29% and 34% of patients receiving 600 mg and 1200 mg achieved endoscopic response, respectively, compared to 11% in the placebo group.”

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Results in population with reported clinical remission (Sarbagili-Shabat et al JPGN 2021; 72: 569-573)

IBD Update (November 2020)

W Reinisch et al. Inflamm Bowel Dis 2020; 1562-1571.Full Text: Association of Biomarker Cutoffs and Endoscopic Outcomes in Crohn’s Disease: A Post Hoc Analysis From the CALM Study n=244.

  • The proportion of patients who achieved the primary end point CDEIS <4 and no deep ulcers was significantly greater for those with FC <250 µg/g (74%; P < 0.001)
  •  Fecal calprotectin <250 µg/g, CRP <5 mg/L, and CDAI <150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS <4 and no deep ulcers 48 weeks after randomization

My take: Fecal calprotectin levels are useful for monitoring mucosal healing. Levels less than 250 are encouraging. Levels less than 100 are better.

Proportion of patients achieving mucosal healing (CDEIS <4) and no deep ulcers in (B) all patients by FC cutoff at week 48 after randomization

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S Danese et al. Clin Gastroenterol Hepatol 2020; 18: 2526-2534. Full text link: Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis “We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies.” n=168. Key findings:

  • Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo)
  • At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group.

X Zhuang et al. Inflamm Bowel Dis 2020; 26: 1636-1647. Full text: Fecal Microbiota Alterations Associated With Clinical and Endoscopic Response to Infliximab Therapy in Crohn’s Disease

Methods: Microbiota was prospectively analyzed in 49 patients with active CD at baseline, week 6, and week 30

Key Findings:

  • Increased proportions of Lachnospiraceae and Blautia were associated with IFX efficacy; the combined increase of these taxa at week 6 showed 83.4% and 84.2% accuracy in predicting clinical response at weeks 14 and 30, respectively, with a predictive value of 89.1% in predicting endoscopic response at week 30
  • IFX diminished CD-related gut microbial dysbiosis by modifying microbiota composition and function

Diagnostic Strategy For Children with Diarrhea and Abdominal Pain

A recent study (E Van de Vijver et al. Pediatrics 2020; 146: e20192235) shows a logical approach for testing children with diarrhea and abdominal pain.

Abstract and video abstract link: Test Strategies to Predict Inflammatory Bowel Disease Among Children With Nonbloody Diarrhea


  • Prospective cohort study: n=193, 6 to 18 years who underwent a standardized diagnostic workup.
  • Patients with rectal bleeding or perianal disease were excluded because the presence of these findings prompted endoscopy regardless of their biomarkers.
  • In addition to symptoms, objective measures included C-reactive protein (>10 mg/L), hemoglobin (<−2 SD for age and sex), and fecal calprotectin (≥250 μg/g).

Key findings:

  • Twenty-two of 193 (11%) children had IBD
  • “Triaging with a strategy that involves symptoms, blood markers, and calprotectin will result in 14 of 100 patients being exposed to endoscopy. Three of them will not have IBD, and no IBD-affected child will be missed.

My take: The approach advocated by the authors of reserving a diagnostic endoscopy for children at high risk for IBD based on stool tests/blood tests in addition to symptoms has merit.  I would add a couple caveats:

  1. In this population, I would recommend checking for celiac disease (eg. tissue tranglutaminase IgA antibody, serum IgA level)
  2. I think in individuals with ‘borderline’ elevations of calprotectin (50-250 μg/g), followup testing is needed and if remains persistently elevated, then ileocolonoscopy is likely warranted.  (Calprotectin values in younger children tend to be higher -so this approach is best suited in children >5 years of age)

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New and Improved Biomarker Blood Test for Crohn’s Disease?

A recent study (G D’Haens, O Kelly, R Battat et al. Gastroenterol 2020; 158: 515-26,editorial 463) describes the development and validation of a blood test panel to assess Crohn’s disease (CD) endoscopic activity level.  The authors evaluated a blood test which measured 13 proteins in the blood using samples from 278 patients.  Then there were two validation cohorts:

  • 116 biologic-naive CD patients -cohort 1
  • 195 biologic-exposed CD patients -cohort 2

The blood tests were used to develop an endoscopic healing index (EHI) score (0-100). Higher scores indicate greater disease activity.

Key findings:

  • EHI values below 20 identified remission with a sensitivity of 97.1%  and 83.2% in cohorts 1 & 2 respectively; specificity was 69% and 37% respectively.
  • EHI values below 50 points identified patients with highest specificity of 100% and 88% in cohorts 1 and 2 respectively.
  • EHI AUROC (area under the receiver operating characteristic curve) did not differ significantly from that of fecal calprotectin and were higher than measurement of serum CRP (in cohort 1 but not cohort 2).

The editorial notes that the EHI performed much better in younger, biologically-naive patients and that the EHI could potentially be incorporated into a treat-to-target strategy which would potentially entail followup endoscopy in those with EHI >50.

My take: While the stool calprotectin has some logistical barriers in many patients, the EHI is likely a much more expensive test and needs further validation.  For now, the combination of CRP and calprotectin are the best noninvasive biomarkers to assess CD activity.

Briefly noted: Vedolizumab-Induced Pulmonary Toxicity -Case report of a patient with ulcerative colitis who developed interstitial lung disease (Gastroenterol 2020; 158: 478-9).

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A Little More Data on Antibiotic Cocktail for Pediatric Acute Severe Ulcerative Colitis

A recent prospective study (D Turner et al. Inflammatory Bowel Diseases, izz298, with 28 children found improvement in 5-day PUCAI scores in patients who received quadruple antibiotics in combination with IV corticosteroids compared to those who received IV corticosteroids alone.

Link: Antibiotic Cocktail for Pediatric Acute Severe Colitis and the Microbiome: The PRASCO Randomized Controlled Trial


Hospitalized children with ASC (pediatric ulcerative colitis activity index [PUCAI] ≥65) were randomized into 2 arms: the first received antibiotics in addition to IVCS (amoxicillin, vancomycin, metronidazole, doxycycline/ciprofloxacin [IVCS+AB]), whereas the other received only IVCS for 14 days. The primary outcome was disease activity (PUCAI) at day 5. Microbiome was analyzed using 16S rRNA gene and metagenome.My t


Twenty-eight children were included: 16 in the AB + IVCS arm and 12 in the IVCS arm (mean age 13.9 ± 4.1 years and 23 [82%] with extensive colitis). The mean day-5 PUCAI was 25 ± 16.7 vs 40.4 ± 20.4, respectively (P = 0.037). Only 3 and 2 children, respectively, required colectomy during 1-year follow-up (P = 0.89). Microbiome data at time of admission were analyzed for 25 children, of whom 17 (68%) had a predominant bacterial species (>33% abundance); response was not associated with the specific species, whereas decreased microbiome

My take: Combination antibiotic therapy appears to improve disease activity in children with acute severe ulcerative colitis.  More and larger studies are needed to determine whether this is associated with improved long-term outcomes as well as which antimicrobials are optimal.

Related blog posts -ASUC:

Related blog posts -Calprotectin:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

What is the Calprotectin Threshold for Disease Progression in Crohn’s Disease?

A recent retrospective study (NA Kennedy et al. Clin Gastroenterol Hepatol 2019; 17: 2269-76) with 918 patients with Crohn’s disease (CD) examined calprotectin levels and disease progression. Median followup was 50.6 months.

Key findings:

  • A calprotectin level cut-off of 115 mcg/g was identified as optimal for separation of those with and without disease disease progression.
  • The authors noted: “Several studies have identified a cut-off value of 250 mcg/g as being useful to distinguish active from inactive disease.  In the present study,…a lower threshold of 115 mcg/g (was identified) suggesting that lower levels of inflammatory activity still may be associated with an adverse outcome.”
  • The authors’ figure 2, as estimated by the empiric transition matrix method, shows disease progression over 30 years.  At that point,  the groups were nearly equally divide between stricturing disease, penetrating disease and inflammatory disease; in contrast at disease onset, ~80% had inflammatory disease behavior.

My take: As more effective therapies have become available, our goals for disease control have changed and focus on altering the disease course with more stringent endpoints.  For calprotectin, the lower number (115 compared to 250) indicates a much lower risk for disease progression.

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An Insurance Company Doing the Right Thing (with Calprotectin)

“An Insurance Company Doing the Right Thing” –not The Onion headline this time.

Recently (April 7. 2019) United Healthcare put out a policy statement explicitly stating:

“Fecal measurement of calprotectin is proven and medically necessary for establishing the diagnosis or for management of the following:

  • Crohn’s Disease
  • Ulcerative Colitis”

Thanks to Kim Conn for identifying this policy.

The policy statement provides an in-depth rationale for why calprotectin is medically-indicated along with supporting recommendations from multiple GI societies and National Institute for Health and Care Excellence (NICE).  The policy statement includes a long list of references and would provide a strong argument in supporting calprotectin testing for all insurance providers.

Here’s the link: FECAL CALPROTECTIN TESTING United Healthcare.

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Lots of lazy river floating. Deschutes River, Bend OR

How Often is Arthritis a Presenting Feature of Pediatric IBD & How to Make the Right Diagnosis

A recent retrospective study (R Levy et al. J Pediatr 2019; 209: 233-5) analyzed the musculoskeletal presenting manifestations of pediatric inflammatory bowel disease (IBD).

In their cohort of 715 patients with IBD, 137 had arthritis and/or arthralgia.  28 of these 137 patients (3.9% of total cohort) had arthritis preceding the diagnosis of IBD and were eligible for this study.  Only 23 had complete data and were compared with 46 children with arthritis due to JIA (n=21), FMF (n=7), and postinfectious arthritis (n=18).

Key findings:

  • Patients with subsequent IBD diagnosis were more likely to have sacroiliac involvement (34.8% vs. 2.2%), more likely to have anemia (mean hgb 10.5 vs 12), more likely to have low albumin (mean 3.5 vs 4.3) and to have higher inflammatory markers (ESR 81 vs 46; CRP 6.6 vs 4.5 mg/dL)
  • In patients with calprotectin levels, 5 of 6 were >300 mg/kg and one was borderline
  • On direct questioning at time of IBD diagnosis, prolonged gastrointestinal symptoms (e.g. abdominal pain, diarrhea, weight loss, aphthous ulcers) were evident in 78%.
  • 4 of the 23 (17.3%) were diagnosed with IBD during the primary investigation. Ultimately, Crohn’s diagnosis was established in 87% of the IBD group.

My take: This study is important for pediatricians and rheumatologists. ~4% of children presenting with arthritis have IBD.  Careful interrogation for GI symptoms (and perianal exam) will avoid diagnostic delay in most patients as would a stool calprotectin. Features like sacroileitis, and abnormal labs should also increase the suspicion for IBD.

Briefly noted: In a study discussing pediatrician beliefs about JIA (MR Pavo, J de Inocencio, J Pediatr 2019; 209: 236-9) there is an important caveat for GI doctors:

“It is clear that booster vaccinations against measles, mumps, rubella, or varicella zoster virus, can be considered in patients receiving < 15 mg/m-squared/week of MTX [methotrexate]”  (Pediatr Rheumatol Online J 2018; 16: 46).

Related blog post:

  • IBD Update Feb 2019 -last entry shows study indicating that patients with IBD and arthritis were more likely to require biologics.


El Retiro Park, Madrid


Keep the Stool Cool for More Reliable Calprotectin

A recent study (S-M Haisma et al. Arch Dis Child shows that stool calprotectin levels stored at room temperature dropped nearly 20% after one day and dropped further over several days compared to baseline values, whereas calprotectin values remained reliable over six days for stool specimens stored at 4 degrees Celsius.

The authors conclude: “Calprotectin is not stable at room temperature. Children with IBD and their caretakers may be falsely reassured by low calprotectin values. The best advisable standard for preanalytical calprotectin handling is refrigeration of the stool sample until delivery at the hospital laboratory.”

Full text (link from KT Park’s twitter feed): Calprotectin instability may lead to undertreatment in children with IBD

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