"Adding DNA-test for Screening of HLA-DQ2 and DQ8 to Improve Early Diagnosis of Celiac Disease"
NCT ID: NCT06179121
Last Updated: 2023-12-21
Study Results
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Basic Information
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ENROLLING_BY_INVITATION
508 participants
OBSERVATIONAL
2022-09-01
2024-11-01
Brief Summary
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Detailed Description
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CD is one of the most common lifelong food- related disorders; it has a frequency of 1% in the general population: this corresponds to 170.000 persons in the Netherlands, and of them at least 30.000 children\[3-7\]. However, CD is frequently unrecognized, partially because of its variable clinical presentations and symptoms, ranging from malabsorption with chronic diarrhoea, poor growth in children and weight loss, to nonspecific signs and symptoms like chronic fatigue, osteoporosis/reduced bone mineral density, gastrointestinal symptoms or elevated liver enzymes \[5,7,8\]. Unrecognized and thereby undiagnosed and untreated disease is associated with short- and long-term complications such as delayed puberty, neuropsychiatric disturbances, associated autoimmune disease, miscarriages, small-for-date-births, osteoporosis, and, rarely, malignancy. CD has a considerable health burden for society and yields extensive negative economic consequences, thereby presenting a resource challenge for current and future health systems \[9\]. Once diagnosed, the patient's health status improves after treatment with a gluten free diet (GFD).
That timely diagnosis and treatment of CD could be achieved by active case-finding, show the preliminary results of the ongoing ZonMw sponsored project GLUTENSCREEN (531002001; www.glutenscreen.nl). In this active case finding project, started at February 2019, all children aged 1-4 years who attend the Preventive Youth Health Care Centres (YHCCs) in the region of Kennemerland are yearly assessed for 10 CD-related symptoms during their regular consultation. If a child has one or more symptoms, the parents of the child are invited to participate. After informed consent, a point of care test (POCT) assessing CD-specific antibodies against tissue-transglutaminase (TGA) from a droplet of blood, is performed onsite at the YHCCs. If the POCT is positive (TGA present), CD is highly suspected and the child is referred to the Leiden University Medical Centre (LUMC) for diagnosis according to the standard of care\[1,2\]. The preliminary results of GLUTENSCREEN are beyond expectations: From the 14.917 children attending the YHCCs, 5.512 (37.0%) of them had one or more CD-related symptoms.
The parents of 3.203 (58.1%) children gave informed consent for a POC-test. In 61 (1.9%) children the POC-test was positive. After additional investigations at our hospital, CD was confirmed in 55 children (1.7% of the tested children) (serum IgA TGA \>10xULN and IgA against endomysium (EMA) positive) and ruled out in 5 children with dubious/positive POC test: in two children HLA-DQ2/8 was negative with negative TGA in serum (ELISA-test), in 3 children with TGA \<10 x ULN (ELISA-test) in whom small bowel biopsies showed Marsh 1 lesions. One child still needs to be seen in the hospital (parents refused till now) (www.glutenscreen.nl). From the parents who were invited for GLUTENSCREEN, almost 80% is willing to participate if the POCT could be performed during the regular visit at the YHCC. All health care professionals reported that early CD detection by case-finding adds value to the preventive care they offer at the YHCCs.
These preliminary results of our active CD case-finding project at the Preventive YHCCs in the Netherlands illustrate that early detection of CD at the Preventive YHC is feasible and well-accepted by parents and health care professionals.
In GLUTENSCREEN all symptomatic children will be annually tested for CD at the Preventive YHCCs till the age of 4 years. In the region Kennemerland, GLUTENSCREEN has already been implemented in the regular care and POCT will be performed during consultation. However, the development of CD requires genetic susceptibility, present in 40% of the general population. Since the disease almost exclusively occurs in individuals with the human leukocyte antigen (HLA)-DQ2 and/or HLA- DQ8 haplotypes, codified by chromosome 6. The absence of HLA-DQ2/-DQ8 can exclude the possibility or future development of CD with a certainty close to 100%. Because of the high negative predictive value of HLA-typing for development of CD, repeated CD testing will be unnecessary in HLA-DQ2/DQ8 negative individuals (60% of the general population) \[10\].
Currently, HLA-typing is not a part of GLUTENSCREEN because current technique presents important drawbacks in settings without the availability of a laboratory, like the Preventive Care setting as the YHCCs, since it requires DNA extraction. Material for DNA extraction is usually obtained from whole blood (minimum quantity 4-5 ml) or from other cells, such as buccal mucosa. However, venipunctures are not feasible at the YHCCs and buccal mucosa DNA extraction in children is time-consuming.
We here propose to validate and implement the test for DNA isolation for HLA typing extracted from the dried blood spots to early detection for CD on the Preventive YHCCs.
Other projects have shown that the usage of real-time polymerase chain reaction (RT-PCR) on DNA acquired from dried blood samples is successful and can easily be applied to HLA-DQ2/DQ8 typing in this setting\[11\].
Adding HLA-DQ2/8 typing to the case finding strategy for CD at the Preventive YHCC is innovative since HLA-typing for CD has not previously been done in dried blood spots in the proposed setting. Furthermore, embedding this technique represents a novel approach to active case-finding of CD and consequently will improve secondary prevention of CD by early diagnosis at the Preventive YHCCs.
The outcome of the proposed study will have impact on the active case finding procedure of CD at the YHCCs. Repeated testing for CD could be omitted in children tested HLA-DQ2/8 negative, this reflects to 60% of the targeted population. This study will result in:
1. More efficient and decrease of the burden of the HLA-DQ2/8 negative children: less children have to be tested.
2. Clarity of the acceptability of HLA typing for CD in parents from young children.
3. Costs saving by reducing unnecessary follow up of children. To embed this technique in the case finding setting at the YHCCs, the test will be offered to a significant part of the general Dutch population between 0-4 years old, since more than 95% of the general population visit the YHCC.
* Consult references at the end of this document
Conditions
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Keywords
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Phase 1 Cohort (Validation of HLA- DQ2/8 typing)
Children (1-18 years old) coming for consultation at the LUMC for (suspicion of) CD
DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease
Phase 1 and 2: After blood collection (in combination with regular care) and informed consent, a blood droplet obtained by an additional fingerprick (Phase 1 and just an extra droplet from an existing finger prick for Phase 2) will be deposited on filter paper S\&S 903™ (Schleicher and Schuell). DNA will be isolated using the QIAamp method designated for this purpose from dried blood spots (Qiagen). The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. Factors that may influence the quality of the material will be taken into account in the validation process.
Phase 2 Cohort (Implementation of HLA-DQ2/8 typing on the Preventive YHCCs)
Children (12 months to 4 years old), at least with one of the 10 CD-related symptoms, not diagnosed with CD, and not on a GFD,
DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease
Phase 1 and 2: After blood collection (in combination with regular care) and informed consent, a blood droplet obtained by an additional fingerprick (Phase 1 and just an extra droplet from an existing finger prick for Phase 2) will be deposited on filter paper S\&S 903™ (Schleicher and Schuell). DNA will be isolated using the QIAamp method designated for this purpose from dried blood spots (Qiagen). The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. Factors that may influence the quality of the material will be taken into account in the validation process.
Interventions
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DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease
Phase 1 and 2: After blood collection (in combination with regular care) and informed consent, a blood droplet obtained by an additional fingerprick (Phase 1 and just an extra droplet from an existing finger prick for Phase 2) will be deposited on filter paper S\&S 903™ (Schleicher and Schuell). DNA will be isolated using the QIAamp method designated for this purpose from dried blood spots (Qiagen). The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. Factors that may influence the quality of the material will be taken into account in the validation process.
Eligibility Criteria
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Inclusion Criteria
* age 1-18 years,
* consultation at the LUMC for (suspicion of) CD,
* parents have a sufficient knowledge of Dutch language,
* written informed consent from child and/or parent
Phase 2:
* age 12 months to 4 years,
* at least one of the 10 CD-related symptoms
* not diagnosed with CD,
* not on a GFD,
* parents have a sufficient knowledge of Dutch language,
* written informed consent from the parent(s)
Exclusion Criteria
* no informed consent,
* insufficient knowledge of Dutch language and/or inability to understand the information provided,
* bleeding disorders.
12 Months
18 Years
ALL
No
Sponsors
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ZonMw: The Netherlands Organisation for Health Research and Development
OTHER
Leiden University Medical Center
OTHER
Responsible Party
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crmeijerboekel
PhD
Principal Investigators
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Caroline R Meijer-Boekel, PhD
Role: PRINCIPAL_INVESTIGATOR
Leiden University Medical Center
Locations
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Leiden University Medical Centre (LUMC)
Leiden, South Holland, Netherlands
Countries
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References
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Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):136-60. doi: 10.1097/MPG.0b013e31821a23d0.
Jansson-Knodell CL, Hujoel IA, West CP, Taneja V, Prokop LJ, Rubio-Tapia A, Murray JA. Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):1954-1968.e13. doi: 10.1016/j.cgh.2018.11.013. Epub 2018 Nov 16.
Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, Kelly CP, Ahuja V, Makharia GK. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037. Epub 2018 Mar 16.
Lindfors K, Ciacci C, Kurppa K, Lundin KEA, Makharia GK, Mearin ML, Murray JA, Verdu EF, Kaukinen K. Coeliac disease. Nat Rev Dis Primers. 2019 Jan 10;5(1):3. doi: 10.1038/s41572-018-0054-z.
Jansen M, van Zelm M, Groeneweg M, Jaddoe V, Dik W, Schreurs M, Hooijkaas H, Moll H, Escher J. The identification of celiac disease in asymptomatic children: the Generation R Study. J Gastroenterol. 2018 Mar;53(3):377-386. doi: 10.1007/s00535-017-1354-x. Epub 2017 Jun 6.
Csizmadia CG, Mearin ML, von Blomberg BM, Brand R, Verloove-Vanhorick SP. An iceberg of childhood coeliac disease in the Netherlands. Lancet. 1999 Mar 6;353(9155):813-4. doi: 10.1016/S0140-6736(99)00243-3. No abstract available.
Steens RF, Csizmadia CG, George EK, Ninaber MK, Hira Sing RA, Mearin ML. A national prospective study on childhood celiac disease in the Netherlands 1993-2000: an increasing recognition and a changing clinical picture. J Pediatr. 2005 Aug;147(2):239-43. doi: 10.1016/j.jpeds.2005.04.013.
Meijer CR, Schweizer JJ, Peeters A, Putter H, Mearin ML. Efficient implementation of the 'non-biopsy approach' for the diagnosis of childhood celiac disease in the Netherlands: a national prospective evaluation 2010-2013. Eur J Pediatr. 2021 Aug;180(8):2485-2492. doi: 10.1007/s00431-021-04068-1. Epub 2021 Apr 15.
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Tran TM, Aghili A, Li S, Ongoiba A, Kayentao K, Doumbo S, Traore B, Crompton PD. A nested real-time PCR assay for the quantification of Plasmodium falciparum DNA extracted from dried blood spots. Malar J. 2014 Oct 4;13:393. doi: 10.1186/1475-2875-13-393.
McCabe ER. Utility of PCR for DNA analysis from dried blood spots on filter paper blotters. PCR Methods Appl. 1991 Nov;1(2):99-106. doi: 10.1101/gr.1.2.99. No abstract available.
Shaik M, Shivanna DK, Kamate M, Ab V, Tp KV. Single Lysis-Salting Out Method of Genomic DNA Extraction From Dried Blood Spots. J Clin Lab Anal. 2016 Nov;30(6):1009-1012. doi: 10.1002/jcla.21972. Epub 2016 Apr 13.
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Other Identifiers
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05550402110016
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
P23.025 (METC LDD)
Identifier Type: -
Identifier Source: org_study_id