A Prospective Study on the Incidence and Risk Factors Related to Infection in Patients With Inflammatory Bowel Disease

Inflammatory Bowel Diseases Clinical Trial

— INFEII  

Official title:

A Prospective Study on the Incidence and Risk Factors Related to Infection in Patients With Inflammatory Bowel Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02904590
• Other study ID #: INFEII
• Status: Completed
• Start date: October 2016

Study information

• Verified date: July 2020
• Source: Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The purpose of this study is to determine the incidence and risk factors related to Infection in patients with Inflammatory Bowel Disease (IBD)

Description:

IBD could lead to an increased risk of infections, particularly related to immunosuppressive therapy. The true effect of having IBD in the development of infections has not been studied in depth since the cohort studies are scarce and the results of studies with different approaches are contradictory.

The limited time period of former studies may not be enough to assess infectious complications that may occur in a long term period.

Moreover, certain polymorphisms demonstrated to confer a higher risk of opportunistic infections under immunosuppressive conditions, for instance HIV, patients with cystic fibrosis and Candida' infections. For this reason, it seems reasonable to think that genetic factors might play a role in the risk of opportunistic infections in IBD.

The hypothesis of this study is that patients with IBD have an increased risk of infection by immunosuppressive treatment.

TYPE OF STUDY Prospective cohort study that evaluates the effect of immunosuppression and other clinical factors in the onset of infection in IBD

STUDY DESIGN PATIENTS & METHODS This study is aimed to all incidental patients diagnosed with Crohn's disease and ulcerative colitis included in the ENEIDA database.

METHODS An infection would be considered as relevant when: 1) requires hospital admission, 2) leads to death or endangers the patient's life (ICU admission, presence of hemodynamic instability, sepsis, tracheal intubation, vasoactive drug requirement), 3) must be treated with specific antibiotics (antibacterials, antivirals, antifungals) 4) affects recurrently (herpes virus, papilloma virus, etc). 5) requires change/withdrawal of immunosuppressive or biological treatment.

The appearance of relevant infection will be prospectively evaluated, performing a subanalysis at 3 and 5 years using ENEIDA platform. ENEIDA is a database from a Spanish national study in IBD on genetic and environmental determinants run under GETECCU (Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa) supervision. This database basically comprises: demographic characteristics, type of IBD, immunosuppressant treatment, biological treatment or surgery)

At the time of inclusion the following variables should be available (and are mandatory):

demographic characteristics, type of IBD, date of diagnosis, phenotypic characteristics of the disease, history of serious infections, information on received treatments particularly the exposure to immunosuppressants, biological treatment or surgery and whether an infection has occurred as a complication of the three treatment groups. It should also be collected the following serologic details: hepatitis type B virus C, HIV, tuberculosis (TB), varicella zoster status.

At the time of registration a blood sample (10cc) will be drawn and sent to a biobank to analyze the DNA for genetic research.

STUDY ANALYSIS Sample calculation

The main objective of this study is to determine the percentage of infections in IBD and the related risk factors for the development of infections in patients with IBD. Given that the reported prevalence of infection varies between 6 and 10%the formula for estimating endless samples, establishing:

• Security level of the confidence interval at 95%

• Expected value for the worst case scenario of 6% (prevalence of infection)

• Precision of 1.5%

• The minimum sample number is set to 963, and assuming a loss rate of 20%

With these assumptions, the total number of patients to be included is 1204 patients.

The statistical analysis will be in three steps: (1) independent clinical factors analysis, (2) genetic factors infection-related analysis and (3) clinical and genetic factors infection- related analysis.

Baseline and follow up data will be compared among patients who develop infection and those who do not. Quantitative variables will be contrast by T-student and Mann-Whitney test. Qualitative variable will be contrast by X2 or Fisher test. Logistic regression will be conducted to analyze independent associations between variables and Kaplan-Meier test to calculate survival curves.

An analysis of Cox proportional hazards will be conducted to assess the effect of exposure to independent predictors of the risk of significant infection or mortality.

Finally the intensity of the significant associations will be measured by calculating the OR, HR and confidence interval of 95%.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1204
• Est. primary completion date: July 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 100 Years

Eligibility

Inclusion criteria:

• All incidental patients with IBD controlled at each participating center, registered in the ENEIDA database could be included, until the expected study sample is reached (n=1204 patients).

• An incidental IBD case is any patient with a diagnosis of Crohn's disease, ulcerative colitis and unclassified colitis after 3-6 month of the conclusive diagnosis of IBD.

Exclusion Criteria:

• HIV infection or any congenital immunodeficiency at the time of inclusion.

• To be under any immunosuppressant therapy for another reason other than IBD at IBD diagnosis.

• No consent to participate.

Related Conditions & MeSH terms

• Infection
• Inflammatory Bowel Diseases
• Intestinal Diseases

Locations

Country	Name	City	State
Spain	Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Reina Sofía	Córdoba
Spain	Hospital Universitario Fuenlabrada	Fuenlabrada	Madrid
Spain	Hospital de Galdakao	Galdakao	Bilbao
Spain	Hospital Universitari Dr. Josep Trueta	Girona
Spain	Hospital General de Granollers	Granollers	Barcelona
Spain	Hospital Universitario de Bellvitge	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Hospital De La Princesa	Madrid
Spain	Althaia, xarxa assistencial universitaria de Manresa	Manresa	Barcelona
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	Corporació Sanitària Parc Taulí	Sabadell	Barcelona
Spain	Hospital Infanta Sofía	San Sebastián De Los Reyes	Madrid
Spain	Hospital Moisès Broggi	Sant Joan Despí	Barcelona
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Consorci hospitalari de Terrassa	Terrassa
Spain	Hospital Mutua de Terrassa	Terrassa	Barcelona
Spain	Hospital General de Tomelloso	Tomelloso	Ciudad REAL
Spain	Hospital Universitari La Fe	Valencia
Spain	Hospital Clínic de València	València
Spain	Complexo Hospital Universitario de Vigo	Vigo	Pontevedra
Spain	Hospital Clinico Universitario Lozano Blesa	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa

Country where clinical trial is conducted

Spain, 

References & Publications (16)

Arts J, D'Haens G, Zeegers M, Van Assche G, Hiele M, D'Hoore A, Penninckx F, Vermeire S, Rutgeerts P. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis. 2004 Mar;10(2):73-8. — View Citation

Beaugerie L, Gerbes AL. Liver dysfunction in patients with IBD under immunosuppressive treatment: do we need to fear? Gut. 2010 Oct;59(10):1310-1. doi: 10.1136/gut.2010.217331. — View Citation

Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056/NEJMoa0904492. — View Citation

Connelly TM, Sehgal R, Berg AS, Hegarty JP, Deiling S, Stewart DB, Poritz LS, Koltun WA. Mutation in TAGAP is protective of anal sepsis in ileocolic Crohn's disease. Dis Colon Rectum. 2012 Nov;55(11):1145-52. doi: 10.1097/DCR.0b013e3182676931. — View Citation

Fidder H, Schnitzler F, Ferrante M, Noman M, Katsanos K, Segaert S, Henckaerts L, Van Assche G, Vermeire S, Rutgeerts P. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study. Gut. 2009 Apr;58(4):501-8. doi: 10.1136/gut.2008.163642. Epub 2008 Oct 2. — View Citation

Ford AC, Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-a therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2013 Aug;108(8):1268-76. doi: 10.1038/ajg.2013.138. Epub 2013 May 7. — View Citation

Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H; International IBD Genetics Consortium (IIBDGC), Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582. — View Citation

Jurevic RJ, Bai M, Chadwick RB, White TC, Dale BA. Single-nucleotide polymorphisms (SNPs) in human beta-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls. J Clin Microbiol. 2003 Jan;41(1):90-6. — View Citation

Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, Pritchard ML, Sandborn WJ. Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry. Clin Gastroenterol Hepatol. 2006 May;4(5):621-30. Erratum in: Clin Gastroenterol Hepatol. 2006 Jul;4(7):931. — View Citation

Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, Langholff W, Londhe A, Sandborn WJ. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol. 2012 Sep;107(9):1409-22. doi: 10.1038/ajg.2012.218. Epub 2012 Aug 14. — View Citation

Obrador A, López San Román A, Muñoz P, Fortún J, Gassull MA; Grupo Español de Trabajo de Enfermedad de Crohn y Colitis Ulcerosa (GETECCU). [Consensus guideline on tuberculosis and treatment of inflammatory bowel disease with infliximab. Spanish Working Group on Crohn Disease and Ulcerative Colitis]. Gastroenterol Hepatol. 2003 Jan;26(1):29-33. Review. Spanish. — View Citation

Papadopoulos AI, Ferwerda B, Antoniadou A, Sakka V, Galani L, Kavatha D, Panagopoulos P, Poulakou G, Kanellakopoulou K, van der Meer JW, Giamarellos-Bourboulis EJ, Netea MG. Association of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms with increased infection risk in patients with advanced HIV-1 infection. Clin Infect Dis. 2010 Jul 15;51(2):242-7. doi: 10.1086/653607. — View Citation

Papadopoulos AI, Ferwerda B, Antoniadou A, Sakka V, Galani L, Kavatha D, Panagopoulos P, Poulakou G, Protopapas K, van der Meer JW, Netea MG, Giamarellos-Bourboulis EJ. Association of Mal/TIRAP S180L variant polymorphism with decreased infection risk in patients with advanced HIV-1 infection. Cytokine. 2012 Oct;60(1):104-7. doi: 10.1016/j.cyto.2012.05.008. Epub 2012 Jun 8. — View Citation

Pine SO, McElrath MJ, Bochud PY. Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS. 2009 Nov 27;23(18):2387-95. doi: 10.1097/QAD.0b013e328330b489. — View Citation

Radovanovic I, Mullick A, Gros P. Genetic control of susceptibility to infection with Candida albicans in mice. PLoS One. 2011 Apr 20;6(4):e18957. doi: 10.1371/journal.pone.0018957. — View Citation

Toruner M, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, Colombel JF, Egan LJ. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008 Apr;134(4):929-36. doi: 10.1053/j.gastro.2008.01.012. Epub 2008 Jan 11. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence of infection and type of infection in patients with ulcerative colitis and Crohn's disease, regardless of treatment received. ulcerative colitis and Crohn's disease, regardless of treatment received.	Serious infection means any untoward medical occurrence that at any dose: Results in death or life-threatening; Requires in patient hospitalization or prolongation of an existing hospitalization; Is a medically important event.; Requires specific chemotherapy treatment; Emerges repeatedly.; Induces a switch or a withdrawal of the immunosuppressive or biological treatment	Change from baseline incidence and type of infection at 3 and 5 years
Primary	Clinical, demographic, epidemiologic and genetic factors associated with the risk of infection in patients with IBDassociated with the risk of infection in patients with IBD.		Change from baseline and at 3 and 5 years
Secondary	The effect of duration and immunosuppressive potency in the development of infections		at baseline and at 3 and 5 years
Secondary	The impact of infection on morbidity and mortality in patients with IBD.		at baseline and at 3 and 5 years
Secondary	The type of infections in IBD patients grouped by systems and whether they are opportunistic or not.		at baseline and at 3 and 5 years