Immune Function in Patients With Obstructive Jaundice

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2012 by University of Nottingham
Sponsor:
Information provided by (Responsible Party):
University of Nottingham
ClinicalTrials.gov Identifier:
NCT01367821
First received: May 31, 2011
Last updated: October 4, 2012
Last verified: October 2012
  Purpose

Patients with obstructive jaundice (OJ) often require surgical, endoscopic or radiological interventions to facilitate biliary drainage and relieve jaundice. However it is known that patients with OJ have increased surgical risks than non-jaundiced patients undergoing the same procedures. Surgery for severe OJ is associated with a significant post-operative mortality (10-15%) and morbidity (30-65%). The commonest complications are related to sepsis but the pathophysiological mechanisms behind this susceptibility to bacterial infection are not clear. Recent work has shown a pivotal role of bile in the maintenance of enterocyte tight junctions and the expression of tight junction-associated proteins which could account for the translocation of enteric bacteria and bacterial products to mesenteric lymph node complexes, the portal circulation and subsequently the liver. Some of these bacterial products, such as endotoxin and quorum sensing signalling molecules (QSSMs), have immunomodulatory properties which may dampen normal immune responses to infection resulting in life-threatening organ dysfunction. Bacterial endotoxin and quorum sensing signalling molecules (QSSMs) represent good candidates for the mediators of this immune suppression and although there is a compelling case for their involvement in the pathogenesis of sepsis, evidence to support their involvement in the aetiology of infection in OJ is currently lacking.


Condition
Obstructive Jaundice
Disease as Reason for ERCP
Immune Dysfunction
Immune Tolerance

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Quorum Sensing Signal Molecules (QSSMs) and Immune Dysfunction in Patients Undergoing Endoscopic Retrograde Cholangiopancreatography (ERCP) for Obstructive Jaundice

Resource links provided by NLM:


Further study details as provided by University of Nottingham:

Primary Outcome Measures:
  • Change in monocyte cytokine responses to endotoxin stimulation [ Time Frame: Baseline (pre ERCP) and post ERCP days 1, 7, 14 and 30 ] [ Designated as safety issue: No ]
    Evaluation of monocyte cytokine responses to endotoxin stimulation at specified time points


Secondary Outcome Measures:
  • Change in concentration of systemic quorum sensing signaling molecules [ Time Frame: Baseline (pre ERCP) and post ERCP days 1, 7, 14 and 30 ] [ Designated as safety issue: No ]
    Evaluation of the presence of quorum sensing signalling molecules in the systemic circulation at specified time points


Biospecimen Retention:   Samples Without DNA

Plasma Bile


Estimated Enrollment: 50
Study Start Date: May 2011
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts
Patients with obstructive jaundice
Patients with obstructive jaundice
Healthy volunteers
Healthy volunteers

Detailed Description:

Obstructive jaundice (OJ) is a condition where a blockage of flow of bile from the liver leads to the accumulation of bile products in the blood resulting in yellowing and itching of the skin. Common causes of OJ include gallstones and also tumours of the pancreas or bile duct. Relieving this type of jaundice and treating the underlying cause can include endoscopic or surgical procedures. It is known however, that patients with OJ have increased surgical risks than non-jaundiced patients who undergo the same operations. Studies have shown that surgery for severe OJ is associated with a postoperative mortality in the region of 10-15% and morbidity rates of 30-65%. Complications related to bacterial infection are common and patients developing severe infections may require treatment with broad spectrum antibiotics with care in intensive or high dependency units.

Although antibiotics have proved invaluable in treating postoperative infections they carry the potential for adverse effects. Antibiotics can suppress normal gut bacteria and allow disease causing bacteria to proliferate, such as Clostridium difficile. This usually manifests as mild-to-moderate diarrhoea but can occasionally cause life-threatening bowel inflammation. The widespread use of antibiotics is also central to the development of bacterial strains with antibiotic resistance. This clinical problem also has economic, political and environmental implications for the National Health Service. Adherence to measures of infection control, education and antibiotic policy can minimise antibiotic resistance; however the limits surrounding such approaches have led to a demand for novel or alternative strategies.

It has recently been discovered that bacteria are able to communicate by producing specialised molecules known as quorum sensing signalling molecules (QSSMs). An accumulation of QSSMs in their surrounding environment allow for the bacteria to quantify the size of colonies. At specific colony sizes the concentration of QSSMs reaches a critical threshold leading to the activation of genes that cause an infection. Disruption of quorum sensing has been shown to reduce the severity of infection in animal studies and this has led to the development of inhibitors of quorum sensing as a possible strategy in antibacterial therapy.

Previous work conducted at the University of Nottingham has demonstrated that QSSMs also influence the number and function of a specific type of immune cell known as 'antigen presenting cells'. These cells are pivotal in allowing the immune system to recognise components of bacteria as foreign and thereby mount the appropriate response. It was found that large numbers of these types of cells underwent programmed cell death (cell suicide) in the presence of QSSMs compared to when QSSMs were absent. This mirrors the situation in blood sampled from patients with severe infections where there is a greater proportion of cell deaths among antigen presenting cells than other types of immune cell.

It is likely that the susceptibility to infectious complications in patients with obstructive jaundice is due to the interplay of various factors. The absence of intestinal bile has implications for the integrity of the bowel wall as a barrier, changes in gut microflora flora and translocation of both bacteria and their products. In addition, it is clear that a form of immune dysfunction occurs, which dampens the normal response following exposure to bacterial products. This immune dysfunction may avert powerful inflammatory cascades resulting in life-threatening multi organ dysfunction but at the expense of conditions that favour bacterial survival. QSSMs represent good candidates for the mediators of this immune dysfunction and although there is a compelling case for their involvement in the pathogenesis of sepsis, definitive evidence to support their role in infective processes in OJ is currently lacking.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Patients referred to tertiary hepatopancreaticobiliary centre for investigation of obstructive jaundice and Healthy volunteers

Criteria

Inclusion Criteria:

  • Obstructive jaundice
  • Willing to participate and able to give informed consent
  • Alcohol abstinence during study

Exclusion Criteria:

  • Acute Physiology and Chronic Health Evaluation (APACHE) II Score ≥8
  • Severe neutropaenia
  • Smokers/substance abuse
  • Diabetes Mellitus
  • Oral/IV Steroids
  • On regular antibiotics
  • Patients with active cholangitis
  • Patients who have a history liver transplantation or chronic liver disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01367821

Contacts
Contact: Abeed H Chowdhury, MBChB MRCS 441158231144 abeed.chowdhury@nottingham.ac.uk
Contact: Dileep N Lobo, FRCS FACS dileep.lobo@nottingham.ac.uk

Locations
United Kingdom
Queen's Medical Centre Recruiting
Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
Contact: Abeed H Chowdhury, MBChB MRCS    441158231144    abeed.chowdhury@nottingham.ac.uk   
Principal Investigator: Abeed H Chowdhury, MBChB MRCS         
Sub-Investigator: Guruprasad Aithal, MD MRCP         
Sub-Investigator: Dileep N Lobo, FRCS FACS         
Sponsors and Collaborators
University of Nottingham
Investigators
Principal Investigator: Abeed H Chowdhury, MBChB MRCS University of Nottingham
  More Information

Publications:
Responsible Party: University of Nottingham
ClinicalTrials.gov Identifier: NCT01367821     History of Changes
Other Study ID Numbers: 10040, 10/H0408/53
Study First Received: May 31, 2011
Last Updated: October 4, 2012
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by University of Nottingham:
Obstructive jaundice
ERCP
Immune dysfunction
Endotoxin tolerance
Quorum sensing

Additional relevant MeSH terms:
Immune System Diseases
Jaundice
Jaundice, Obstructive
Hyperbilirubinemia
Pathologic Processes
Skin Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on July 22, 2014