Invasive Fungal Infections in Severe Alcohol-associated Hepatitis

Assessment of Invasive Fungal Infections as a Result of Fungal Dysbiosis in Patients With Severe Alcohol-associated Hepatitis

Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet little is known about the role of intestinal fungi, or mycobiota in liver disease. Although the intestinal microbiome contains bacteria, fungi, and viruses, research in the field of liver disease has almost exclusively focused on the interaction between the host and gut bacteria. The fungal microbiota is an integral part of the gastrointestinal micro-ecosystem with up to 106 microorganisms per gram of faeces. Numerous interactions between fungi and bacteria and the complex immune response to gastrointestinal commensal or pathogenic fungi have been demonstrated in prior studies. Alcohol-dependent patients display a reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients also demonstrate systemic exposure and immune response to mycobiota. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease especially alcoholic hepatitis. In this study, we will attempt to find out the natural fungal mycobiome in Severe alcoholic hepatitis when compared with apparently healthy asymptomatic controls from their family. This will allow us to therapeutically modify the unbalanced gut microbiota and improve patient outcomes. Secondly, it will provide further insight as to why alcohol-associated hepatitis patients are particularly susceptible to fungal infections. In the age of frequent antibacterial drug therapy, the role of commensal and pathogenic fungi in the human gut has gained paramount importance.

Study Overview

• Status: Unknown
• Conditions: Severe Alcoholic Hepatitis; Chronic Liver Disease and Cirrhosis
• Intervention / Treatment: Other: Testing stool mycobiota

Detailed Description

The patients of severe alcohol-associated hepatitis admitted under Department of Hepatology, in Liver intensive Care Unit (LICU) Male or Female medical wards or coming to follow up in Liver clinic of Postgraduate Institute of Medical Education and Research, Chandigarh, India from will be screened for enrolment after ethical approval from the institute ethics committee. Both previously compensated and decompensated patients will be enrolled in this prospective observational pilot study. All patients will be followed up at 30 and 90 days from inclusion into the study.

Estimation of sample size Sample size will be estimated based on previous studies. This is a pilot prospective observational study. Based on currently available data from our centre on acute-on chronic liver failure, 22.5% of cirrhotics have suspected IFI, and up to 25% of SAH have suspicion for IFI, it is estimated that a total sample size of 60 patients would be required, with an effect size of 0.5, alpha 0.05, and power 0.85. Therefore, 80 patients will be required to enroll to account for 15% attrition. Hence, we propose to enroll 80 consecutive patients with SAH with 80 matched controls from their family starting from 15th August 2019.

• Study Type: Observational
• Enrollment (Anticipated): 160

Contacts and Locations

Study Locations

• India
  • Choose Any State/Province
    • Chandigarh, Choose Any State/Province, India, 160012
      • Recruiting
      • Postgraduate Institute of Medical Education and Research
      • Contact: Madhumita Premkumar

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Alcohol-associated hepatitis (AH) is defined by National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria as biopsy proven or clinically diagnosed AH in patients with heavy alcohol use and typical liver tests without confounding factors

Description

Inclusion Criteria:

• Severe Alcoholic Hepatitis
• Aged between 18 Years to 70 Years
• Either gender
• Study will also include age matched healthy controls from the patient's family

Exclusion Criteria:

1. Inability to obtain informed consent from patient or relatives.
2. Severe cardiopulmonary disease
3. Pregnancy
4. HIV infection
5. Recent abdominal surgery (with in last 6 months)
6. Patient on immunosuppressive drugs
7. Malignancies including Hepatocellular carcinoma
8. Gastrointestinal (GI bleed) in the last 4 weeks
9. Oral antibiotics or antifungals taken in last 2 weeks.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Severe alcohol- associated hepatitis; Severe alcohol associated hepatitis as defined by probable/ conformed National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria	Other: Testing stool mycobiota; Both cohorts of SAH and their family controls will be tested for fecal mycobiota
Control; Apparently healthy Family controls	Other: Testing stool mycobiota; Both cohorts of SAH and their family controls will be tested for fecal mycobiota

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Patients who survive till Day 28 and Day 90	at Day 28 and Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-elective hospital admissions	Number of hospital admissions will be documented	90 Days
Clinical and biochemical parameters will be compared at 0 and 90 days	Change in biochemical parameters including liver function tests, renal function tests, ammonia etc.	90 days
Clinical events like decompensation in the form of new onset ascites, variceal bleed, renal dysfunction, hepatic encephalopathy, infections	Number of decompensation events [ascites, variceal bleed, renal dysfunction, hepatic encephalopathy, infections]	90 days

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Study Chair: Radha Dhiman, MD DM, Postgraduate Institute of Medical Education and Research

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2019
• Primary Completion (Anticipated): October 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: September 1, 2019
• First Submitted That Met QC Criteria: September 24, 2019
• First Posted (Actual): September 26, 2019

Study Record Updates

• Last Update Posted (Actual): April 1, 2020
• Last Update Submitted That Met QC Criteria: March 30, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Hepatitis, Viral, Human; Bacterial Infections and Mycoses; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Liver Diseases; Hepatitis; Hepatitis A; Mycoses; Invasive Fungal Infections; Hepatitis, Alcoholic
• Other Study ID Numbers: IEC-08/2019-1270

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No