Exhaled Breath Analysis in the Early Detection of Aspergillosis (AENEASII)

The Application of an Electronic Nose in the Early Detection of Aspergillosis II

Although the clinical outcome in patients with Invasive Aspergillosis (IA) is largely dependent on early initiation of effective treatment with antifungal drugs, diagnosing IA is still a critical problem. Symptoms are non-specific and available diagnostic tools are either invasive or have low sensitivity and specificity. This often results in a diagnostic delay, with patients developing more extensive disease. Furthermore, as long as IA is present, oncological follow-up treatment is not feasible. Inaccuracy in diagnosing IA can cause serious treatment delay and increased mortality. However, an empirical strategy with prophylactic anti-mould therapy is not feasible considering both possible side effects and costs. In order to safely continue the use of a pre-empirical strategy, improved (non-invasive) diagnostic tools are desirable.

In a pilot study de Heer et al. showed that it is possible to discriminate between patients with IA and their neutropenic controls by exhaled breath analysis using an electronic nose (eNose). In this study the investigators aim to test whether an eNose could be useful as a diagnostic tool in a prospective setting.

The gold standard in exhaled breath analysis is Gas Chromatography - Mass Spectrometry (GC-MS). This technique enables identification of volatile organic compounds (VOCs) in breath of patients. It is possible that there are Aspergillus specific VOCs in the breath of patients with IA.

The composition of the lung microbiome seems to be an important factor in both health and disease. It is likely that the microbiome of the lung changes in prolonged neutropenia, therefore possibly creating a niche for molds and yeasts. Comparing the microbiome of patients with prolonged neutropenia who develop IA with those who do not, can learn us more about the pathogenesis of this disease. This knowledge could be used to investigate new treatment options for Invasive Aspergillosis.

Hypothesis The investigators hypothesize that airway microbial (viral, bacterial) presence and exhaled molecular profiles as obtained from patients with prolonged neutropenia due to treatment of hematological malignancies, are different between patients who develop IA and patients who do not.

Study Overview

• Status: Completed
• Conditions: Invasive Aspergillosis

Detailed Description

Aims

1. To compare the exhaled molecular profiles (GC-MS and eNose) between neutropenic patients who develop IA and neutropenic controls.
2. To investigate whether exhaled molecular profiles can serve as surrogate to predict IA at an early stage.
3. To compare the alterations in the viral/bacterial microbial profiles during the neutropenic episode between patients who develop IA and controls.
4. To examine the relationship between microbial and molecular profiles in order to generate mechanistic hypotheses.

• Study Type: Observational
• Enrollment (Actual): 120

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Academic Medical Center
  • Utrecht, Netherlands, 3584CX
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients aged 18 or older, admitted at the hematology department of the AMC or UMCU, that will undergo treatment for a hematological malignancy expected to result in prolonged neutropenia (neutrophil counts <0.5 x 10 ^9/L for more than seven days).

Description

Inclusion Criteria:

Patients are:

• aged 18 years or older;
• diagnosed with a hematological malignancy;
• treatment is expected to result in prolonged (>7 days) neutropenia (<0.5 x 10^9/L)
• able to give written and dated informed consent prior to any study specific procedures.

Exclusion Criteria:

• Patients are unable to perform the breathing manoeuvre needed for eNose-analysis of exhaled air

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
neutropenic patients; Patients receiving treatment for hematological malignancies expected to result in prolonged neutropenia (neutrophil counts <0.5 x 10 ^9/L for more than seven days).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
molecular profiles in exhaled breath	Exhaled molecular profiles (by eNose and GC-MS) and the accuracy with which serial analysis of these profiles can discriminate between patients with probable or proven invasive pulmonary aspergillosis and neutropenic controls in terms of sensitivity, specificity and accuracy of the predictive algorithm. Breath will be collected twice weekly during the neutropenic episode, resulting in an average of 5 exhaled breath measurements (eNose as well as GC-MS) per patient. Approximately 150 patients will be included for exhaled breath analysis.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome analysis of throat swabs	The alteration in the distribution of the pulmonary microbial community in neutropenic subjects developing invasive pulmonary aspergillosis compared to neutropenic subjects who do not. A throatswab will be taken once a week during the neutropenic episode, resulting in an average of 3 swabs per episode. Microbiome analysis will be performed in 60 patients.	3 years

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: UMC Utrecht
• Investigators: Principal Investigator: M.H.J. van Oers, Prof. dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: M.C. Minnema, MD PhD, UMC Utrecht

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: July 10, 2013
• First Submitted That Met QC Criteria: April 7, 2014
• First Posted (Estimate): April 8, 2014

Study Record Updates

• Last Update Posted (Actual): July 3, 2018
• Last Update Submitted That Met QC Criteria: July 1, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Aspergillosis
• Other Study ID Numbers: AENEAS II