Diagnostic and Management Strategies for Invasive Aspergillosis

Diagnostic and Management Strategies for Invasive Aspergillosis in Neutropenic Adult Haemato-Oncology Patients With a Proposal for Investigation of a Novel Potential Marker for Early Diagnosis: a Prospective Cohort Study

Fungal infections caused by Aspergillus fumigatus are now identified in up to 45% of patients dying from haematological malignancy. There has been a significant increase in deaths from IA over the last 20 years. Our current diagnostic approach is neither sensitive nor specific. The purpose of this study is to prospectively assess the value of current diagnostic tools, as well as test other new diagnostic methods for the diagnosis of IA among haemato-oncology patients undergoing chemotherapy or stem cell transplantation.

Study Overview

• Status: Completed
• Conditions: Neutropenia; Invasive Aspergillosis

Detailed Description

The basis of the diagnosis of invasive aspergillosis is usually based on radiological appearances, which are neither sensitive nor specific. The burden of this problem is also not properly documented and there is paucity of prospective data in the literature. Therefore, we want to prospectively collect complete epidemiological data on all our patients. In addition we want to collaborate with radiological, respiratory, and microbiological colleagues to develop a unified approach to diagnosis. In the initial 12-18 months of the study all adult haemato-oncology patients likely to be rendered neutropenic during their treatment will be enrolled. All clinical data will be collected including dose, duration, and side-effects of anti-fungals administered. We will evaluate accepted diagnostic modalities for IA including the determination of optimum cut-offs for galactomannan and B-D-glucan in serum and urine in this cohort. In addition we would investigate the utility of other approaches for the diagnosis of IA such as markers for tissue injury and cytokine profiling.

We would test the urine in parallel with blood for galactomannan and B-D glucan to assess its usefulness with respect to blood.

CT scanning forms an important cornerstone of our diagnostic workup currently. However, there is paucity of data on the natural history and spectrum of CT changes in neutropenic patients with IA. Thus, our aim is to carefully document such changes in our cohort. We aim to rationalise CT imaging in the following way:

1. Baseline CT:

   We aim to perform an initial non-contrast enhanced thin-section continuous volume acquisition thoracic CT study on all the study patients. This will allow us to establish a "baseline" of normality in addition to potentially identifying those patients with pre-existing but indeterminate pulmonary lesions prior to chemotherapy or stem-cell transplantation.

2. Diagnostic CT:

   Neutropaenic patients with febrile episodes that are unresponsive to standard second-line broad-spectrum antibiotics combination (currently meropenem and vancomycin) will be referred for a contrast-enhanced thin section continuous volume CT scan. The purpose of this CT study is primarily to support the clinical suspicion of a diagnosis of IA and to determine its morphological extent. The purpose of the contrast injection is to test the hypothesis that in patients with IA, regions of necrotic lung (in contrast to other "inflammatory" or infective lesions) should not demonstrate any contrast enhancement.

3. Follow-up CTs (x2):

In patients with CT features of IA on the Diagnostic CT (see No. 2 above) and who have been commenced on antifungal chemotherapy, two follow-up, low-dose CTs (without iv contrast) will be performed at 10 days and 4 weeks after the diagnostic CT. These CT studies will not only allow us to evaluate the serial changes on CT but also determine the potential relationships between the initial CT features, haematological factors and outcome.

To increase the diagnostic yield, patients who are referred for lung biopsy, will undergo the technique of preoperative "labeling": small indeterminate lung nodules are frequently invisible and impalpable. There is an encouraging literature which indicates that preoperative labeling of lung lesions with a small (0.3-0.5ml) volume of methylene blue which acts a guidance track for the surgeon, may significantly improve the diagnostic yield from surgical (open or video-assisted thoracoscopic) biopsy.

Transplant patients typically would have 2-4 cycles of chemotherapy prior to admission for transplant. As such they have more chance of developing neutropenic infection and IA. Therefore we would perform a baseline bronchoscopy and washing (BAL) to assess the cytokine profile at admission and ensure that no infection is apparent before the initiation of transplant conditioning. A small amount of the BAL sample would be frozen and stored for future studies. Additional bronchoscopy may be done later during admission for both transplant and non-transplant patients if the clinical situation warrants it according to our current clinical practice.

Management strategies would also be assessed prospectively to evaluate the role of both prophylaxis and treatment. We are currently using itraconazole as our prophylactic agent of choice. Serum itraconazole levels will be measured on a weekly basis in all patients to ensure therapeutic levels are achieved.

We will be conducting costing analysis.

• Study Type: Observational
• Enrollment (Actual): 203

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King'S College Hospital Nhs Foundation Trust

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

Haemato-oncology patients undergoing high dose chemotherapy or stem cell transplantation likely to render them neutropenic.

Description

Inclusion Criteria:

• All adult haemato-oncology patients admitted for transplant or high dose chemotherapy and able to consent.

Exclusion Criteria:

• children (< 18 years old) or inability or refusal to consent.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
neutropenia; Patients undergoing stem cell transplantation or chemotherapy likely to lead to prolonged neutropenia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the incidence of IFD using a comprehensive diagnostic approach	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluation of established and experimental diagnostic methods	2-3 years
Costing analysis	2-3 years
Establish the prognostic value of CT appearances in patients with IA	2-3 years
Assessing the value of methylene blue 'tattooing' prior to surgical biopsy	2-3 years

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Investigators: Principal Investigator: M.Mansour Ceesay, FRCPath, Kings College Hospital; Principal Investigator: Antonio Pagliuca, FRCPath, Kings College Hospital; Principal Investigator: Jim Wade, FRCPath, Kings College Hospital; Principal Investigator: Melvyn Smith, PhD, Kings College Hospital; Principal Investigator: Sujal Desai, FRCR, Kings College Hospital

Publications and helpful links

General Publications

• Buckner SL, Ceesay MM, Pagliuca A, Morgan PE, Flanagan RJ. Measurement of posaconazole, itraconazole, and hydroxyitraconazole in plasma/serum by high-performance liquid chromatography with fluorescence detection. Ther Drug Monit. 2011 Dec;33(6):735-41. doi: 10.1097/FTD.0b013e3182381bb1.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: December 30, 2008
• First Submitted That Met QC Criteria: December 30, 2008
• First Posted (Estimate): December 31, 2008

Study Record Updates

• Last Update Posted (Estimate): December 23, 2014
• Last Update Submitted That Met QC Criteria: December 22, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: chemotherapy; Stem cell transplantation
• Additional Relevant MeSH Terms: Infections; Hematologic Diseases; Bacterial Infections and Mycoses; Mycoses; Agranulocytosis; Leukopenia; Leukocyte Disorders; Neutropenia; Aspergillosis
• Other Study ID Numbers: 08/H0808/154; 08HA11