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
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
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
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.
Observational Model: Cohort, Time Perspective: Prospective
To improve understanding of current clinical practice for diagnosis and management of IA.
M.Mansour Ceesay, FRCPath
Kings College Hospital
United Kingdom: Medicines and Healthcare Products Regulatory Agency