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Early Molecular Detection for the Improved Diagnosis of Invasive Pulmonary Aspergillosis and Invasive Pulmonary Zygomycosis


N/A
1 Year
N/A
Not Enrolling
Both
Immunocompromised Host, Invasive Pulmonary Fungal Infection, Invasive Pulmonary Aspergillosis, Invasive Pulmonary Zygomycosis

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Trial Information

Early Molecular Detection for the Improved Diagnosis of Invasive Pulmonary Aspergillosis and Invasive Pulmonary Zygomycosis


Background:

Invasive fungal infections are an important cause of infectious disease, morbidity and
mortality in immunocompromised patients with cancer, hematopoietic stem cell
transplantation, aplastic anemia, autoimmune diseases, and primary immune deficiencies.

Foremost among the more lethal of these infections are invasive pulmonary aspergillosis and
zygomycosis. Early detection of these infections allows timely initiation of specific
antifungal therapy, which may be life saving. However, early diagnosis of respiratory fungal
infections is difficult, often leading to delay in therapy and inaccurate treatment.

The Immunocompromised Host Section has developed a series of sensitive and highly specific
PCR assays for the detection of these life-threatening infections. We also have
characterized the expression of cell wall derived biomarkers, (1-3)-Beta-D-glucan and
galactomannan in vitro and in vivo. Laboratory animal studies indicate that these assays may
complement current diagnostic modalities and allow for more accurate and earlier detection
of invasive pulmonary fungal infections in immunocompromised patients.

Objectives:

The primary objective of this study is to improve the early diagnosis of invasive pulmonary
aspergillosis and invasive pulmonary zygomycosis in immunocompromised patients through the
addition of molecular biomarker detection methodology to the standard diagnostic systems
used in clinical microbiology laboratories.

The secondary objectives are:

A. To compare the diagnostic yield and analytical performance of the PCR, galactomannan and
(1-3)-Beta-D-glucan to standard diagnostic systems.

B. To evaluate the effect of different independent variables on expression of the
aforementioned assays

C. To characterize the variables that may contribute to therapeutic outcome (global
response; survival)

D. To characterize the use of these biomarkers in the context of EORTC/MSG definitions

E. To identify genetic markers which may predispose patients to invasive fungal pulmonary
infections.

Eligibility:

Immunocompromised patients currently enrolled in any NIH IRB approved Clinical Center
protocol for the evaluation and/or treatment of his/her primary disease, or patients
receiving treatment at the Children's National Medical Center (CNMC) who develop a pulmonary
infiltrate radiologically compatible with invasive pulmonary aspergillosis or invasive
pulmonary zygomycosis, by EORTC/MSG criteria.

Design:

This is a multi-center, prospective diagnostic interventional study.

Patients referred to the Clinical Center for evaluation and treatment in primary research
protocols will be eligible for enrollment in this protocol at the Clinical Center. Patients
meeting eligibility criteria may also be enrolled from the CNMC.

Patients who have compatible radiologic signs and are at risk for development of invasive
pulmonary aspergillosis and invasive pulmonary zygomycosis will have specimens of
bronchoalveolar lavage (BAL) fluid supernatant and /or tissue from lung biopsy when
available, obtained for the measurement of diagnostic PCR for Aspergillus and Zygomycete
identification, proteomics, cytokines and for the presence of galactomannan and
(1-3)-Beta-D-glucan. The BAL will be performed only if clinically indicated as part of the
patient's routine care of pneumonic infiltrates.

Blood will be obtained from patients meeting the eligibility requirements, regardless of
whether they have had a BAL or lung tissue biopsy, to be submitted for the measurement of
diagnostic PCR for Aspergillus and Zygomycete identification, proteomics, cytokines,
presence of galactomannan and (1-3)-Beta-D-glucan and host genomics.

Digital copies of computer tomography (CT) images, that are part of routine care will
utilized to reconstruct multi-dimensional volumetric images and correlate clinical and
laboratory outcomes with the extent of lung volume involvement.

Background:

Invasive fungal infections are an important cause of infectious disease, morbidity and
mortality in immunocompromised patients with cancer, hematopoietic stem cell
transplantation, aplastic anemia, autoimmune diseases, and primary immune deficiencies.

Foremost among the more lethal of these infections are invasive pulmonary aspergillosis and
zygomycosis. Early detection of these infections allows timely initiation of specific
antifungal therapy, which may be life saving. However, early diagnosis of respiratory fungal
infections is difficult, often leading to delay in therapy and inaccurate treatment.

The Immunocompromised Host Section has developed a series of sensitive and highly specific
PCR assays for the detection of these life-threatening infections. We also have
characterized the expression of cell wall derived biomarkers, (1-3)-Beta-D-glucan and
galactomannan in vitro and in vivo. Laboratory animal studies indicate that these assays may
complement current diagnostic modalities and allow for more accurate and earlier detection
of invasive pulmonary fungal infections in immunocompromised patients.

Objectives:

The primary objective of this study is to improve the early diagnosis of invasive pulmonary
aspergillosis and invasive pulmonary zygomycosis in immunocompromised patients through the
addition of molecular biomarker detection methodology to the standard diagnostic systems
used in clinical microbiology laboratories.

The secondary objectives are:

A. To compare the diagnostic yield and analytical performance of the PCR, galactomannan and
(1-3)-Beta-D-glucan to standard diagnostic systems.

B. To evaluate the effect of different independent variables on expression of the
aforementioned assays

C. To characterize the variables that may contribute to therapeutic outcome (global
response; survival)

D. To characterize the use of these biomarkers in the context of EORTC/MSG definitions

E. To identify genetic markers which may predispose patients to invasive fungal pulmonary
infections.

Eligibility:

Immunocompromised patients currently enrolled in any NIH IRB approved Clinical Center
protocol for the evaluation and/or treatment of his/her primary disease, or patients
receiving treatment at the Children's National Medical Center (CNMC) who develop a pulmonary
infiltrate radiologically compatible with invasive pulmonary aspergillosis or invasive
pulmonary zygomycosis, by EORTS/MSG criteria.

Design:

This is a multi-center, prospective diagnostic interventional study.

Patients referred to the Clinical Center for evaluation and treatment in primary research
protocols will be eligible for enrollment in this protocol at the Clinical Center. Patients
meeting eligibility criteria may also be enrolled from the CNMC.

Patients who have compatible radiologic signs and are at risk for development of invasive
pulmonary aspergillosis and invasive pulmonary zygomycosis will have specimens of
bronchoalveolar lavage (BAL) fluid supernatant and /or tissue from lung biopsy when
available, obtained for the measurement of diagnostic PCR for Aspergillus and Zygomycete
identification, proteomics, cytokines and for the presence of galactomannan and
(1-3)-Beta-D-glucan. The BAL will be performed only if clinically indicated as part of the
patient's routine care of pneumonic infiltrates.

Blood will be obtained from patients meeting the eligibility requirements, regardless of
whether they have had a BAL or lung tissue biopsy, to be submitted for the measurement of
diagnostic PCR for Aspergillus and Zygomycete identification, proteomics, cytokines,
presence of galactomannan and (1-3)-Beta-D-glucan and host genomics.

Digital copies of computer tomography (CT) images, that are part of routine care will be
utilized to reconstruct multi-dimensional volumetric images and correlate clinical and
laboratory outcomes with the extent of lung volume involvement.

Inclusion Criteria


- INCLUSION CRITERIA:

Patients currently enrolled in any NIH IRB approved Clinical Center protocol or under
treatment at the CNMC who are undergoing bronchoscopy or lung biopsy for diagnosis of
possible invasive pulmonary aspergillosis or invasive pulmonary zygomycosis.

Informed consent of the patient or the patient's legally authorized representative.

Fulfillment of one or more of the following EORTC/MSG host criteria:

- History of neutropenia (ANC < 500/mm(3)) within the past 3 months temporally related
to the onset of radiographic changes

- Receipt of an allogeneic HSCT

- Receipt of solid organ transplantation

- Prolonged use of corticosteroids at an average minimum dose of 0.3 mg/kg/day
prednisone equivalent for > 3 weeks

- Treatment with other recognized T-cell immune suppressants such as cyclosporine, TNF
alpha blockers, specific monoclonal antibodies such as alemtuzumab, nucleoside
analogues during the past 90 days

- Myelodysplastic syndrome

- Severe aplastic anemia

- Cushing's disease

- HIV/AIDS

- Primary immunodeficiencies (such as chronic granulomatous disease, severe combined
immunodeficiency)

The presence of one or more of the following signs on chest CT or radiograph:

- Dense well circumscribed lesions with or without a halo sign

- Air crescent sign

- Cavity

- Focal, segmental or lobar infiltrates

EXCLUSION CRITERIA:

Interstitial or diffuse infiltrates on chest CT or radiograph

Inability to provide informed consent

Children weighing less than 10 kg

Any other concomitant condition, which in the opinion of the investigator would place the
patient at risk by participating in the study

Type of Study:

Observational

Study Design:

Time Perspective: Prospective

Authority:

United States: Federal Government

Study ID:

090109

NCT ID:

NCT00923832

Start Date:

March 2009

Completion Date:

November 2009

Related Keywords:

  • Immunocompromised Host
  • Invasive Pulmonary Fungal Infection
  • Invasive Pulmonary Aspergillosis
  • Invasive Pulmonary Zygomycosis
  • Fungal Infections
  • PCR Assays
  • Cell Wall Derived Biomarkers
  • EORTC/MSG Definitions
  • Molecular Assays
  • Lung Fungal Infection
  • Invasive Pulmonary Fungal Infection
  • Invasive Pulmonary Aspegillosis
  • Invasive Pulmonary Zycomycosis
  • Aspergillosis
  • Lung Diseases, Fungal
  • Mycoses
  • Zygomycosis
  • Mucormycosis
  • Invasive Pulmonary Aspergillosis
  • Pulmonary Aspergillosis

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Childrens National Medical CenterWashington, District of Columbia