Early Molecular Detection for the Improved Diagnosis of Invasive Pulmonary Aspergillosis and Invasive Pulmonary Zygomycosis
Condition: Immunocompromised Host; Invasive Pulmonary Fungal Infection; Invasive Pulmonary Aspergillosis; Invasive Pulmonary Zygomycosis
MeSH terms: Infections; Mycoses; Aspergillosis; Pulmonary Aspergillosis; Invasive Pulmonary Aspergillosis; Lung Diseases, Fungal; Zygomycosis; Mucormycosis
Study type: Observational

Summary: 
      Background:

        -  Fungal infections of the lung (pneumonia) can be caused by molds, such as Aspergillus
           and Zygomycetes, but these causes are often difficult for a doctor to diagnose. Early
           and accurate diagnosis of these infections can help doctors to select the correct
           medicines for proper treatment.

        -  A number of methods are used to diagnose fungal pneumonia. Ones that are commonly used
           in clinical practice include radiographic imaging (chest X-rays and computed tomography
           (CT) scans), blood tests, and cultures taken from fluid from the lungs (broncho-alveolar
           lavage (BAL) fluid). Other new methods may improve the diagnosis of fungal pneumonias.
           These methods include tests that can detect DNA from the fungal germ in blood and BAL
           fluid of some patients with these infections.

      Objectives:

        -  To help develop better and more accurate methods of diagnosing fungal lung infections.

        -  To detect fungal DNA and chemicals in the bloodstream and BAL fluid of immunocompromised
           patients with pneumonia.

      Eligibility:

      - Immunocompromised patients who are currently enrolled in another NIH protocol and who have
      a CT scan that shows a possible fungal infection of the lung.

      Design:

        -  Researchers will review patients' existing medical records and CT scans, and current
           pneumonia treatment plans.

        -  Patients will provide blood and BAL samples for the duration of their treatment for
           pneumonia, as required by researchers. Additional CT scans will not be performed, except
           as part of existing treatment plans.
    

Detailed description: 
      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.
    

Time perspective: Prospective
Keywords: 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