Mycobacterium Avium-Intracellulare Infection Clinical Trial
Official title:
A Study of Adjuvant Cytokine Therapy in Pulmonary Mycobacterium Avium Complex and Other Pulmonary Nontuberculous Mycobacterial Infections
Mycobacterium avium complex (MAC) are ubiquitous organisms that cause isolated pulmonary
disease in otherwise healthy patients with yet undefined susceptibilities. Patients typically
present with a history of chronic cough, eventually progressing to hemoptysis, fever, and
hypoxia. With half or more of all patients failing standard three-drug therapy, this is an
insidious disease with a poor prognosis. Under the natural history protocol of nontuberculous
mycobacterial infection (NTM; #01-I-0202), 46 patients with diagnosed pulmonary MAC disease
are being studied. Numerous studies have suggested that a dysregulation in cytokine
production may make these patients susceptible to mycobacterial infection. Cytokines are
particularly important in the activaction of macrophages, which help to clear mycobacterial
infection. Interferon gamma 1b (Actimmune) and GM-CSF (Leukine) are two cytokine therapies
that have been approved in the treatment of chronic granulomatous disease and
post-transplantation hematopoietic reconstitution, respectively. A number of in vitro studies
suggest that either or both of these therapies may help to clear MAC infection. Given the
poor outcomes of therapy and the persistent, debilitating nature of the disease, new
therapies are desperately needed, and many are being tried without benefit of scientific
foundation. Currently, there are no prospective trials that show any effect of these drugs in
the lung delivered subcutaneously. This protocol proposes to perform a pilot study to
evaluate the effects, if any, of these macrophage stimulating cytokines in the context of
ongoing pulmonary MAC infection.
Aims:
To determine the local and systemic effect, if any, of adjuvant IFN gamma and GM-CSF in
pulmonary MAC patients.
Methods:
Fifteen patients will be randomized into three treatment groups of five patients each. The
first group will receive a standard drug regimen, based on the 1997 ATS guidelines. The
second and third groups, in addition to receiving the standard therapy, will also receive
three months of (IFN{gamma}) and GM-CSF, respectively. All patients will undergo bronchoscopy
with bronchoalveolar lavage (BAL) at the beginning of the study, after three months, and at
six months.
In addition to obtaining traditional subjective and objective clinical measures, both
proteomic and genomic analysis of the BAL will be performed to determine if cytokine therapy
effects any detectable change in the lungs. In vitro studies on typ...
Mycobacterium avium complex (MAC) and other pulmonary nontuberculous mycobacteria (P-NTM) are
ubiquitous organisms that cause isolated pulmonary disease in otherwise healthy patients with
yet undefined susceptibilities. Patients typically present with a history of chronic cough,
eventually progressing to hemoptysis, fever, and hypoxia. With half or more of all patients
failing standard three-drug therapy, this is an insidious disease with a poor prognosis.
Under the natural history protocol of nontuberculous mycobacterial infection (NTM;
#01-I-0202), 46 patients with diagnosed pulmonary MAC disease, 20 patients with M. abscessus
disease, and 14 with other types of mycobacteria (M. fortuitum, M. massiliense, M.
mucogenicum and M. chelonae) are being studied.
Numerous studies have suggested that a dysregulation in cytokine production may make these
patients susceptible to mycobacterial infection. Cytokines are particularly important in the
activation of macrophages, which help to clear mycobacterial infection. Interferon gamma 1b
(Actimmune) and GM-CSF (Leukine) are two cytokine therapies that have been approved in the
treatment of chronic granulomatous disease and post-transplantation hematopoietic
reconstitution, respectively. A number of in vitro studies suggest that either or both of
these therapies may help to clear MAC infection. Given the poor outcomes of therapy and the
persistent, debilitating nature of the disease, new therapies are desperately needed, and
many are being tried without benefit of scientific foundation. Currently, there are no
prospective trials that show any effect of these drugs in the lung delivered subcutaneously.
This protocol proposes to perform a pilot study to evaluate the effects, if any, of these
macrophage stimulating cytokines in the context of ongoing pulmonary mycobacterial infection.
Aims:
To determine the local and systemic effect, if any, of adjuvant IFN gamma and GM-CSF in P-NTM
patients.
Methods:
Fifteen patients will be randomized into three treatment groups of five patients each. The
first group will receive a standard drug regimen, based on the 1997 ATS guidelines. The
second and third groups, in addition to receiving the standard therapy, will also receive
three months of (IFN{gamma}) and GM-CSF, respectively. All patients will undergo bronchoscopy
with bronchoalveolar lavage (BAL) at the beginning of the study, after, after three months,
and at six months.
In addition to obtaining traditional subjective and objective clinical measures, both
proteomic and genomic analysis of the BAL will be performed to determine if cytokine therapy
effects any detectable change in the lungs, In vitro studies on type II alveolar macrophages
culled from these patients before and after cytokine therapy will also be performed.
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