Our Science – Walsh Website

Thomas J. Walsh, M.D.

Pediatric Oncology Branch Head, Immunocompromised Host Section Senior Investigator Building 10CRC, 1W, Rm. 1-5740 NCI-Bethesda Bethesda, MD 20892 Phone:   301-402-0023 Fax:   301-480-2308 E-Mail:   walsht@mail.nih.gov

Biography

Dr. Walsh received his M.D. from the Johns Hopkins University School of Medicine. He completed training in infectious diseases and oncology at Johns Hopkins, the University of Maryland, and the NCI. During these ten post-doctoral years, he also received additional training in pathology, pharmacology, immunology, and medical mycology. As chief of the Immunocompromised Host Section in the Pediatric Oncology Branch, Dr. Walsh has combined these areas of expertise in addressing the multidisciplinary problems of infections in immunocompromised patients with cancer and HIV infection.

Research

Treatment of Infections in Immunocompromised Children with Cancer, Hematopoietic Stem Cell Transplantation, and other Immunodeficiencies

Introduction. Infectious diseases are a major cause of morbidity and mortality in immunocompromised patients with cancer, hematopoietic stem cell transplantation (HSCT), and other immunodeficiencies. Our Section is dedicated to the mission of relieving the suffering and improving the outcome of these patients though advances in translational research of infectious diseases supportive care. Our studies of infections complicating children with neoplastic disease, HSCT, and other immunodeficiencies focus on development of new approaches to treatment and prevention of life-threatening infections, rapid molecular detection, and augmentation of innate host defenses against emerging pathogens. Our strategies reflect those used to manage such infections: pharmacologic intervention; detection and therapeutic monitoring; and immune augmentation. Using a translational research approach, we advance findings made in vitro to a series of unique animal model systems in vivo that reflect the microbiological, immunological, and histologic characteristics of these emerging infectious diseases. These studies establish a scientific rationale for conducting clinical trials that provide our patients with key advances from bench to bedside. These advances are improving patient outcome, increasing survival, and reducing suffering from the infectious complications of cancer, HSCT, and other immunodeficiencies.
Among the emerging infectious diseases afflicting our immunocompromised patients, the invasive mycoses have emerged as important causes of morbidity and mortality, particularly in patients with hematological malignancies, HSCT recipients, and children with inherited immunodeficiencies. The Section has achieved significant advances in the areas of augmentation of host defense, molecular detection and pharmacology of these life-threatening infections.
Augmentation of Host Defenses. Immunopharmacological interactions between innate host defenses and antimicrobial agents are a key component of developing new strategies for augmenting host response against emerging or resistant pathogens. We have extensively characterized the immunopharmacological interactions between phagocytic effector cells (pulmonary alveolar macrophages, monocytes, and neutrophils) of the innate host defense and antifungal agents (polyenes, echinocandins, and triazoles) with and without immunomodulators (IFN-gamma, GCSF, GMCSF) against several of the key pathogens infecting oncology patients: Aspergillus fumigatus, Fusarium solani, Scedosporium spp., and Zygomycetes in collaboration with Dr. Emmanuel Roilides of the University of Thessaloniki. We have further extended our work in Th1/Th2 dysimmunoregulation of invasive candidiasis to the filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp., and Zygomycetes) with particular focus on IL-15, IL-4, and TGF-beta. Reversal of the Th2 immunophenotypic expression augments host response against these organisms. We are continuing are studies of augmentation of mucosal host defenses with selected antimicrobial peptides, including adrenomedullin and histatins, in order to develop new protective approaches for patients receiving myeloablative chemotherapy or radiation.
In collaboration with Dr. Shayam Kottilil (NIAID), we have completed the systematic characterization of the normal functional genomic response of innate host defenses of human monocytes to the major opportunistic pathogens infecting patients with cancer and HSCT: Candida albicans Aspergillus fumigatus, Rhizopus oryzae, and Fusarium solani. These studies will provide fundamental guidance to investigators worldwide in understanding the coordinated transcriptional responses of their selected genes of interest for further exploration. Understanding the normal host functional genomic response will guide new strategies for immune reconstitution and immunoaugmentation against these pathogens. In collaboration with the Stephen Chanock of the Advanced Technology Consortium, we also have characterized single nucleotide polymorphisms (SNPs) of innate host defense molecules that may increased the risk of infection due to Cryptococcus neoformans and Blastomyces dermatitidis. This work builds upon our earlier studies of the immunopathogenesis of hepatosplenic (chronic disseminated) candidiasis, where common IL4 promoter haplotypes were associated with an increased risk of this frequently refractory infection.
In order to further understand the host factors contributing to infections in pediatric and adult oncology and HSCT patients, as well as other populations immunocompromised children, we have completed a series of complementary targeted population-based studies in collaboration with the Centers for Disease Control, Roswell Park Cancer Center (Dr. Brahm Segal), Children's Hospital al of Philadelphia (Dr. Theoklis Zaoutis), and Duke University (Dr. Daniel Benjamin). As a translational study from our laboratory investigations of augmentation of host defenses, we demonstrated that immunomodulation with interferon-gamma and colony-stimulating factors improves outcome in patients with refractory invasive fungal infections in patients with leukemia in collaboration with University of Arkansas Medical Center (Dr. Elias Anaissie) and University of Colorado (Dr. Mark Abzug). In collaboration with Roswell Park Cancer Center (Dr. Brahm Segal) and the NIAID (Dr. Stephen Holland), and as a translational extension of these immunomodulatory studies, we have contributed to the immunopharmacological studies of phase I agents (pegylated GCSF and talabostat) with the POB PET Section in pediatric oncology patients.
Molecular Detection. Early and rapid detection of emerging pathogens is important for pathogen-directed therapy in immunocompromised patients. In continuing our laboratory and clinical studies for improved detection systems, we have characterized the expression in vitro, in vivo and in patients for several key surrogate markers, including but not limited to enolase, d-arabinitol, d-mannitol, galactomannan, glucans, sterols, and circulating DNA. Studies of the variables determining expression of serum galactomannan in our rabbit models of invasive pulmonary aspergillosis contributed to the development and understanding of iterative platforms for detection of galactomannan an (GM) antigenemia, as well as subsequent clinical evaluation. The laboratory animal findings correlated with and were predictive of the results of expression of GM antigenemia in oncology and HSCT patients with invasive aspergillosis. We further characterized the kinetics of GM antigenemia in vitro, in vivo and in patients in recipients of piperacillin-tazobactam, where a newly recognized interfering effect has been increasingly recognized. We have further characterized the expression of GM as a marker of therapeutic response in vivo and in different patient populations. Parallel studies are being conducted with new species-specific molecular diagnostic platforms, probes, and primers for multiplex PCR. We are now transferring our newly developed species-specific qPCR assay for Aspergillus fumigatus from bench to bedside to the Clinical Center Clinical Microbiology Laboratory for prospective validation and clinical application in our patients undergoing bronchoalveolar lavage (BAL) to enhance diagnostic yield, promote early detection, and direct therapeutic interventions.
We are currently characterizing the simultaneous expression of target candidate molecules for direction and therapeutic monitoring of emerging pathogens in selected animal model systems, as well as in a parallel large prospective clinical surveillance study. These surrogate markers currently include GM, glucans, phospholipase B, HSPs, cyclopentols, cyclohexitols, gliotoxins, as well as other small molecules for measurement by novel detection systems.
In working toward improvement of rapid detection of resistant pathogens, we have conducted a series of studies characterizing fluorescent and metabolic probes of enzymatic and mitochondrial activity of pathogenic fungi. We have further developed metabolic assays for the rapid detection of resistance in isolates from immunocompromised patients that may better direct therapy.
Pharmacology. In exploring new molecules, our sustained collaboration with the USDA has yielded a series of novel water-soluble agriculturally derived plant molecules with potent antimicrobial activity. In studying CAY-1, we recently demonstrated synergism between CAY-1 and amphotericin B or itraconazole against Aspergillus species and Candida albicans.
In studying the pharmacology of lipid formulations of amphotericin B, we have demonstrated the effects of front loading, utilizing the safety profile and high volume of distribution, for treatment of experimental chronic disseminated candidiasis, an uncommon but debilitating infection in patients with hematological malignancies.
In developing newer methods for rapidly assessing circulating concentrations of antimicrobial agents for adaptive pharmacotherapy, we introduced a non-invasive measurement of amphotericin B levels in rabbit aqueous humor by resonant Raman spectroscopy-A. Such novel approaches may provide a rapid means of monitoring therapeutic levels in patients for dosage optimization.
As part of our ongoing effort to understand the properties of newer antimicrobial agents for pediatric patients, we are characterizing the plasma pharmacokinetics, safety and efficacy of novel triazoles, cis-pentacins, and echinocandins in predictive rabbit models of experimental pulmonary aspergillosis, esophageal candidiasis, subacute disseminated candidiasis, and hematogenous candida meningoencephalitis, as well as pulmonary zygomycosis, scedosporiosis, and fusariosis. These laboratory studies have provided a rational translational foundation for design and interpretation of interventional clinical trials in profoundly immunocompromised patients.
Early intervention is critical for successful treatment of invasive mycoses in neutropenic patients. As our culture-based diagnostic tools are lack sensitivity in detecting these infections, early intervention is important in improving outcome. Early intervention may be in the form prophylactic, empirical, or pre-emptive therapy. Fluconazole is a standard of care for prophylaxis during neutropenia. Having previously demonstrated that echinocandins initiated early in the course of infection are active against subacute disseminated candidiasis and invasive pulmonary aspergillosis, we then proceeded to a multicenter randomized double blind trial in collaboration with the NIAID Bacteriology and Mycology Study Group (BAMSG) demonstrating proof of principle that an echinocandin was superior to fluconazole as prophylaxis in HSCT recipients. As part of our ongoing anti-infective collaboration with the NHLBI HSCT program, we demonstrated a high response rate and improved survival in steroid-refractory acute graft-versus-host disease using a daclizumab-based strategy with targeted comprehensive anti-infective prophylaxis.
As prophylactic strategies may expose more patients to antifungal agents, targeting a higher risk patient population is attempted with empirical or preemptive therapy to reduce unnecessary exposure. The initial two open label randomized trials of empirical antifungal therapy with amphotericin B demonstrated reduced frequency of infections and improved survival in those receiving therapy versus those not treated. As empirical antifungal therapy became a standard of care, subsequent randomized trials have endeavored to improve safety and efficacy. We recently demonstrated in an international multicenter randomized double blind trial of empirical antifungal therapy that early initiation of an echinocandin was as effective as lipid formulation of amphotericin B but superior in conferring increased survival and in improving the outcome of baseline infections in patients with acute leukemia. These clinical findings further reinforce the importance of early antimicrobial intervention in targeted high-risk patients.
As a continuity of our efforts to advance the understanding of the infectious diseases supportive care in pediatric oncology patients, we have systematically studied the safety and plasma pharmacokinetics of all of the systemic antifungal agents. These studies provide a rational basis for selection of correct dosages that provide plasma levels comparable to those of adults. These studies have demonstrated that approximately one-half of all agents studied required new dosage adjustments in order to optimize plasma-concentration time curves in our pediatric oncology patients. We found that an inverse relation between clearance and age may occur as a function of the metabolic pathway and chemical structure of the individual compound. Optimal dosing becomes particularly critical in profoundly immunocompromised pediatric patients where host response is abrogated and clearance of infection dependent upon the principally upon compound.
Among the clinical trials completed arising from our translational research program, we are completing an extensive series of studies of double and triple combination therapy strategies in vitro and in vivo against Aspergillus spp. In applying powerful mathematical modeling analyses to these data, we are able to detect significant interactions documenting synergy or antagonism as a guide to clinical trial development.

Resource to the Oncology/HSCT Community. The Section serves as an international resource (available on a 24/7 basis) in assisting in the care of pediatric and adult oncology patients with life-threatening infections. On urgent notice Dr. Walsh has traveled to the bedside of critically ill pediatric patients to assist in their care.

Summary. These advances have and will substantially benefit children and adults with cancer, HSCT, and other immunodeficiencies. Commensurate with the mission of the NCI, our laboratory serves the pediatric and adult oncology communities of the nation and of the international community to provide leading-edge contributions in infectious diseases supportive care.

This page was last updated on 6/12/2008.