Brahm H. Segal, MD

Author address: 

Roswell Park Cancer Institute, USA


Invasive aspergillosis is a major cause of morbidity and mortality in highly immunocompromised persons. Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase complex in which phagocytes are defective in generating superoxide anion. Activation of preformed granular proteases is likely to be principal mechanism for NADPH oxidase-mediated destruction of pathogens. As a result of the defect in this key host defense pathway, CGD patients suffer from recurrent life-threatening bacterial and fungal infections. Invasive aspergillosis is the most important cause of mortality in CGD. Genetically engineered CGD mice recapitulate several of the features of the human disease and are highly susceptible to Aspergillus infection. There are important differences between invasive aspergillosis in CGD compared to other immunocompromised conditions. In neutropenic animals and patients, invasive pulmonary aspergillosis is characterized by hyphal angioinvasion, coagulative necrosis and paucity of inflammatory cells. A similar pathologic phenotype may occur in non-neutropenic allogeneic hematopoietic stem cell transplant recipients (HSCT) with graft-versus-host disease (GVHD). In contrast, Aspergillus infection causes robust pyogranulomatous responses in genetically engineered p47phox -/- CGD mice. Angioinvasion was not observed in CGD mice nor is it a feature of invasive aspergillosis in CGD patients. Serum galactomannan was not elevated above baseline in CGD mice with invasive pulmonary aspergillosis, possibly a reflection of lack of vascular invasion. Lethality from pulmonary aspergillosis in CGD mice was related to excessive inflammation rather than necrosis. The CGD mouse model may be exploited to understand NADPH oxidase-independent mechanisms that defend against vascular invasive aspergillosis. CGD is also characterized by excessive inflammatory responses that are independent of the host defense deficit. Intratracheal administration of sterile zymosan, a ligand of toll-like receptor 2 and dectin-1 led to pyogranulomatous pulmonary lesions in CGD mice that histologically resembled inflammation associated with experimental aspergillosis. Inflammation in similarly treated wildtype mice was close to nil. These findings demonstrate a key role of NADPH oxidase in downregulating inflammation induced by specific ligands of pathogen recognition receptors. Recent studies point to defective tryptophan catabolism underlying impaired host defense and pathogenic inflammation in CGD. Prophylaxis with a mould-active agent should be offered to CGD patients. Itraconazole was safe and effective as prophylaxis in a randomized study. Bone marrow transplantation is curative in CGD, but is associated with expected frequencies of transplant-related morbidity and mortality. Gene therapy is a promising tool, but has so far been limited by lack of ability to maintain stable population gene-corrected stem cells.

abstract No: 


Full conference title: 

3rd Advances Against Aspergillosis
    • AAA 3rd (2008)