Roswell Park Cancer Institute Aspergillosis in CGD Brahm Segal, MD Roswell Park Cancer Institute brahm.segal@roswellpark.org

Aspergillosis in CGD

Pleural fluid in a CGD patient with invasive aspergillosis

Invasive aspergillosis in a mouse model of chronic granulomatous disease Segal, BH, N Engl J Med. 2009 Apr 30;360(18):1870-84

NADPH oxidase

Invasive Fungal Infections in CGD Invasive mould infection is the most important cause of mortality in CGD, with Aspergillus being the most common isolate 0.1 fungal infections per patient year, despite gamma interferon prophylaxis X-linked likely at higher risk than autosomal recessive forms Winkelstein et al. Medicine. 2000

Invasive aspergillosis in CGD Signs of infection in CGD patients may be blunted or non-specific In a review of aspergillosis in CGD patients at the NIH, one-third of patients were asymptomatic at diagnosis and ~20% had fever Infection may be detected on routine chest radiographs Extension to bone may occur Patients with CGD may have concurrent bacterial and fungal infections Very important to establish a definite diagnosis Gallin JI et al., Ann Intern Med, 1983; Segal BH et al., Medicine, 1998

Aspergillus and CGD: European experience Review of 429 European patients with CGD 67% X-linked most frequent infections: Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Aspergillus (111 cases) was the most common cause of pneumonia Bone infection (osteomyelitis) seen in 84 episodes in 56 patients (13%), was caused mostly by Aspergillus spp., followed by Serratia marcescens Thirty-one patients (7%; 34 episodes) developed a brain abscess, mostly caused by Aspergillus Van den Berg et al, PLoS One 2009;4:e5234

Innate Immunity against Aspergillus Segal, BH, N Engl J Med. 2009 Apr 30;360(18):1870-84

Aspergillosis in CGD

Interaction of Aspergillus with the host A unique microbial-host interaction CGD CGD Acute IA ABPA Allergic sinusitis Subacute IA CNPA Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic cavitary Chronic fibrosing Immune dysfunction Immune hyperactivity . www.aspergillus.man.ac.uk www.aspergillus.man.ac.uk

Mulch pneumonitis Acute severe respiratory illness in CGD patients resulting from inhalation of a high level of moulds Treated with antifungal agents to control the fungal infection But also with steroids to reduce the excessive inflammation Siddiqui et al. Clin Infect Dis, 2007

Mulch pneumonitis: successful response to antifungal and steroid therapy Siddiqui et al. Clin Infect Dis, 2007

Current therapy for CGD Prophylaxis Antibacterial and antifungal prophylaxis Recombinant gamma interferon Therapy Prolonged courses of therapy White cell transfusions for severe infections may be administered

Examples of antifungal drugs

Itraconazole prophylaxis in CGD randomized, double-blind, placebo-controlled study Patients 13 years of age or older and all patients weighing at least 50 kg received a single dose of 200 mg of itraconazole per day; those less than 13 years old or weighing less than 50 kg received a single dose of 100 mg per day One patient (who had not been compliant with the treatment) had a serious fungal infection while receiving itraconazole, compared with seven who had a serious fungal infection while receiving placebo (P=0.10). Itraconazole was well-tolerated Gallin et al. N Engl J Med. 2003

Voriconazole Standard of care as therapy for invasive aspergillosis Substantial experience in patients with hematological cancers and transplant recipients More limited experience in CGD Usual maintenance dose in adults: 200 mg or 4 mg per kg of body weight twice daily Children require higher mg dosing per kg of body weight Walsh TJ et al. Pediatr Infect Dis J. 2002

Posaconazole Only available orally Effective as prophylaxis in certain patients with hematological malignancies and stem cell transplant recipients Evaluated as salvage therapy for several fungal infections, with the most substantial database in aspergillosis Experience in CGD patients with mould infections difficult to treat other antifungals is limited, but encouraging Segal BH et al., Clin Infed Dis

Gamma interferon Activates white cells Reduced frequency of severe bacterial infections in CGD by ~ 65% Benefit in reducing fungal infections is less clear administered by injection (subcutaneously), usually 3-times weekly Generally well-tolerated, can sometimes cause fatigue or mild flu-like symptoms Used together with antibacterial and antifungal prophylaxis N Engl J Med, 1991; Bemiller LS et al. Blood Cells Mol Dis. 1995

What you can do to prevent aspergillosis and other mould infections in CGD Prophylaxis with itraconazole or another agent active against Aspergillus Mould spores are everywhere in the environment, and it’s impossible to eliminate mould exposure entirely Avoidance of places and activities likely to be associated with high levels of mould exposure e.g., Gardening, mulching, construction sites, stagnant water

Stem cell transplantation Can be curative But, there are substantial risks related to transplantation Best suited to CGD patients with an HLA-matched sibling donor Prior aspergillosis is not a contra-indication to stem cell transplantation

Gene therapy In theory, CGD would be an ideal candidate for gene therapy Stem cell disorder in which a small proportion of long-lived gene-corrected stem cells might be sufficient to protect against infections Effective in mouse models of CGD Main problem has been to maintain a persistent number of gene-corrected circulating white cells Newer approaches to gene therapy offer hope that these problems can be addressed Ott MG et al. Curr Gene Ther, 2007