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 Interaction of AspergillusAspergillus with the host with the host

A unique microbial-host interactionA unique microbial-host interaction

Immune dysfunction

Frequency

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Immune hyperactivity

Frequency

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Acute IA

Subacute IACNPA

AspergillomaChronic cavitaryChronic fibrosing

ABPAAllergic sinusitis

. www.aspergillus.man.ac.ukwww.aspergillus.man.ac.uk

CGD CGD

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 n=39 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