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Aspergillosis in CGD
Brahm Segal, MD
Roswell Park Cancer Institute
[email protected]
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
Frequency of aspergillosis
CGD
Acute IA
ABPA
Allergic sinusitis
Subacute IA
CNPA
Aspergilloma
Chronic cavitary
Chronic fibrosing
Immune dysfunction
Frequency of aspergillosis
CGD
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
 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 HLAmatched sibling donor
• Prior aspergillosis is not a contraindication 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