1. Roswell Park Cancer Institute
Aspergillosis in CGD
Brahm Segal, MD
Roswell Park Cancer Institute

2. Aspergillosis in CGD

3. Pleural fluid in a CGD patient with invasive aspergillosis

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

7. NADPH oxidase

8. 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

9. 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

10. 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

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

13. Aspergillosis in CGD

14. 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 .

15. 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

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

17. 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

18. Examples of antifungal drugs

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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