Chronic Granulomatous Disease Medical Management N I C H O L A S H A R T O G, M D D i r e c t o r o f P e d i a t r i c / A d u l t P r i m a r y I m m u n o d e f i c i e n c y C l i n i c A s s i s t a n t P r o f e s s o r M i c h i g a n S t a t e U n i v e r s i t y C o l l e g e o f H u m a n M e d i c i n e S p e c t r u m H e a l t h / H e l e n D e v o s C h i l d r e n s H o s p i t a l
Disclosures H o r i z o n P h a r m a S p e a k i n g a n d c o n s u l t i n g
Medical Management C o r n e r s t o n e o f T h e r a p y P r e v e n t i n f e c t i o n s L i f e l o n g a n t i b a c t e r i a l a n d a n t i f u n g a l p r o p h y l a x i s I m m u n o m o d u l a t o r y t h e r a p y E a r l y i d e n t i f i c a t i o n o f i n f e c t i o n A g g r e s s i v e t r e a t m e n t o f i n f e c t i o n s
Prevention A v o i d a n c e : S w i m i n p o o l o r s a l t w a t e r Avoid freshwater, pond, brackish water A v o i d m u c h / p o t t i n g s o i l Mulch pneumonitis from Aspergillus A v o i d o t h e r p o t e n t i a l m o l d e x p o s u r e Compost, potting plans, damp cellar/basement, demolition, digging in dirt, cutting grass, hay rides, raking leaves, smoking marijuana
Identification of Infections E a r l y d i a g n o s i s o f i n f e c t i o n s c r i t i c a l S e r i o u s i n f e c t i o n s c a n b e m i n i m a l l y s y m p t o m a t i c o r a s y m p t o m a t i c a t p r e s e n t a t i o n M o n i t o r f o r o c c u l t i n f e c t i o n Personally I check ESR/CRP every visit, elevation prompts aggressive search for infections P a r e n t s m o n i t o r f o r l y m p h a d e n o p a t h y M o n i t o r f o r m u s c u l o s k e l e t a l c h a n g e s
Treatment of Infections C u l t u r e, c u l t u r e, C U L T U R E Unless life threatening infections, need cultures before empiric antimicrobials Bacterial, mycobacterial, and fungal cultures (hold for nocardia) Lymph node excisional biopsy Identification of microbe is critical for treatment A G G R E S S I V E T r e a t m e n t Empiric antifungal and antibacterial after cultures obtained Steroids sometimes used L o o o o o o o n g T r e a t m e n t Typically prolonged IV followed by prolonged oral medication for serious infections
Treatment of Infections S u m m a r y 1. Culture identification of microbe critically important in proper treatment 2. Early treatment once cultures done 3. Aggressive treatment IV antifungal and antibiotic after proper cultures 4. Prolonged treatment required for full eradication
Triple Therapy
Triple Therapy A n t i b a c t e r i a l ie t r i m e t h o p r i m / s u l f a m e t h o x a z o l e ( T M P - S M X ) A n t i f u n g a l ie i t r a c o n a z o l e I m m u n o m o d u l a t o r y I n t e r f e r o n g a m m a - 1b
Antibacterial T M P - S M X B a t e r i c i d a l a n d e f f e c t i v e a g a i n s t m o s t c o m m o n p a t h o g e n s ~ 1 L i f e t h r e a t e n i n g i n f e c t i o n e v e r y 1 0 m o n t h s w i t h o u t p r o p h y l a x i s W i t h T M P / S M X ~ 1 l i f e t h r e a t e n i n g i n f e c t i o n e v e r y 4 0 m o n t h s D e c r e a s e d r a t e o f h o s p i t a l i z a t i o n s a n d s u r g e r i e s O t h e r a n t i m i c r o b i a l o p t i o n s a v a i l a b l e i f i n t o l e r a n t t o T M P - S M X
Antifungal A s p e r g i l l u s s p p a c c o u n t f o r > 3 5 % o f a l l C G D d e a t h s A n t i f u n g a l ie. I t r a c o n a z o l e, p o s a c o n a z o l e, v o r i c o n a z o l e D e c r e a s e d r a t e s o f s e r i o u s i n v a s i v e f u n g a l i n f e c t i o n > 5 0 % I n c r e a s e d l i f e s p a n
Immunomodulatory I n t e r f e r o n g a m m a - 1b 1 9 8 0 s d a t a s h o w e d i n c r e a s e d p h a g o c y t e - m e d i a t e d k i l l i n g w i t h I F N - γ D e c r e a s e d i n f e c t i o n s a n d m o r t a l i t y r a t e Most studies done before antifungals S i d e e f f e c t s Flu like symptoms (fever, chills, fatigue) and injection site pain M e c h a n i s m Largely unknown Increased nitric oxide Enhanced macrophage bactericidal activity L e a s t a g r e e u p o n o f t r i p l e t h e r a p y u s e d l e s s f r e q u e n t l y i n E u r o p e t h a t U S A
Effect of Triple Therapy E f f e c t i v e w h e n t a k e n S u r v i v a l 9 0 % a t 1 0 y e a r s o l d B e s t c u r r e n t d a t a median age of death 30-40 years old Marciano BE, et al. Clin Infect Dis. 2015;60(8):1176.
Bone Marrow Transplant S h o u l d w e p e r f o r m a b o n e m a r r o w t r a n s p l a n t?
Bone Marrow Transplant https://beyondthedish.wordpress.com/tag/bone-marrow/page/2/
Bone Marrow Transplant https://cancer.uams.edu/patients-family/treatment/treatment-options/bone-marrow-transplant/allogenic/
Bone Marrow Transplant S o u r c e D o n o r s Bone marrow Peripheral blood stem cells Cord blood Related Matched sibling Haploidentical (parents) Do not use X-linked carriers Matched unrelated
Bone Marrow Transplant H L A T y p i n g C e l l s u r f a c e m a r k e r s r e c o g n i z e d b y i m m u n e c e l l s P r e s e n t o n e v e r y c e l l
Bone Marrow Transplant C o n d i t i o n i n g F u l l y M y e l o a b l a t i v e C o n d i t i o n i n g ( M A C ) More toxicity R e d u c e d - I n t e n s i t y C o n d i t i o n i n g ( R I C ) Various degrees of myelosuppression Higher rates of mixed chimerism Less toxicity R e d u c e d - T o x i c i t y C o n d i t i o n i n g ( R T C )
Bone Marrow Transplant R i s k s Death Acute graft vs host disease Chronic graft vs host disease Veno-occlusive disease Loss of future fertility Toxicities from conditioning B e n e f i t s Curative therapy
Bone Marrow Transplant W h o t o T r a n s p l a n t? Are risks of transplant less than no transplant? Consider comorbidities and end organ damage Consider HLA matches and cell source Consider experience of transplant center Avoid active infections Steroid dependent inflammatory manifestations No universal criteria to transplant X-linked consider genetics Residual oxidase activity Previous neutrophil transfusions Previous blood transfusions (McLeod phenotype) Time of year
Bone Marrow Transplant C u r r e n t r e s u l t s Survival 80-90% Graft vs host disease ~10-15% Improved quality of life Statistics are in studies at experienced centers Connelly, JA, et al. Allogeneic Hematopoietic Cell Trasplantation for CGD: Controversies and State of the Art. JPID supplement 2018
Bone Marrow Transplant G o a l Transplant patients who the risk of medical management is greater than the risk of transplant
Gene Therapy
Gene Therapy
Gene Therapy G a m m a r e t r o v i r u s p r e v i o u s s t u d i e s Only can insert into dividing cells High rate of insertional oncogenesis (ie. cancer) L e n t i v i r u s c u r r e n t s t u d i e s Can insert into non-dividing cells Self-inactivating vector (SIN) C R I S P R / C a s 9 May enable repair at native gene site (very specific) Promising pre-clinical data Amount of customization required may limit therapy
Gene Therapy C u r r e n t T r i a l Boston, Bethesda, and Los Angeles >23 months old with no HSCT match and history of serious infections or inflammatory complications SIN lentiviral vector Currently ongoing P r o g n o s i s No insertional oncogenesis Promising results in other diseases
CGD Associated Colitis Treatment Questions