The X factor in a blue moon. Monique Lee Campbelltown Hospital

Transcription

1 The X factor in a blue moon Monique Lee Campbelltown Hospital

2 Mrs MD 73 year old Increasing dyspnoea, hypoxia Recurrent lower respiratory tract infections Two hospital admissions parenteral antibiotics Azithromycin, moxifloxacin, ciprofloxacin Bronchoalveolar lavage & blood cultures negative Parameter Result WCC 13.0 x 10 9 /L Hb 115 g/l Neutrophils 10.8 x 10 9 /L ALP 195 U/L GGT 539 U/L ALT 274 U/L AST 164 U/L CRP mg/l

3 Burkholderia cepacia Deterioration Acute respiratory failure Fevers, rash, hypotension ICU, vasopressor, high flow nasal prong oxygen Results Hb 84 g/l PLT 86 x 10 9 /L ALP 345 U/L ALT 126 U/L GGT 776 U/L AST 197 U/L Triglyceride 2.3 mmol/l Ferritin 10,903 µg/l CRP mg/l Bone marrow biopsy Hypercellular, prominent haemophagocytosis, reactive

4 Background Chronic granulomatous disease carrier Genetics c. 764hetdelA; p.lys255argfs*14 on CYBB Arginine deletion, frameshift mutation Presented 2012 Several mild lower respiratory tract infections Persistent mediastinal lymphadenopathy Deranged liver function tests NBT/ DHR 2% neutrophils normal respiratory burst after PMA stimulation Polymyalgia rheumatica Intermittent oral glucocorticosteroids Right scalp tenderness, headache Temporal artery biopsy, CT brain, LP normal Hyperparathyroidism Previous biliary sepsis 2 episodes 4 years ago P

5 Progress Infection Tobramycin (nebulised) 160mg BD Ceftazidime 2g BD Bactrim (5+25 mg/kg QID) Voriconazole 300mg BD (Meropenem/ciprofloxacin /azithromycin; briefly) Filgrastim 300 µg 2 nd daily Macrophage Activation Syndrome Pulse methylprednisolone 1g x 3 prednisone 50mg IVIg (2g/kg bodyweight) Cyclosporin (1.5mg/kg bodyweight) Multiple blood transfusions Discharged home on Bactrim DS, cyclosporine, itraconazole, weaning prednisone

6 Summary Ferritin Haemoglobin C Reactive Protein Extreme lyonisation of elderly X-linked CGD carrier causing pathologic phenotype Macrophage activation syndrome secondary to B. cepacia

7 CGD Epidemiology 1/ 250,000 80% male Usually present <2yrs Recurrent bacterial & fungal infections Dysregulated inflammation: granuloma, discoid lupus X-linked CGD CYBB: deletions, frameshift, missense, non sense, splice site mutations Residual NADPH oxidase activity leads to attenuated disease, better prognosis 30% CYBB mutations are de novo Song et al. (2011). Clinical and molecular allergy. 9:10. Roos (2016). British Medical Bulletin. 118:53-66.

8 X-linked carriers Immune dysregulation Increased autoimmunity Higher risk of SLE Granulomatous organ involvement Extreme lyonisation Skewed non-random X inactivation Non-CGD: increased autoimmunity Lupus, autoimmune thyroiditis, scleroderma, MS Increasing lyonisation with age Typical infections in carriers when <5% neutrophils capable of respiratory burst Brooks (2010). Clinic Rev Allerg Immunol 39:20-29.

9 MAS 13 case reports of MAS in CGD patients 2014 case report: 8wk old male presenting with HLH, disseminated Candida during cyclosporin/ dexamethasone, CYBB mutation detected Most associated with infection: B. cepacia, leishmania, stenotrophomonas, staphylococcus, enterobacter, HHV6, BCG, pseudomonas B. cepacia complex Motile gram negative bacillus Involved in 3-7% pneumonia and 18% of deaths in CGD Interferes with phagosome maturation Reduces NADPH oxidase activity to survive in phagocyte vacuoles Valentine, et al. (2014). Pediatrics 134: Maignan, et al. (2013). Case reports in pulmonology. Article ID

10 MAS & CGD pathophysiology Hyperactive inflammation in CGD Defective NADPH Persistent infection impaired pathogen killing TH cells: ++IL2, TNF-α, IFN-γ activate macrophages Macrophages: ++IL1, IL6, IL18 activate TH cells Macrophages with p47 phox mutation Reduced regulatory T cell induction & T cell suppression impaired regulation of inflammatory response T cells express NADPH oxidase NADPH deficiency reduces T cell receptor signal favours production of TH1 cytokines (murine model) induce macrophage activation B. cepacia further impairs NADPH oxidase Parakh, et al. (2011). Pediatric blood cancer 56: Alvarez-Cardona., et al (2012). JCI 32:

11 Treatment Immune activation IVIG Effective first-line; 1-3g/kg/dose Corticosteroids Treat refractory infection in addition to antimicrobials Suppress inflammation in MAS Cyclosporin Recommended; low dose promotes Treg induction & expansion G-CSF Targeted antimicrobials Prophylaxis HSCT Alvarez-Cardona., et al (2012). JCI 32:

12 Survivors All cases receiving IVIG and pathogen-specific therapy Deaths Inadequate pathogen-specific therapy Immunosuppressive therapy Alvarez-Cardona., et al (2012). JCI 32: Song et al. (2011). Clinical and molecular allergy. 9:10. Roos (2016). British Medical Bulletin. 118:53-66.

13 Acknowledgements Dr Karuna Keat Dr Nicolas Urriola