Overview (N Engl J Med 2000;343:1703)
• Include congenital neutropenias (cyclic neutropenia, severe congenital neutropenia, Shwachman–Diamond), adhesion defects (leukocyte adhesion deficiency), abnormal chemotaxis (Hyper IgE syndrome), intracellular killing defects (CGD), defects in formation/fxn of neutrophil granules (Chediak–Higashi)
• Consider phagocytic disorder if pt continues having severe or unusual bacterial or fungal infxns and all other workup for B- and T-cell deficiencies negative
Chronic Granulomatous Disease (CGD) (N Engl J Med 2000;343:1703)
• Definition: Defect in NADPH oxidase resulting in impaired ability to kill bacteria + fungi
• Pathophysiology:
• Normally, NADPH oxidase → hydrogen peroxide formation → hypochlorous acid (bleach) formation → respiratory burst
• In CGD, 5 known gene mutations affect assembly and activation of NADPH oxidase → failure to activate neutrophil resp burst → failure to kill catalase positive bacteria
• Most common mutation (gp91phox) is X-linked, accounts for 70%
• Epidemiology: Quite rare, 4–5/million, 2/3 are male; can be X-linked or AR
• Clinical manifestations: (J Allergy Clin Immunol 2011;127:1319)
• Most infxns 2/2 S. aureus, S. marcescens, Burkholderia cepacia, nocardia, & Aspergillus
• Commonly develop PNA, lymphadenitis, liver abscess, osteo, skin + soft tissue infxn
• Noncaseating granulomas in brain, lung, liver, spleen, GI tract; autoimmune dz
• X-linked: Earlier diagnosis, higher mortality rate
• Diagnostic studies: (Clin Rev Allergy Immunol 2010;38:3)
• See “Evaluating for PID” above: Abnormal neutrophil oxidase function suggests CGD
• NBT testing replaced by dihydrorhodamine oxidation (DHR) testing
• Management: (J Allergy Clin Immunol 2011;127:1319)
• Hematopoietic transplant is only curative Rx, 90–95% survival over previous 10 yr
• Antibacterial (TMP-SMX) and antifungal (itraconazole) prophylaxis +/−
immunomodulatory therapy (IFN-gamma)
• Steroids used to decrease granulomas, low-dose prednisone
• Complications: Gastric outlet or ureteral obstruction from granulomas
Chediak–Higashi Syndrome (N Engl J Med 2000;343:1703)
• Definition: Rare defect in chemotaxis w/ ↑ susceptibility to bacterial infections, neuropathy, platelet dysfxn, oculocutaneous albinism
• Pathophysiology: AR disorder w/ abn degranulation of lysosomal granules
• Mutation in LYST cytoplasmic protein involved in vesicle transport affecting all cells including melanocytes, which results in poor delivery pigment to skin and hair
• Epidemiology: Rare; 1 in 1 million, AR, dx early childhood, fatal by early adulthood
• Clinical manifestations:
• Oculocutaneous albinism, progressive periph neuropathy, mild MR, periodontal dz
• Infections: Sinopulmonary, skin, susceptible to S. aureus, and β-hemolytic-strep
• Defective platelets: Easy bruising, mucosal bleeding
• Diagnostic studies: # of neutrophils slightly ↓ and smear w/ giant cytoplasmic granules
• Management: Prophylactic antibiotics
• BMT (does not correct/prevent central and peripheral neuro defects) (Bone Marrow Transplant 2007;39:411)
• Complications: (J Clin Oncol 2006;24:3505)
• Accelerated dz in 85% of pts: Lymphoma-like syndrome (nonmalignant cells) w/ pancytopenia, fever, lymphocyte infiltration of liver, spleen, nodes that may be related to EBV infection, often becomes uncontrolled and leads to death
• If pt survives, can lead to severe neuro manifestations by 20s and wheelchair bound