Phagocyte deficiencies Notes

NOTES NOTES PHAGOCYTE DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited immunodeficiency disorders: mutations in genes that code immune-cell functioning ▪ Impaired immune function: recurrent, often severe, life-threatening infections SIGNS & SYMPTOMS ▪ Recurrent infection history DIAGNOSIS LAB RESULTS ▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Genetic testing TREATMENT MEDICATIONS ▪ Infection prophylaxis/treatment OTHER INTERVENTIONS ▪ Hematopoietic cell transplantation ▪ Characteristic findings upon physical examination CHEDIAK–HIGASHI SYNDROME osms.it/chediak-higashi_syndrome PATHOLOGY & CAUSES ▪ Rare, inherited immunodeficiency disorder; impaired leukocyte lysosomal granules function in phagocytes, NK cells → recurrent pyogenic infections ▪ Autosomal recessive; lysosomal trafficking regulator gene CHS1/LYST defect ▫ Trafficking: protein movement within cell ▪ Genetic mutation → impaired trafficking → absent/partially functioning CHS1/LYST protein → large, abnormal intracellular granules → decreased phagocytosis → infections primarily affect skin, mucous 212 OSMOSIS.ORG membranes, respiratory tract ▪ Accelerated disease phase: profound lymphohistiocytic organ infiltration, worsening immunodeficiency RISK FACTORS ▪ Parental consanguinity COMPLICATIONS ▪ Related to impaired intracellular trafficking ▫ Oculocutaneous albinism (reduced skin, eye pigment) ▫ Neurologic abnormalities ▫ Coagulation defects

Chapter 34 Phagocyte Deficiencies ▫ Hemophagocytic lymphohistiocytosis (disorder resembles lymphoma) ▫ If bone marrow transplant unsuccessful → childhood death from infection usually occurs SIGNS & SYMPTOMS ▪ Presents in infancy: frequent/severe bacterial, viral, fungal infections ▪ Neurological: nystagmus, ataxia, peripheral neuropathy, seizures, Parkinsonian-like features may develop ▪ Coagulation defect presents as easy bruising ▪ Photosensitivity ▪ Hair has silvery tint DIAGNOSIS LAB RESULTS ▪ Microscopic hair examination: pigmentation clumping ▪ CBC: neutropenia ▪ Peripheral blood smear analysis: giant intracellular granules ▪ Bone marrow aspiration: large inclusion bodies in precursor cells ▪ Genetic testing TREATMENT MEDICATIONS ▪ Prophylactic antibiotics ▪ Prompt, aggressive infection treatment OTHER INTERVENTIONS ▪ Hematopoietic cell transplant; cord blood transplant ▫ Does not address debilitating neurological manifestations/albinism OSMOSIS.ORG 213

CHRONIC GRANULOMATOUS DISEASE (CGD) osms.it/chronic-granulomatous-disease PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Rare immune-system disorder; affects neutrophils, monocytes, macrophages → serious, life-threatening infections (bacterial/fungal), granuloma formation ▫ X-linked: CYBB encoded ▫ Autosomal recessive form common with consanguinity—CYBA encoded ▫ De novo mutations also occur ▪ Mutations: genes encoding for phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes lysosomal reactive oxygen species ▪ Impaired NADPH → phagocytes unable to effectively phagocytize, destroy certain microbes → ↑ infection susceptibility; especially catalase-positive bacteria/fungi ▪ History of disorder-characteristic recurrent infections, granulomatous lesions ▪ Fever, leukocytosis, lymphadenopathy, abnormal wound healing, diarrhea, chronic disease anemia, growth failure (children) Host immune system response ▪ Recruiting additional phagocytes, activating T cells ▪ Immune cells collect around microbe → granulomas form ▪ Childhood/adulthood diagnosis (underlying mutation-dependent) Frequent infection sites ▪ Lung, skin, lymph nodes, liver Common infections ▪ Pneumonia, bacteremia, fungemia, impetigo, cellulitis, granulomatous lesions (skin, organs), gingivitis, gastroenteritis, otitis Inflammation manifestations ▪ Esophageal/urethral strictures, colitis, cystitis, interstitial pneumonitis, dermatosis 214 OSMOSIS.ORG DIAGNOSIS LAB TESTS ▪ ↑ inflammation markers: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) ▪ Immune stimulation → hypergammaglobulinemia ▪ Neutrophil function tests: e.g. dihydrorhodamine (DHR) 123 test measure neutrophils ability to produce oxidative burst ▪ Genetic testing TREATMENT MEDICATIONS ▪ Antimicrobial prophylaxis using combination of therapies ▫ Antibacterial: TMP/SMX ▫ Antifungal: itraconazole ▫ Immunomodulatory: interferon-gamma ▪ Aggressive acute infection treatment ▪ Inflammatory manifestations: oral glucocorticoids ▪ Avoid live bacterial vaccines OTHER INTERVENTIONS ▪ Hematopoietic cell transplantation: curative if successful

Chapter 34 Phagocyte Deficiencies LEUKOCYTE ADHESION DEFICIENCY (LAD) osms.it/leukocyte-adhesion-deficiency PATHOLOGY & CAUSES ▪ Rare, inherited immunodeficiency disorders; mutations in genes encoding leukocyte adhesion molecules → impaired leukocyte function, deficient immunological response (foreign antigens), ↓ inflammatory response to injury ▫ Autosomal recessive inheritance ▪ Leukocyte adhesion cascade initiated in response to infection/injury ▫ Involves adhesion molecule-activation on vascular endothelial cells which bind to glycoproteins on leukocyte surface ▪ Stepwise adhesion, activation process ▫ Capture: temporary leukocyte to endothelial cell tethering ▫ Rolling: leukocyte rolls along endothelial cells (weak, reversible initial adherence) ▫ Slow rolling: endothelial cell ligands interact with leukocyte selectins → slow movement along vessel wall ▫ Firm adhesion: leukocyte integrins bind to endothelial intercellular adhesion molecules (ICAMs) → leukocyte stops (arrest) on endothelial surface ▫ Transmigration: leukocyte movement between endothelial cells, into interstitium/infected tissue TYPES ▪ Categorization: specific genetic defects ▪ LAD I: integrin beta-2 gene mutation (ITGB2) encoding CD18 subunit → CD18 requires activation before endothelial ligand adhesion can occur ▫ Integrins: glycoproteins that mediate firm adhesion, transmigration along endothelium (via endothelial cell counter-receptors) ▫ LAD I defect prevents leukocyte bloodstream → interstitium migration ▪ LAD II: guanosine diphosphate (GDP)fucose transporter gene (SLC35C1) mutation → absent ligands for selectins ▫ Selectins: endothelial, leukocyte adhesion glycoproteins that mediate margination, leukocyte rolling (slows velocity → allows endothelial ligand adhesion) ▫ Fucose (monosaccharide; cellular glycans, glycolipids component) metabolism defect → absent fucosylated endothelial ligands for selectins ▪ LAD III: mutations in CalDAG-GEF1, kindlin-3; FERMT3 genes → defects all beta integrins (e.g. 1, 2, 3) activation ▫ Integrin glycoproteins remain inactivated, unable to adhere to endothelial ligands ▫ Beta-3 defect impairs platelet aggregation → severe bleeding tendency ▫ Also involves natural killer (NK) cell activity impairment COMPLICATIONS ▪ Specific mutation dependent ▫ Poor wound healing ▫ Bleeding tendencies (may involve neonatal cerebral hemorrhage, gastrointestinal tract bleeding) ▫ Developmental delay ▫ Decreased lifespan (e.g. infection) OSMOSIS.ORG 215

SIGNS & SYMPTOMS DIAGNOSIS ▪ High index of suspicion at birth with delayed umbilical cord separation, leukocytosis, along with additional findings ▫ LAD I: recurrent soft tissue infections ▫ LAD II: psychomotor impairment, Bombay blood group presence ▫ LAD III: bleeding complications from birth LAB RESULTS ▪ White blood cell count with differential: elevated leukocyte count ▫ Leukocytes unable to leave bloodstream → persistent leukophilia (basal) + ↑↑ during infection (especially neutrophils) ▪ Flow cytometry ▫ LAD I: CD18, alpha subunit molecules (CD11a, CD11b, CD11c) absence 216 OSMOSIS.ORG ▫ LAD-II: SLeX expression (CD15a) absence ▪ LAD-II: genetic testing confirms defect of gene that encodes for guanosine diphosphate (GDP)-fucose transporter ▪ LAD III: impaired integrin activation TREATMENT MEDICATIONS ▪ Antibiotics: mild–moderate infections OTHER INTERVENTIONS ▪ Control periodontitis: scrupulous oral hygiene, dental care ▪ Bacterial infection treatment: mitigate severity ▪ Fucose supplementation (LAD II) ▪ Hematopoietic cell transplantation