NOTES

NOTES
PHAGOCYTE DEFICIENCIES

GENERALLY, WHAT ARE THEY?

LAB RESULTS
PATHOLOGY & CAUSES ▪ Complete blood count (CBC)
▪ Peripheral blood smear analysis
▪ Inherited immunodeficiency disorders:
mutations in genes that code immune-cell ▪ Genetic testing
functioning
▪ Impaired immune function: recurrent, often
severe, life-threatening infections TREATMENT
MEDICATIONS
SIGNS & SYMPTOMS ▪ Infection prophylaxis/treatment

▪ Recurrent infection history

OTHER INTERVENTIONS
▪ Hematopoietic cell transplantation
DIAGNOSIS
▪ Characteristic findings upon physical
examination

CHEDIAK–HIGASHI SYNDROME
osms.it/chediak-higashi_syndrome
membranes, respiratory tract
PATHOLOGY & CAUSES ▪ Accelerated disease phase: profound
lymphohistiocytic organ infiltration,
▪ Rare, inherited immunodeficiency disorder; worsening immunodeficiency
impaired leukocyte lysosomal granules
function in phagocytes, NK cells →
recurrent pyogenic infections RISK FACTORS
▪ Autosomal recessive; lysosomal trafficking ▪ Parental consanguinity
regulator gene CHS1/LYST defect
▫ Trafficking: protein movement within COMPLICATIONS
cell ▪ Related to impaired intracellular trafficking
▪ Genetic mutation → impaired trafficking ▫ Oculocutaneous albinism (reduced skin,
→ absent/partially functioning CHS1/LYST eye pigment)
protein → large, abnormal intracellular
▫ Neurologic abnormalities
granules → decreased phagocytosis →
infections primarily affect skin, mucous ▫ Coagulation defects

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 Chapter 34 Phagocyte Deficiencies

▫ Hemophagocytic lymphohistiocytosis
(disorder resembles lymphoma) DIAGNOSIS
▫ If bone marrow transplant unsuccessful
→ childhood death from infection LAB RESULTS
usually occurs ▪ Microscopic hair examination: pigmentation
clumping
▪ CBC: neutropenia
SIGNS & SYMPTOMS ▪ Peripheral blood smear analysis: giant
intracellular granules
▪ Presents in infancy: frequent/severe ▪ Bone marrow aspiration: large inclusion
bacterial, viral, fungal infections bodies in precursor cells
▪ Neurological: nystagmus, ataxia, peripheral ▪ Genetic testing
neuropathy, seizures, Parkinsonian-like
features may develop
▪ Coagulation defect presents as easy TREATMENT
bruising
▪ Photosensitivity MEDICATIONS
▪ Hair has silvery tint ▪ Prophylactic antibiotics
▪ Prompt, aggressive infection treatment

OTHER INTERVENTIONS
▪ Hematopoietic cell transplant; cord blood
transplant
▫ Does not address debilitating
neurological manifestations/albinism

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 CHRONIC GRANULOMATOUS
DISEASE (CGD)
osms.it/chronic-granulomatous-disease

PATHOLOGY & CAUSES SIGNS & SYMPTOMS

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

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LEUKOCYTE ADHESION
DEFICIENCY (LAD)
osms.it/leukocyte-adhesion-deficiency

PATHOLOGY & CAUSES ▪ LAD II: guanosine diphosphate (GDP)-

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

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 SIGNS & SYMPTOMS

▫ LAD-II: SLeX expression (CD15a)

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

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