First Aid, Chapter 8, Immunologic Disorders, Phagocytic Cell Disorders Flashcards
What are the general categories of infections that occur with phagocytic cell disorders?
Phagocytes defend against bacteria and fungi. Patients with defects of phagocytic cell number, function, or both experience recurrent and severe infections of fungal (especially Candida and Aspergillus species) and bacterial origin.
Respiratory tract and cutaneous infections predominate, but deep-seated abscesses are also common. Recurrent oral stomatitis is present in most cases.
Suspicion should be raised if infections are associated with neutropenia or lack of neutrophilia.
What are some defects intrinsic to phagocytes?
Abnormal bone marrow production or release
Defect in adhesion or chemotaxis
Leukocyte granule formation
Oxidative killing
What phagocytic disorders does a CBC help evaluate?
LAD 1, 2 and 3 (leukocyte-adhesion deficiency) Cyclic neutropenia SCN ( severe congenital neutropenia) AIN (classical) (autoimmune neutropenia) SDS (Shwachman-Diamond syndrome)
What tests are used to evaluate CGD?
NBT ( nitroblue tetrazolium chloride)
DHR (dihydrorhodamine flow cytometric assay)
What assay is used to evaluate for MPO deficiency? What types of infections occur? In what comorbid condition does this occur secondarily?
MPO assay
Primary MPO deficiency and secondary MPO deficiency ex. Candida albicans or C. tropicalis infection in patient with diabetes mellitus
What phagocytic deficiencies are chemotaxis assays useful in identifying?
SDS (Shwachman-Diamond syndrome)
Chediak-Higashi syndrome LAD ( leukocyte-adhesion deficiency)
Rac2 mutation
What phagocytic deficiencies are bacteriocidal assays useful in evaluating?
Neutrophil-specific granule deficiency
CGD
What phagocytic deficiency is a CD18 assay useful in evaluating?
LAD1
What phagocytic deficiency is a CD15a assay useful in evaluating?
LAD2
What phagocytic disorders are defects in bone marrow production or release?
WHIM syndrome (warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis.)
SCN ( severe congenital neutropenia)
Cyclic neutropenia
What phagocytic disorders are defects in adhesion and chemotaxis?
LAD1-3
What phagocytic disorders are defects in leukocyte granule formation?
Chediak-higashi syndrome
What phagocytic disorder is a defect in oxidative killing?
CGD
What is the presentation of WHIM?
Sinopulmonary infections Papillomavirus infection Warts with risk of malignant transformation No other viral/opportunistic infections
What is the treatment of WHIM?
Rx: G-CSF, IVIG, Rx warts, CXCR4 inhibitor (in trial)
What are the lab findings in WHIM?
Neutropenia (ANC 100– 500/mm3) due to retention of mature granulocytes in bone marrow (myelokathexis) Normal phagocyte functions
ALC
What is the molecular defect in WHIM?
Activating mutation in CXCR4 (important in bone marrow homing and trafficking of progenitor cells)
What is the clinical presentation of severe congenital neutropenia?
Early onset, severe bacterial infections: Omphalitis, URTI (upper respiratory tract infection) or LRTI (lower respiratory tract infection), oral ulcer, skin and liver abscess, cellulitis, meningitis.
What is the treatment for severe congenital neutropenia?
Rx: G-CSF (not working for G-CSF-R mutation), HSCT, monitor for myelodysplasia, AML
What are the lab findings in severe congenital neutropenia?
Persistent neutropenia ANC maturation arrest of neutrophil precursors at promyelocyte-myelocyte stage
What is the molecular defect in severe congenital neutropenia?
AR- HAX 1a (Kostmann syndrome)
AD-Elastase (ELA2), GFI1, GCSF-R XL- WASP
What is the clinical presentation in cyclic neutropenia?
Oral ulcers, fever, skin infection/abscess during periods of neutropenia
What is the treatment of cyclic neutropenia?
prophylactic ABx or GCSF during the cycling nadir
What are the lab findings in cyclic neutropenia?
↓ Neutrophils, platelets, monocytes, reticulocytes in 21-day cycle; last for 3–6 days
CBC with differential 2–3 times weekly for 6 week
What is the molecular defect in cyclic neutropenia?
ELA-2- AD
What is the clinical presentation for LAD1?
Recurrent pyogenic infections, delayed wound healing, necrotic skin, infections, impaired pus formation, gingivoperiodontitis, omphalitis, delayed umbilical cord separation
What is the treatment for LAD1?
ABx Rx and prophylaxis, G-CSF, HSCT
What are the lab findings in LAD1?
Leukocytosis;
↓ CD18 on neutrophils by flow cytometry: Severe:
What is the molecular defect in LAD1?
Common chain of β2-intergrin family (CD18) from ITGB2 gene mutation
Defect in WBC adhesion (arrest)
What is the clinical presentation of LAD2?
Less severe skin/lung infections, no delayed umbilical cord separation, pus formation is impaired but not absent
Developmental delay, microcephaly, and short stature
Rx: Abx prophylaxis, fucose supplementation
What are the lab findings in LAD2?
Leukocytosis Absence of CD15a
Bombay blood phenotype (hh)
Sequence analysis of GDPfucose transporter
What is the molecular defect in LAD2?
Mutation in FUCT1 -> absence of fucosylation -> no Sialyl-LewisX (CD15a) Defect in WBC rolling
What is the clinical presentation in LAD3?
LAD 1 + bleeding diathesis.
What is the treatment for LAD3?
Same as LAD1- ABx Rx and prophylaxis, G-CSF, HSCT
What are the lab findings in LAD3?
Leukocytosis
Normal expression of CD18 Abnormality of Rap1 GTPase function
What is the molecular defect in LAD3?
CalDAG-GEF1 mutation -> failure of cytokine activation of integrins
What is the clinical presentation of chediak-higashi syndrome?
Oculocutaneous albinism, hypopigmented skin, iris, hair, recurrent infections, bleeding tendency, neurologic defects, lymphoma-like syndrome, risk of HLH
What are the lab findings in chekiak-higashi syndrome?
Enlarged primary granules in neutrophils, eosinophils, neutropenia, decreased neutrophil chemotaxis, and absent NK cytotoxicity.
Evenly distributed larger melanin granules on hair shaft examination
What is the molecular defect in chekiak-higashi syndrome?
CHS1 or LYST
What is the clinical presenation of CGD?
Infections with catalase positive organisms
Bacteria: S. aureus, Burkholderia cepacia, Serratia marcescens, Nocardia sp. Aspergillus fumigatus Aspergillus nidulans
Fungi: Not associated with Streptococcus pneumoniae or Pneumocystis jiroveci infections
Granuloma formation (GI and GU tract outflow obstruction), poor wound healing, and autoimmune disease
What are the lab findings in CGD?
Abnormal NBT and pattern of DHR DHR is a fluorescent dye that is reduced by superoxide radicals (produced by phagocytes stimulated with PMA). This leads to a change in flow cytometry-detected fluorescence(see Fig.8-2)
What is the treatment of CGD?
TMP-SMZ and itraconazole prophylaxis IFNγ Systemic corticosteroids for granuloma formation HSCT
What is the molecular defect of CGD?
PHOX (phagocytic NADPH oxidase system); >50% g91phox (Xlinked form); and
AR-p22, p47, and p67.
What molecular defects occur in LAD type 1 and 2?
CD18 and CD 15a
