First Aid, Chapter 8, Immunologic Disorders, Phagocytic Cell Disorders

Question 1

What are the general categories of infections that occur with phagocytic cell disorders?

Answer 1

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.

Question 2

What are some defects intrinsic to phagocytes?

Answer 2

Abnormal bone marrow production or release

Defect in adhesion or chemotaxis

Leukocyte granule formation

Oxidative killing

Question 3

What phagocytic disorders does a CBC help evaluate?

Answer 3

LAD 1, 2 and 3  (leukocyte-adhesion deficiency)
Cyclic neutropenia 
SCN ( severe congenital neutropenia)
AIN (classical) (autoimmune neutropenia)
SDS (Shwachman-Diamond syndrome)

Question 4

What tests are used to evaluate CGD?

Answer 4

NBT ( nitroblue tetrazolium chloride)

DHR (dihydrorhodamine flow cytometric assay)

Question 5

What assay is used to evaluate for MPO deficiency? What types of infections occur? In what comorbid condition does this occur secondarily?

Answer 5

MPO assay

Primary MPO deficiency and secondary MPO deficiency ex. Candida albicans or C. tropicalis infection in patient with diabetes mellitus

Question 6

What phagocytic deficiencies are chemotaxis assays useful in identifying?

Answer 6

SDS (Shwachman-Diamond syndrome)
Chediak-Higashi syndrome LAD ( leukocyte-adhesion deficiency)
Rac2 mutation

Question 7

What phagocytic deficiencies are bacteriocidal assays useful in evaluating?

Answer 7

Neutrophil-specific granule deficiency

CGD

Question 8

What phagocytic deficiency is a CD18 assay useful in evaluating?

Answer 8

LAD1

Question 9

What phagocytic deficiency is a CD15a assay useful in evaluating?

Answer 9

LAD2

Question 10

What phagocytic disorders are defects in bone marrow production or release?

Answer 10

WHIM syndrome (warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis.)

SCN ( severe congenital neutropenia)

Cyclic neutropenia

Question 11

What phagocytic disorders are defects in adhesion and chemotaxis?

Answer 11

LAD1-3

Question 12

What phagocytic disorders are defects in leukocyte granule formation?

Answer 12

Chediak-higashi syndrome

Question 13

What phagocytic disorder is a defect in oxidative killing?

Answer 13

CGD

Question 14

What is the presentation of WHIM?

Answer 14

Sinopulmonary infections Papillomavirus infection Warts with risk of malignant transformation No other viral/opportunistic infections

Question 15

What is the treatment of WHIM?

Answer 15

Rx: G-CSF, IVIG, Rx warts, CXCR4 inhibitor (in trial)

Question 16

What are the lab findings in WHIM?

Answer 16

Neutropenia (ANC 100– 500/mm3) due to retention of mature granulocytes in bone marrow (myelokathexis) Normal phagocyte functions
ALC

Question 17

What is the molecular defect in WHIM?

Answer 17

Activating mutation in CXCR4 (important in bone marrow homing and trafficking of progenitor cells)

Question 18

What is the clinical presentation of severe congenital neutropenia?

Answer 18

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.

Question 19

What is the treatment for severe congenital neutropenia?

Answer 19

Rx: G-CSF (not working for G-CSF-R mutation), HSCT, monitor for myelodysplasia, AML

Question 20

What are the lab findings in severe congenital neutropenia?

Answer 20

Persistent neutropenia ANC maturation arrest of neutrophil precursors at promyelocyte-myelocyte stage

Question 21

What is the molecular defect in severe congenital neutropenia?

Answer 21

AR- HAX 1a (Kostmann syndrome)

AD-Elastase (ELA2), GFI1, GCSF-R XL- WASP

Question 22

What is the clinical presentation in cyclic neutropenia?

Answer 22

Oral ulcers, fever, skin infection/abscess during periods of neutropenia

Question 23

What is the treatment of cyclic neutropenia?

Answer 23

prophylactic ABx or GCSF during the cycling nadir

Question 24

What are the lab findings in cyclic neutropenia?

Answer 24

↓ Neutrophils, platelets, monocytes, reticulocytes in 21-day cycle; last for 3–6 days
CBC with differential 2–3 times weekly for 6 week

Question 25

What is the molecular defect in cyclic neutropenia?

Answer 25

ELA-2- AD

Question 26

What is the clinical presentation for LAD1?

Answer 26

Recurrent pyogenic infections, delayed wound healing, necrotic skin, infections, impaired pus formation, gingivoperiodontitis, omphalitis, delayed umbilical cord separation

Question 27

What is the treatment for LAD1?

Answer 27

ABx Rx and prophylaxis, G-CSF, HSCT

Question 28

What are the lab findings in LAD1?

Answer 28

Leukocytosis;

↓ CD18 on neutrophils by flow cytometry: Severe:

Question 29

What is the molecular defect in LAD1?

Answer 29

Common chain of β2-intergrin family (CD18) from ITGB2 gene mutation

Defect in WBC adhesion (arrest)

Question 30

What is the clinical presentation of LAD2?

Answer 30

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

Question 31

What are the lab findings in LAD2?

Answer 31

Leukocytosis Absence of CD15a

Bombay blood phenotype (hh)

Sequence analysis of GDPfucose transporter

Question 32

What is the molecular defect in LAD2?

Answer 32

Mutation in FUCT1 -> absence of fucosylation -> no Sialyl-LewisX (CD15a) Defect in WBC rolling

Question 33

What is the clinical presentation in LAD3?

Answer 33

LAD 1 + bleeding diathesis.

Question 34

What is the treatment for LAD3?

Answer 34

Same as LAD1- ABx Rx and prophylaxis, G-CSF, HSCT

Question 35

What are the lab findings in LAD3?

Answer 35

Leukocytosis

Normal expression of CD18 Abnormality of Rap1 GTPase function

Question 36

What is the molecular defect in LAD3?

Answer 36

CalDAG-GEF1 mutation -> failure of cytokine activation of integrins

Question 37

What is the clinical presentation of chediak-higashi syndrome?

Answer 37

Oculocutaneous albinism, hypopigmented skin, iris, hair, recurrent infections, bleeding tendency, neurologic defects, lymphoma-like syndrome, risk of HLH

Question 38

What are the lab findings in chekiak-higashi syndrome?

Answer 38

Enlarged primary granules in neutrophils, eosinophils, neutropenia, decreased neutrophil chemotaxis, and absent NK cytotoxicity.

Evenly distributed larger melanin granules on hair shaft examination

Question 39

What is the molecular defect in chekiak-higashi syndrome?

Answer 39

CHS1 or LYST

Question 40

What is the clinical presenation of CGD?

Answer 40

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

Question 41

What are the lab findings in CGD?

Answer 41

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)

Question 42

What is the treatment of CGD?

Answer 42

TMP-SMZ and itraconazole prophylaxis IFNγ Systemic corticosteroids for granuloma formation HSCT

Question 43

What is the molecular defect of CGD?

Answer 43

PHOX (phagocytic NADPH oxidase system); >50% g91phox (Xlinked form); and
AR-p22, p47, and p67.

Question 44

What molecular defects occur in LAD type 1 and 2?

Answer 44

CD18 and CD 15a