Benign Leukocyte Disorders

Benign

not malignant
same are acquired notmal responses
some are inherited defects
some are abnormal but not pathologic while others are life threatening

Malignant

leukemias and lymphomas
Pre-malignant
Plasma cell neoplasma

Neutrophilia

produces a leukocytosis
> 7.0 × 10⁹ /L 

Redistribution of marginating PNMs

pseudo-neutrophilia
release of marginating neutrophils into circulation
severe mucle contractions (violent exercise or convulsions)
adrenaline (epi administration, emotional stress, anxiety/panic)
anethesia/surgery

Bacterial infection

acquired neutrophilia
infections → marginating PNMs → diapedesis → new PMNs marginate → neutropenia → BM release → neutrophilia → left shift → phagocytosis
Produces a leukemoid reaction

Leukemoid reaction

an abosolute increase in circulating neurophils and shift in neutrophil distribution from mature states to more immature stages called a left shift. A natural, normal physiological reaction to a pathological situtation

Other causes of acquired neutrophilia

Malignancy
inflammation
drugs
metabolic disease (hemolytic anemia, uremia, and glomerularnephritis)

Neutropenia

< 1.5 × 10⁹/L
produces a leukopenia
results in recurrent bacterial infections

Mechanisms of neutropenia

decreased production
accelerated utilization
decreased survival
altered distribution
impaired release

Viral infections

Acquired neutropenia
lymphocytosis no neutrophilia
neutropenia due to increased use from tissue damage

Bone marrow failure

Acquired neutropenia
HSC failure - aplastic anemia (panytopenia)
myelophythesis (malignant infiltrate)(metastatic cancer)

Autoimmune neutropenia

Acquired neutropenia
decreased survivial
anti_PMN abs
isoimmune neutropenia
mom anti-PMN Ab crosses placenta

Splenomegaly

Acquired neutropenia
altered distribution
hyperactive spleen (pulls out PMN)

Pseudo-neutropenia

Acquired neutropenia
altered distribution
increased marginating pool

organic acidemia

Acquired neutropenia
diabetic ketoacidosis

Severe congential Neutropenia

Congenital neutropenia
1/200,000
6 subtypes
SCN 1-5 + SCNX from 6 different gene mutations
Autosomal recessive/dominant/X-linked
Neonatal severe neutropenia (True PMN BM arrest)
Normal RBC and Plt with some exceptions
increased Mono and Eos to compensate
1/3 of SCN3 have seizures/learning disabilities/developmental delays
rick of developing myeloproliferative neoplasms or AML
trate with G-CSF, antibiotic, TX

Cyclic Neutropenia

Congenital neutropenia
autosomal recessive
mutiation of ELANE gene
Periodic marrow failure
Humoral and cell mediated immune deficiency
Treat with G-CFS and antibiotics

Bengin Neutropenia

Congenital neutropenia
autosomal recessive 
depletion of storage pool
stress may increased neutrophils
usually not serious but can recure
responds to G-CSF and antibiotics

WHIM

Congenital neutropenia
autosomal dominant
mutated chemokine receptor
Warts caused by HPV infections on hands and feet
hypogammaglobulinemia from defective lymphocytes
Myelokathexis
treat with human gamma globulin and G-CSF/GM-CSF
CxCR4 antagonist with promising results (increases release of neutrophils from BM)

Shwachman- Diamond Syndrome

Congenital neutropenia
1/75,000
Autosomal Recessive
SBDS gene that controls protein synthesis
BM failure at birht
Pancreatic insufficiency (poor digestion of fat)
Skeletal abnormalities (short stature)
stress may increase neutrophils
Treatment (G-CSF, antibiotic, BMTX)(Pancreatic insufficiency with enzyme supplements

Fanconi’s Anemia

Congenital neutropenia (pancytopenia)
1/130,000
autosomal recessive
Abnormal chromosome analysis
BM failure between 5-10 years but before 20 years
skeletal abnormalities (No thumb or stubs and short stature)
abnormal hyperpigmentation
Treat with CSFs, EPO, BMTx

Dyskeratosis congenita

Congenital neutropenia (pancytopenia)
1/million
Complex genetic disorder
x linked, autosomal dominant and recessive
no chromosomal abnormality
Triad presentation
Pancytopenia to aplastic anemia by 5-10 years
may develop MDS, leukemia, or solid tumors
progressive BM failure
treat with CSFs or BMTx

Dyskeratosis congenita Triad presentation

abnormal skin pigmentation (Neck/chest)
abnormal finger and toenails
leukoplakia (white patches) in the mouth

Acquired morphologic Abnormalities

Toxic granulation
vaculolization
Dohle bodies

Acquired morphologic Abnormalities are seen in

severe infections and toxic states
pregnancy and burns
cancer

Pelger-Huet Anomaly

inherited morphologic Abnormalities
autosomal dominant and 1/5000 births
completely asymptomatic
neutrophil nucleus in ≤ 2 lobes
normal nuclear chromatin (mature)
no infection, toxic granulation or dohle bodies

May-Hegglin Anomaly

inherited morphologic Abnormalities
autosomal dominant
mutation of MYH9 gene
asymptomatic, few with mild bleeding

May-Hegglin Anomaly differential

Granulocytes contain Dohle-like inculsions
inclusions contain RNA
Giant hypogranular platelets with decreased lifespen
can have mile leukopenia and thrombocytopenia

Alder-Reilly anomaly

inherited morphologic Abnormalities
autosomal recessive
inherited anzyme deficiency for mucopolysaccharides
mucopolysaccharides accumulate in lysosomes
Asymptomatic then symptoms
Gargoylism, corneal blurring, mental retardation
associated with Hurlers, Hunters, and Tay-Sachs Disease (lipid storage disorders)

Alder-Reilly Anomaly Differential

Large purple toxic-like granules in leukocytes
can affecr only one lineage, but often multiple lineages
accumulates in lysosomes

Jordan’s Abomaly

Negin familial Abnormality
mutations in the PNPLA2 gene → codes for enzyme
enzyme adipose triglyceride lipase (ATGL) → fatty vaculose
Presentation/symptoms - associated with muscular dystrophy and ichthyosis (scaly skin)

Jordan’s anomaly differential

empty vacuoles in Wright’s stain
vacuoles actually contain lipids
Sudanophilic vacuoles in PMNS and monos

Chediak-Higashi Syndrome

Autosomal recessive
mutation of CHS1 LYST Gene - causes vesicle fusion
fusion of primary granules in neutrophils
presents with abnormal melanosomes (albinism, photophobia, silver hair, lymphadenopathy and heptaosplenomegaly)
die in infancy or childhood from infections withoug treatment

yes

is BM transplant curative for Chediak-Higashi Syndrome

Chediak-Higashi Syndrome differential

giant gray-green bodies in EBCs and tissues
fusion or primary granules
abnormal chemotaxis and killing
sometimes neutropenia and thrombocytopenia

Chronic Granulomatous Disease

X-linked recessive with some autosomal recessive
manifests in first 1-3 years of life

Chronic Granulomatous Disease differential and defect

PMNs have abnormal lysosomal enzyme systems
decreased NADPH oxidase
Normal PMN morphology and phagocytosis
abnormal organism killing → recurrent infections → granulomas
Catalase + organisms destroy peroixde
NBT negative no conversion from yello to blue (stays yellow)

Chronic Granulomatous Disease prognosis/treatment

death by age 7 wihout treatment BM treansplant 50% but survive to age 30-40 years

Lazy Leukocyte Syndrome

Rare - autosomal recessive
mutation in actin genes (actinopathies)
Recurrent infections, especially respiratory/skin
Stomatitis (mouth), gingivitis (gums), otitis media (ear)
normal BM → neutropenia
decreased chemotaxis
abnormal skin window and Boyden chamber

Myeloperoxidase Deficiency

Autosomal Recessive
Deficiency of MPO and PMNs and monos
Eos have different peroxidase and are normal
Delayed bacterial killing and poor yeast killing
Acquired with certain metabolic conditions (diabetes, leukemia, myeloproliferative, megaloblastic anemia)

Lactoferrin Deficiency

no secondary granules
Nicro-lobulated nucleus
abnormal chemotaxis
other granule contents are decreased
mild skin infections

WBC adhesion deficiency

autosomal recessive
chromosome 21 mutation
decreased synthesis of beta-chain of LFA-1
Three types
neutropenia and abnormal chemotaxis
recurrent bacterial infections and fungal
bone marrow transplant is treatment of choice

Eosinophilia

allergic reactions
Parasitic infections
asthma
certain skin disorders like dermitis/vasculitis
brucella
hypereosinophilc syndrome
Hematologic malignancies

Basophilia

hematologic malignancies
immediate hypersensitivity
inflammatory diseases
estrogen therapy
Myxedema (hypoparathyroidism)
radiation
stress
infections
chronic hemolytic anemia

Eosinopenia

clinically irrelevant
acute stress
inflammatory reactions
Glucocorticosteroids, ACTH, epinephrine, prostaglandins
Cushing’s Syndrome

Basopenia

clinically irrelevant
degranulation from anaplylactic shock
Leukocytosis of infection
Urticaria (wheal and flare)
long-term adrenal glucocoticoid therapy
inflammation
immunologic reactions
Neoplams
hemorrhages

Monocytosis

myelodysplastic syndrome
disorders of the monocytic/macrophage system
recovery phase of bacterial infections
myeloproliferative syndrome
lymphocytic tumors
inflammatory disorders

Monocytopenia

clinically irrelevant
aplastic anemia
Hairy cell leukenia
glucocorticosteroids

viral infection

most common cause of lymphocytosis

Lymphocytosis signs and symptoms

fever, chills, lethargy, lymphadenopathy

Acute infections lymphocytosis

causative agent - unknown, probably a virus or bacteria
clinical features - GI stress, diarrhea, respiratory infection, fever, stiff neck

Acute infections lymphocytosis Lab findings

leukocytosis in 1 week of symptoms
60-97% small, normal appearing lymphs
normal Hb, RBC, Plt, ESR

Whooping cough

Absolute lymphocytosis
Causative agent - bordetella pertussis
clinical features - sore throat, fever, whooping cough

Whooping cough lab findings

increased WBC of 15-25
Lymphocytosis with small folded nuclei
Possible neutrophilia with toxic granulation

Infectious mononucleosis

Absolute lymphocytosis
causative agent - epstein barr virus infects B cells

Infectious mononucleosis clinical features

13-25 yo, fever, lethargy, pharyngitis
lymphadenopathy
splenomegaly
EBV → B cells → spread → Tc Cell clears virus

Infectious monoculeosis Lab findings

WBC 12-25 (>50% lymphs)
>20% atypical lymphs
large blue cytoplasm, can indent around RBCs
Monospot test

Davidohn’s Differential Test

differentiates the 3 of heterophile Abs

IM heterophil Abs

made by the immune sytem when patient has mono

Serum sickness herophile Abs

made in response to injecion with animal serum (Pre-antibiotic and anti-venom_)
can have anaphylactic reaction with 2nd injection

Forssman heterophil Abs

Ab made for unknown reasons

Serum + Sheep RBCs = No Agg (-)

Davidohn’s Differential Test
differentiation not necessary

Serum + Sheep RBCs = Agg (+)

Davidohn’s Differential Test
react with Beef RBC and Guinea Pig Kidney Ag

Beef RBC

Davidohn’s Differential Test
absorbs serum sickness and IM abs

Guinea Pig Kidney Ag

Davidohn’s Differential Test
Absorbs Forssman and Serum sickness Abs

Toxoplasmosis

Absolute Lymphocytosis
resembles IM
no heterophile antibodies
diagnosed by anti-toxoplasma gondii antibodies (IgM or IgG)

Cytomegalovirus (CMV)

Absolute Lymphocytosis
resembles IM
no heterophile antibodies
diagnosed by anti-CMV antibodies (IgM or IgG)

Lymphocytopenis

Disseminated neoplasm
chemotherapy
Raditation therapy
congenital immune deficiency syndromes
acquired immune deficiency diseases
corticosteroids
acute inflammatory conditions
chronic infections
connective tissue diseases
acute or chronic renal diseases
stress
drugs

SCID Pathogenesis

X-linked or autosonal recessive and most severe but varies
deficient or absent lymphoid tissue → infections → death by 1 -2 years old

SCID Defect

decreased lymphs (<1.5)
decreased T,B and plasma cells in lymphoid tissue and BM
No lymphoid tissue in spleen, tonsils, or GI
BM is almost deficient in plasma cells and lymph precursors
peripheral lymphs are unresponsive to mitogens
decreased Ig
bone marrow transplant is only hope of survival

Wiscott-Aldrich pathogenesis

X-linked (mostly in males)
decreased T/B function → infections → death by 10 years
Eczema and thrombocytopenia

Wiscott-Aldrich functional defect

normal total lymphs
normal B cells numbers but abnormal function
decreased to normal T cell number and abnormal function
decreased IgM with normal IgG, IgE, and IgA
can develop histocytic, lymphocytic, myelocytic neoplasms

Wiscott-Aldrich prognosis and treatment

complications of bleeding, infections, and malignancy
histocytic, lymphocytic, and myelocytic neoplasms
reduced lifespan without BM/HSC transplant

Hereditary Ataxia-telangiectasia pathogenesis

autosomal recessive
Hypo or dysplasia of the thymus
depletion of thymic dependent areas of the LN
Chronic respiratory infections → death

Hereditary Ataxia-telangiectasia defect

decreased T cells and CMI
decreased B cells and antibdoy
Ataxia - abnormal mucle coordination → abnormal gait
telangiectasia - spider-like vasular lesions on face and thigh
progressive neurological decline and increased infections

DiGeorge Syndrome pathogenesis

congenital athymic/aparathyroid state

DiGeorge Syndrome functional defect

decreased T cells → lymphocytopenia
normal B cell and normal to decreased Ig
Increased susceptibility to viral, fungal, and bacterial infections
death in first year without thymic transplant

Bruton-Type Agammaglobulinemia pathogenesis

X-linked agammaglobulinemia (males)
frequent respiratory and skin infections

Bruton-Type Agammaglobulinemia functional defect

decreased B cells and Plasma cells → decreased IgG, IgM, IgA
normal T cells
Monthly injections of gammaglobulin
normal life span

AIDS etiology

human immunodeficiency virus
serotype I and II with → subtypes
HIV infects Th cells primarily
Multiplie in Th cells → kills Th cells → released from Th cells

AIDS mode of transmission

homosexual or bisexual men
I.V drug users
blood transfusions prior to 1985
hemophiliacs
promiscuous heterosexuals/polygamous
transplacental

AIDS clinical features

virus infects T helper cells
Asymtomatic period
oppotunistic infections
increased malignancies like kaposis sarcoma
emaciation

AIDS Lab findings

Lymphopenia (<0.5)
decreased Th number and function
Decreased CD4/CD8 ratio
decreased NK and Mono function
polyclonal activation of B cells → increased Ig → no mitogen resp
screen by detecting anti-HIV Abs
confirm with Western blot or nucleic acid detection
Monitor with viral load testing

Plamsacytosis

chronic infections
sever viral ifnections
Neoplasms (multiple myeloma, Waldenstron’s macroglobulinemia)
Allergic states