Neutrophilia new version

ACUTE NEUTROPHILIA- Pseudoneutrophilia Demargination - shift of cells from the marginal; partially from the spleen; other vascular beds, particularly the pulmonary capillaries - increase

Dr Truc PhanUniversity of Medicine and Pharmacy, HCMC

Self-renewal ProliferativeDifferentiationApoptosis

DEFINITION & TERMINOLOGY

- Definition: ANC greater than 2SD above the mean value

- ≥1 years: 7.5 x 109/L

- At birth, mean ANC is 12 x 109/L

- Neutrophilia = Neutrophilic leukocytosis = Polymorphonuclear leukocytosis = Granulocytosis

- Leukocytosis?

- Granulocytosis?

- Leukemoid reaction?

DIURNAL RYTHYMS

- Morning pseudoneutropenia?

MECHANISMS OF NEUTROPHILIA

Mitotic Pool = Myeloblast + Promyelocyte + Myelocyte

Maturation Pool = Metamyelocyte + Band + SN

Storage Pool = Mature neutrophil reserve

The total blood neutrophil pool (TBNP) = Circulating + Marginal Pool

à The flow of cells is unidirectional

MECHANISMS OF NEUTROPHILIA

- Marginal à circulating pools: a few minutes, freely exchangeable

- Marrow à blood: a few hours

- Increases in the production à at least a few days

- Sustained moderate to marked neutrophilia?

ACUTE NEUTROPHILIA

- Pseudoneutrophilia (Demargination)

- shift of cells from the marginal; partially from the spleen; other vascular beds, particularly the pulmonary capillaries

- increase heart rate and cardiac output

- within a few minutes

- account for about a doubling in neutrophil count => ?

- distinguishing neutrophilia from the response to infections, protracted stress, or glucocorticoid administration?

ACUTE NEUTROPHILIA

- Marrow Storage Pool Shift

- release of neutrophils from the marrow neutrophil reserves

- response to inflammation and infections

- The marrow reserve pool consists of SN and bands

- Metamyelocytes are not released except under extreme situations

- The postmitotic marrow neutrophil pool is #10 times the size of

the blood neutrophil pool => ?

CHRONIC NEUTROPHILIA

- Proliferation of neutrophil precursors.

- Repeated doses of endotoxin, glucocorticoids, or CSF

- Stimulation of cell divisions within the mitotic precursor pool

=> postmitotic pool size ↑ => M/E?

- increases severalfold with chronic infections

- Even greater increases?

- MPN, AL

- Leukemoid reaction

- G-CSF > Maximum: 1 week => ?

Case study

A 54-year-old man is brought to the emergency department with 2 days of severe diarrhea and 6 hours of abdominal pain He is confused and lethargic His daughter, who is at the bedside, notes that the patient has a history of hypertension and was recently treated for

“strep throat”; Temperature is 38.7 C, blood pressure is 92/58 mm Hg, pulse is 128/min, and respirations are 24/min The patient appears agitated The abdomen is mildly

distended, and the patient winces with deep palpation of the left lower quadrant

Laboratory results are as follows:

Case study

Intravenous fluids and antibiotics are administered The next morning, the patient’s

temperature is still elevated Repeat laboratory examination shows a leukocyte count of 52,000/mm3 with a similar differential The leukocyte alkaline phosphatase score is high Which of the following is the likely cause of this patient’s hematologic abnormalities?

Case study

OTHER MECHANISMS

- The neutrophil cell membrane defect CD11a/CD18 deficiency

- cannot mobilize neutrophils to sites of inflammation when they develop infections, extreme neutrophilia is observed

- Glucocorticoids may produce a functionally similar state

- In patients recovering from infections à tissue demand↓ à

persistence of neutrophilia => ?

OTHER MECHANISMS

- In chronic myelogenous leukemia, accumulation of neutrophils with a longer than normal half-life in the blood partially explains the extreme neutrophilia

DISODERS ASSOCIATED WITH NEUTROPHILIA

Dr Truc PhanUniversity of Medicine and Pharmacy, HCMC

INFLAMMATION AND STRESS

- Inflammation or tissue necrosis

- Burns, electric shock, trauma, infarction, gout, vasculitis, antigen-antibody complexes, complement activation

- Drugs, hormones, and toxins

- Colony-stimulating factors, epinephrine, etiocholanolone, endotoxin, glucocorticoids, smoking tobacco, vaccines, venoms

INFLAMMATION AND STRESS

arthritis, vasculitis, thyroiditis, Sweet syndrome

- Tumors

- Gastric, bronchogenic, breast, renal, hepatic, pancreatic, uterine, and squamous cell cancers; rarely Hodgkin lymphoma, lymphoma, brain tumors, melanoma, and multiple myeloma

INFLAMMATION AND STRESS

- Chronic Neutrophilia

- Drugs, hormones, and toxins

- Continued exposure to many substances that produce acute neutrophilia, lithium; rarely as a reaction to other drugs

- Metabolic and endocrinologic disorders

- Eclampsia, thyroid storm, overproduction of adrenocorticotropic hormone

- Hematologic disorders

- Rebound from agranulocytosis or therapy of megaloblastic anemia, chronic hemolysis or hemorrhage, asplenia,

myeloproliferative disorders, chronic idiopathic leukocytosis

- Hereditary and congenital disorders

- Down syndrome, congenital

CANCER AND HEART DISEASE

- Neutrophilia is associated with many nonhematologic

malignancies

- tumor cells produce CSF

- Tumor necrosis and superinfections

- Neutrophilia is a marker for the occurrence and severity of a

variety of illnesses

- associated with an increased incidence and severity of

coronary heart disease, independent of smoking status

- associated with increased cancer mortality

- In patients with cancer, subarachnoid hemorrhage, and other serious inflammatory conditions, neutrophilia portends a less favorable prognosis

HEREDIETARY AND HEMATOLOGIC DISORDERS

- MPN, AL

- Down syndrome: transient neonatal leukemoid reactions

- defect in regulation of neutrophil production caused by

chromosome 21 trisomy

- Chronic hereditary neutrophilia:

- activating mutation in the G-CSF receptor (CSF3R) gene

- Idiopathic neutrophilic leukocytosis

- Well-known effects of epinephrine, other catecholamines, and glucocorticoids

- Lithium salts cause sustained neutrophilia

- The counts return to normal when the drug is discontinued

- The drug increases levels of CSF

- Cases of neutrophilia have been reported with ranitidine and quinidine therapy (very uncommon)

KEY RECOMMENDATIONS

FOR PRACTICE

Dr Truc PhanUniversity of Medicine and Pharmacy, HCMC

Case study

A 34-year-old man is brought to the emergency department due to several hours of confusion His wife reports that he has had fever, malaise, and cough for the past 2 days A year ago, the patient required prolonged hospitalization and extensive surgery for multiple gunshot wounds to the abdomen He takes no medications regularly and has no other medical problems The patient does not use tobacco, alcohol, or illicit drugs He has

no history of recent travel Temperature is 40.5 C, blood pressure is 80/50 mm Hg, pulse is 110/min, and respirations are 32/min Mucous membranes are moist and no

cervical lymphadenopathy is present Dullness to percussion and crackles over the left lower chest are present Cardiovascular examination reveals normal first and second heart sounds and bounding peripheral pulses The abdomen has several well-healed surgical scars Intravenous fluids and broad-spectrum antibiotics are initiated The next day, blood cultures show gram-positive cocci Which of the following is the most likely underlying mechanism leading to this patient’s clinical presentation?

A Complement deficiency

B Destruction of CD4+ cells

C Immunoglobulin A deficiency

D Impaired antibody-facilitated phagocytosis

E Impaired B cell isotype switching

F Impaired chemotaxis

G Impaired oxidative burst

A 68-year-old woman with a history of chronic leukocytosis was referred for a second opinion She has no significant past medical history She has smoked a pack of cigarettes weekly for the past 30 years She initially presented with a mild neutrophilic leukocytosis, which has been slowly progressive throughout the past 17 years (WBC 13.3-32.7 × 109/L; absolute neutrophil count 26.5 × 109/L at the time of referral) The hemoglobin and platelet count are

normal She has remained asymptomatic during this period and does not have palpable lymphadenopathy or hepatosplenomegaly

on examination A peripheral blood smear is shown below