GranulocytopeniaCritical care clinics

Dr Pratyush Chaudhuri

Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils.

Granulocytopenia (neutropenia) is defined specifically as

A decrease in the number of circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores.

Value of less than 1500/mm3 is used to define neutropenia.

Neutropenia is classified as mild, moderate, or severe, based on the ANC, which is calculated by Absolute Neutrophil count= [Total WBC X N% ] + band forms

Mild neutropenia - 1000-1500/mm3 moderate neutropenia - 500-1000/mm3 severe neutropenia - less than 500/mm3.

Neutropenia can be caused by

insufficient or injured bone marrow stem cells

shifts in neutrophils from the circulating pool to the marginal blood or tissue pools

increased destruction in the circulationcombination of these mechanisms.

Intravascular stimulation of neutrophils by plasma-activated complement 5 (C5a) and endotoxin may cause increased margination along the vascular endothelium, decreasing the number of circulating neutrophils.

The term pseudoneutropenia refers to neutropenia caused by increased margination.

Pathophysiology

Disorders of the pluripotent myeloid stem cells and committed myeloid progenitor cells include some congenital forms of neutropeniaaplastic anemiaacute leukemiamyelodysplastic syndrome.

Other examples include

bone marrow tumor infiltration Radiation infection (especially viral) bone marrow fibrosis. Cancer chemotherapy, other drugs, and toxins may

damage hematopoietic precursors by directly affecting bone marrow.

immunologic destruction triggered by autoimmune diseases (eg, Felty syndrome) and by drugs acting as haptens.

The risk of serious infection increases as the ANC falls to the severely neutropenic range (<500/mm3).

The duration of severe neutropenia directly correlates with the total incidence of all infections and those infections that are life threatening.

Bacterial organisms most often cause fever and infection in neutropenic patients.

gram-negative aerobic bacteria (eg, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa)

gram-positive cocci, especially Staphylococcus species and Streptococcus viridans.

Note

After treating neutropenic patients with broad-spectrum antibiotics for several days, superinfection with fungi is common.

Indian Data awaited Data from US National Health and Nutritional

examination 1999 to 2004 survey showed the prevalence of neutropenia was 4.5% among black participants relative to 0.79% in

white individuals and 0.38% in Mexican-Americans participants.

History

Hallmarks of significant neutropenia are fever and recurrent infection, primarily of the oropharynx and skin. Obtaining a careful drug history is important.

Common presenting symptoms of neutropenia Low-grade fever Sore mouth Odynophagia Gingival pain and swelling Skin abscesses Recurrent sinusitis and otitis Symptoms of pneumonia (eg, cough, dyspnea) Perirectal pain and irritation

Congenital neutropenia –personal history of lifelong infections family history of recurrent infections limited survival.

Chronic, benign familial neutropenia – long-standing neutropenia without an

increased risk of infection.

Physical findings on examination of a patient with neutropenia may include the following:

Fever Stomatitis Periodontal infection Cervical lymphadenopathy Skin infection Splenomegaly Associated petechial bleeding Perirectal infection Growth retardation in children

Acquired neutropenia (disorder of neutrophil production)

Intrinsic bone marrow diseases Aplastic anemia Hematologic malignancy (eg, leukemia, lymphoma,

myelodysplasia, myeloma) Ionizing radiation Tumor infiltration Granulomatous infection Myelofibrosis

Drugs, including, but not limited to, the following:

Acetaminophen Aminoglutethemide Antithyroid drugs: propylthiouracil,

carbimazole, methimazole Cytotoxic chemotherapeutic

agents Gold salts Chloramphenicol Indomethacin Phenylbutazone Phenothiazines Semi-synthetic penicillins Cephalosporins

Antituberculosis drugs Trimethoprim/sulfamethoxazole Anticonvulsants Cimetidine Clonazepam Ranitidine Ibuprofen Hydralazine Captopril, enalapril Tocainide Chlorpropamide Benzodiazepines Ticlopidine Zidovudine Sulfasalazine Propranolol Digoxin Ticlopidine

Infection, including, but not limited to, the following:

Bacterial sepsis Viral infections (eg, influenza, measles, Epstein Barr

virus [EBV], cytomegalovirus [CMV], viral hepatitis, human immunodeficiency virus [HIV]-1)

Toxoplasmosis Brucellosis Typhoid Tuberculosis Malaria Dengue fever Rickettsial infection Babesiosis

Acquired neutropenia (disorder of neutrophil production)

IdiopathicNutritional deficiency

(eg, vitamin B-12, folate, copper, cachexia and debilitated states)

Acquired neutropenia (disorder of neutrophil production)

Acquired neutropenia (peripheral destruction of neutrophils is usually immune mediated)

Alloimmune neutropenia in the neonate usually reflects a transplacental transfer of maternal alloantibodies to neutrophil antigens present on the neutrophils of the fetus.

Drug immune-mediated neutropenia

Aminopyrine Quinidine Cephalosporins Penicillins Sulfonamides Phenothiazines Phenylbutazone Hydralazine Other medications have been implicated.

Autoimmune neutropenia may be associated with the following:

Crohn disease Rheumatoid arthritis (with or without Felty syndrome) Sjogren syndrome Chronic, autoimmune hepatitis Hodgkin lymphoma Systemic lupus erythematosus Thymoma Goodpasture disease Wegener granulomatosis Pure red blood cell (RBC) aplasia. Transfusion reactions. Large granular lymphocyte proliferation or leukemia

Acquired neutropenia (shifts of neutrophils from the circulating to the marginated pool of neutrophils)

Bacterial infection Cardiopulmonary bypass Hemodialysis Splenic sequestration Sepsis Congenital neutropenia Cyclic neutropenia Cartilage-hair hypoplasia syndrome Chediak-Higashi syndrome Dyskeratosis congenita Infantile genetic agranulocytosis (Kostmann syndrome) Lazy leukocyte syndrome Myelokathexis Shwachman-Diamond syndrome Reticular dysgenesis

Eosinopenia may be associated with the following:

Acute bacterial infection Glucocorticoid administration Hypogammaglobulinemia Physical stress Thymoma Decreased circulating basophils may be associated with the following: Anaphylaxis Acute infection Drug-induced hypersensitivity Congenital absence of basophils Hemorrhage Hyperthyroidism Ionizing radiation Neoplasia Ovulation Urticaria Drugs (eg, corticosteroid, adrenocorticotropic hormone [ACTH] therapy, chemotherapeutic

agents, thyroid hormones)

Differential diagnosis

Acute Lymphoblastic LeukemiaInfluenzaAcute Myelogenous LeukemiaMyelodysplastic SyndromeAgranulocytosisMyelophthisic AnemiaAplastic AnemiaNeutropeniaBone Marrow FailureParoxysmal Nocturnal HemoglobinuriaBrucellosisPernicious Anemia

CytomegalovirusSepsis, BacterialEhrlichiosisSplenomegalyFelty SyndromeSystemic Lupus ErythematosusFolic Acid DeficiencyToxoplasmosisHairy Cell LeukemiaTuberculosisHepatitis, ViralWegener GranulomatosisInfectious Mononucleosis

Other Problems to Be Considered

Autoimmune diseasesChronic myelomonocytic leukemiaCongenital neutropeniaCyclic neutropeniaDrug-induced neutropeniaLarge granular lymphocytic leukemiaPseudoneutropenia

Work up

Laboratory StudiesPrevious to a major workup, rule out

infectious and drug-induced causes of neutropenia; then, obtain the following laboratory studies:Complete blood cell (CBC) countDifferential WBC countPlatelet countWright-stained peripheral smear

The following studies are applicable in some patients with neutropenia:

Antinuclear antibody (ANA) Rheumatoid factor (RF) Serum immunoglobulin (Ig) studies Liver function tests (LFTs)

Imaging Studies

Perform long-bone radiographs if a form of congenital neutropenia is suspected.

Obtain liver-spleen radionuclide scans if the presence of splenomegaly and splenic sequestration are suspected in a patient with neutropenia .

Other Tests

Obtain vitamin B-12 and folate levels. infection workup, including blood cultures for

anaerobic and aerobic organisms. complete fever workup include the following:

Urinalysis Urine culture and sensitivity Culture of wound or catheter discharge Stool for Clostridium difficile Skin biopsy, if new erythematous and tender skin lesions are

present Broad-spectrum antibiotics should be started within 1

hour of cultures.

Procedures

bone marrow aspiration and obtain a biopsy

Medical Care

Discontinue drugs if they are suspected.Corticosteroid therapy could be effective

in immune-mediated neutropenia.Correct nutritional deficiency (cobalamin

or folic acid deficiency) if detected.

Treat the fever as an infection, as follows:

Third-generation cephalosporins (eg, ceftazidime, cefepime) or imipenem-cilastatin and meropenem can be used as a single agent.

Gentamicin or another aminoglycoside should be added if the neutropenic patient's condition is unstable or the individual appears septic.

Beta-lactam antibiotics (eg, ticarcillin, piperacillin) are usually used in combination with a third-generation cephalosporin or an aminoglycoside.

Vancomycin should be added if methicillin-resistant Staphylococcus aureus or Corynebacterium species is suspected.

If the neutropenic patient's fever does not respond within 4-5 days or if the fever recurs with the administration of broad-spectrum antibiotics after an initial afebrile interval consider adding empiric antifungal coverage

with amphotericin B (preferably lipid formulation)

a broad-spectrum azole (eg, voriconazole) an echinocandin (eg, caspofungin).

Fever in patients with low-risk neutropenia can be treated on an outpatient basis with oral antibiotics.

Myeloid growth factors

granulocyte colony-stimulating factors (GCSFs)

granulocyte-macrophage colony-stimulating factor (GM-CSFs) may shorten the duration of neutropenia in

patients who have undergone chemotherapy.

Neutrophil (granulocyte) transfusion

some clinical usefulness in treating neonatal sepsis.

Cyclic neutropenia patients .Congenital neutropenia patients.

Important supportive measuresCareful handwashingMeticulous care of indwelling catheters

Surgical Care

In individuals with neutropenia and Felty syndrome who have recurrent life-threatening bacterial infections, splenectomy is the treatment of choice.

Indwelling central venous catheters should be removed in febrile neutropenic patients if septic thromboembolism is suspected. Other indications for catheter removal include the following: Corynebacterium jeikeium infection Infection with Candida species Polymicrobial infection Persistent fevers Pocket-space abscess Tunnel infections

Thank You…