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Leukocyte Disorders

Leukocyte Disorders. Quantitative Disorders of the Neutrophil. Neutrophil function in the immune system Age specific WBC & differential counts Neutropenia & ANC Neutropenias with etiologies extrinsic to the bone marrow Intrinsic disorders of proliferation & maturation

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Leukocyte Disorders

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  1. Leukocyte Disorders Quantitative Disorders of the Neutrophil

  2. Neutrophil function in the immune system • Age specific WBC & differential counts • Neutropenia & ANC • Neutropenias with etiologies extrinsic to the bone marrow • Intrinsic disorders of proliferation & maturation • Neutropenias associated with phenotypic abnormalities • Evaluation of children with neutropenia • Principles of neutropenia therapy

  3. Neutrophil Functions In the Immune system • Inflammation • Phagocytosis • Bactericidal effect • Immune regulation

  4. Age Specific Leukocyte Differential

  5. Neutropenia & ANC • Neutropenia:A decrease in the absolute number of circulating segmented neutrophils and bands in the blood {CBC & differential count} • ANC: Total WBC * segmented & band % • ANC for the general population ranges between 1500-8000 cells /mm3 for Caucasian children> 6yrs. • ANC = 1000-1500/mm3 :mild neutropenia • ANC = 500-1000/mm3 : moderate neutropenia • ANC <500 : sever neutropenia

  6. Neutropenia…..cont. • Neutropenic pts are mostly infected with endogenous flora, but colonization with nosocomial organisms is observed. • Susceptibility to bacterial infections, even with sever neutropenia, varies. • Some pts with chronic neutropenia do not have serious infections even with ANC<200 , because other parts of the IS are intact. • With immunosuppressive drugs, esp. with malignancy , serious bacterial infections occur.

  7. Neutropenia….cont. • Most frequent pyogenic infection : cutaneous cellulitis,abscesses or furunculosis,pneumonia, septicemia,stomatitis,gingivitis,perirectal infections & otitis media. • Susceptibility to parasitic , viral or fungal infections or bacterial meningitis is not increased. • The most common pathogens are Staph.aureus & G –ve organisms. • Signs & symptoms of local infection & inflammation : exudate , abscess formation & regional LN enlargement are less evident. • Erythema , pain , tenderness , warmth & fever are present

  8. Neutropenias : Extrinsic vs. Intrinsic. • Pathophysiologic classification of neutropenias : • Intrinsic disorders of bone marrow affecting production , proliferation & maturation of myeloid cells. • Factors extrinsic to bone marrow : redistribution between marginating and circulating neut`s ,shortened survival . • Extrinsic are more common than intrinsic.

  9. Neutropenias with extrinsic etiologies: Infection • Among the most common causes. • Multifactorial: • Direct marrow suppression • Depletion of marrow reserves of neut`s and bands • Redistribution due to endothelial activation( TNF, IL-1 , ICAM 1-2 ) • Aggregation &sequestration ( Complement activation ) • Direct destruction of neut`s ( Pathogens) • Indirect destruction ( antibodies )

  10. Infection….cont. • Viral infections: the commonest ( RSV, varicella, influenza A&B,measles & rubella . • Develops in 1st 24-48 hrs , may persist 3-8 days. • Correlates with acute viremia • Common viral infxns may cause sever neutropenia , short lived , rare 2ndary bact infection. • Rarely requires specific management.

  11. Infections ….cont. • IM, hepatitis , HIV may cause sever , protracted neutropenia & cytopenia, due to infxn of precursor cells , or neut sequestration. • Neutropenia occurs in bact, protozoal ,rickettsial & sever fungal infxns. • Chronic infxns : TB , brucella ,typhoid , malaria . • Sepsis .

  12. Drug Induced Neutropenia • Toxic vs. hypersensitivity. • Immune mediated • Withdraw all unessential drugs. • Withdraw the offending drug. • If no response : consider rhG-CSF (5-10 mcg/kg subcut.)

  13. Immune neutropenia • Associated with anti –neutrophil antibodies. • Complement mediated lysis & splenic phagocytosis of opsonized neutrophils. • Antibodies are detected by a combination of immunofluorescence & microcapilary agglutination assays.

  14. Alloimmune Neonatal Neutropenia: • Transplacental passage of maternal IgG against fetal neutrophils. • Presents in the 1st 2 weeks : delayed separation of umbilical cord , skin infxn , fever & pneumonia . • Sever neutropenia which corrects by ~ 7 wks • Treatment : supportive care and appropriate antibiotics.

  15. Autoimmune neutropenia of Infancy: • Primary autoimmune neutropenia (AIN): granulocyte specific autoantibodies. • Infants : 5-15 months , F:M =6:4. • In 90% no risk of sever pyogenic infxn , even if neutropenia is severe. • 95% undergo spontaneous remission within 7-24 months. • Patients with severe infections , or surgical candidates can be treated with rhG-CSF .

  16. Reticuloendothelial Sequestration • Splenic enlargement : portal HTN ,splenic disease or hyperplasia . • Moderate neutropenia , thrombocytopenia & anemia. • Bone marrow compensation. • Treatment of the underlying cause. • Splenectomy.

  17. Replacement of the Bone Marrow: • Bone Marrow infiltration : • Malignancies: Leukemias, lymphomas,Neuroblastoma, rhabdomyosarcoma& Ewing sarcoma. • Peripheral cytopenias

  18. Ineffective Myelopoiesis: • Deficiencies: B12, Folic acid. • Starvation:Anorexia nervosa, marasmas. • Prolonged parenteral feeding.

  19. Cytotoxic Chemotherapy & Radiation Therapy: • Drop of WBC count occurs at 7-10 days , may persist for 3-7 weeks. • Pts are predisposed to serious infections.

  20. Intrensic Disorders of Proliferation and Maturation: • Cyclic Neutropenia : • Rare cytopoietic disorder (1/1000,000) • Autosomal dominant. • Regular periodic oscillations of neutrophilic count • Period 21-+4 days • Variable infxns • 10% used to develop fatal Clostridium perfringensinfxn • Cyclic hematopoiesis

  21. Cyclic Neutropenia • Dx • Obtain 3 bld counts / wk , for 2 months. • Genetic studies : mutation in elastase gene. • Rx: • RhG-CSF: cycle will change from 21 to 9 –11 days. • Fatal infxns and extensive antibiotic use have diminished.

  22. Intrensic disorders ….cont. • Severe Congenital Neutropenia : Kostmann • Arrest in maturation at the promyelocytic stage. • Sporadic disorder, occurs in early childhood. • ANC less than 200/mm3 • Pts present with variable infxns. • Gingivitis is the most frequent finding. • Mild hepatosplenomegaly is common • S areus , Streptococcus are the most frequent organisms.

  23. SCN… • Anemia , eosinophilia , monocytosis , mid plt elevation. • Bone marrow shows maturation arrest. • 10% of patients convert to MDS/ AML, associated with monosomy 7 , trisomy 21. • In 80% of MDS/AML , point mutations in G-CSF receptor gene occur. • More than 90% of patients respond to CSF, the other 10 % are candidates for stem cell transplantation.

  24. Intrensic Disorders….cont. • Severe Chronic Idiopathic Neutropenia: • Children beyond 2 yrs. • ANC below 500.recurrent pyogenic infxns( skin , mucous membranes , lungs , LN ) • Occasionally associated with disorders of immunoglobulin production. • The onset of mucous membrane involvement helps distinguish it from other entities.

  25. Intrensic Disorders …cont. • Chronic Benign Neutropenia of Childhood: • Neutropenia in an otherwise normal child. • Mild to moderate neutropenia, not associated with severe infxns. • Spontaneous remissions ? • Patients should not be subjected to prolonged corticosteroid therapy , cytotoxic drugs,or splenectomy.

  26. Netropenias Associated with Phenotypic Abnormalities • Shwachman-Diamond Syndrome • Familial Disorder, AR trait. • Chronic moderate neutropenia & pancreatic insufficiency. • Malabsorption and growth failure. • Different from CF : normal sweat chloride , no pulmonary involvement. • Occasionally anemia , thrombocytopenia., hypocellular bone marrow.

  27. Shwachman-Diamond Syndrome ..cont. • Metaphyseal Dysostosis in toddlers. • Recurrent bacterial infections. • Aplastic anemia develops in 25% of patients. • Leukemic transformation.

  28. Cartilage-Hair Hypoplasia: • AR, in Amish populations. • Dwarfism , fine hair,moderate neutropenia. • Impaired cellular immunity. • Life threatening VZV infections. • Rx: Allogenic, HLA identical BMT.

  29. Dyskeratosis Congenita: • X-linked recessive. • Nail dystrophy, leukoplakia, skin hyperpigmentation. • Marrow hypoplasia. • 1/3 have neutropenia. • No severe infections and pts survive to adulthood.

  30. Evaluation of Children With Neutropenia: • Obtain a thorough history: • Onset , frequency,severity of infxns. • Drug history for toxic exposure. • Family history of recurrent infxns, or unexplained infant death. • Physical examination: • Growth and development . • Phenotypic abnormalities. • Sites of bacterial infxns • Lymphadenopathy, hepatosplenomegaly. • Pallor, ecchymosis , petechiae. • Fever (not rectally)

  31. Evaluation of Neutropenic Patient: • Laboratory tests: • Confirm neutropenia, according to age. • Further evaluation depends on clinical setting , duration and severity of neutropenia. • CBC • Bone marrow aspirate & Bone marrow cyto genetics. • Antineutrophil antibodies • Serum folate , B12 • Antinuclear antibodies • Pancreatic enzymes, skeletal evaluation. • Immunological evaluation.

  32. Principles of Therapy for Neutropenia: • Approach varies according to type of neutropenia. • The significance of fever. • Septicemia is a major risk. • Acute septicemia is more common in the acute neutropenias .

  33. Acute Onset Neutropenia: • Management of infection: • Early recognition & treatment. • Pattern of fever & blood cultures. • Other investigations. • Withdraw ongoing chemotherapy.

  34. Management….cont. • Antibiotic regimens: • IV broad spectrum antibiotics. • Combination therapy. • Duration of treatment: • Persistence of fever , neutropenia. • Identification of pathogen. • Repeat cultures with spikes of fever.

  35. Management of Neutropenia …cont. • Acute neutropenia: • Possibility of fungal infection. • rhG-CSF • Chronic neutropenia: • Management depends on pts history. • Antibiotics. • rhG-CSF, complications ? • Corticosteroids for autoimmune neutropenia

  36. QUIZ: • In a 2-year old Caucasian child , neutropenia is defined as an absolute neutrophil count less than : • 500 • 1500 • 2500 • 3500 • 4500

  37. QUIZ: • Which one of the following is the most common cause of neutropenia in a 4-year old child: • Acute lymphoblastic leukemia • Cyclic neutropenia • Intercurrent viral infection • Kostmann syndrome • Nutritional deficiency

  38. QUIZ: • Cyclic neutropenia is characterized by regularly recurring episodes of neutropenia that last for 3-6 days. The interval between the neutropenic phases is most likely to be: • 1 week • 3 weeks • 6 weeks • 12 weeks • 16 weeks

  39. QUIZ: • A 4-year old boy has a culture positive staph skin infection.Absence of which of the following signs would be most consistent with a neutropenia ? • Erythema • Exudate • Pain • Warmth • Tenderness

  40. QUIZ: • You have diagnosed primary autoimmune neutropenia in a 9-month old girl. You are most likely to tell the parents that: • Periodic examination of the bone marrow is required . • Repeated gynogenic infection will occur throughout life. • Severe neutropenia is not an associated finding. • Spontaneous remission occurs in 95% of patients. • Treatment with rhG-CSF is recommended for any infection

  41. THANK YOU !!

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