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Neutropenia

Neutropenia. Definition:. 2 weeks to 1 year : Less than 1,000/ L Over 1 year : Less than 1,500/ L It is variable with race , age and other factors. Epidemiology of Neutropenia :. Ethnic groups (African and Arabs) 10% Premature and SGA(6%) specially pre-eclampsia

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Neutropenia

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  1. Neutropenia

  2. Definition: • 2 weeks to 1 year: Less than 1,000/L • Over 1 year: Less than 1,500/L • It is variable with race , age and other factors

  3. Epidemiology of Neutropenia: • Ethnic groups (African and Arabs) 10% • Premature and SGA(6%) specially pre-eclampsia • Septic Newborns and Infants • Post infection • Congenital neutropenia ( 2/1,000,000)

  4. Classification of Neutropenia:(Etiology) • Autoimmune(21%) • Chronic idiopathic(27%) • Drug induced(4%) • Post infection(28%) • Ethnic(13%) • Congenital(7%)

  5. Classification of Neutropenia:(Etiology) • Congenital • 1)Maturation arrest at promyelocyte/myelocyte level presenting in infancy • 2)Identified mutation in genes known to cause neutropenia

  6. Classification of Neutropenia:(Etiology) • Autoimmune • 1)Prescence of anti-neutrophil antibodies • 2)Granulocyte immunofloscence test • 3)Granulocyte agglunitation test • 4)Monoblonal antibody-specific immobilization of granulocyte antigens

  7. Classification of Neutropenia:(Etiology) • Congenital • Pro-LL-37 level is predictive of congenital severe neutropenia

  8. Classification of Neutropenia:(Etiology) • Post infection • 1)Influenza like viruses • 2)Common colds

  9. Classification of Neutropenia:(Neutrophil Count) • Mild Neutropenia: Neutrophils 1,000 to 1,500/L • Moderate Neutropenia: Neutrophils 500 to 1,000/L • Severe Neutropenia: Neutrophils Less than 500/L

  10. Severe Neutropenia: • Risk of pyogenic infection;Particularly if neutropenia persist • Endogenous bacteria are the most frequent invaders • Monocyte provide only marginal protection against pyogenic infection • Cutaneous abscesses , furunculous, pneumonia ,septicemia

  11. Severe Neutropenia(continue): • Cutaneous abscesses , furunculous, pneumonia ,septicemia • Stomatitis,gingivitis periodontitis,perirectal inflammation,Otitis media • S.aureus,gram-negative bacteria are the most common isolated organism

  12. Classification of Neutropenia:(Etiology) • 1)Neutropenia caused by intrinsic defects in Myeloid cells or their progenitor • 2) Neutropenia caused by Extrinsic Factors

  13. Intrinsic defects in Myeloid cells or their progenitor • Reticular Dysgenesis • Severe congenital neutropenia(Kostmann’s Dis.) • Cyclic Neutropenia • Myelokathexis • Schwachman’s Syndrome • Dyskeratosis Congenita • Familial benign neutropenia • Bone marrow failure syndromes

  14. Neutropenia caused by Extrinsic Factors • Infection • Drug induced • Autoimmune neutropenia • Immune neonatal neutropenia • Neutropenia associated with immune dysfunction • Neutropenia associated with metabolic diseases • Nutritional deficiencies • Reticuloendothelial sequestration • Bone marrow infiltration • Chronic idiopathic neutropenia

  15. Reticular Dysgenesis: • Selective failure of stem cells committed to myeloid & lymphoid • Severe neutropenia and moderate to severe lymphopenia • Agammaglobulinemia • Inherited disorder • BMT is the choice treatment

  16. Severe Congenital Neutropenia (Kostmann’s Dis.): • Autosomal recessive • Typically appear from first month of life • Monocytosis and moderate eosinophilia • Fever,skin infection, abscess,stomatitis • BMA: normal till promyelocytes and myelocytes and depletion of mature cells • G-CSF treatment and BMT

  17. Cyclic Neutropenia: • Regular periodic oscillations approximately every 21 days in peripheral blood neutrophils • In most cases,retculocytes ,platelets and other leukocytes also cycle. • Malaise,fever,oral ulcers,gingivitis and periodontitis,and pharyngitis associated with lymph node enlargement.

  18. Cyclic Neutropenia(cont): • Pneumonias and peritonitis sepsis (Clostridium perfringens) are the most common cause of death. • Monocytosis and eosinophilia occur when neutrophil counts are at their lowest. • To establish the diagnosis of cyclic neutropenia , neutrophil counts must be monitored at least two times a week for 6 to 8 weeks. • Treatment: BMT & G-CSF

  19. Myelokathexis • Uncommon form of moderate to severe neutropenia. • Bizarre morphologic disturbances of PMN nucleus. • Neutrophil motility is abnormal. • One patient, has been successfully with G-CSF.

  20. Schachman’s Syndrome: • Autosomal Recessive Trait • Metaphyseal Chondrodysplasia,dwarfism, Pancreatic exocrine insufficiency , Neutropenia • Almost all infants develop malabsorption by 4 months of age • There is no reciprocal Monocytosis. • Treatment: Pancreatic replacement + G-CSF

  21. INFECTION: • The most common cause of transient neutropenia is Viral Infection . • Neutropenia develops during the first 24 to 48 hours of illness and may persist for 3-6 days.

  22. INFECTION(Continue): • Hepatitis A &B • RSV • Influenza A & B • Measles • Rubella • Varicella • HIV(Leukopenia) • Sepsis(specially in newborns)

  23. Drug Induced Neutropenia: • Disorder characterized by severe and selective reduction in the levels of circulating blood neutrophils and is due to an idiosyncratic reaction to offending drug • Mortality rate is reported as 32 percent in one series.

  24. Drug Induced Neutropenia(Continue): • Antimicrobial Drugs:Penicillins,Sulfonamides • Anti-thyroid Drugs • Phenothiazines • Antipyretics:phenylbutazone,aspirin,acetaminophen • Anti-rheumatics:gold,levamisole,penicillamine • Sedatives:Benzodiazepines,Barbiturates

  25. Drug Induced Neutropenia(Cont): • Duration of drug induced neutropenia is highly variable • Acute idiosyncratic:only few days • Chronic idiosyncratic:months to years • Immune-mediated: 6-8 Days

  26. Evaluation of the Patient with Neutropenia: • History & Physical Examinations: • 1)Related phenotypic abnormality • 2)Determination of bacterial infection • 3)Evaluation of organomegaly • 4)History of recent infection or drug exposure

  27. Evaluation of the Patient with Neutropenia(continue): • If the patient has isolated neutropenia and is asymptomatic and if other findings are absent; Clinical observation for several weeks is usually the best approach.

  28. Evaluation of the Patient with Neutropenia(Lab Test): • Persistent Neutropenia:CBC twice weekly for 6-8 weeks • Coomb’s Test & Serum Immunoglobulins • T-cell Assay & HIV • BMA & BMB in selected patients (anemia,macrocytosis,thrombocytosis)

  29. Evaluation of the Patient with Neutropenia(Lab test-continue): • Anti-neutrophilic anti-body • ANA,Complement(for Collagen Vascular Dis. • Metabolic and exocrine pancreatic disease • CXR and Long Bone survey • Vitamin B12,Folate and Copper levels

  30. Neutropenia in premature infants Natural course Sepsis Eclampsia Recover till 7 days Administration of G-CSF & IVIG controversial

  31. Neutropenia in full-term infants Immune-mediated disorders Alloimmune, Isoimmune Autoimmune neutropenia (AIN).

  32. Neonatal alloimmuneneutropenia The consequences may be quite severe, including severe omphalitis, cellulitis, acteraemia and meningitis. Diagnosis: Knowing possibility testing maternal serum for anti-neutrophil antibodies to the antigens HNA1a, HNA-1b and HNA 1c and others that may be present on the infant and the infant’s father

  33. Neonatal iso-immune neutropenia Iso-immune neutropenia is caused by transplacental transfer of pre-existing IgG antibodies from mothers with AIN or who are FccRcRIIIb deficient Diagnosis: mother neutropenia

  34. Autoimmune neutropenia AIN overlaps with alloimmune and iso-immune neutropenia because the neutrophil-specific antigens are often the same (i.e., HNA1a, HNA-1b and HNA 1c), but in AIN there are no neutrophil-specific antibodies in the maternal serum.

  35. Autoimmune neutropenia Primary AIN usually occurs in the first 2 years of life, with a very high spontaneous remission rate, perhaps greater than 90%. There are similar cases with and without neutrophil-specific autoantibodies.

  36. Congenital causes for childhood neutropenia Congenital or hereditary neutropenia usually presents in the first year of life as recurrent fever attributable to a common typ more severe and recurrent infections. the severe oral manifestations associated with the congenital disorders

  37. ELANE mutation: Mutations in ELANE, the gene for neutrophil elastase, are the most common cause for cyclic and severe congenital neutropenia (SCN), both primarily autosomal dominant diseases ELANE is only expressed in myeloid tissues, and therefore mutations only affect neutrophils and monocytes.

  38. Severe congenital neutropenia SCN usually presents within the first year of life as fever and infections that do not resolve or resolve only very slowly congenital anomalies and functional abnormalities in other systems are rare in patients with ELANE-associated neutropenia.

  39. Severe congenital neutropenia The diagnosis of SCN is usually based on a series of ANCs showing very severe neutropenia and a bone marrow aspirate showing maturation arrest Genetic sequencing (selective, single gene, gene panels or exome sequencing) is helpful for diagnosis and prognosis.

  40. Severe congenital neutropenia In patients with mutations in ELANE, there is now sufficient genotype-phenotype information available to identify mutations which are more likely to be associated with poor response to G-CSF, risk of death from infections and a high risk of developing myelodysplasia (MDS) and acute myeloid leukaemia (AML)

  41. Cyclic neutropenia Cyclic neutropenia (CyN) is a rare disorder characterized by oscillating levels of blood neutrophils and monocytes, usually at 21-day intervals ELANE-associated cyclic neutropenia (ELANE-CyN). G-CSF, usually 1–3 lg/kg/day given daily or every other day, is warranted

  42. HAX1-neutropenia Kostmann syndrome, autosomal recessive SCN, is now attributable to mutations in HAX1, HCLS1 Associated Protein X-1, a protein associated with Lyn substrate 1 and with the F-actin-binding protein, cortactin. ‘maturation arrest’ at the promyelocyte stage of neutrophil development, very similar to those seen in patients with mutations in ELANE.

  43. G6PC3-neutropenia This is a rare autosomal recessive condition attributable to mutations in the glucose 6 phosphatase catalytic subunit 3 gene. less severe marrow changes, less severe neutropenia and a variety of other haematological, cardiac and urogenital anomalies have now been described

  44. Glycogen storage disease 1b SLC37A4 (G6PT1)-neutropenia rare hereditary disorder recurrent and severe hypoglycaemia, hepatomegaly, enterocolitis, neutropenia and recurrent infections.

  45. Barth syndrome TAZ-neutropenia X-linked disease Phospholipid metabolism ( mitochondrial membranes) Childhood cardiomyopathy, proximal myopathy, delayed motor development, growth delay and neutropenia, chronic and recurrent infections.

  46. Barth syndrome TAZ-neutropenia The diagnosis is suggested by a five-fold or greater increase in urinary 3-methylglutaconic acid increased monolysocardiolipin:cardiolipin ratio DNA sequencing showing a disease-associated variant of TAZ

  47. Shwachman-Diamond syndrome SBDS neutropenia an autosomal recessive disorder attributable to mutations in the SBDS gene Failure to thrive with steatorrhoea Skeletal abnormalities Bacterial infections very early in life MDS and AML are well known complications.

  48. Shwachman-Diamond syndrome SBDS neutropenia(Diagnosis) evidence of exocrine pancreatic insufficiency, skeletal abnormalities, Neutropenia, Findings of typical mutations in the SBDS gene are diagnostic, but there are patients with typical findings of SDS who lack mutations in SBDS

  49. Wiskott-Aldrich syndrome WASneutropenia Rare X-linked primary immunodeficiency disease small platelets, Eczema, Recurrent infections, Autoimmunity Predilection to malignancies

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