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  1. 1. Neutropenia Kaipol Takpradit
  2. 2. Outline• Definition• Clinical presentation• Etiology• Management* • Febrile neutropenia
  3. 3. Definition• Absolute Neutrophil Count (ANC) less than 1,500/uL • Grading • Grade 1 : 1,500/uL - lower limit of normal • Grade 2 : 1,000/uL - <1,500/uL (mild) • Grade 3 : 500/uL - <1,000/uL (moderate) • Grade 4 : < 500/uL (severe) Common Terminology Criteria for Adverse Events v4.0 (CTCAE). NIH 2009v4.03(113)
  4. 4. Pseudoneutropenia• Delayed examination of drawn specimens• Paraproteinemia• Anticoagulant
  5. 5. the blood has been drawn. The presence of paraproteinemia or the use of certain anticoagulants can likewise result in neutrophil clumping and spuriously low neutrophil counts ( 13). A final cause of pseudoneutropenia is the asymmetric distribution of circulating neutrophils to the marginatedClinical presentation pool ( 14). P.1528 Bodey GP, Buckley M, Sathe YS, Freireich EJ. Ann Intern Med 1966;64:328
  6. 6. Clinical presentation • Common site of infection • Oral cavity and mucous membrane • Skin • Perianal area • Common pathogen • Endogenous bacterial floras
  7. 7. Cause of neutropenia• Acquired • Congenital • Infection • Kostmann syndrome, cyclic neutropenia, • Drug and chemical neutropenia with phenotypic anomaly, • Nutritional etc. • Immune neutropenia • Felty syndrome • Complement activation
  8. 8. Infection induce
  9. 9. Infection induce• Virus : DHF, HBV, EBV, HIV• Bacteria : gram negative, brucellosis, typhoid, tularemia• Fungus : histoplasmosis• Protozoa : malaria• Rickettsia : typhus fever
  10. 10. Viral induce• Many virus can cause neutropenia • Redistribution to marginal pool • Aggregating and sequestration after complement activation • Destruction by antibody• Onset on peak of viremia and last 3-7 days• Rarely clinical significant
  11. 11. Viral induce• Few virus can cause prolong neutropenia • HBV, EBV, HIV• Mechanism by • Direct marrow infection • Autoantibody• Can cause dangerous clinical illness
  12. 12. Bacterial induce• Most common by gram negative endotoxin• Spacial population • Neonate, undernourish, alcoholic, post chemo/RT,• Most case experience short episode• Rare case with progressive neutropenia and overwhelming neutropenia may benefit from G-CSF
  13. 13. Other agents• Similar mechanism with viral induce neutropenia• Produce toxin that destroy and suppress neutrophil production• Infection-mediated decrease myeloid growth factor• Migration of neutrophil to site of infection• Neutrophil destruction via complement activation
  14. 14. Drug induce
  15. 15. Drug induce• First described in 1931 with aminopyrine (Pyramidon)• Incidence 1-3/million/year• Usually under report
  16. 16. Mechanism of drug induce• Immune-mediated• Dose-dependent inhibition of granulopoiesis• Direct toxic to myeloid precursor or marrow microenvironment
  17. 17. Immune mechanism• Hapten induce antibody • aminopyrine, penicillin, PTU, antithyroid drug, gold• Circulating immune complex • Quinidine-induce neutropenia
  18. 18. Dose-dependent suppression• β-lactam ATB• Carbamazipine• Valproic acid
  19. 19. Valproic acidConcentration (µg/ml) CFU-GM inhibition(%) 60 26 ± 4 120 67 ± 15 240 84 ± 27 Watts RG, Emanuel PD, Zuckerman KS, Howard TH. J Pediatr 1990;117:495–499.
  20. 20. Direct marrow damage• Genetic predispose • Slow acetylator and sulfasalazine• Captopril-induce agranulocytosis in renal insufficiency• Cumulative dose of phenothiazine (onset after 3-4 weeks)
  21. 21. Time onset of drug induce• Depend on mechanism • 1-2 days for immune mechanism • Weeks for myelosuppression mechanism• Very vary duration • mean 12 days (3-56 days)
  22. 22. Diagnosis of druginduce neutropenia• Marrow finding may not specific • Hypocellularity marrow with maturation arrest • Hypercellularity marrow with increased myeloid precursor• Diagnosis base on recognition agranulocytosis during drug
  23. 23. Treatment• Withdraw drug if possible• G-CSF indicate only in refractory case
  24. 24. Immune induce
  25. 25. Immune induce• Similar to AIHA and ITP• Cause by neutrophil-specific antibody (antibody to HNA)• HLA and some red cell antigen also express on neutrophil• Most HNA are known molecule• Can occur with or without other cytopenia
  26. 26. are identified through the investigation of immune neutropenia. Thestructure of several of the specific neutrophil antigens is known. Forexample, the HNA1 (Human Neutrophil Antigen) Immune inducefamily of antigens is isoforms of the neutrophil Fc IIIB receptor, whereasHNA - 4 and HNA - 5 are the CD11b and CD11a antigens, respectively ( 87). P.1531 Table 61.4 Human Neutrophil -Specific Antigens Antigen Protein Frequency (%) a HNA - 1 Fc RIIIb 58% HNA - 2 CD 117 97% HNA - 3 70–95 kDa 97% HNA - 4 CD 11b 99% HNA - 5 CD 11a 96% a Frequency represents phenotype in Caucasian population group.
  27. 27. Immune induce• Primary immune or secondary from broader autoimmune• Immune specific to single HNA suggesting primary and clonality disease• Panantibody suggesting secondary causes• Grave disease can associated with clonal antibody
  28. 28. Clinical• ANC usually less than 500/µL• Marrow usually show hypercellularity with lack of mature neutrophil• Only demonstration of neutrophil antibody can help with diagnosis
  29. 29. Example of immune neutropenia• Neonatal Alloimmune Neutropenia• Autoimmune neutropenia• Large Granular Lymphocytosis (LGL)
  30. 30. Autoimmune neutropenia• May be transient or prolong course• Associated with several condition • Wegener granulomatosis, RA, SLE, chronic hepatitis, systemic infection, malignancy• In adult usually take prolong but benign clinical course• Skin and lower respiratory tract are most common site
  31. 31. Autoimmune neutropenia• Secondary autoimmune usually have worse prognosis, depend on associated autoimmune disease• Primary isolated immune neutropenia rarely need treatment others than supportive• There is uncertain benefit of G- CSF
  32. 32. Large granularlymphocytosis (LGL) • Autoimmune neutropenia associated with marrow infiltration of large granular lymphocyte • Clonal disorder: leukemia of large granular lymphocyte • CD3, CD8, CD16 and CD57 positive with clonal T-cell receptor rearrangement • Associate with RA or other autoimmune disease
  33. 33. Felty syndrome• RA (severe type)• Splenomegaly• Neutropenia
  34. 34. Mechanism• LGL and Felty syndrome have shared the same mechanism • Antineutrophil antibody • Immune complex cause neutrophil adherence to vessel and sequestration in marginating pool • FAS mediate apoptosis • Other mechanism (impaired myelopoiesis, destruction by spleen)
  35. 35. Clinical• LGL and Felty syndrome increase risk of infection• Growth factor can be use as supportive along with specific treatment• First line drugs include MTX or cyclosporine• Cyclophophamide with prednisilone can be used in refractory case• Splenectomy is now rarely indicated
  36. 36. Other causes
  37. 37. Complement activation• Complement induce neutrophil aggregate and adherence to endothelial surface (often in lungs) resulting in cardiopulmonary syndrome• C3a or C5a• Exposure to artificial membrane • hemodialysis, cardiopulmonary bypass, apheresis, ECMO• Onset as soon as after blood expose to membranes
  38. 38. Splenic sequestration• Can occur regardless of etiology of splenomegaly• Related to spleen size and marrow response• Rarely cause severe infection
  39. 39. Congenitalneutropenia
  40. 40. Approach toneutropenia
  41. 41. Approach to neutropenia• History • Infection type, frequency, severity, duration, age of onset. • Medication• Physical exam • Site of infection • Lymph node and spleen • Sign of other cytopenia and other disease
  42. 42. Approach to neutropenia• Laboratory • CBC, PBS, BMA • Cytogenetic study • Antineutrophil antibody • HIV screening
  43. 43. Febrileneutropenia* *Chemotherapy/RT associate
  44. 44. Febrile neutropenia• ANC < 500/µL or < 1,000/µL and decreasing to < 500/µL in next 48hr• Fever 38.3°c or 38.0°c over 1 hr (orally)
  45. 45. Risk assessment• High risk • Need hospitalization and IV antibiotic• Low risk • Can be manage as outpatients in selected case
  46. 46. High risk• Inpatient status at onset• Unstable or significant medical comorbidity• Severe ANC ≤ 100/µL and prolonged ≥ 7 days• Hepatic impaired (transaminitis > 5 times ULN)• Renal insufficiency (CreClr < 30 ml/min• Pneumonia or grade 3-4 mucositis or complex infection
  47. 47. Low risk• Outpatient status at onset• No comorbidity• Short duration of neutropenia• ECOG 0-1• No hepatic or renal impairment
  48. 48. Antibiotic consideration• ESBL, MRSA, VRE risk• Site of infection• Local susceptibility pattern• Broad spectrum• Bactericidal activity• Antipseudomonal coverage
  49. 49. IV Monotherapy• Imipenem/cilastatin• Meropenem• PIP/Tazo• Cefepime• Ceftazidime* (Category 2A)
  50. 50. IV combination• Aminoglycoside + Antipseudomonal penicillin ± betalactamase inhibitor• Aminoglycoside + extended spectrum cephalosporin (cefepime, ceftazidime)• Ciprofloxacin + Antipseudomonal penicillin
  51. 51. Oral therapy• Ciprofloxacin + amoxicillin/ clavulanate or clindamycin• Should not be use if previous ciprofloxacin prophylaxis was used
  52. 52. Follow up• Reassess in 3-5 days• Consider antifungal if not response• Initial regimen should continue until ANC ≥ 500/µL and increasing
  53. 53. Therapeutic use of growth factor• Age > 65• Prolonged (>10 days) and severe (ANC < 100/µ/L)• Sepsis syndrome• Pneumonia• Invasive fungal infection
  54. 54. Question?