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Neutropenia
Neutropenia is defined as an abnormally low absolute neutrophil count (ANC) below 1,500/uL. It can be caused by infection, drugs, chemotherapy, radiation, autoimmune disorders, or genetic conditions. Common symptoms include oral infections and skin infections. Treatment depends on the severity and cause of the neutropenia but may include antibiotics, growth factors, treating the underlying cause, or supportive care. Febrile neutropenia requires prompt treatment with IV antibiotics and hospitalization for high-risk patients.
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Neutropenia
- 1. Neutropenia Kaipol Takpradit
- 2. Outline • Definition • Clinicalpresentation • Etiology • Management* • Febrile neutropenia
- 3. Definition • Absolute NeutrophilCount (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. Pseudoneutropenia • Delayed examinationof drawn specimens • Paraproteinemia • Anticoagulant
- 5. the blood hasbeen 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 marginated Clinical presentation pool ( 14). P.1528 Bodey GP, Buckley M, Sathe YS, Freireich EJ. Ann Intern Med 1966;64:328
- 6. Clinical presentation •Common site of infection • Oral cavity and mucous membrane • Skin • Perianal area • Common pathogen • Endogenous bacterial floras
- 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.
- 9. Infection induce • Virus: DHF, HBV, EBV, HIV • Bacteria : gram negative, brucellosis, typhoid, tularemia • Fungus : histoplasmosis • Protozoa : malaria • Rickettsia : typhus fever
- 10. Viral induce • Manyvirus 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. Viral induce • Fewvirus can cause prolong neutropenia • HBV, EBV, HIV • Mechanism by • Direct marrow infection • Autoantibody • Can cause dangerous clinical illness
- 12. Bacterial induce • Mostcommon 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. Other agents • Similarmechanism 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.
- 15. Drug induce • Firstdescribed in 1931 with aminopyrine (Pyramidon) • Incidence 1-3/million/year • Usually under report
- 16. Mechanism of drug induce • Immune-mediated • Dose-dependent inhibition of granulopoiesis • Direct toxic to myeloid precursor or marrow microenvironment
- 17. Immune mechanism • Hapten induce antibody • aminopyrine, penicillin, PTU, antithyroid drug, gold • Circulating immune complex • Quinidine-induce neutropenia
- 18. Dose-dependent suppression • β-lactam ATB • Carbamazipine • Valproic acid
- 19. Valproic acid Concentration (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. 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. 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. Diagnosis of drug induceneutropenia • Marrow finding may not specific • Hypocellularity marrow with maturation arrest • Hypercellularity marrow with increased myeloid precursor • Diagnosis base on recognition agranulocytosis during drug
- 23. Treatment • Withdraw drugif possible • G-CSF indicate only in refractory case
- 24.
- 25. Immune induce • Similarto 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. are identified throughthe investigation of immune neutropenia. The structure of several of the specific neutrophil antigens is known. For example, the HNA1 (Human Neutrophil Antigen) Immune induce family of antigens is isoforms of the neutrophil Fc IIIB receptor, whereas HNA - 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. Immune induce • Primaryimmune 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. Clinical • ANC usuallyless than 500/µL • Marrow usually show hypercellularity with lack of mature neutrophil • Only demonstration of neutrophil antibody can help with diagnosis
- 29. Example of immune neutropenia • Neonatal Alloimmune Neutropenia • Autoimmune neutropenia • Large Granular Lymphocytosis (LGL)
- 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. 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. Large granular lymphocytosis (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. Felty syndrome • RA(severe type) • Splenomegaly • Neutropenia
- 34. Mechanism • LGL andFelty 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. Clinical • LGL andFelty 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.
- 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. Splenic sequestration • Can occur regardless of etiology of splenomegaly • Related to spleen size and marrow response • Rarely cause severe infection
- 39.
- 40.
- 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. Approach to neutropenia • Laboratory • CBC, PBS, BMA • Cytogenetic study • Antineutrophil antibody • HIV screening
- 43. Febrile neutropenia* *Chemotherapy/RT associate
- 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. Risk assessment • Highrisk • Need hospitalization and IV antibiotic • Low risk • Can be manage as outpatients in selected case
- 46. High risk • Inpatientstatus 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. Low risk • Outpatientstatus at onset • No comorbidity • Short duration of neutropenia • ECOG 0-1 • No hepatic or renal impairment
- 48. Antibiotic consideration • ESBL, MRSA, VRE risk • Site of infection • Local susceptibility pattern • Broad spectrum • Bactericidal activity • Antipseudomonal coverage
- 49. IV Monotherapy • Imipenem/cilastatin •Meropenem • PIP/Tazo • Cefepime • Ceftazidime* (Category 2A)
- 50. IV combination • Aminoglycoside+ Antipseudomonal penicillin ± betalactamase inhibitor • Aminoglycoside + extended spectrum cephalosporin (cefepime, ceftazidime) • Ciprofloxacin + Antipseudomonal penicillin
- 51. Oral therapy • Ciprofloxacin+ amoxicillin/ clavulanate or clindamycin • Should not be use if previous ciprofloxacin prophylaxis was used
- 52. Follow up • Reassessin 3-5 days • Consider antifungal if not response • Initial regimen should continue until ANC ≥ 500/µL and increasing
- 53. Therapeutic use of growth factor • Age > 65 • Prolonged (>10 days) and severe (ANC < 100/µ/L) • Sepsis syndrome • Pneumonia • Invasive fungal infection
- 54.
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