1. Neutropenia
Kaipol Takpradit

2. Outline
• Definition
• Clinical presentation
• Etiology
• Management*
• Febrile neutropenia

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. Pseudoneutropenia
• Delayed examination of drawn specimens
• Paraproteinemia
• Anticoagulant

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 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. Infection induce

9. Infection induce
• Virus : DHF, HBV, EBV, HIV
• Bacteria : gram negative,
brucellosis, typhoid, tularemia
• Fungus : histoplasmosis
• Protozoa : malaria
• Rickettsia : typhus fever

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. Viral induce
• Few virus can cause prolong
neutropenia
• HBV, EBV, HIV
• Mechanism by
• Direct marrow infection
• Autoantibody
• Can cause dangerous clinical illness

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. 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. Drug induce

15. Drug induce
• First described 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
induce 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. Treatment
• Withdraw drug if possible
• G-CSF indicate only in refractory
case

24. Immune induce

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. are identified through the 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
• 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. 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. 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 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. 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. Other causes

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. Congenital
neutropenia

40. Approach to
neutropenia

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
• High risk
• Need hospitalization and IV
antibiotic
• Low risk
• Can be manage as outpatients in
selected case

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. Low risk
• Outpatient status 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
• Reassess in 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. Question?