Neutropenia

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. Clinical presentation
P.1528
Recurrent infections are the hallmark of significant neutropenia, and
neutropenia in the absence of infections is not necessarily a disease
state. Common sites of infection include the oral cavity and mucous
membranes ( Fig. 61.2), with mouth ulcers, pharyngeal inflammation, and
periodontitis common. The skin is a second sentinel site of infection, with
rashes, ulcerations, abscesses, and poor wound healing. Perirectal and
genital areas are also susceptible to repeated infections. The classic signs
of local infection—especially swelling (tumor) and heat (calor)—are less
evident in neutropenic patients than in non-neutropenic patients ( 12).
With persistent, severe neutropenia, systemic infections of the lungs,
gastrointestinal tract, and bloodstream appear and may prove fatal.
Isolated neutropenia does not increase susceptibility to viral or parasitic
infections.
Endogenous bacterial floras are the most common pathogens:
Staphylococcus aureus from the skin and Gram-negative organisms from
the gastrointestinal and genitourinary systems. Other rare bacterial
pathogens, nosocomial organisms, and fungi are possible pathogens in
cases of prolonged severe neutropenia, especially in patients with
multiple antibiotic exposure, indwelling catheters, or prolonged
hospitalization. As discussed in the section General Principles of
Management of Neutropenia, initial and subsequent antibiotic choice must
take these epidemiologic features into consideration.
Differential Diagnosis
The differential diagnosis of neutropenia includes congenital and acquired,
benign and severe disorders and is outlined in Table 61.1. Neutropenia is
also a common manifestation of more global marrow defects, such as the
aplastic anemias, and acquired intrinsic marrow defects, such as leukemia
and myelodysplasia. These global hematopoietic defects are discussed in
Chapters 41 and 42. This chapter concentrates on disorders in which
neutropenia is an isolated or predominant feature.
Pseudoneutropenia
An obvious initial step in the differential diagnosis of neutropenia is to
ensure that the number of circulating neutrophils is actually low. In
today’s computerized society, many laboratories report white blood cell
differential counts generated by automated counters. In all cases in which
neutropenia is reported by automated examination, a manual differential
white blood cell count is necessary to confirm automated data. Factitious
neutropenia can occur if blood cell counts are performed a long time after
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
pool (14).
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
•Infection
•Drug and chemical
•Nutritional
•Immune neutropenia
•Felty syndrome
•Complement
activation
•Congenital
•Kostmann syndrome,
cyclic neutropenia,
neutropenia with
phenotypic anomaly,
etc.

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. Immune induce
HNA-1 FcRIIIb 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.
Adapted from Stroncek D, Bux J. Is it time to standardize
granulocyte alloantigen nomenclature? Transfusion 2002;42:393–
395.
Immune neutropenia may occur as an isolated condition involving mature
neutrophils only, as a myeloid-specific neutropenia manifested by
absence of some or all myeloid forms, or in association with other
cytopenias. Autoimmune neutropenia is also classified as primary, if
neutropenia is the sole abnormality, or secondary, if the neutropenia is a
manifestation of a broader autoimmune condition. The clinical
presentation depends on the lineage distribution of the antigen targeted
by the autoantibody ( 88,89). Recent studies suggest that in primary
autoimmune neutropenia, the neutrophil autoantibody is specific for a
single HNA isoform, whereas in secondary autoimmune neutropenia, the
antibodies react with all HNA isotypes (panantibodies) (91). Another key
determinant of the clinical course is whether the antineutrophil antibody
is of restricted or nonrestricted clonality (88). Autoantibodies produced
during the course of immune reaction to another foreign antigen by
chance cross-reactivity are polyclonal in nature and thus are composed of
mixtures of and light-chain Igs. This is the usual pattern in self-
limited neutropenias after or associated with infections or medication
exposure. In contrast, antibodies associated with the loss of suppression
of a clone of cells reacting with autoantigens are produced from a single
clone (monoclonal) and express a single light-chain type. Monoclonal
autoantibodies imply a more fundamental defect of the immune system
and predict a longer and more severe degree of neutropenia. An example
of neutropenia caused by neutrophil antibodies of restricted clonality is
that associated with Graves disease ( 92), an autoimmune disease in its
own right.
Lalezari reported the first demonstration of circulating antibodies reactive
against neutrophil-specific antigens in neutropenic patients in 1975 ( 93).
Since that initial report, the methodology available to detect antibodies
has improved markedly, allowing much of the progress in understanding
the pathophysiology and antigenic targets of immune neutropenia. In
general, antibodies can be detected directly on the neutrophil surface, or
the effect of antibody binding to the neutrophil can be determined by
indirect methods. Each method has its own strengths and weaknesses, a
discussion too complex for this text. Further, technology continues to
change and improve, and the superiority of one method today may not
persist in the future. It is important to recognize the complexity and
pitfalls of neutrophil antibody testing and invoke the help of expert
laboratories when evaluating specific patients ( 94).
Immune-mediated neutropenia is clinically similar to other forms of
acquired neutropenia. The ANC is usually <500 cells/mm
3
. Bone marrow
examination reveals variable results dependent on the lineage specificity
of the antibody. In general, however, the bone marrow is hypercellular or
normocellular and lacking in mature neutrophils (95). Only the finding of
antineutrophil antibodies distinguishes cases of immune-mediated
disease. Antineutrophil antibodies are involved in the pathophysiology of
neutropenias occurring in several settings, including infection, drug
exposure, and immune deficiencies. Each of these clinical presentations is
discussed elsewhere. In addition, three distinct disorders in which the
neutropenia is caused specifically by characteristic immune mechanisms
P.1531
Calcium dobesilate 77.84 4.50–1,346.20
Antithyroid drugs 52.75 5.82–478.03
Dipyrone 25.76 8.39–79.12
Spironolactone 19.97 2.27–175.89
Carbazepine 10.96 1.17–102.64
Sulfonamides 8.04 2.09–30.99
-Lactam antibiotics 4.71 1.74–12.77
Adapted from Ibanez L, Vidal X, Ballarin E, Laporte JR. Population
based drug induced agranulocytosis. Arch Intern Med
2005;165:869–874.
Nutritional Causes of Neutropenia
Severe, generalized nutritional deficiencies occurring in the setting of
starvation, anorexia nervosa, marasmus, or cachexia may produce
pancytopenia or selective hematologic defects including neutropenia
(79,80,81,82). The pathogenesis is usually impaired blood cell production
caused by lack of protein building blocks. Megaloblastic pancytopenia
results from deficiencies of vitamin B 12 or folic acid. Lack of these
essential cofactors interferes with nucleic acid synthesis of myeloid
precursors in the bone marrow and results in ineffective granulopoiesis
(83). One morphologic hallmark of megaloblastic granulopoiesis is
hypersegmented polymorphonuclear leukocytes, with a lobe count of
>5/cell common. The administration of folic acid antagonists
(trimethoprim-sulfamethoxazole, methotrexate) may mimic nutritional
deficiencies. Copper deficiency is also reported to cause neutropenia
(84), although the mechanism remains incompletely defined ( 85).
Secondary copper deficiency and resulting cytopenias is also reported
with excess zinc supplementation ( 86).
Immune Causes of Neutropenia
Neutropenia may result from the presence of specific antineutrophil
antibodies that mediate destruction either by splenic sequestration of
opsonized cells or by complement-mediated neutrophil lysis. Immune-
mediated neutropenia is analogous to similar disorders of the platelet
(immune thrombocytopenic purpura; see Chapter 51) and the red blood
cells (immune hemolytic anemia; see Chapter 33). Selective immune-
mediated neutropenia results from the presence and expression of unique
neutrophil-specific antigens not shared with other hematopoietic cells.
The most common and best characterized neutrophil-specific antigens are
shown in Table 61.4 (87). Neutrophils also express HLA antigens and
several erythrocyte antigens, including the Kx antigen of the McLeod
system (88). Each of these antigenic determinants is associated with
cases of immune neutropenia; in fact, most neutrophil-specific antigens
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)
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).
Table 61.4 Human Neutrophil-Specific Antigens
Antigen Protein
Frequency (%)
a

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?