Page 791 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 48 Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia 677

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mm ; granulocytes: 9000/mm to 62,000/mm ), unusual bleeding, and no obvious other underlying disorder, this can be assumed to be
thickened calvariae, and hepatosplenomegaly. They had no increase the cause.
in infections. The LAP score was high, BM revealed few Gaucher-like
histiocytes, karyotype was normal by routine G-banding, but chro-
matid breaks and gaps were increased. In 2009, French investigators NEUTROPENIA (AND AGRANULOCYTOSIS)
identified a mutation in the CSF3R gene in a kindred with hereditary
chronic neutrophilia. The point mutation led to constitutive activa- The risk of neutropenia-related infection begins to rise at an ANC
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tion of the G-CSF receptor, driving neutrophil proliferation and near 1000/mm , rising dramatically below 500/mm and more so
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differentiation. One of 12 affected individuals in this kindred devel- below 100/mm ; thus, an ANC of 500/mm to 1000/mm is consid-
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oped overt myelodysplastic syndrome (MDS). The frequency of this ered moderate neutropenia, and below 500/mm is considered severe.
and other mutations are unknown with hereditary neutrophilias. This corresponds to National Cancer Institute criteria for medication
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adverse hematologic event reporting: grade 1 toxicity is 1500/mm
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to lower limit of normal, grade 2 is 1000/mm –1500/mm , grade 3
Smoking is 500/mm to 1000/mm , and grade 4 is less than 500/mm . Beyond
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the ANC, the risk for infection is greatly influenced by the nature of
Smoking has been well associated with mild neutrophilia in epide- the underlying problem, the BM myeloid reserve, and whether other
miologic and animal studies. Perry et al found a 27% higher WBC risk factors for infection are present (e.g., immunoglobulin deficiency
count in smokers. Sunyer et al correlated the degree of leukocytosis or breaks in mucosal barriers). The course with mild and moderate
and percentage of neutrophils with the number of cigarettes smoked. neutropenia is often benign.
The effect can persist up to 5 years in those who stop smoking. A The history focuses on the severity and duration of neutropenia,
suggested mechanism is chronic inflammation because inflammatory whether infectious complications have occurred (including severe
markers, including C-reactive protein (CRP) and fibrinogen, are stomatitis or gingivitis), and whether prior blood counts can be
elevated. In a rodent model, cigarette smoke caused overexpression obtained. A history of drug exposures and their timing is especially
of hematopoietic growth factor genes IL-6, G-CSF, and GM-CSF. relevant, not only for prescribed medications but also for over-the-
Thus, mild neutrophilia without other symptoms in a smoker could counter, herbal, and illicit drugs. Symptoms of systemic inflammatory
be attributed to this practice without further evaluation. illness, such as arthritis, skin rash, and photosensitivity, can bear on
the etiology and significance of the low WBC count. Fevers, weight
loss, and sweats could be clues to many disorders, including malig-
Drugs nancy. Liver disorders commonly present with cytopenias, so a history
of hepatitis, jaundice, and HIV risk factors should be specifically
Systemic glucocorticoids cause neutrophilia mainly by interfering sought. Symptoms of anemia or bleeding could be clues to more
with neutrophil adhesion to the capillary wall and decreasing neutro- general hematologic disorders. As with most hematologic problems,
phil turnover rate. Maximal neutrophil counts occur 4–6 hours after physical examination should devote extra attention to lymph node
dexamethasone use in normal volunteers. G-CSF increases circulating areas and the spleen. Oropharynx and skin examination also take on
neutrophils by increasing BM production and mobilization. Epi- added importance.
nephrine increases proinflammatory cytokines and demargination. Peripheral blood smear review is irreplaceable to direct the
Suggested mechanisms for lithium-induced neutrophilia are induc- workup. MDS does not characteristically present with isolated neu-
tion of G-CSF and downregulation of CXC-chemokine receptor 4, tropenia, but this occasionally is the predominant presenting feature
thus facilitating egress from the BM. in this relatively common syndrome affecting older patients. Specific
blood smear findings which could suggest MDS include pseudo-
Pelger–Huet neutrophils, hypogranularity, Dohle bodies, and macro-
Malignancy cytic and/or dimorphic RBCs with a hypochromic population.
Megaloblastic processes, such as vitamin B 12 and folic acid deficiency,
Leukocytosis is frequently associated with solid tumors without direct similarly do not characteristically present with isolated neutropenia,
BM involvement. Some malignant tumors have been reported to but this occasionally predominates (especially in the presence of acute
produce G-CSF or GM-CSF, occasionally producing leukocytosis in infection). Hypersegmentation of neutrophils is always present with
the range of a leukemoid reaction. megaloblastic processes, including those that are drug-induced (e.g.,
methotrexate, hydroxyurea). Hypersegmented neutrophils are also
seen with uremia, as an autosomal dominant benign polymorphism,
Asplenia and in MDS and MPN. In a neutropenic patient, one should always
specifically look for large granular lymphocytes (LGLs). A modest
Whereas neutrophilia is classically observed early after splenectomy, increase could indicate a reactive T-cell natural killer (NK) cell
lymphocytosis predominates in the long run. Nevertheless, chronic process, and a more dramatic increase could alert to clonal T-NK or
mild neutrophilia can also be seen in functionally asplenic individu- NK cell proliferations (LGL leukemia). Hairy cells, other morpho-
als. Furthermore, there may be an exaggerated neutrophil response logic types of circulating lymphoma cells, and blasts are obvious
to infections or other stresses. On the blood smear, Howell–Jolly indicators of hematologic malignancy. Morphologic suspicions for
bodies are a very sensitive and specific (when numerous) sign of such processes could be confirmed by flow cytometry. Reactive
functional asplenia. lymphocytes may suggest viral infection but also occur with drug
reactions and other processes.
Further laboratory testing in patients with neutropenia may often
Obesity be unnecessary. Especially in mild or moderate cases, the lack of
specific diagnostic tests has created some overlap and confusion
Chronic mild neutrophilia has been observed with obesity. Fat tissue among what have been called chronic idiopathic neutropenia, chronic
can release inflammatory cytokines, creating a state of low-grade benign neutropenia, ethnic neutropenia, and autoimmune neutropenia.
inflammation manifest by elevated CRP. Leptin, a hormone released Autoimmune neutropenia is a relatively common cause of both mild
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by adipocytes, may act on CD34 cells to promote neutrophil dif- and more severe neutropenia, but tests for antineutrophil antibodies
ferentiation. More recently, chronically inflamed visceral adipose are not clinically validated (see later). Serologic tests for antinuclear
tissue in obesity was found to simulate BM hematopoietic progenitor antibodies and rheumatoid factor can be helpful when autoimmune
cells to proliferate and expand, causing both neutrophilia and mono- neutropenia is considered, as positive results may raise suspicion for
cytosis via IL-1β. In an obese patient with chronic mild neutrophilia an undiagnosed collagen vascular disorder or may just support a less