Page 790 - Hematology_ Basic Principles and Practice ( PDFDrive )

676 Part VI Non-Malignant Leukocytes

TABLE Causes of Neutrophilia or BCR–ABL1 fusion product by fluorescence in situ hybridization
48.1 or reverse-transcriptase polymerase chain reaction. When other
MPNs are judged reasonably possible, JAK2 V617F mutational status
1. Hematologic malignancy (CML, CNL, CMML) may be informative. In cases with very high suspicion for MPNs but
2. Infection negative JAK2 V617F mutation, JAK2 exon 12, MPL, and CALR
3. Inflammation, physiologic stress, hemorrhage, hemolysis mutations can be assessed in a serial manner.
4. Hereditary or congenital neutrophilias
5. Smoking
6. Drugs: colony-stimulating factors, glucocorticoids, epinephrine, Infection
lithium
7. Nonhematologic malignancy To protect against the ever-present threats to health and longevity,
8. Asplenia evolution has armed us with reactant cytokine cascades designed to
9. Obesity increase the number of phagocytes and dispatch them to threatened
10. Recovery from neutropenia locales. Neutrophilia is classically seen as a response to bacterial
CML, Chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; infection, responding to such cytokines as IL-6, tumor necrosis factor
CNL, Chronic neutrophilic leukemia. (TNF), and G-CSF. Neutrophilia is also a frequent response to other
types of infections, such as fungal, parasitic, mycobacterial, and
sometimes viral.
Changes in neutrophil morphology may be useful in predicting
Leukemoid Reaction Versus Chronic Leukemia whether bacterial or other infection underlie a neutrophilic response.
The authors have confirmed some published reports that prominent
A relatively common reason for hematologic consultation is for very neutrophil vacuolization is highly specific and moderately sensitive
high WBC count. CML is reviewed elsewhere in this text, as are for serious bacterial infection, as are prominent Dohle bodies (in the
chronic myelomonocytic leukemia (CMML) and the very rare chronic absence of a primary hematologic disorder). The authors blindly
neutrophilic leukemia. Marked neutrophilic leukocytosis or overt leu- scored blood smears from 50 patients with serious bacterial infection
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kemoid reaction (WBC count >50,000/mm ) can represent an overly (half bacteremic), 25 with influenza, 25 with noninfectious fever, and
exuberant reaction to any stimulus associated with neutrophilia. In 25 control smears. Toxic granulation of neutrophils, touted as a sign
patients with leukemoid reaction, a disproportionate number have of bacterial infection, was found useless in distinguishing infections
infection with Clostridium difficile, an organism that elicits a vigor- from other febrile illnesses.
ous neutrophil response. Leukemoid reactions may be associated
with solid tumors, sometimes due to paraneoplastic production of
colony-stimulating factor (e.g., granulocyte colony-stimulating factor Inflammation and Stress
(G-CSF) or granulocyte-macrophage colony-stimulating factor [GM-
CSF]) or other cytokines (e.g., interleukin [IL]-6 or IL-17), or to Acute or chronic inflammation can cause neutrophilia by mechanisms
particularly aggressive tumors with necrotic areas. The course of similar to infection, mediated by the proinflammatory cytokines
neutrophilia usually correlates with the course of solid cancer. It is G-CSF, GM-CSF, TNF, IL-1, IL-6, IL-8, and others. Diseases such
important to quickly differentiate a reactive neutrophilic leukocytosis as rheumatoid arthritis (RA), vasculitis, inflammatory bowel disease,
from a clonal leukemic proliferation. thyrotoxicosis, eclampsia, and many others are commonly accompa-
The history and clinical context are usually quite different between nied by neutrophilia. Another rare but notable example is familial
leukemoid reaction and CML. Most patients with leukemoid reac- Mediterranean fever, in which an inherited MEFV mutation leads to
tion are encountered very ill in the hospital with obvious underlying dysfunctional pyrin downregulation of neutrophil activation, leading
illnesses (e.g., sepsis, organ rejection). Prior WBC counts, which are to chronic inflammatory serositis and secondary AA amyloidosis.
often available, demonstrate normal WBC counts until the recent Physiologic stresses, including exercise and emotional stress, lead
onset of acute illness. This contrasts with CML, typically presenting to endogenous catecholamine and glucocorticoid release in addition
in outpatients with hypermetabolism (weight loss, sweats, low-grade to inflammatory cytokines. This causes a rapid doubling of circulat-
fever), symptoms referable to splenomegaly, or frequently asymptom- ing neutrophils caused by demargination and by more rapid BM
atic. On physical examination, the spleen is palpable (occasionally egress of maturing neutrophils. Paulsen found early peaks in M-CSF,
massive) in the great majority of patients with CML but splenomegaly growth hormone, and cortisol after exercise followed by increases in
is unusual with leukemoid reaction (in the absence of comorbidities G-CSF, IL-6, and monocyte chemoattractant protein 1. Acute hem-
such as liver disease). orrhage and hemolytic anemia are other physiologic stresses. This
Laboratory findings reliably differentiate CML from leukemoid contributes to increased steady-state neutrophil counts recorded in
reaction. The total leukocyte count is commonly extremely high with patients with sickle cell anemia, and the degree of elevation correlates
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CML (median 100,000/mm in some series), but counts above with pain crisis frequency, other complications, and mortality; leu-
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100,000/mm are rare and above 150,000/mm virtually unheard of kocyte reduction has been postulated to be one mechanism of
with leukemoid reaction. Circulating myelocytes and even a few hydroxyurea’s beneficial actions. The stress of acute myocardial infarc-
blasts are more typical of CML, but may be seen in both disorders. tion is commonly accompanied by mild neutrophilia, and the early
Similarly, changes in platelet number and morphology can be seen magnitude of rise has correlated with poor outcomes.
with both but are more characteristic of CML (especially when
changes are extreme). RBC changes do not reliably separate the dis-
orders except in a few cases with prominent teardrops, which point Hereditary and Congenital Neutrophilias
toward MPN. More helpful is the leukocyte differential: patients with
CML almost always have some degree of absolute basophilia and In newborns, neutrophilia and leukoerythroblastosis are among the
eosinophilia, but infection and glucocorticoid excess induce eosino- hematologic abnormalities associated with trisomy 13, trisomy 18,
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penia. (When the leukocyte count is 100,000/mm , realize that 2% and trisomy 21 (Down syndrome). A transient clonal MPN can be
to 3% basophils is a substantial absolute increase.) seen in children with Down syndrome and is usually self-limited, but
The leukocyte alkaline phosphatase (LAP) score, high with leuke- it does put patients at increased risk for later acute megakaryoblastic
moid reaction and classically low with CML, has limited utility now leukemia.
that more sensitive and specific tests for CML have emerged. When Very rare hereditary neutrophilias are sometimes first appreciated
CML is reasonably considered, testing should be done for the Phila- in adults. In 1971, Herring reported a mother and three of her four
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delphia chromosome, t(9;22)(q34;q11.2) by chromosome G-banding, children with lifelong neutrophilia (WBC: 14,000/mm to 164,000/