Page 793 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 48 Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia 679

lymphocytes with the more common T-NK proliferations or may TABLE
−
+
show CD3 CD56 clones with “pure” NK cell proliferation. Somatic 48.2 Drugs Commonly Associated With Neutropenia
activating mutations in the signal transducer and activator of tran-
scription 3 gene (STAT3) were found in 40 % of patients with LGL 1. Antibiotics: vancomycin, semisynthetic penicillins,
leukemia, suggesting aberrant STAT3 signaling pathway is an under- chloramphenicol, sulfa, linezolid
lying mechanism of this disease. Somatic activating STAT5b muta- 2. Antithyroid drugs: methimazole, propylthiouracil
tions were also found in minority of patients. Variably effective 3. Cardiovascular: ticlopidine, procainamide
treatments for indolent proliferations are corticosteroids, methotrex- 4. Antipsychotics: clozapine, olanzapine, chlorpromazine
ate, cyclosporine, cyclophosphamide, and purine nucleoside analogs. 5. Anticonvulsants: phenytoin, carbamazepine, valproic acid
6. Antiinflammatory agents: indomethacin, sulfasalazine,
phenylbutazone
Neutropenia With Infectious Diseases 7. H2 blockers: cimetidine, ranitidine
8. Analgesics: dipyrone
Leukocytosis is the expected response to most bacterial infections, 9. Antineoplastic: rituximab
but leukopenia also occurs and is characteristic of infection by certain 10. Anthelmintic: levamisole
organisms. Viral infections often cause transient mild leukopenia, so
restraint is wise in the diagnostic approach to a newly recognized
moderate leukopenia in a febrile, modestly ill patient. Nonbacterial
infections in which neutropenia is frequent or even characteristic The utility of prophylactic antibiotics is problematic because of
include HIV, EBV, cytomegalovirus (CMV), hepatitis A and B, the wide array of potential pathogens and because of concerns of
measles, rubella, varicella, rickettsia, and anaplasmosis (ehrlichiosis). inducing antibiotic resistance. Prophylactic quinolones have had
Bacterial infections with characteristic leukopenia include typhoid some favorable impact in very high-risk patients after consolidation
fever and brucellosis, and granulomatous infections (tuberculosis, therapy for acute leukemia or stem cell transplant.
histoplasmosis) also commonly cause neutropenia, especially when G-CSF is widely used for primary or secondary prevention of
the BM is directly involved. In patients with poor BM reserve (e.g., neutropenia to decrease morbidity and mortality of febrile neutrope-
prior chemotherapy, malnutrition, myelodysplasia) an acute infection nia. Primary prophylaxis is recommended by various guidelines if the
very often lowers, rather than raises, the neutrophil count. Profound risk of developing febrile neutropenia is greater than 20%. This risk
neutropenia is a known consequence of overwhelming sepsis and has is calculated from age, extent of primary cancer, comorbidities, and
been associated with poor outcomes. the known myelotoxicity of the chemotherapy regimen. G-CSF is
begun 24–72 hours after the completion of myelotoxic chemotherapy.
Pegfilgrastim allows prophylaxis to be given more conveniently (once
Hypersplenism per cycle).

Hematologists are frequently consulted for cytopenias, only to find
an unappreciated large spleen as the etiology (this most commonly Drug-Induced Neutropenia
due to liver disease with portal hypertension). Splenic enlargement
can lead to sequestration and reduction of circulating WBCs, RBCs, Drug reactions account for a high percentage of acquired neutrope-
platelets, or any combination of these. The degree of cytopenia is nias, both mild but moreover severe cases (agranulocytosis; Table
somewhat proportional to the degree of splenic enlargement. Sub- 48.2). Neutropenia often develops abruptly, within 4 weeks of initia-
stantial neutropenia out of proportion to the depletion of other cell tion of a causative agent. Pathophysiology may involve immune
lines and to the degree of splenomegaly suggests an autoimmune mechanisms or more direct toxicity such as enhancement of reactive
component (which can be seen with hepatitis C or autoimmune oxygen species made by nicotinamide adenine dinucleotide phosphate
hepatitis) or medication effect (e.g., interferon). oxidase or myeloperoxidase on neutrophil precursors. The diagnosis
is generally strongly suspected from an accurate history that plots
leukocyte numbers against the time course of drug exposure; confir-
Chemotherapy-Induced Neutropenia mation is leukocyte recovery after drug withdrawal. More specific
confirmatory testing, such as for drug-dependent antibodies, is
The major dose-limiting toxicity of most cancer chemotherapy regi- mainly an area of research laboratory investigation. BM examination
mens continues to be neutropenia. This results in hospitalizations, is not usually required but may be helpful when pathophysiology and
antibiotic costs, reduced quality of life, infectious morbidity, dose diagnosis are in doubt, when the course is atypical, and to provide
reductions and treatment delays that compromise efficacy and out- prognostic information (earlier recovery may be anticipated with a
comes, and result in some deaths: 75% of chemotherapy-related picture of “maturation arrest” than one of myeloid aplasia). Treatment
mortality. Febrile neutropenia is defined as an ANC less than 500/ demands discontinuation of suspected offending drugs. Although the
3
3
mm (or expected to decrease to <500/mm over the next 48 hours) efficacy of myeloid growth factors (G-CSF) has been questioned,
with fever (>38.3°C or sustained >38°C). most recommend this therapy because even a modest shortening of
Principles of empiric antibiotic coverage for acute febrile episodes severe neutropenia can occasionally be lifesaving. Mortality of drug-
in severely neutropenic patients are covered in detail elsewhere. Basi- induced agranulocytosis is generally reported to be 10%.
cally, there is a high risk of sepsis (even when the source is occult), The most commonly implicated drugs are listed in Table 48.2.
and a favorable outcome depends on prompt effective antimicrobial Some merit additional comment. Some drugs have a direct myelo-
coverage, so empiric administration of broad-spectrum antibacterial toxic effect rather than induce an idiosyncratic immune-based reac-
agents is considered medically emergent. There must be coverage of tion. Neutropenia will have more gradual onset related to dose and
the traditional aerobic gram-negative rod culprits (particularly Pseu- duration, and may be accompanied by suppression of other hemato-
domonas), yet vigilance must be maintained for the gram-positive logic cell lines. Linezolid and most instances of chloramphenicol
organisms that have emerged as major pathogens. With prolonged or myelosuppression are examples.
repeated episodes of neutropenia, invasive fungi become common Beginning 2007, an epidemic of agranulocytosis was found among
threats to survival, particularly Aspergillus, Candida, Mucor, and intravenous cocaine users. The adulterant levamisole was found in
Fusarium spp. Published guidelines can aid the choice of empiric 71% of confiscated cocaine by the Drug Enforcement Agency, with
antimicrobials. Because of difficulty demonstrating favorable impact, the incidence of agranulocytosis 2.5% to 13% in those exposed.
enthusiasm for granulocyte transfusions has waned in the past 30 Nadir BM showed severe myeloid hypoplasia. Levamisole had long
years; clinical studies are readdressing this in the modern era. been linked to agranulocytosis, having been used as an antihelminth