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432 Part IV Disorders of Hematopoietic Cell Development

familial forms of neutropenia. The etiology of this condition is TABLE
unknown, but the pathogenesis involves ANAs, detectable in the 32.6 Drugs Associated With Agranulocytosis
majority of patients. The antibodies are generally directed against
similar antigens as seen in adult AIN, especially those involving NA, Etiologic Fraction
NB, and ND loci. In about 25% of cases, the antibody is against an Agranulocytosis (%) Aplastic Anemia (%)
allele of neutrophil FcγRIII opsonin receptor called NA1. Immuno-
suppressive therapy leads frequently to responses supporting the Overall 64 62
immune pathogenesis of this disease. Although the neutrophil count IAAAS 12 27
can be severely depressed, serious infectious complications are United States 72 17
uncommon, and therefore treatment to raise the ANC is generally
not indicated except if recurrent infections occur. Antibiotics are used Thailand 70 2
to treat infections, and granulocyte colony-stimulating factor (G-CSF) Drugs associated with agranulocytosis (IAAAS and other drugs of interest)
has been shown to be effective in elevating neutrophil counts. Acetyldigoxin 172
ACE inhibitors 173,174
175–177
SECONDARY FORMS OF NEUTROPENIAS Allopurinol 178
Amodiaquine
Clinical Associations Benzafibrate 179
172,180
β-Blockers
β-Lactam antibiotics 181
Drug-Induced Neutropenia/Agranulocytosis Carbamazepine 182
Cinepazide 183,184
Corticosteroids 185
Drug-induced neutropenia is common. The association was first Cotrimoxazole, 186 other sulfonamides
when agranulocytosis was observed in patients taking aminopyrine. Dipyridamole 172
The incidence in various studies is 1 to 3.4 cases per million per year. Deferasirox (Exjade) 187
Drugs may induce granulocytopenia by (1) direct toxicity leading to Dypirone 171,188
inhibition of myelopoiesis frequently observed in drugs like valproic Histamine-2 receptor antagonist 189
acid, carbamazepine, and β-lactam antibiotics; (2) immune mediated Indomethacin 190
(either antibody- or complement-mediated) as seen with penicillin Isoniazid 191,192
and antithyroid drugs or immune complex–mediated (quinidine) Macrolides 193,194
destruction of myeloid progenitors and mature neutrophils; and (3) Mefloquine 195
induction of CTL responses to genetic predisposition because of Nifedipine 196
polymorphisms in various genes coding for cytokine and cytokine Phenytoin 197,198
receptors as demonstrated for clozapine with tumor necrosis factor Procainamide 199,200
and HLA polymorphisms as well as variants of genes coding for a Salicylates 201
variety of metabolizing enzymes. 169,170 Of interest are drugs that Sulfasalazine 202,203
directly antagonize important vitamin cofactors necessary in normal Sulfonylureas 204,205
bone marrow development. Neutropenia observed in patients treated Tetracyclines 171
with trimethoprim-sulfamethoxazole is caused by the inhibitory Thenalidine
effects on granulopoiesis by trimethoprim, owing to its antifolate Thyrostatics 206–208
action, which is reversed by folinic acid. A similar finding can be seen Troxerutine 171
with methotrexate owing to its antifolate action.
Most patients present with either asymptomatic neutropenia ACE, Angiotensin-converting enzyme; IAAAS, International Agranulocytosis and
Aplastic Anemia Study.
discovered on routine examination or symptomatic neutropenia
with infectious complications, including fever, angular stomatitis,
or pneumonia. The reported mortality rates vary from 1% to 25%.
Most patients recover with withdrawal of the offending drug without
further complications. It has been estimated that drugs account for hematopoiesis, granulocyte sequestration, margination, and periph-
72% of cases of agranulocytosis. The usual time to development of eral destruction. Neutropenia generally improves when the viremia
overt neutropenia is around 1–2 weeks, and neutropenia resolves resolves. Neutropenia has been associated with hepatitis A, B, and C
upon discontinuation of the offending drug within a 2-week period, viruses, EBV, influenza, measles, roseola, CMV, and parvovirus B19
although time to recovery may vary. The recovery in neutrophil infections. Neutropenia is also frequently encountered in patients
counts is usually preceded by increases in peripheral blood monocytes with AIDS, with approximately 70% of patients being neutropenic
and immature granulocytes. The International Agranulocytosis and during their illness. The mechanisms vary and may include antibody
Aplastic Anemia Study has identified the most commonly associated formation against neutrophils, direct viral inhibition of hematopoietic
agents and the relative odds ratios for developing agranulocytosis progenitor cells, abnormal expression of growth factors and other
171
(Table 32.6). In some instances, the severity of neutropenia is cytokines, and inhibitory effects exerted by HIV-infected accessory
related to the dose and duration of the therapy. The therapy includes cells. The HIV virus not only suppresses hematopoiesis but also
discontinuation of the potentially offending agents. In some instances, increases the risk for acquiring other infections. Furthermore, therapy
associated with infections or prolonged recovery, G-CSF may be with antiretroviral agents may dramatically decrease neutrophil
administered. counts (see Table 32.4).
Systemic bacterial, fungal, and parasitic infections can be accom-
Neutropenia as a Manifestation of Systemic Diseases panied by neutropenia, including typhoid fever, tularemia, brucel-
losis, mycobacterial infections, histoplasmosis, malaria, leishmaniasis,
and ehrlichiosis. The pathogenesis includes margination and seques-
Postinfectious Neutropenia tration of leukocytes as observed in malaria, in which there is reduc-
tion in the circulating neutrophil pool and enlargement of the
Neutropenia is commonly associated with viral infections, particularly marginating granulocytes, primarily in the spleen and lung. Neutro-
in children. Various mechanisms have been implicated in neutropenia penia can be present during sepsis, especially in newborns or debili-
associated with systemic viral infections, including inhibition of tated individuals. In such situations, neutropenia may be caused by