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Neutropenia and Agranulocytosis - Overview and Definition

Neutropenia is defined as a decrease in circulating neutrophils in the peripheral blood. Neutrophils or polymorphonuclear neutrophils (PMNs) are derived from pluripotent bone marrow stem cells and constitute the majority (about 60% to 70%) of blood leukocytes. Neutrophils are released from the bone marrow as mature cells unable to proliferate and undergo constitutive apoptosis in the circulation. In response to infection or disease, neutrophil production in the bone marrow is increased, which results in release of both immature and mature cells into the periphery.2903  A healthy adult produces 60 billion neutrophils daily, each with a half-life of only 6 to 20 hoursErythrocytes have a far longer life span (120 days) and vastly outnumber neutrophils by about 1000:1 in the peripheral blood.10286,  3018 

Neutrophils play a key role in host defense through phagocytosis and in destruction of pathogens through proteases and antimicrobial proteins within cytoplasmic granules and release of high concentrations of superoxide.2903  In response to chemotactic stimuli, neutrophils marginate (adhere to endothelial cells) and migrate from the blood into tissues and sites of infection. There they engulf microorganisms within vacuoles called phagosomes, after which they fuse with lysosomes to form phagolysosomes, in which ingested organisms are destroyed.10286  Although tissue damage can occur as a result of neutrophil activation, serum, extracellular matrix proteases, and scavenger proteins can usually limit damage. However, with chronic neutrophil activation, these control mechanisms can be ineffective.2903 

Normal neutrophil counts vary from 1.8–7.0 x 109/L with a mean of about 4.0 x 109/L; although there may be significant variation based on age and race.3018  Studies have shown that people of African origin have normal neutrophil counts that are lower than Caucasians. In one population-based study in the US, mean neutrophil counts for black adult males were 0.83 x 109/L lower than those of white adult males and mean neutrophil counts were approximately 0.7 x 109/L lower in black adult females compared to white adult females.11855  The same study found that mean neutrophil counts were approximately 0.6 x 109/L lower in subjects younger than 18 years of age when compared to adult subjects.11855 

When a patient is found to be neutropenic, the absolute neutrophil count (ANC) serves as a rough guide to the relative severity of the disorder. ANC is determined by multiplying the total white blood cell count by the percentage of neutrophils and band forms. ANC varies widely in healthy individuals and can be influenced by such factors as exercise, emotional state, and time of day, but is normally >1.5 x 109/L . Thus, neutropenia is defined as an ANC of <1.5 x 109/L. Neutropenia is usually classified as mild, moderate, or severe, the grades that correspond, respectively, to ANC values of 1.0–1.5 x 109/L, 0.5–1.0 x 109/L , and <0.5 x 109/L.3018,  2944 

Agranulocytosis is a term often used synonymously with severe neutropenia. Although agranulocytosis literally means a complete absence of neutrophils, standardized definitions for agranulocytosis are an ANC of <0.5 x 109/L.3032  This is exactly the same definition as severe neutropenia and the two will be used interchangeably here.

Pathophysiology of Drug-Induced Agranulocytosis

Agranulocytosis is one of the most commonly reported adverse hematologic effects from drugs. Drug-induced neutropenia is one of the most commonly reported causes of neutropenia. Although the mechanisms for this are not fully understood, in general, drug-induced agranulocytosis (DIA) is thought to occur at the bone marrow level from toxic, idiosyncratic, or hypersensitivity mechanisms or peripherally via an immune-mediated increase in neutrophil destruction. An immune-type mechanism leads to the rapid destruction of circulating mature granulocytes and likely their progenitors in the bone marrow, as well. This is not dose dependent, and onset occurs quickly and rapidly upon re-exposure. A direct toxic effect on bone marrow generally occurs through interference with protein synthesis or cell replication. This mechanism is dose dependent and is insidious in onset. Regardless of mechanism, laboratory tests to confirm the role of a given drug are not readily available, and those that are often yield equivocal results.3032 

Clinical Manifestations of Drug-Induced Agranulocytosis

Patients with drug-induced agranulocytosis (DIA) are highly susceptible to virtually every type of bacterial or fungal infection. Patients with chronic agranulocytosis have compensating mechanisms, while patients with acute disease fare worse because compensating mechanisms have not developed. In contrast, the effects of DIA on host-defense functions are extensive and include the barrier role of mucosal cells starting in the mouth through the entire gastrointestinal tract.2944,  10286,  2928,  3032 

While the most common presenting signs of DIA include stomatitis, gingivitis, perirectal inflammation, or cellulitis,2944  patients with DIA will often present with high fever, sore throat, diarrhea, malaise, headache, chills, myalgia, or arthralgia.2928  Many patients develop infections, such as pneumonia, anorectal, skin, or oropharyngeal infections, as well as septicemia.2910,  2980,  2928  In elderly patients, clinical manifestation are generally more severe, with sepsis being present in the vast majority.2910  The results of 1 study in elderly patients are outlined in the figure below.

Figure 651 – Clinical Manifestations in Elderly Patients Aged ≥65 Years With Idiosyncratic Drug-Induced Agranulocytosis Followed Up in the Hôpitaux Universitaires de Strasbourg (n=54)

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Centocor Ortho Biotech Inc. Adapted. Andres E, Noel E, Kurtz JE, Henoun Loukili N, Kaltenbach G, Maloisel F. Life-threatening idiosyncratic drug-induced agranulocytosis in elderly patients. Drugs Aging. 2004;21(7):427-435.

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References:

2903.  Eyles JL, Roberts AW, Metcalf D, Wicks IP. Granulocyte colony stimulating factor and neutrophils–forgotten mediators of inflammatory disease. Nat Clin Pract Rheumatol. 2006;2(9):500-510.
2910.  Andres E, Noel E, Kurtz JE, Henoun Loukili N, Kaltenbach G, Maloisel F. Life-threatening idiosyncratic drug-induced agranulocytosis in elderly patients. Drugs Aging. 2004;21(7):427-435.
2928.  Andrès E, Kurtz JE, Maloisel F. Nonchemotherapy drug-induced agranulocytosis: experience of the Strasbourg teaching hospital (1985-2000) and review of the literature. Clin Lab Haematol. 2002;24(2):99-106.
2944.  Boxer L, Dale DC. Neutropenia: causes and consequences. Semin Hematol. 2002;39(2):75-81.
2980.  Julia A, Olona M, Bueno J, et al. Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes. Br J Haematol. 1991;79(3):366-371.
3018.  Sievers EL, Dale DC. Non-malignant neutropenia. Blood Rev. Jun 1996;10(2):95-100.
3032.  Vial T, Gallant C, Choquet-Kastylevsky G, Descotes J. Treatment of drug-induced agranulocytosis with haematopoietic growth factors. A review of the clinical experience. Biodrugs. 1999;11(3):185-200.
10286.  Bhatt V, Saleem A. Review: Drug-induced neutropenia—pathophysiology, clinical features, and management. Ann Clin Lab Sci. 2004;34(2):131-137.
11855.  Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med . 2007;146(7):486-492.

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