Hematology

Leukopenia

Leukopenia

What every physician needs to know about leukopenia:

"Leukopenia" is a general term referring to a reduced number of white blood cells in the peripheral blood. It is almost always due to a decrease in one subset of white blood cells. It can be due to:

  • Granulocytopenia: A general term referring to all granulocytes, including neutrophils, monocytes, eosinophils, and basophils

  • Neutropenia: A reduction in the number of neutrophils

  • Lymphopenia: A reduction in the number of lymphocytes

Since monocytes, eosinophils, and basophils comprise a relatively small proportion of the total circulating white blood cell pool, leukopenia is almost always due to neutropenia or lymphopenia. Consequently, the terms granulocytopenia and neutropenia are often used interchangeably. A complete lack of one of the other granulocytic series is also abnormal and may have an impact on innate immunity, but is rarely a cause of a depressed total white blood cell count.

The definition of "leukopenia" varies, but in most laboratories the lower limit of a normal total white cell count is 3000/μl to 4000/μl. Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500/μl. However, this number has been determined largely in cohorts of Caucasian individuals, and there are several ethnic groups in which the range of normal neutrophil counts is shifted toward a lower number. This is discussed in the entry on ethnic neutropenia. Agranulocytosis, a complete lack of granulocytes, refers to a specific subset of neutropenia that has a unique differential diagnosis.

Mild or chronic reductions in white blood cells can be benign and in the absence of alarming symptoms may not require further evaluation. However, new or severe leukopenia, especially neutropenia, especially when accompanied by any of the signs or symptoms described below, should prompt a thorough investigation.

What features of the presentation will guide me toward possible causes and next treatment steps:

Age of presentation

Severe congenital neutropenia syndromes typically present in infancy. Leukopenia associated with congenital immunodeficiency syndromes present in childhood.

Acuity of presentation

Neutropenia that has been present since childhood may indicate the presence of a congenital syndrome. Leukopenia that develops acutely should prompt an evaluation for drug-induced agranulocytosis, acute infections, or acute leukemia. Leukopenia that develops over weeks to months should prompt an evaluation for a chronic infection or primary bone marrow disorder.

Severity of cytopenia

Although the severity of the cytopenia is not helpful in delineating its cause, patients with an ANC of less than 800/μl should be considered to be immunocompromised, and appropriate precautions as outlined below should be taken. Patients with an ANC of less than 500/μl who are febrile, should be admitted to the hospital for intravenous antibiotics and expedited evaluation.

Associated symptoms

Leukopenia itself is usually asymptomatic. Concomitant constitutional symptoms, including fever, chills, diaphoresis, or weight loss, may indicate the presence of an infection (which can be either a cause for, or a result of, leukopenia), malignancy, or autoimmune disorder. Other signs or symptoms that may help guide workup and management include:

  • Localizing signs or symptoms of infection

  • Lymphadenopathy

  • Hepatomegaly or splenomegaly,

  • Signs of anemia (pallor, cyanosis),

  • Signs of thrombocytopenia (mucosal bleeding, petechiae, purpura

  • Inflamed joints

  • Skin rashes.

Appearance of peripheral smear

A smear is essential for determining which white cell line is responsible for the decrease in total white cell count. Furthermore, it should be examined for the presence of abnormal forms. The presence of immature ("left-shifted") white cells can indicate infection or malignancy, especially myelodysplasia or acute leukemia, while abnormal red cells can indicate the presence of autoimmune destruction, myelodysplasia, or a bone marrow failure syndrome.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

All patients with a low white blood cell count should have the following:

  • Repeat complete blood count (CBC) to confirm the low white blood cell count (WBC) and assess the erythrocyte and platelet cell lines

  • Manual differential to determine which cell line is reduced and to look for abnormal cells

  • Examination of prior CBCs to determine the acuity of the leukopenia

Further testing should be guided by the type of deficient cell and the features of the presentation. These may include:

  • Complete metabolic panel, including liver enzymes

  • Prothrombin time (PT) and partial thromboplastin time (PTT)

  • Blood cultures

  • Human immunodeficiency virus (HIV) serology and viral load

  • Polymerase chain reaction (PCR) viral loads for Parvovirus, Epstein-Barr virus, Cytomegalovirus, herpes simplex viruses and hepatitis viruses

  • PCR for tick-borne illnesses, including Rickettsia and Anaplasma

  • Serum assays for drugs associated with neutropenia or lymphopenia (see below)

  • Serologies for autoimmune disease (antinuclear antibody [ANA], rheumatoid factor);

  • Immunoglobulins

  • Peripheral blood flow cytometry for B and T cell lymphoma markers

  • Peripheral blood flow cytometry for large granular lymphocytes

  • Bone marrow aspirate and biopsy.

What conditions can underlie leukopenia:

See and Table II .

Table I

Causes of neutropenia
Congenital Acquired
Severe congenital neutropenia Infection
Cyclic neutropenia Post-infection
Shwachman-Diamond syndrome Drug-induced
Fanconi anemia Immune-mediated: Primary immune neutropeniaAutoimmune disease:Rheumatoid arthritisFelty's syndromeLarge granular lymphocyte diseaseSystemic lupus erythematosusWegener's granulomatosisGraves diseasePure white cell aplasia (associated with thymoma)Large granular lymphocyte disease (sporadic, not associated with rheumatoid arthritis)Primary bone marrow failureAplastic anemiaMyelodysplastic syndromeAcute leukemiaMyelofibrosis
Dyskeratosis congenita Margination/hypersplenism
Glycogen storage disease type 1b Nutritional deficiency
Myelokathexis Chronic idiopathic neutropenia in adults (CINA)
Chediak-Higashi syndrome  
Griscelli syndrome type 2  
Hermansky-Pudlak syndrome type II  

Table II

Causes of lymphopenia
 Congenital  Acquired
   Infection
 Granulomatous disease
   Autoimmune disease
 Radiation
   Drugs/toxins
   Malnutrition
   Protein-losing enteropathy
 Malignancy: Acute LeukemiaLymphoma

When do you need to get more aggressive tests:

Leukopenic patients who are acutely ill or unstable require aggressive evaluation and management to determine the cause of the leukopenia, as well as the source of any concurrent infection.

Leukopenic patients who do not appear acutely ill or unstable may still require aggressive testing if their leukopenia is new or newly severe, if the manual smear shows concerning signs, such as a left shift of dysplastic forms, or if an otherwise exhaustive work-up has failed to determine the cause of the leukopenia. In general, consideration of more aggressive testing should also prompt consultation with a hematologist.

Aggressive tests that may be necessary in the evaluation of leukopenia include bone marrow aspirate and biopsy, lumbar puncture (if there are new focal neurologic deficits or altered mental status), or lymph node biopsy.

What imaging studies (if any) will be helpful?

Imaging studies are usually not helpful in determining the cause of leukopenia. However, abdominal ultrasound may confirm the presence of splenomegaly and other imaging may document the presence of lymphadenopathy. Leukopenic or neutropenic patients with signs or symptoms of infection should undergo appropriate imaging to help identify potential sources of infection.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Any patient with fever in the setting of an ANC less than 500/μl or a steadily declining ANC less than 1000/μl should be admitted to the hospital for expedited evaluation and intravenous antibiotics. The antibiotic regimen should always include coverage for gram-negative bacteria, including Pseudomonas. Although the exact choice of antibiotic will vary depending on local resistance patterns and hospital formularies, common choices include:

  • Third or fourth generation cephalosporins with pseudomonal coverage (ceftazidime, cefepime, cefoperazone)

  • Anti-Pseudomonal penicillins (piperacillin or ticarcillin)

  • Carbapenems (imipenem or meropenem)

  • Aminoglycosides (gentamicin, tobramycin, or amikacin)

  • Aztreonam plus a fluoroquinolone (levofloxacin or ciprofloxacin)

Fluoroquinolones should not be used as monotherapy, as resistance can develop quickly.

Further extension of empiric coverage to include gram-positive, anaerobic, fungal, or viral coverage should depend on the clinical presentation.

The use of granulocyte colony-stimulating factor (G-CSF) is controversial. In patients with life-threatening infection and profound neutropenia, G-CSF may shorten the duration of neutropenia and is recommended; it is also recommended in cases of clear drug-induced neutropenia. However, since G-CSF administration may complicate the diagnosis of the underlying cause of the neutropenia, it is generally preferable to obtain a bone marrow aspirate and biopsy before initiating G-CSF, if the inciting cause is unknown. Long acting G-CSF (pegylated G-CSF, neulasta) is not recommended for the acute therapy of febrile neutropenia.

What other therapies are helpful for reducing complications?

As previously noted, G-CSF can help reduce the duration of neutropenia of diverse etiology. It has been suggested that cytokines may stimulate the growth of underlying hematologic malignancy. Although these data are controversial, these risks must be considered and appropriate diagnostic evaluation completed, prior to the administration of G-CSF if possible. Therapy should be guided by a hematologist.

What should you tell the patient and the family about prognosis?

Given the broad range of potential conditions that can give rise to leukopenia, prognosis cannot be determined until the underlying cause has been identified.

“What if” scenarios.

Manual smear shows evidence of acute leukemia

Signs of acute leukemia may include the presence of obvious circulating blast forms. This is an indication for urgent hematology consultation for the initiation of appropriate diagnosis and therapy.

CBC shows pancytopenia

This is another indication for urgent hematologic consultation, to rule out aplastic anemia or acute leukemia.

Patient presents with fever in the setting of neutropenia

Patient should be hospitalized and treated as outlined above.

Pathophysiology

Leukopenia or neutropenia may develop as the result of many underlying conditions, most of which are described in detail elsewhere. The following is a brief description of the known pathophysiology underlying some forms of neutropenia:

Congenital neutropenias

  • Severe congenital neutropenia (SCN)

- Severe congenital neutropenia is a heterogeneous disease. Autosomal dominant SCN is most commonly caused by mutations in neutrophil elastase (ELANE), which leads to the accumulation of mutant protein in the endoplasmic reticulum of neutrophils, triggering the unfolded protein response. This accounts for about 60% of cases of SCN. Autosomal recessive SCN (Kostmann's syndrome) is caused by absence of Hax-1, a mitochondrial protein. Loss of Hax-1 leads to mitochondrial membrane destabilization and apoptosis. Rarer causes of SCN include mutations in Wiskott-Aldrich Syndrome Protein (WASp) and mutation of glucose-6 phosphatase catalytic subunit 3 (G6PC3).

  • Cyclic neutropenia (CN)

- Cyclic neutropenia (CN) is most often associated with mutations in ELANE, and is autosomal dominant. Although most of the mutations leading to CN are distinct from those causing SCN, there are some described mutations that can give rise to both syndromes within a single pedigree. The reason for this heterogeneity is unknown, but is presumed to reflect the effect of other genes that contribute to the phenotype.

  • Shwachman-Diamond syndrome (SDS)

- Shwachman-Diamond syndrome (SDS) is an X-linked disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS), which encodes part of the ribosomal ribonucleic acid (RNA) complex. SDS is one of the growing list of diseases termed "ribosomopathies".

  • Fanconi anemia

- Fanconi anemia is caused by mutations in genes regulating DNA mismatch repair. It is a heterogeneous autosomal recessive disease that is frequently associated with pancytopenia and bone marrow failure.

  • Dyskeratosis congenita

- Dyskeratosis congenita can be caused by mutations in any of a number of genes involved in telomere maintenance, and is associated with pancytopenia, skin abnormalities, and pulmonary fibrosis. It can be autosomal dominant, autosomal recessive, or X-linked.

  • Glycogen storage disease Ib

- Glycogen storage disease Ib is an autosomal recessive disease caused by mutations in glucose-6-phosphatase translocase, which inhibits the neutrophil respiratory burst.

  • Myelokathexis

- Myelokathexis is an autosomal dominant disorder caused by a mutation in the chemokine receptor gene CXCR4, which is associated with aberrant adhesion of neutrophils and failure of release of neutrophils from the bone marrow.

  • Chediak-Higashi syndrome (CHS)

- Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder associated with a failure of lysosomal granule trafficking. It is associated with mutations in the lysosomal trafficking regulator (LYST) gene. Patients have neutropenia with characteristic large granular neutrophil inclusions, oculocutaneous albinism, and immunodeficiency.

  • Griscelli syndrome type 2

- Griscelli syndrome type 2 is an autosomal recessive disorder associated with neutropenia and immunodeficiency. It is caused by mutations in the guanosine triphosphatase RAB27A.

  • Hermansky-Pudlak syndrome 2

- Hermansky-Pudlak syndrome 2 is an autosomal recessive disorder caused by a defect in AP-3 complex subunit beta-1 (AP3B1), a vesicle-trafficking protein. Like CHS, patients also display oculocutaneous albinism.

Acquired neutropenias

  • Drug-induced agranulocytosis is a rare idiosyncratic reaction, that results in immune destruction of neutrophil precursors within the marrow. It resolves with discontinuation of the offending agent, but may be associated with significant morbidity and mortality from sepsis. Many other drugs cause a dose-related suppression of neutrophil proliferation that is more benign and may often be tolerated without stopping the drug

  • Autoimmune neutropenia:

    • Primary autoimmune neutropenia is caused almost exclusively by antibodies directed against neutrophil antigens, including human neutrophil antigen (HNA1) and CD11b (HNA-4a), two surface antigens, or FcγRIIIb, an immune complex receptor involved in secretion of toxic products. Cross-linking of these autoantibodies leads to neutrophil destruction in the spleen or to complement-mediated lysis. It is seen almost entirely in infants and toddlers, and resolves spontaneously in over 90% of cases over the course of 1 to 2 years.

    • Secondary autoimmune neutropenia is usually associated with another autoimmune disorder such as Graves' disease, Wegener's granulomatosis, rheumatoid arthritis, or systemic lupus erythematosus. The pathogenesis is not clearly defined. Many patients have anti-neutrophil antibodies, but the correlation between the presence of antibodies and the degree of neutropenia is poor.

    • Both Felty's syndrome and large granular lymphocyte syndrome occur in the setting of rheumatoid arthritis. Since over 90% of patients in both groups are positive for HLA-DR4, it is hypothesized that these two syndromes reflect a spectrum of a single disease. Several autoimmune mechanisms have been proposed, including antibody-mediated and cell-mediated cytotoxicity

  • Hypersplenism usually causes only mild neutropenia, often in a setting of mild pancytopenia. Suppression of counts reflects increased margination of blood cells in the enlarged spleen

  • Nutritional deficiencies, especially those of Vitamin B12, folate, and copper, can lead to neutropenia

  • Chronic idiopathic neutropenia in adults (CINA) is a benign disorder whose etiology is totally unknown

What other clinical manifestations may help me to diagnose leukopenia?

As previously noted, the clinical manifestations of leukopenia reflect either the underlying disease or infections that arise as a complication of leukopenia. Leukopenia itself is asymptomatic.

What other additional laboratory studies may be ordered?

This is discussed above and in the chapters on each of the individual disorders.

What's the evidence?

Anderson, F, Knozen, C, Garbe, E. "Systematic review: agranulocytosis induced by non-chemotherapy drugs". Ann Intern Med. vol. 146. 2007. pp. 657-665 .

[A comprehensive review of the drugs most commonly implicated in agranulocytosis, including an analysis of long-term outcomes and predictors of prognosis.]

Andres, E, Maloisel, F. "Idiosyncratic drug-induced agranulocytosis and acute neutropenia". Curr Opin Hematol. vol. 14. 2008. pp. 15-21 .

[Another thorough review of the causes and management of drug-induced neutropenia.]

Beekman, R, Touw, IP. "G-CSF and its receptor in myeloid malignancy". Blood. vol. 115. 2010. pp. 5131-5136 .

[A comprehensive summary of the pathobiology of the G-CSF receptor and neutrophil mechanics in the development of acute myeloid leukemia and myelodysplasia, and a review of the use of G-CSF in these disorders.]

Berliner, N. "Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis". Blood. vol. 111. 2008. pp. 5427-5432 .

[An historical review of major advances in understanding severe congenital neutropenia and their implications for our greater understanding of myeloid development.]

Dinauer, MC, Coates, TD, Hoffman, R, Benz, EJ, Shattil, SJ. "Disorders of phagocyte function and number". Hematology; Basic Principles and practice. Churchill Livingstone. 2005. pp. 737-762 .

[A comprehensive review of granulocyte disorders, including neutropenia and agranulocytosis, from the current edition of one of the classic textbooks of hematology.]

Lewis, D, Nadeau, K, Cohen, A, Hoffman, R, Benz, EJ, Shattil, SJ. "Disorders of lymphocyte function". Hematology; Basic Principles and Practice . Churchill Livingstone. 2009. pp. 721-745.

[A comprehensive review of lymphocyte disorders from the Hoffman text.]

Wilcox, RA. "Cancer-associated myeloproliferation: old association, new therapeutic target". Mayo Clin Proc. vol. 85. 2010. pp. 656-762 .

[A summary of our current understanding of myeloid function and its application in the search for targeted cancer therapies.]
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