Leukopenia

Table II

Congenital	Acquired
	Infection
	Granulomatous disease
	Autoimmune disease
	Radiation
	Drugs/toxins
	Malnutrition
	Protein-losing enteropathy
		Malignancy: Acute Leukemia Lymphoma

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. 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
. 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.]