Page 792 - Hematology_ Basic Principles and Practice ( PDFDrive )

678 Part VI Non-Malignant Leukocytes

specific autoimmune problem. Direct antiglobulin test and antiphos- smear may require no further diagnostic workup. It may be reassuring
pholipid antibodies can also be supportive when there is suspicion to the patient (and the doctor) if prior blood counts can be retrieved
for an autoimmune process. Quantitative immunoglobulin levels to document the chronic, nonprogressive and complication-free
may reveal an underlying immunodeficiency when there is evidence course of the neutropenia.
of autoimmunity or when infectious complications are dispropor-
tionate. Serologic tests for some viral infections (HIV, hepatitis,
Epstein-Barr virus [EBV]) may sometimes be appropriate. The main Autoimmune Neutropenia (Primary and Secondary)
utility of flow cytometry occurs when peripheral blood smear suggests
an abnormal lymphocyte population (e.g., LGLs or hairy cells). Autoimmune neutropenia can be primary or secondary to an auto-
Because LGL leukemia is a relatively common cause of significant immune disorder such as SLE or RA. Neutropenia can be mild or
neutropenia and because this is a diagnosis frequently initially missed, severe. Classically, it is caused by antineutrophil autoantibodies,
one should have a low trigger to obtain flow cytometry, assuring that although autoreactive cytotoxic lymphocytes may also cause this
proper markers are analyzed (see later). BM examination may not be problem. When performed, BM examination often is normocellular
helpful or warranted with mild or even moderate isolated neutropenia or hypercellular, with a late “maturation arrest” picture. Severe cases
or in straightforward cases of severe neutropenia (e.g., after drug can display pure WBC aplasia (similar to drug-induced agranulocy-
exposure), but can be essential when the diagnosis is in doubt and tosis, which may sometimes also be antibody-mediated). There are
especially if other cell lines are compromised. several challenges to making the diagnosis. One is that the maturation
arrest BM picture is highly nonspecific with regard to mechanism: it
could indicate a true stem cell differentiation defect, or the early
Severe Congenital Neutropenias release of later precursors (as with sepsis or splenic sequestration), or
an immune attack aimed at antigens on later myeloid precursors or
It is beyond the scope of this chapter to review in detail the hetero- early recovery from a toxic insult. Another problem is the lack of
geneous genetic disorders that manifest in early childhood as severe validated, clinically reliable neutrophil antibody tests. Experimentally,
congenital neutropenia (SCN); nevertheless, consultant hematolo- several methods have been used, generally suffering from high false-
gists should have some familiarity with this problem both because negative and false-positives rates in detecting antibodies against
modern therapy has extended survival for many into adulthood, and neutrophil antigens or immune complexes that bind to neutrophil Fc
because milder forms of these disorders may go undiagnosed until receptors. With no definitive test, diagnosing autoimmune neutrope-
young adulthood. More severe forms of SCN present in infancy with nia rests largely on clinical context and judgment.
severe stomatitis and recurrent bacterial infections. The molecular Neutropenia caused by antineutrophil antibodies has been seen in
bases have been greatly elucidated in recent years, among them being: infants about 1 year old, usually running a benign clinical course with
(1) an autosomal dominant mutation of the neutrophil elastase gene spontaneous remission in 95% within 2 years. Newborns are at risk
ELANE in 50% to 60% of patients, (2) an autosomal recessive of alloimmune neutropenia in the first months of life, but this is not
mutation of HAX1, which is associated with mental retardation and generally accompanied by infectious complications. Secondary
other congenital defects found in Kostmann syndrome, and (3) an autoimmune neutropenias are most common in adults, related to
autosomal recessive mutation of SBDS in Schwachman-Bodian- disorders such as SLE, RA, Sjögren syndrome, thymoma, and
Diamond syndrome, which presents with variable degree of neutro- common variable immunodeficiency. In SLE, neutrophil counts
penia, BM failure, and exocrine pancreatic insufficiency. In young correlate with disease activity and have been related to the induction
children, the differential diagnosis of SCN includes transient of TNF–related apoptosis-inducing ligand (TRAIL), a ligand that
postinfectious neutropenia, alloimmune neutropenia, or hematologic increases myeloid apoptosis and killing by autologous T cells. Immu-
malignancy. BM examination often shows a pattern of maturation nosuppressive therapy of the SLE or the use of G-CSF can improve
arrest. The majority of affected patients are responsive to G-CSF, the WBC count.
which has favorably impacted infectious morbidity and mortality. Felty syndrome was classically described as severe neutropenia
Allogeneic stem cell transplant is another therapeutic option. An and splenomegaly complicating RA, and has been attributed to
intrinsic risk of acute myeloid leukemic transformation, 15% at 20 antineutrophil antibodies, but the distinction between this syndrome
years, accompanies these disorders, with higher risk in those requiring and other causes of neutropenia with RA have become blurred. In
higher doses and/or responding poorly to G-CSF. particular, classic Felty syndrome and LGL syndrome appear to
Cyclic neutropenia is a rare autosomal dominant disorder with represent points on a disease continuum. About 1% of patients with
variable expression, also caused by autosomal dominant mutations of RA develop Felty syndrome, and it predisposes many to serious
ELANE or rarely its transcription regulator. Neutrophil counts vary infections. Effective therapies have often included methotrexate, gold
from mildly to severely low with predictable periodicity, usually about salts, and rituximab. Because of some risk of exacerbating underlying
21 days. The great majority of cases are responsive to G-CSF at low inflammatory problems, G-CSF should be used with caution.
dosage.
Large Granular Lymphocyte Syndrome and Natural
Benign Ethnic Neutropenia Killer Cell Proliferations

Americans of African descent may have chronic mild neutropenia not Proliferations of LGLs (T-NK cells and NK cells) are covered else-
associated with infectious complications. The 1999–2004 National where, but mention is required here because these are common
Health and Nutrition Survey found that black individuals had mean considerations in adults with neutropenia. These represent heteroge-
3
leukocyte counts 900/mm lower than white individuals, with ANCs neous disorders, varying from nonclonal reactive processes to indolent
3
below 1500/mm in 4.5% (compared with 0.8% of white individu- clonal proliferations to highly aggressive neoplasms. Both reactive and
als). The neutropenia correlates in some individuals with a polymor- clonal increases in T-NK cells can be seen with RA, representing a
phism in the Duffy antigen receptor chemokine, a cytokine receptor form of Felty syndrome. Reactive LGLs can be seen with other
also responsible for a Duffy-negative RBC phenotype. Some reports autoimmune disorders, after organ transplantation, with tyrosine
find this neutropenia more common in males, but other reports find kinase inhibitor therapy, or they may be idiopathic. These prolifera-
autosomal dominant inheritance. Marrow granulocyte reserve or tions are associated with variable degrees of neutropenia, commonly
release (or both) may be compromised. Benign neutropenia has also splenomegaly, and increased infectious risks. The diagnosis is sug-
been seen in other ethnic populations, including those of Middle gested on blood smear by large lymphocytes with mature chromatin,
Eastern or Japanese descent. Thus, an asymptomatic mildly neutro- excessive cytoplasm, with or sometimes without prominent cytoplas-
+
+
penic person of appropriate ethnicity without abnormalities on blood mic granules. Flow cytometry demonstrates increased CD3 CD57