Page 879 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 62 Immunohematological Disorders 851

which might suggest an alternative diagnosis. The marrow
Myelopoiesis in Immune Neutropenia examination may also be helpful in confirming T-LGL leukemia. 30
In primary immune neutropenia, bone marrow is typically Detection of antineutrophil antibodies. Antibodies are assayed
normocellular or mildly hypercellular with an increased propor- clinically using indirect assays (i.e., by measuring the binding
tion of early myeloid forms (particularly myelocytes and pro- of antibodies from patient sera to fixed granulocytes from
myelocytes) and decreased mature forms (neutrophils, bands, unrelated individuals). The granulocyte immunofluorescence
and metamyelocytes), a pattern designated maturation arrest. test (GIFT), which exploits flow cytometry for detection, is most
Although maturation arrest can also be seen in a number of commonly used because of its high sensitivity. The granulocyte
other diseases, in this setting, it suggests an expansion in immature agglutination test (GAT) is less sensitive but is particularly valuable
precursors with early release of mature components into blood. used in conjunction with GIFT to detect antibodies against
Rigorous kinetic studies in children with primary neutropenia HNA-3a or HNA-1b. Once the presence of an antibody has been
are not available, but the available data suggest myelopoiesis in confirmed, MAIGA is a valuable technique in identifying the
this setting is increased. target molecule recognized by the antibody, information that
The findings are more complex in Felty syndrome and T-LGL may be very helpful in identifying antibody specificity and in
leukemia. In vivo neutrophil kinetic studies and in vitro assays distinguishing granulocyte-specific antibodies from alloantibodies
of marrow function often document reduced myelopoiesis in directed against HLA determinants. More precise epitope typing
these settings. 20,21 This has been attributed to T-cell–mediated still requires a panel of granulocytes of varied phenotype.
and cytokine-mediated suppression. T-LGL leukemia cells Unfortunately, to date, granulocyte panels are both difficult to
constitutively express Fas ligand on their surface and also release prepare and impossible to store. Consequently, antibody typing
significant quantities of soluble Fas ligand into plasma in vivo. remains a laborious, difficult task. At the second international
Reduced myelopoiesis in T-LGL leukemia and some patients granulocyte serology workshop, 12 centers independently tested
with Felty syndrome may be linked to apoptosis instigated by a series of unknown sera. Many laboratories could detect strong
the binding of Fas ligand expressed on the abnormal cells to Fas HNA-1a antibodies, but the success rate was much lower in
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expressed on the surface of myeloid precursors. Whatever the defining HNA-1b or HNA-2a antibodies, and individual labo-
precise mechanism, reductions in myelopoiesis appear to be a ratories varied greatly in their proficiency. 25
common element in patients with these forms of secondary Clinical use of antineutrophil antibody studies. In young
immune neutropenia. children with neutropenia, a positive result is very helpful in
distinguishing between immune-mediated and congenital causes.
Diagnosis Isoimmune and congenital disease may be apparent from birth,
Clinical Presentation and the former usually resolves within 2–6 months. Using GIFT
Isoimmune neutropenia presents at birth and may persist for or GAT assays, ANAs can be detected in more than 70% of
up to 6 months. Self-limiting primary autoimmune neutropenia children with primary immune neutropenia. When both are
typically presents in early childhood. In older children and adults, used in tandem the yield increases further. A strong positive
neutropenia is more commonly associated with other systemic result strongly supports the diagnosis of immune neutropenia.
autoimmune disease, especially rheumatoid arthritis and SLE However, a negative result does not exclude the diagnosis. 28
or T-LGL leukemia. Drug-induced neutropenia must always be Primary autoimmune neutropenia in adults is difficult to
considered in patients taking medications. distinguish from the ill-defined entity chronic idiopathic neu-
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tropenia. Because there is no “gold standard” for distinguishing
Laboratory Findings immune disease from nonimmune disease in this setting, the
Blood counts typically demonstrate isolated neutropenia, diagnostic sensitivity and specificity of the ANA assays are unclear.
sometimes with monocytosis. More generalized leukopenia, Assays are positive in perhaps a third of adults referred with
anemia, and/or thrombocytopenia suggest concurrent SLE or a chronic neutropenia, and a positive result in the absence of other
primary bone marrow disorder, especially aplastic anemia or systemic autoimmune disease certainly supports a diagnosis of
myelodysplasia. immune neutropenia. Again, a negative result does not preclude
Examination of the blood film for evidence of abnormalities an immune etiology, but it is more consistent with chronic
in other cell lines or increased numbers of LGL is essential. The idiopathic neutropenia.
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persistent presence of >2000 LGL/mm for 6 months in itself is In patients with systemic autoimmune disease or T-LGL
diagnostic of T-LGL leukemia; however, normal LGL counts leukemia, hyperglobulinemia and circulating immune complexes
in blood do not preclude this diagnosis. Perhaps a quarter of greatly complicate laboratory evaluation. ANA assays are fre-
patients with T-LGL leukemia and immune neutropenia have quently positive even in the absence of neutropenia. Since the
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fewer than 500 monoclonal LGL/mm in blood. The evaluation specificity of a positive result is low, its diagnostic value is very
of patients with small T-LGL clones detected in blood on flow limited, and the clinician must be vigilant for other possible
cytometric or molecular testing without clear tissue infiltration causes, especially drug-induced neutropenia.
remains problematic. At least some of these patients probably
have self-limiting “T-cell gammopathies of unknown origin” Therapy
(Chapter 80) unassociated with overt lymphoproliferation or Overview
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autoimmunity. All patients with neutrophil counts below 1000/mm have some
Bone marrow findings in immune neutropenias (as briefly increased risk of infection, but some remain asymptomatic even
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reviewed above) can vary substantially. Perhaps the most impor- with absolute neutrophil counts of 500/mm or less. Growth
tant function of the bone marrow examination is to rule out factors can usually improve neutropenia and reduce the risk of
hypoplasia/aplasia, myelokathexis, marked megaloblastic dysplastic infection, but given their expense, inconvenience, and possible
changes, or abnormal infiltration with nonhematopoietic cells, side effects, they should be reserved for use in patients with a