Nonmalignant White Blood Cell Disorders

From WiserWiki

[edit] Nonmalignant White Blood Cell Disorders

Philip A. Lowry

The primary nonmalignant disorders of white blood cells encountered in adult practice represent abnormalities of number, although repetitive or unusual infections in face of normal leukocyte counts may suggest a functional abnormality. This chapter initially recounts the normal mechanisms of hematopoiesis, then reviews the various nonmalignant abnormalities of leukocyte subclasses. It concludes with a brief discussion of the role of hematopoietic growth factors in the treatment of these disorders.

[edit] NORMAL HEMATOPOIESIS

An understanding of the basic concepts of normal hematopoiesis forms the foundation for approaching the diagnosis and therapy of both malignant and nonmalignant blood disorders. Normal hematopoiesis proceeds from a pluripotent hematopoietic stem cell in the bone marrow that is theoretically capable of both self-renewal and proliferation and differentiation into all the mature hematologic lineages. This process is under the control of the various hematopoietic cytokines.Fig. 114-1 summarizes this scheme. Leukocytes derived from this process can be divided into two general classes: the myelomonocytic and lymphocytic. All leukocytes function to monitor for and react to infection, inflammation, and endogenous tissue damage or degeneration.

Figure 114-1 Stem cell–based model of hematopoiesis. A pluripotential early progenitor cell progresses through a sequence of progressive lineage restriction and ultimate terminal differentiation into mature blood cells. Individual steps are presumably under the control of hematopoietic growth factors. The various hematologic malignancies may represent an arrest at one of these developmental stages.

Myelomonocytic cells (neutrophils, eosinophils, basophils, and monocyte/macrophages) are capable of phagocytosis of infecting agents or cellular debris and release of inflammatory or chemotactic mediators. These cells have no inherent specificity but react to foreign antigens that have been opsonized by antibody or complement. Mature segmented neutrophils are released from the marrow and circulate for 6 to 8 hours before migrating to extravascular tissues, where they perform their bactericidal function and persist for only a few days. Less is known about the kinetics of basophils and eosinophils though they are probably similar. They participate in allergic reactions and in the response to parasitic and fungal infections.

Monocytes have a similarly short half-life in circulation but are longer lived in extravascular tissues. Monocytes that have developed specialized phagocytic function are recognized as macrophages. In addition to phagocytic functions, monocyte/macrophages play a key role in antigen presentation.

Lymphocytes synthesize specialized reactive molecules that interact with foreign antigens, forming the specific arm of the immune response. Differentiated B cells are responsible for humoral immunity through production of immunoglobulins, which circulate and initiate complementmediated lysis or opsonized phagocytosis, particularly of bacterial pathogens. Differentiated T cells have a surface-bound T cell receptor that is similar to immunoglobulin in its unique structure and specificity for a limited antigen repertoire. T cells control cell-mediated immunity and, in addition to specific recognition and destruction of endogenous tissues altered by viral infection or neoplastic degeneration, modulate the overall immune response through direct cell-cell interaction with B cells and monocytes and the release of lymphokines and inflammatory modulators.

Development of these specialized reactive molecules starts with apparently random rearrangements of multiple genetic loci, which are ultimately combined to produce mature immunoglobulin and T cell receptor molecules. After initial development in the marrow, final lymphocyte proliferation and differentiation proceed in specialized tissues capable of antigen presentation, with selection of appropriate clones and elimination of pathologically autoreactive cells. This final lymphocyte development is summarized in Fig. 114-2.

Figure 114-2 Lymphopoiesis begins with the formation of a common lymphoid progenitor in the marrow derived from the pluripotential hematopoietic stem cell. After initial commitment to B or T cell lineage and initial random rearrangement of loci for immunoglobulin or T cell receptor molecules, final proliferation and differentiation proceed in specialized tissues and are subject to antigen presentation and the control of modulating cells and lymphokines. Killer, natural killer, and null cell subsets are rare, are poorly characterized, and apparently do not undergo antigen-dependent and restricted proliferation and differentiation.

[edit] GENERAL FEATURES OF NONMALIGNANT LEUKOCYTE DISORDERS

Abnormalities of leukocytes most often present as susceptibility to infections or inflammation. Inherent qualitative abnormalities are rare, and most are typically congenital and manifest in childhood, with the notable exception of the acquired immunodeficiency syndrome (AIDS).Table 114-1 presents a general approach to the evaluation of a patient with suspected immunodeficiency.^[1]

Table 114-1 Approach to the Patient With Suspected Immunodeficiency

Adult practitioners will more often encounter problems related to quantitative leukocyte disorders. Depression of leukocyte counts results from either an abnormality of production or an increased rate of loss or destruction. Production problems typically reflect abnormalities of the marrow due to inherent abnormalities of the hematopoietic stem cell, to acute toxic insults such as the cytopenias following chemotherapy or irradiation, to a metabolic abnormality such as vitamin deficiency, or to malignant or storage disorders that invade or replace the marrow cavity. These mechanisms affect all of hematopoiesis and therefore rarely manifest as a single lineage deficit and more often as pancytopenia.

Unusual disorders may be due to specific growth factor abnormalities. These disorders are rare, but those such as cyclic neutropenia and Kostmann's syndrome are now recognized to be the result of specific deficiencies of granulocyte colony-stimulating factor, a cytokine involved in the direction of terminal granulocyte differentiation and ultimate function. Increased loss or destruction may relate to severe infections, extensive tissue necrosis, splenic hyperfunction, or autoimmune mechanisms.

Syndromes of cellular excess are most typically due to malignant transformation with autonomous proliferation orare reactive to a specific pathologic state.Table 114-2 lists normal ranges of leukocyte numbers and related evaluations, and Box 114-1 summarizes the quantitative leukocyte disorders.

Table 114-2 Summary of Normal Values

[edit] GRANULOCYTE DISORDERS

Qualitative granulocyte defects are rarely encountered de novo in adult practice. They are marked by recurrent suppurative bacterial infections, but can sometimes be successfully managed with antibiotics. The nitroblue tetrazolium test is a rapid screen for neutrophil dysfunction. One specific defect, the Chédiak-Higashi syndrome, can be diagnosed by flow cytometric demonstration of altered CD11b expression on the neutrophil cell surface.

Neutropenia is probably seen most often in the context of previous treatment with cytotoxic therapy and in such a situation is usually anticipated and recognized prior to the onset of major secondary problems. Acute neutropenia may be due to acute destruction complicating certain severe infections, particularly bacterial sepsis; due to vitamin B₁₂ or folate deficiency resulting from abnormal maturation (usually in combination with macrocytic anemia); or seen as the first manifestation of an acquired marrow disorder such as myelodysplasia, aplastic anemia, or leukemia or other malignancy involving the marrow leading to decreased production of normal elements. More chronic forms of neutropenia may be seen as an expression of a congenital disorder such as cyclic neutropenia; maybe seen in the context of autoimmune disease, particularly with systemic lupus erythematosus or Felty's syndrome; or may be a manifestation of hypersplenism.

Neutropenia, particularly when the absolute count is less than 500 neutrophils per mcl, constitutes a potential medical emergency requiring prompt evaluation and, in the context of manifestations of infection, immediate intervention to forestall life-threatening complications. A complete history and physical examination should focus on antecedent treatments or conditions. Review of peripheral blood and marrow smears may identify potential malignant forms or signs of vitamin deficiency. Additional tests that may be helpful include antinuclear antibody, rheumatoid factor, serum immune electrophoresis, and determination of folic and vitamin B₁₂ levels. Antineutrophil antibodies are available on an investigational basis, but are rarely returned in time to help with acute decision making and may not be sufficiently reliable to determine treatment.

Although definitive therapy for neutropenia and its underlying causes may require the intervention of a hematologist, several immediate measures may be required and often should be instituted by the initial identifying physician, even in advance of hematologic consultation. Potential toxic drugs should be eliminated and other contributing causes immediately obvious at the time of diagnosis should be appropriately addressed. Any signs of infection including fever, even without other localizing signs, require prompt initiation of broad-spectrum antibiotics. This issue has been nicely reviewed in the classic monograph by Pizzo.^[2]

Neutrophilia, in contrast, is rarely a medical emergency in and of itself except as a marker of a more serious underlying disorder. Neutrophilia is seen acutely most often as a manifestation of underlying infections, particularly those caused by bacterial organisms. It may also be seen in response to acute stress related to burns, major trauma, or organ infarction. In all these cases, the primary disorder is usually manifestly evident from the history and physical examination. Treatment with drugs such as epinephrine, corticosteroids, or the more recently available recombinant growth factors may also induce neutrophilia. A mild neutrophilia may be seen occasionally as a response to extreme heat or cold exposure, or with exercise, convulsions, or severe pain.

Chronic neutrophilia may be seen in the context of persistent infections or inflammatory conditions or occasionally as a chronic response to untreated malignancies of another organ system. Chronic neutrophilia may complicate chronic therapy with steroids or lithium or may be a manifestation of certain endocrinologic disorders such as adrerocorticotropic hormone (ACTH)- or glutocorticoid-producing tumors or occasionally thyroid storm. Chronic neutrophilia is rare as a congenital abnormality, although it may be seen particularly in association with Down's syndrome. In all these forms, the neutrophilia represents a reactive process, and its treatment is simply the treatment of the primary disorder.

The primary differential concern in neutrophilia is to detect a primary myeloproliferative disorder. Although a definitive evaluation may require bone marrow aspiration and biopsy with performance of cytogenetics to search for the characteristic Philadelphia chromosome (t9:22 translocation), a screen of leukocyte alkaline phosphatase levels may provide initial clues as to which of these two diagnoses is operative. Whereas leukemoid reactions or other reactive causes of neutrophilia are usually associated with an elevated leukocyte alkaline phosphatase level, chronic myelocytic leukemia is typically associated with the depression of its value.

[edit] EOSINOPHIL DISORDERS

Worldwide, the most common cause of eosinophilia is infection with helminthic parasites, particularly schistosomiasis but also ascariasis, Toxocara infection, filariasis, strongyloidiasis, trichomoniasis, and Echinococcus infection. In industrialized countries, allergic conditions, underlying malignancy, allergic bronchopulmonary aspergillosis, and primary eosinophil proliferations figure more prominently in the differential diagnosis.

Polyarteritis nodosa and Churg-Strauss syndrome may be accompanied by eosinophilia, but have a clinical presentation dominated more by the clinical consequences of systemic vasculitis. Of historic significance are the toxin-induced eosinophilic syndromes eosinophilic myalgia due to contaminated tryptophan ingestion and the toxic oil syndrome in Spain in 1981 due to substitution of rapeseed oil for olive oil.

Patients presenting with excess numbers of eosinophils require evaluation of stool for ova and parasites; cultures and evaluation for fungal, mycobacterial, or other chronic bacterial diseases; and evaluation for autoimmune or chronic allergic disorders, all of which may be associated with a reactive eosinophilia. Extreme hypereosinophilia or eosinophilia that persists for more than 6 months where reactive forms of eosinophilia have been excluded suggests a primary hypereosinophilic syndrome.

Hypereosinophilic syndrome most often afflicts caucasian males. Total white blood cell counts may be elevated to the range of 10 to 50 × 10⁹ per liter, with differential showing that 30% to 70% of cells are mature-appearing eosinophils. Hypereosinophilic syndrome is an idiopathic syndrome that may range from totally mature-appearing eosinophils to a very immature eosinophilic leukemic-like picture.

Chronic eosinophilia from any cause may result in severe cardiac toxicity with restrictive congestive heart failure andmitral valve regurgitation and also may be associated with chronic pulmonary infiltrates or effusions. Primary hypereosinophilic syndrome was uniformly fatal historically when severe and prolonged. More recently the prognosis has dramatically improved with treatment including steroids, hydroxyurea and leukapheresis.

[edit] BASOPHILIA

Basophilia may be seen in association with allergic or inflammatory conditions or with certain infectious conditions such as viral or tuberculosis infection. The underlying cause is usually obvious in these conditions and the treatment is directed toward it. Basophilia may also be a marker, particularly for the myeloproliferative diseases or for occult carcinoma, and a search for these disorders should be undertaken when no other cause for the abnormality is manifest.

[edit] MONOCYTE DISORDERS

Monocytosis is most often the result of underlying malignant disease such as myelodysplastic or myeloproliferative disorders or occasionally is a marker of underlying lymphoma or carcinoma. Monocytosis may also be noted with chronic inflammatory and immune disorders and may be particularly seen in the context of mononucleosis syndromes, collagen vascular disease, inflammatory bowel disease, sarcoidosis, or chronic infectious states, particularly tuberculosis, subacute bacterial endocarditis, and, historically, syphilis. Monocytopenia may nonspecifically result from marrow aplasia or may accompany human immunodeficiency virus (HIV) infection, hairy-cell leukemia, or treatment with radiotherapy, steroids, or interferon.

Although the role of monocytes and monocyte-derived tissue-based cells in antigen presentation has long been recognized conceptually, the specific mechanisms of that process are just now being characterized. That characterization will probably shed light on previously unrecognized subtle or perhaps not-so-subtle functional defects.

[edit] LYMPHOCYTE DISORDERS

Lymphocytopenia or qualitative lymphocyte disorders may be due to a variety of causes and, although perhaps not associated with the immediately explosive infectious susceptibility of severe neutropenia, may nevertheless be a marker of severe immune compromise, with significant consequences for the patient. Congenital lymphocyte disorders typically present in childhood with variable infectious complications; they may be fatal at an early age, particularly in the case of the combined disorders.

B cell disorders such as X-linked agammaglobulinemia are associated with recurrent pyogenic infections due to loss of opsonization, but can also be associated with autoimmune disorders. Common variable immunodeficiency is an acquired condition with similar clinical characteristics and a particular predilection toward the development of a sprue-like syndrome. Both disorders can be reasonably managed with regular immunoglobulin replacement and prompt antibiotic therapy for infections. More focused IgG subclass deficiencies have also been described with variable infectious risk.

IgA deficiency is the most common congenital immunodeficiency disorder affecting 1 in 700 people. About 80% of affected patients do not show a clinically significant increased risk of infection, but 20% have simultaneous deficiencies of IgG₂ and IgG₄ subclasses and show a pattern of infections similar to other hypoglobulinemic syndromes, with a similar response to immunoglobulin maintenance and antibiotics. All patients with IgA deficiency are at risk for developing an IgE directed against IgA, with the clinical consequence of anaphylactic reactions to the infusion of IgA-containing blood products. IgA deficiency should be suspected as the cause of any severe, unexplained reaction to transfusion.^[3]

Qualitative T cell disorders produce a more severe, so-called combined immune compromise, both directly from impaired T cell immune function and the indirect compromise of B cell function due to loss of T cell modulation. Severe combined immunodeficiency, ataxia telangiectasia, and the Wiskott-Aldrich syndrome are congenital conditions that have unique individual features but share a susceptibility to severe and often fatal infection early in life. Homologous stem cell transplantation offers the possibility for cure. The DiGeorge syndrome is a noninherited developmental disorder resulting in congenital thymic aplasia and a pattern of infectious risk similar to the above conditions. Transplantation of fetal thymic tissue may help correct the deficiency.

Lymphopenias or abnormalities of lymphocyte function also are often a secondary manifestation of a variety of other autoimmune states and of malignancies such as lymphoma and Hodgkin's disease. Chronic therapy with glucocorticoids or antineoplastic agents may induce functional or numerical abnormalities of lymphocytes as well. With the recent emergence of AIDS, an entirely new category of lymphopenia and lymphocyte functional abnormalities has emerged (see Chapter 32 ). Screening for HIV infection should be a standard part of the evaluation of a patient presenting with lymphopenia.

Lymphocytosis, as with the other disorders of white cell excess, can be divided into two broad categories: a manifestation of a primary hematologic malignancy is a reactive process. Lymphocytosis may be particularly seen with the various mononucleosis syndromes due to Epstein-Barr virus, cytomegalovirus, or toxoplasma infection, and may also be paradoxically seen in early presentation of HIV-1 infection. Acute lymphocytosis may be seen with a number of other viral infections and may also be manifest in the context of noninfectious inflammatory processes particularly associated with autoimmune disease or hypersensitivity reactions.

With the increasing use of screening laboratories, patients with chronic lymphocytic leukemia (CLL) are frequently diagnosed in an asymptomatic and early stage on the basis of an elevated lymphocyte count noted on a “routine” complete blood count determination. CLL is discussed more completely in Chapter 119 . Lymphocytosis is best evaluated initially by a complete history and physical examination, light microscopic inspection of the peripheral blood smear, and flow cytometric analysis of the peripheral blood.

[edit] HEMATOPOIETIC GROWTH FACTORS

A major addition to the therapeutic armamentarium in the treatment of hematologic disorders has been the identification, production, and clinical administration of the hematopoietic growth factors. Particularly notable in this regard are the dramatic increase and use of agents such as erythropoietin, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF).

Erythropoietin first saw use in the clear deficiency state associated with renal failure, with dramatic reduction in transfusion requirements and improvements in quality of life. Its use has now been extended to patients with chronic anemias complicating HIV infection, malignancy, and their treatment. The evolution of more practical weekly administration schedules has particularly fueled a modest but nevertheless improved quality of life for these patients as well. Attempted facilitation of autologous blood donation and better tolerance of surgery through preoperative or perioperative erythropoietin administration have not borne fruit, and alternate strategies such as acute hemodilution will probably better serve this purpose.

Myeloid cytokines arrived with even greater expectations. However, other than in the treatment of usual congenital neutropenic disorders or in the context of stem cell transplant, myeloid cytokines have not yet shown clear improvement in patient outcomes as measured by survival. The greatest temptation has been to apply G-CSF in the context of acute febrile neutropenia with the hopes of reducing the duration and severity of that illness. Although its application in this context seems logical, there is as yet no definitive scientific data as to the efficacy in this regard, with the possible exception of cases complicated by particularly resistant infections or signs of high patient threat such as hypotension or multi-organ failure. Particularly in the context of the need to control health care costs, it is essential that the medical community continue to critically evaluate the efficacy of these new agents and rigorously establish the appropriate contexts for their use.^[4]Table 114-3 summarizes current uses of the myeloid growth factors.

Table 114-3 Quantitative Leukocyte Disorders

[edit] REFERENCES