CHAPTER 87 LYMPHOCYTOSIS AND LYMPHOCYTOPENIA
CHAPTER 87 LYMPHOCYTOSIS AND LYMPHOCYTOPENIA
THOMAS J. KIPPS
Secondary (Reactive) Lymphocytosis
Idiopathic CD4+ T Lymphocytopenia
The causes of lymphocytosis or lymphocytopenia are many and varied. This chapter outlines the conditions associated with abnormalities in the numbers of circulating lymphocytes in the blood. It also serves as a useful road map to other chapters in the book that describe in detail those conditions that commonly are associated with abnormalities in the absolute numbers of circulating lymphocytes.
Acronyms and abbreviations that appear in this chapter include: EBV, Epstein-Barr virus; NK, natural killer; PPBL, persistent polyclonal lymphocytosis of the B lymphocytes; PUVA, psoralen and ultraviolet A irradiation.
Lymphocytosis is defined as an absolute lymphocyte count exceeding 4 × 109/liter (4000/µl),1 although somewhat lower threshold values (>3.1 × 109/liter (>3100/µl)) are sometimes used.2 The normal absolute lymphocyte count is significantly higher in childhood. The methods for determining the absolute lymphocyte count and the normal range for such counts are described in Chap. 2.
The blood film of patients with lymphocytosis should be evaluated for a predominance of reactive lymphocytes associated with infectious mononucleosis (see Chap. 90), large granular lymphocytes associated with large granular lymphocytic leukemia (see Chap. 100), smudge cells associated with chronic lymphocytic leukemia (see Chap. 98), or blasts of acute lymphocytic leukemia (see Chap. 97). A description of normal lymphocyte morphology is provided in Chap. 80.
Characterization of cell surface markers is valuable in distinguishing primary lymphocytosis (leukemic) from secondary lymphocytosis (reactive). New improvements in flow cytometry techniques and reagents have allowed clinical laboratories to perform flow cytometric immunophenotyping to distinguish benign from neoplastic lymphoproliferative disease (see Chap. 13).3,4,5,6,7,8,9,10 and 11 Analysis for immunoglobulin or T-cell receptor gene rearrangement also may provide evidence for monoclonal B-cell or T-cell proliferation, respectively.12
Primary lymphocytosis defines conditions associated with an increase in the absolute number of lymphocytes secondary to an intrinsic defect in the expanded lymphocyte population (Table 87-1). These conditions also are referred to as lymphoproliferative disorders and most commonly are secondary to the neoplastic accumulation of monoclonal B cells, T cells, natural killer (NK) cells, or less fully differentiated cells of the lymphoid lineage. The chapters describing each of these conditions are indicated in Table 87-1.
TABLE 87-1 CAUSES OF LYMPHOCYTOSIS
Although patients with lymphocytosis secondary to lymphoproliferative disease generally maintain abnormal lymphocyte counts that may rise over time,13 this is not invariable. Patients with large granular lymphocytic leukemia (see Chap. 100) may have only transient lymphocytosis that is induced by stress or exercise.14
MONOCLONAL B-CELL LYMPHOCYTOSIS
The advent of flow cytometric and molecular diagnostic techniques has identified a syndrome in patients who have expanded populations of monoclonal B cells without other associated clinical signs or symptoms.15,16,17 and 18 This syndrome may resemble that of patients with essential monoclonal gammopathy who otherwise do not have the clinical features of myeloma. Such patients also were identified after improved technology was introduced for evaluating serum immunoglobulins (see Chap. 104 and Chap. 105). Similar to the latter, some patients who have expanded populations of monoclonal B cells may develop progressive neoplastic lymphoproliferative disease.19
PERSISTENT POLYCLONAL LYMPHOCYTOSIS OF B LYMPHOCYTES
Lymphocytosis can be secondary to an expansion in the numbers of B cells that are “polyclonal” in their expression of immunoglobulin. Patients with this disorder, termed persistent polyclonal lymphocytosis of B lymphocytes (PPBL), each have increased numbers of kappa and lambda light-expressing B cells that are heterogeneous in their rearrangements of immunoglobulin heavy-chain genes.20,21 and 22 Occasional reports of clonal immunoglobulin rearrangements in this disorder suggest that the polyclonal expansion in some cases may be followed by the emergence of one predominant clone.23,24
The cause or causes of PPBL are unknown. Epstein-Barr virus (EBV) genomes have been detected in blood lymphocytes of patients with this disorder.25,26 and 27 One study found a 69 base-pair deletion variant of the gene encoding the EBV latent membrane protein 1 in the lymphocytes of a PPBL patient but not in the lymphocytes of unaffected siblings, suggesting a role for altered LMP1 in the pathogenesis of PPBL.28 Gender and genotype also may be important in the pathogenesis, since the patients most commonly are young to middle-aged women who often are HLA-DR7 positive.24 In addition, there are reports of shared cases of PPBL among identical twins,29 suggesting a possible hereditary or genetic contribution to the pathogenesis. However, the causes of this abnormality may be heterogeneous, as PPBL may not be a single disease entity.
Patients with PPBL can have features that resemble those of patients with various monoclonal B-cell malignancies. In one manifestation of this syndrome, first identified in Japan as hairy B-cell lymphoproliferative disorder,30 the patients can present with anemia, thrombocytopenia, and splenomegaly, and have an excess of polyclonal B lymphocytes that appear similar in morphology to the neoplastic B cells in hairy-cell leukemia. In another manifestation of this syndrome, the patients have an accumulation of polyclonal B cells that coexpress CD19, CD5, and CD23, thus displaying an immunophenotype similar to that of B-cell chronic lymphocytic leukemia.31,32
In perhaps the most common manifestation of PPBL, however, the patients have an accumulation of polyclonal B cells that have an unusual binucleate appearance on the blood film.21,24,33 These patients often have mild splenomegaly and raised serum IgM levels. This disorder appears more common among cigarette smokers20,23,34 and most typically is associated the HLA-DR7 haplotype.24
Although the lymphocytosis of PPBL generally is not progressive, most patients will have small numbers of blood B cells that have chromosomal abnormalities. These most commonly include an additional isochromosome +i(3q) and premature chromosome condensation,21,35 although t(14;18) involving the BCL-2 and the immunoglobulin heavy chain loci also have been detected.22,36,37 In any one patient, these chromosomal abnormalities are restricted to B lymphocytes independent of their expression of immunoglobulin kappa or lambda light chain.21 For PPBL associated with smoking, these cytogenetic abnormalities apparently persist after the discontinuation of tobacco use.24 The finding of such chromosome abnormalities is consistent with the notion that PPBL may represent a preneoplastic state. Consistent with this, a small proportion of patients with PPBL ultimately will develop monoclonal B-cell lymphoma or B-cell leukemia.38,39
SECONDARY (REACTIVE) LYMPHOCYTOSIS
Secondary lymphocytosis defines conditions associated with an increase in the absolute number of lymphocytes secondary to a physiologic or pathophysiologic response to infection, toxins, cytokines, or unknown factors.40
The most common reactive lymphocytosis is infectious mononucleosis (see Table 87-1). This syndrome is described in Chap. 90.
ACUTE INFECTION LYMPHOCYTOSIS
A disorder possibly related to infectious mononucleosis is acute infection lymphocytosis, a contagious disease that is characterized by an increase in circulating lymphocytes, often to 20 to 30 × 109/liter (20,000 to 30,000/µl)41 and occasionally to 100 × 109/liter (100,000/µl).42 The patients are usually asymptomatic but may have fever, abdominal pain, or diarrhea. Lymph node enlargement and splenomegaly do not occur, and the patient’s serum usually is negative for heterophil antibodies. In this regard, the disease resembles infectious mononucleosis caused by viruses other than EBV, such as cytomegalovirus (see Chap. 90).43,44,45 and 46 In some cases, the lymphocytosis has been found in association with acute infection by coxsackievirus B2.47 Clinical symptoms last for a few days, but the lymphocytosis may persist for several weeks. Eosinophilia may be present. The marrow has been examined in a few patients and has shown minimal increases in lymphocytes, but marked infiltration with lymphocytes has also been observed.
Toxoplasmosis also can present with reactive lymphocytosis in the absence of lymphadenopathy, especially in the immune-compromised host.48 Lymphocytosis with atypical lymphocytes also can be part of the early manifestation of acute infection with Falciparum malaria.49
A marked increase in the number of morphologically normal lymphocytes occurs in patients infected with the gram-negative bacterium Bordetella pertussis. Absolute lymphocyte counts range from 8 to 70 × 109/liter (8,000 to 70,000/µl), with a mean of approximately 30 × 109/liter (30,000/µl).50 The lymphocytes are predominantly CD4+ T cells.51,52
The lymphocytosis primarily results from the failure of lymphocytes to leave the blood because of a toxin, termed pertussis toxin, released by the bacteria.53 Pertussis toxin is an ADP-ribosylase that modifies Gi proteins in mammalian lymphocytes and inhibits their capacity to traffic from blood into lymphoid tissues, primarily through the inhibition of chemokine receptors.54,55 Pertussis toxin also may stimulate egress of maturing T cells from the thymus52,56 and may bind to neuraminic acid residues of T-cell–surface glycoproteins to induce T-cell activation.57
Trauma, surgery, acute cardiac failure, septic shock, myocardial infarction, sickle cell crisis, or status epilepticus may be associated with an elevated lymphocyte count, often above 5 × 109/liter (5000/µl),58,59 which may revert to normal or below-normal levels within hours.2 The increased lymphocyte count appears promptly after the event and appears secondary to lymphocyte redistribution.60 A transient lymphocytosis can be induced by the adrenaline released and/or administered in response to the medical episode.61,62 and 63 Characteristically, two phases are recognized after catecholamine administration: a quick (<30 min) mobilization of lymphocytes, followed by an increase in granulocyte numbers with decreasing lymphocyte numbers.63
Patients undergoing splenectomy for staging of Hodgkin’s disease may develop a chronic postoperative polyclonal lymphocytosis.64 An absolute lymphocyte count ranging from 4.0 to 8.7 × 109/liter often is noted 4 to 242 (median 70) months after splenectomy and can persist for prolonged periods (e.g., >50 months).65
Patients may have subacute or chronic lymphocytosis, termed persistent lymphocytosis, in association with a variety of clinical situations (see Table 87-1).
Autoimmune Disease Patients with rheumatoid arthritis and related disorders may have lymphocytosis secondary to increased numbers of large granular lymphocytes.66 Occurring in less than 0.6 percent of patients with rheumatoid arthritis, large granular lymphocytic lymphocytosis almost invariably is associated with neutropenia in the absence of splenomegaly and thus may represent a subset disorder of patients with Felty syndrome.66,67 Patients with autoimmune pure red-cell aplasia or immune thrombocytopenia also may have expanded numbers of polyclonal T cells68 or NK cells.69
Cancer Patients with lymphocytosis may be found to have underlying neoplastic disease.70 Most notably, patients with malignant thymoma may have a polyclonal T-cell lymphocytosis thought to be secondary to the aberrant release of thymic hormones by the neoplastic thymic epithelium.71,72,73,74 and 75 A reactive lymphocytosis or plasmacytosis may be detected in up to 7 percent of patients with acute myeloid leukemia.76
Chronic Inflammatory Diseases Persistent lymphocytosis has been reported in patients with systemic diseases associated with inflammation.70,77 It has been noted in patients with sarcoidosis78 or Wegener granulomatosis.70
Cigarette Smoking Cigarette smokers may have a persistent lymphocytosis secondary to an increase in polyclonal CD4+ T cells and B cells, some of which have an unusual binuclear morphology.20,34,79
Hypersensitivity Reactions Delayed hypersensitivity reactions to insect bites may be associated with a large granular lymphocytic lymphocytosis and adenopathy.80 Idiosyncratic drug reactions also may be associated with subacute lymphocytosis.81
The methods for determining the absolute lymphocyte count and the normal range for such counts are presented in Chap. 2. Lymphocytopenia is defined as a total lymphocyte count of less than 1.0 × 109/liter (1,000/µl),100 but some consider the lower limit of normal to be 1.5 × 109/liter (1500/µl).101 Because approximately 80 percent of normal adult blood lymphocytes are T lymphocytes and nearly two-thirds of blood T lymphocytes are CD4+ (helper) T lymphocytes, most patients noted to have lymphocytopenia have reductions in the absolute numbers of T lymphocytes, particularly CD4+ T lymphocytes. The average absolute number of T lymphocytes in normal adult blood is 1.9 × 109/liter (1900/µl), ranging from 1.0 to 2.3 × 109/liter (1000 to 2300/µl).102 The average absolute number of CD4+ T lymphocytes is 1.1 × 109/liter (1100/µl), ranging from 7.2 to 14 × 108/liter (720 to 1400/µl). The average absolute number of cells of the other major T-cell subgroup, CD8+ T lymphocytes, is 6.5 × 108/liter (650/µl), ranging from 3.8 to 9.7 × 108/liter (380 to 970/µl). Some Asians and blacks may lack or be heterozygous for an epitope on the CD4 molecule that is recognized by the mouse monoclonal antibody OKT4A, thus making these patients appear to have a deficiency in the absolute number of CD4 T cells. The use of other anti-CD4 monoclonal antibodies (e.g., Leu-3a) that bind other epitopes of the CD4 molecule may help rule out factitious CD4+ T-cell depletion.
Table 87-2 summarizes the conditions associated with lymphocytopenia. The mechanism of lymphocytopenia is not established for many of these disorders, and several possible mechanisms exist. Further discussion of lymphocytes and of the diseases associated with lymphocytopenia are presented in the cited reports (see Table 87-2).
TABLE 87-2 CAUSES OF LYMPHOCYTOPENIA
The relative incidence of each of these conditions will vary, depending upon the patient population. In one New Zealand survey of patients who had significant lymphocytopenia (<0.6 × 109/liter), the patients fell into several categories with some overlap.103 In order of decreasing frequency, the factors associated with lymphocytopenia were bacterial or fungal sepsis (250 patients), major surgery (228 patients), definite (153 patients) or suspected (53 patients) corticosteroid therapy, malignancy (180 patients), cytotoxic therapy and/or radiotherapy (90 patients), recent trauma or hemorrhage (86 patients), renal allograft (38 patients), marrow allograft (35 patients), “viral infections” other than human immunodeficiency virus (HIV; 26 patients), or infection with HIV (13 patients). Only one patient was suspected of having idiopathic CD4+ T lymphocytopenia.
Patients with inherited immunodeficiency diseases may have associated lymphocytopenia (Table 87-2) (see Chap. 88). Inherited immunodeficiency disorders may have a quantitative or qualitative stem cell abnormality, resulting in ineffective lymphopoiesis (see cited references in Table 87-2). Others, such as the Wiskott-Aldrich syndrome, have associated lymphopenia due to premature destruction of T cells secondary to a defect in the lymphocyte cytoskeleton.104
Acquired lymphocytopenia defines syndromes associated with depletion of blood lymphocytes that are not secondary to inherited disease.
The most common infectious disease associated with lymphopenia is the acquired immunodeficiency syndrome. The lymphocytopenia is due in part to destruction and/or clearance of CD4+ T cells infected with HIV-1 or HIV-2.102,105,106,107,108 and 109 The lymphocytopenia also may reflect impaired lymphocyte production and proliferation secondary to loss of the normal thymic or lymphoid architecture and the high levels of transforming growth factor b that often are noted in patients with this disease (see Chap. 89).
Other viral and bacterial diseases may be associated with lymphocytopenia (see Table 87-2). Patients presenting with active tuberculosis often have lymphocytopenia that usually resolves 2 weeks after initiating appropriate antimicrobial therapy.110 In acute viral infection, the lymphocytes may be destroyed by the infection, may be trapped in the spleen or nodes, or may migrate to the respiratory tract.106,111
Radiotherapy, neoplastic chemotherapy, glucocorticoids, and the administration of antilymphocyte globulin all lead to lymphocytopenia by destroying circulating lymphocytes.103,112,113,114,115 and 116 Long-term treatment of psoriasis with psoralen and ultraviolet A irradiation (PUVA) may result in T-lymphocyte lymphopenia, possibly through destruction of cells circulating through the cutaneous vasculature.117 The mechanism by which glucocorticoids cause lymphocytopenia is not clear but may be secondary to a glucocorticoid-induced redistribution of lymphocytes118,119 in addition to an induced cell destruction.112,119,120 Redistribution also may be responsible for the lymphocytopenia occurring after surgery.121,122 and 123 In thoracic duct drainage, the lymphocytes are lost from the body.124 Platelet apheresis similarly lowers the lymphocyte count because of an inadvertent removal of lymphocytes with the platelets.125
SYSTEMIC DISEASE ASSOCIATED WITH LYMPHOCYTOPENIA
Patients with systemic autoimmune disease can have lymphocytopenia, either secondary to the underlying disease or to therapy.126 The lymphocytopenia of patients with systemic lupus erythematosus may be autoantibody mediated.127,128 The lymphocytopenia of sarcoidosis and renal failure may be due to impaired T-lymphocyte proliferative responses.129,130 In conditions such as protein-losing enteropathy, lymphocytes may be lost from the body.131 Severe thermal injury may result in profound T-cell lymphopenia secondary to redistribution of blood T cells to the tissues.132
NUTRITIONAL OR DIETARY
Zinc is essential for normal T-cell development and function.133 Zinc therapy corrects the lymphocytopenia of zinc deficiency, and lymphocytic function also is restored. Excessive intake of ethanol and/or chronic ethanol use may impair lymphocyte proliferative responses. The associated lymphopenia may resolve with abstinence from alcohol.134
IDIOPATHIC CD4+ T LYMPHOCYTOPENIA
The advent of immunophenotyping and HIV serologic testing has identified a syndrome of isolated CD4+ T-cell depletion in the absence of evidence for retroviral infection. The syndrome, termed idiopathic CD4+ T lymphocytopenia by the Centers for Disease Control and Prevention in 1993, is defined by a CD4+ T-lymphocyte count of less than 3 × 108/liter (300/µl) on two separate occasions in patients without serologic or virologic evidence of HIV-1 or HIV-2 infection.135 It is important to exclude congenital immunodeficiency diseases, such as common variable immunodeficiency, that may lead to altered CD4 T-cell counts that are recognized in later life (see Chap. 88).102,136 The pathogenesis of this disorder is not known, although one study found that the CD4+ T cells from patients with this abnormality were unusually sensitive to programmed cell death induced by T-cell–receptor cross-linking.137
Although some patients with idiopathic CD4+ T lymphocytopenia do not have any clinical manifestations,138,139 and 140 over half of all reported cases have had prior opportunistic infections indicative of a cellular immunodeficiency (e.g., recurrent herpes zoster, pulmonary Mycobacterium avium, Pneumocystis carinii pneumonia, or cryptococcal osteomyelitis).141,142,143,144 and 145 Patients who have such a clinical history are classified by the World Health Organization as having idiopathic CD4+ T lymphocytopenia and severe unexplained HIV-seronegative immune suppression.102
The exact proportion of patients with this disorder is unknown, since patients who are not affected clinically by the isolated CD4+ T-cell depletion may not come to medical attention. There are several reports of this abnormality in aged individuals, suggesting that the incidence may be increased in the aged population.143,146,147 CD4+ T-lymphocytopenic patients with this condition differ from those infected with HIV in that they generally have stable CD4+ counts over time and may manifest reductions in other lymphocyte subgroups.139,148 Also, patients with this abnormality may have a complete or partial spontaneous reversal in the CD4+ T lymphocytopenia.139
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn