CHAPTER 77 MONOCYTOSIS AND MONOCYTOPENIA
CHAPTER 77 MONOCYTOSIS AND MONOCYTOPENIA
MARSHALL A. LICHTMAN
Normal Blood Monocyte Concentration
Disorders Associated with Monocytosis
Inflammatory and Immune Disorders
Exogenous Cytokine Administration
Disorders Associated with Monocytopenia
The blood monocyte is in transit between the marrow and tissues, where it transforms into a macrophage. It participates in virtually all inflammatory and immune disorders, and thus its concentration may be increased in many such conditions, including autoimmune diseases, gastrointestinal disorders, sarcoidosis, and several viral and bacterial infections. Monocytosis may occur in some patients with cancer and several unrelated conditions, such as partuition, depression, and exogenous cytokine administration. The inconsistency and unpredictability in the monocyte response is a function of its relatively small blood pool size, the dampening effect of a large tissue pool, and the ability to expand macrophage numbers by local mitosis in tissues. The most striking increases in blood monocyte concentration occur with hematopoietic malignancies, especially monocytic or myelomonocytic leukemia. The reader is referred to Table 77-1 for a comprehensive list of causes of monocytosis. Monocytopenia is notable in patients with aplastic anemia or hairy-cell leukemia. Although other cytopenias accompany the monocytopenia, the latter is of particular functional importance and, often, in hairy-cell leukemia an aid to diagnosis.
Acronyms and abbreviations that appear in this chapter include: M-CSF, macrophage colony-stimulating factor.
TABLE 77-1 DISORDERS ASSOCIATED WITH MONOCYTOSIS
The blood monocyte is a cell in transit from marrow to tissues.1,2 and 3 There are two populations of blood monocytes: one is thought to represent a less mature stage, has a higher buoyant density, is smaller in volume, lacks Fc receptors, and has greater tumoricidal activity; the second is thought to represent a more mature stage, has a lower buoyant density, is larger in volume, displays Fc receptors, and has less tumoricidal activity.3 Thus, this heterogeneity is analogous to that of the blood band and segmented neutrophil.4 About 90 percent of blood monocytes strongly express CD14 (lipopolysacchride receptor) and do not express CD16 (Fcg receptor III), while 10 percent of blood monocytes have weak expression of CD14 and strong expression of CD16.5,6 and 7
In tissues, the monocyte is capable of transformation, under the influence of local environmental factors, into a macrophage. The monocyte plays an important role in acute and chronic inflammatory reactions, including granulomatous inflammation; immunologic reactions, including those involved in delayed hypersensitivity; tissue repair and reorganization; atheroma formation; and the reaction to neoplasia and allografts. Because of the monocyte’s key role in a variety of pathophysiologic reactions, a modest elevation in blood monocyte count can occur in many disparate conditions. In addition, in circumstances in which large increases in the number of macrophages are required in tissue sites, the demand may be met by local proliferation of macrophages and not be reflected either in increased transit of monocytes through the blood compartment from marrow to tissue or in an increased concentration of blood monocytes.8 Thus, unlike the case of neutrophils, increased tissue needs can be met locally. Occasionally, T-cell clones release only macrophage colony-stimulating factor (M-CSF), and their conditioned medium stimulates growth only of macrophage colonies, providing a hypothetical model for local control of macrophage proliferation.9
NORMAL BLOOD MONOCYTE CONCENTRATION
Monocytes constitute 1 to 9 percent of blood leukocytes.10 In the first 2 weeks of life, the average absolute blood monocyte count is about 1000/µl (1 × 109/liter).10,11 There is a gradual decline in the normal monocyte count to a mean of 400/µl (0.4 × 109/liter) in adulthood. Monocytosis is present when the absolute count exceeds 800/µl (0.8 × 109/liter) in adults.10,12 Men tend to have slightly higher monocyte counts than women.12 Increments in the number of blood monocytes correlate directly with increases in the total blood monocyte pool and the monocyte turnover rate.13 The blood monocyte count cycles with a periodicity of 5 days.14
DISORDERS ASSOCIATED WITH MONOCYTOSIS
Table 77-1 outlines the diseases reported to be associated with monocytosis. In one review, hematologic disorders represented more than 50 percent, collagen vascular diseases about 10 percent, and malignant disease about 8 percent of cases of monocytosis.15
About one-quarter of patients with myelodysplastic states have an increase in the absolute monocyte count.16,17 and 18 Occasionally, patients may have monocytic leukemoid reactions with the absolute monocyte count as high as 30,000/µl (30 × 109/liter).18,19 Chronic monocytosis may be the principal feature of a clonal hemopathy (preleukemic syndrome) and precede by years the development of acute leukemia.20,21 The number of promonocytes and monocytes may be increased in patients with acute myelogenous leukemia of the myelomonocytic17 or monocytic type.21,22 and 23 Patients with chronic myelogenous leukemia may have an increased proportion of monocytes in the blood, and in variants of chronic myelogenous leukemia the monocytosis may be striking. Such cases have been classified as subacute or chronic myelomonocytic25,26,27,28,29,30 and 31 or monocytic leukemia.32 In some cases the monocytes are immature and have features of monoblasts or promonocytes, but in many cases they are indistinguishable by light microscopy from blood monocytes.
Monocytosis occurs in a number of neutropenic states: cyclic neutropenia,33 chronic granulocytopenia of childhood,34 familial benign chronic neutropenia,35 infantile genetic agranulocytosis,36,37 and chronic hypoplastic neutropenia.38 Transient elevations of the monocyte count have been reported in the acute phases of drug-induced agranulocytosis.39,40 Monocytosis characteristically appears later in the recovery phase of agranulocytosis.41,42 Several reports39,41,42 have indicated that a normal or increased number of monocytes is a harbinger of recovery from agranulocytosis, but a few studies found monocyte counts to be of no prognostic value.35,43 Monocytosis has also been noted to precede agranulocytosis due to chlorpromazine use.44 A rare form of agranulocytosis with an accompanying monocytosis has been described as leukopenic infectious monocytosis.45
Monocytosis can occur with lymphomas and can increase with exacerbation of disease activity.46 Monocytosis has been noted in about 25 percent of cases of Hodgkin disease, although it does not correlate with prognosis.47,48 and 49 Blood monocytosis is likely to occur in diseases associated with histiocytic proliferation, such as the rare cases of true malignant histiocytosis.50 Monocytosis may also occur in individuals who have had splenectomy.51,52 and 53 A statistically significant increase in blood monocyte concentration has been reported in multiple myeloma54,55 and has been correlated with the presence of g light chains–containing monoclonal antibody.55 Rarely, cases of M-CSF–secreting lymphoid tumors have been associated with monocytosis.56,57
INFLAMMATORY AND IMMUNE DISORDERS
Collagen vascular disease, including rheumatoid arthritis,58 systemic lupus erythematosus, temporal arteritis, myositis, and periarteritis nodosa, may be associated with monocytosis, although monocytosis is not common in these diseases. The usual alterations of the white cell count of systemic lupus erythematosus, for example, are neutropenia and lymphopenia,59 but 10 percent of patients have a mild monocytosis.60
Infectious disease is an uncommon cause of monocytosis. Only a few instances of infection were noted in a comprehensive review of causes of monocytosis, including tonsillitis, dental infection, recurrent liver abscesses, candidiasis, and one instance of tuberculous peritonitis.15 Tuberculosis was once a leading cause of monocytosis, because of the role of monocytes in granuloma (tubercle) formation,61 and monocytic leukemoid reactions have been reported in the disease.62 Neither the monocyte count nor the ratio of monocytes to lymphocytes correlates with the stage or activity of tuberculosis.63,64
Monocytosis is found in 15 to 20 percent of patients with subacute bacterial endocarditis65,66 but is not correlated with the presence of blood macrophages, which may be present in this disease.67 Rarely, in acute bacterial infections, blood monocytes can exceed 20,000/µl (20 × 109/liter), and an increase in monocytes and monocyte precursors in the marrow can mimic acute monocytic leukemia.68
A number of infections formerly thought to be associated with monocytosis have been found not to be, when examined systematically. These include rickettsial diseases,69,70,71 and 72 brucellosis,73 leishmaniasis,74 typhoid fever,75 malaria,76 and disseminated candidiasis.77
A monocytosis in the resolution phase of acute infections has been noted,78 and monocytosis appears in neonatal, primary, and secondary syphilis.79 Occasionally, cases of neonatal syphilis have been associated with monocytic leukemoid reactions.80 Certain viruses, especially cytomegalovirus and varicella zoster virus, induce an increase in blood monocytes.81,82
Sprue, ulcerative colitis, and regional enteritis have been associated with monocytosis.15,83 Elevation of the blood monocyte count occurs in sarcoidosis84 and is inversely related to a reduction in circulating T lymphocytes.85 A similar correlation has also been noted in patients with malignant disease.86
Sixty percent of patients with nonhematologic malignancy exhibit a monocytosis that is independent of the presence or absence of metastatic disease.87 Thus, unexplained monocytosis should raise the possibility of a malignancy.
EXOGENOUS CYTOKINE ADMINISTRATION
The administration of granulocyte-macrophage colony-stimulating factor88 or interleukin-1089 may result in mild increases in blood monocyte counts. Administration of M-CSF89,90 and 91 results in an invariable increase in blood monocyte counts. At doses of 40 to 120 µg/kg/day, the peak increase, which may reach three-to fourfold baseline, is reached at about 8 days.
Other disorders associated with monocytosis include alcoholic liver disease,92 tetrachloroethane poisoning,93 and Langerhans cell histiocytosis.94 Increased monocyte counts do not occur in Niemann-Pick disease95 or Gaucher disease.96 Monocytosis is a frequent finding at the time of parturition.97,98 An increase in blood monocytes occurs in healthy volunteers99,100 or, rarely, in preleukemic patients101 given moderately high, therapeutic-level doses of glucocorticoids. Psychiatric depression is associated with a conjoint increase in neutrophils and monocytes.102,103
Spurious elevations of the blood monocyte count can occur when blood is obtained from the fingertips of patients who have peripheral vascular disease, such as Raynaud syndrome.104
DISORDERS ASSOCIATED WITH MONOCYTOPENIA
Although monocytopenia may occur in any hematopoietic stem cell disease associated with pancytopenia (e.g., myelogenous leukemia), a decrease in monocytes is notable and constant in aplastic anemia as part of the global decrease in production of blood cells.105 It is also a constant and important feature of hairy-cell leukemia, in which monocytopenia can be a helpful diagnostic clue and also a contributor to the predisposition to infection, which is an important morbid feature of the disease.106 Monocytopenia occurs in a small proportion of patients with chronic lymphocytic leukemia, and these patients may have a higher frequency of infections, especially by viruses.107 Cyclic neutropenia is also notable for intermittent periods of monocytopenia. Severe thermal injuries also can result in monocytopenia.108 Rare cases of conjoint severe neutropenia and monocytopenia occur.109,110
Automated blood cell counts in large numbers of subjects have demonstrated that decreased absolute monocyte counts are frequent in patients with rheumatoid arthritis,111 systemic lupus erythematosus,112 and human immunodeficiency virus infection.113
Glucocorticoid hormones produce a monocytopenia transiently about 6 h after administration to human volunteers114 or to patients.99,115 Administration of interferon a and tumor necrosis factor a may also cause monocytopenia.116 Monocytopenia may follow radiotherapy.117
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