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Table 70–1 outlines the diseases reported to be associated with monocytosis. In one review, hematologic disorders represented more than 50 percent, collagen vascular diseases approximately 10 percent, and malignant disease approximately 8 percent of cases of monocytosis.11
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HEMATOLOGIC DISORDERS
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Approximately 25 percent of patients with a myelodysplastic syndrome have an increase in the absolute monocyte count.12,13,14,15,16 Occasional patients with a myelodysplastic syndrome may develop an absolute monocyte count as high as 30,000/μL (30 × 109/L). Chronic monocytosis may be the principal feature of a clonal myeloid disease and precede by years the development of acute myelogenous leukemia. Patients with myelodysplasia and monocytosis have a high propensity to evolve into acute or chronic myelomonocytic leukemia. Monocytosis, as a feature of primary myelofibrosis, may be a harbinger of rapid progression.17 The number of promonocytes and monocytes in blood and marrow may be increased in patients with acute myelogenous leukemia of the monocytic18,19 or myelomonocytic type.20 Acute myelogenous leukemic cells with a histiocytic (macrophagic)21 or dendritic cell phenotype have been described.22,23,24 Patients with chronic myelomonocytic leukemia have, by definition, an increased absolute number of monocytes in the blood (≥1.0 × 109/L). The monocytosis may be more striking in some cases.25,26,27 Juvenile myelomonocytic leukemia, also, is defined in part by the increased number of monocytes in the blood and marrow.28 In some cases of acute monocytic leukemia, the monocytes are immature and have features of monoblasts or promonocytes, but in some cases they are indistinguishable by light microscopy from normal blood monocytes. Some automated instruments are dependent on the α-naphthol acetate esterase reaction to detect the proportion of monocytes in white cell differential counts. These instruments may underestimate leukemic monocytes counts, especially in cases of chronic myelomonocytic leukemia, because the leukemic monocytes have a decreased activity of the enzyme.25 An uncommon variant of Ph-positive chronic myelogenous leukemia (CML), expressing a p190 BCR-ABL transcript, is associated with a striking monocytosis in approximately 50 percent of cases.29,30
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Monocytosis occurs in a number of neutropenic states: cyclic neutropenia,31 chronic granulocytopenia of childhood,32 familial benign chronic neutropenia,33 infantile genetic agranulocytosis34,35 and chronic hypoplastic neutropenia.36 In human cyclic neutropenia, monocyte oscillation is reciprocal to the neutrophil cycle; the peak monocytosis, which often exceeds 2000/μL (2.0 × 109/L), occurs at the end of the neutropenic period. Monocytes often stay above 500/μL (0.5 × 109/L) throughout the cycle. In the variety of other neutropenias mentioned, monocytopoiesis often is preserved in the face of neutropenia. Transient elevations of the monocyte count have been reported in the acute phases of drug-induced agranulocytosis.37,38,39 Monocytosis characteristically appears later in the recovery phase of agranulocytosis and may be a harbinger of recovery.37,40,41 Some observers dispute the validity of the latter observation.42
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Monocytosis can occur with lymphomas and can increase with exacerbation of disease activity.43 Monocytosis has been noted in approximately 25 percent of cases of Hodgkin lymphoma, although it does not correlate with prognosis.43,44 In contrast, one treatise on the disease reports the hematologic values of patients with Hodgkin lymphoma at the time of diagnosis; only 4 of 100 have nominal increases in absolute blood monocyte counts.45 A statistically significant increase in blood monocyte concentration has been reported in myeloma and has been correlated with the presence of λ light-chain-containing monoclonal immunoglobulin.46,47 Rare cases of M-CSF secreting lymphoid tumors have been associated with monocytosis.48,49 Monocytosis at diagnosis has been correlated with decreased survival in several lymphoma types and chronic lymphocytic leukemia.50,51 Pseudolymphoma syndrome, induced by drugs such as carbamazepine, phenytoin, phenobarbital, and valproic acid, is associated with monocytosis.52
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Monocytosis is a common feature in individuals who have had splenectomy.53,54
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INFLAMMATORY AND IMMUNE DISORDERS
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Connective tissue diseases, including rheumatoid arthritis,55 systemic lupus erythematosus, temporal arteritis, myositis, and periarteritis nodosa, may be associated with monocytosis, although monocytosis is not common in these diseases.11 The usual alterations of the white cell count in systemic lupus erythematosus, for example, are neutropenia and lymphopenia, but 10 percent of patients have a mild monocytosis.56 An elevation of the blood monocyte count occurs in sarcoidosis57 and is inversely related to a reduction in circulating T lymphocytes.58
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Infectious diseases are 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.11 Tuberculosis was once a leading cause of monocytosis, because of the role of monocytes in granuloma (tubercle) formation. Neither the monocyte count nor the ratio of monocytes to lymphocytes correlates with the stage or activity of tuberculosis.59,60,61 Mycobacterium fortuitum infection, usually in the setting of AIDS, also is associated with monocytosis.62
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Monocytosis is found in 15 to 20 percent of patients with subacute bacterial endocarditis,63,64 but is not correlated with the presence of blood macrophages, which may be present in this disease.65
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A number of infections formerly thought to be associated with monocytosis are not, when examined systematically. These include rickettsial diseases, leishmaniasis, typhoid fever, malaria, and disseminated candidiasis, brucellosis,66 and dengue hemorrhagic fever.67
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A monocytosis in the resolution phase of acute infections has been noted,68 and monocytosis occurs in cases of neonatal, primary, and secondary syphilis.69,70 Certain viruses, especially cytomegalovirus varicella-zoster virus, and influenza virus induce an increase in blood monocytes.71,72,73
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GASTROINTESTINAL DISEASES
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Sprue, ulcerative colitis, regional enteritis, and alcoholic liver disease are associated with monocytosis.11,74,75
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NONHEMATOPOIETIC MALIGNANCIES
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Sixty percent of patients with nonhematologic malignancy exhibit a monocytosis that is independent of the presence or absence of metastatic disease.76 An inverse relationship of monocyte count (elevated) and T-lymphocyte concentration (decreased) has also been noted in patients with malignant disease.77 Reports of hematologic values in metastatic colon cancer and soft-tissue sarcoma have emphasized the frequency of monocytosis in patients with cancer.78,79 Consequently, if unexplained monocytosis persists, malignancy should be considered.
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EXOGENOUS CYTOKINE ADMINISTRATION
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The administration of granulocyte-macrophage colony-stimulating factor (GM-CSF),80 IL-10,81 or granulocyte colony-stimulating factor (G-CSF)82,83 may result in mild increases in blood monocyte counts. Administration of M-CSF84,85 results in an invariable increase in blood monocytes. Doses of 40 to 120 mcg/kg per day result in the peak increase, which may reach three- to fourfold baseline, in approximately 8 days. Administration of human macrophage inflammatory protein-1α to patients or normal volunteers is associated with a brief monocytopenia followed by a monocytosis that is proportional to the dose administered.86
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MYOCARDIAL INFARCTION
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Monocytosis occurs after myocardial infarction, reaching a peak on day 3. A correlation exists between serum creatine kinase activity and monocyte count, suggesting a relationship between extent of infarction and monocytosis.87 After myocardial infarction, persistent monocytosis is correlated with pump failure.88,89,90 Monocytosis is a frequent finding after cardiopulmonary bypass surgery.91 In the latter circumstance, CD14 (lipopolysaccharide [LPS] receptor) is markedly decreased on the monocyte surface and plasma-soluble CD14 is increased, changes compatible with monocyte activation.
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MISCELLANEOUS CONDITIONS
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Other disorders associated with monocytosis include tetrachloroethane poisoning.92 Monocytosis is a frequent finding at the time of parturition.93,94 An increase in blood monocytes occurs in healthy volunteers95,96 and in patients with myelodysplastic syndrome (MDS)97,98 who are given moderately high, therapeutic-level doses of glucocorticoids. Psychiatric depression is associated with a conjoint increase in neutrophils and monocytes.99,100,101 The monocytosis in depressive and anxiety disorders is associated with high plasma levels of β endorphins and dysfunctional (hypophagocytic) monocytes.101 Thermal injury is accompanied by monocytosis.102,103 Competitive marathon runners have a monocytosis associated with elevated plasma levels of several cytokines, including M-CSF.104,105 An increase in blood monocytes accompanies several rare syndromes: holoprosencephaly,106 Kawasaki disease,107 and Wiskott-Aldrich.108