Chapter 70: Monocytosis and Monocytopenia

The blood monocyte is a cell in transit from marrow to tissues.¹ There are two major populations of blood monocytes based on physical properties: a smaller population thought to represent a less-mature stage, has a higher buoyant density, a smaller cell volume, lacks Fc receptors, and has greater tumoricidal activity; the larger population represents a more-mature stage, has a lower buoyant density, has a larger cell volume, displays Fc receptors, expresses more peroxidase activity, secretes larger amounts of interleukin (IL)-1, presents antigen, and mediates antibody-dependent cell-mediated cytotoxicity more efficiently. The larger population, classical monocytes that are highly phagocytic and proinflammatory, composes approximately 90 percent of blood monocytes, and strongly expresses CD14 (lipopolysaccharide receptor) but does not express CD16 (FcγRIII), designated the CD14⁺⁺CD16⁻ subset. These monocytes carry chemokine receptors CCR2^hiCX3CR1^lo. Of the remaining monocyte population, approximately 5 percent exhibit strong expression of CD14 and modest expression of CD16, the CD14⁺⁺CD16⁺ “intermediate” subset, which expresses the chemokine receptors CCR2^midCX3CR1^hiCCR5^mid, are proinflammatory and less phagocytic, and the “nonclassical” subset, which exhibits strong expression of CD16, the CD14⁺CD16⁺⁺ subset, which expresses the chemokines CCR^loCX3CR1^hi, the so-called patrolling subset.² The latter subset contains dendritic cell precursors.³ The major subsets can each be further stratified based on the expression of CD64 (FcγRI) (Chaps. 67 and 68).⁴

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 and thrombus formation; and the reaction to neoplasia and allografts. Because of the key role of monocytes 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 an increased transit of monocytes through the blood compartment from marrow to tissue or in an increased concentration of blood monocytes.⁵ Occasionally, T-cell clones release only macrophage/monocyte colony-stimulating factor (M-CSF), which can stimulate the growth of macrophage colonies, providing a model for local control of macrophage proliferation.⁶

In the first 2 weeks of life, the average absolute blood monocyte count is approximately 1000/μL (1 × 10⁹/L; Chap. 7). There is a gradual decline in the normal monocyte count to a mean of 400/μL (0.4 × 10⁹/L) in adulthood, at which time monocytes constitute 1 to 9 percent (mean: 4 percent) of blood leukocytes (Chap. 2). Monocytosis is present when the absolute count exceeds 800/μL (0.8 × 10⁹/L) in adults. Men tend to have slightly higher monocyte counts than women.⁷ Increments in the number of blood monocytes correlate directly with increases in the total blood monocyte pool and the monocyte turnover rate.⁸ The blood monocyte count cycles with a periodicity of 5 days.⁹ Older persons have a decrease in the proportion of CD14⁺⁺CD16⁻ to CD14⁺CD16⁺ monocytes as compared to younger persons, although the functional significance of this difference has not been established.¹⁰

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

HEMATOLOGIC DISORDERS

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 monocytic^18,19 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

Monocytosis occurs in a number of neutropenic states: cyclic neutropenia,³¹ chronic granulocytopenia of childhood,³² familial benign chronic neutropenia,³³ infantile genetic agranulocytosis^34,35 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

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

SPLENECTOMY

Monocytosis is a common feature in individuals who have had splenectomy.^53,54

INFLAMMATORY AND IMMUNE DISORDERS

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

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

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

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

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

GASTROINTESTINAL DISEASES

Sprue, ulcerative colitis, regional enteritis, and alcoholic liver disease are associated with monocytosis.^11,74,75

NONHEMATOPOIETIC MALIGNANCIES

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.

EXOGENOUS CYTOKINE ADMINISTRATION

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-CSF^84,85 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

MYOCARDIAL INFARCTION

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.

MISCELLANEOUS CONDITIONS

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 volunteers^95,96 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

Differential monocyte subset responses (CD14⁺⁺CD16⁻ vs. CD14⁺CD16⁺) without deviation of total monocyte counts outside the normal range have been observed in older subjects and those with sepsis, AIDS, allergic disorders, dermatitides, hemodialysis, and atherosclerosis.^4,10,91,109 These monocytic subset variations usually are not measured in clinical laboratories and, as yet, have little diagnostic or prognostic importance.

Table 70–2 lists the disorders associated with monocytopenia. Although monocytopenia may occur in any hematopoietic multipotential cell disease associated with pancytopenia (e.g., acute myelogenous leukemia), a decrease in monocytes is notable and constant in aplastic anemia¹¹⁰ and hairy cell leukemia,¹¹¹ 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. 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.¹¹² Severe thermal injuries also can result in monocytopenia.¹¹³ Cyclic neutropenia is also notable for intermittent periods of monocytopenia.¹¹⁴ Rare cases of conjoint severe neutropenia and monocytopenia occur.¹¹⁵ Transient monocytopenia is a feature of hemodialysis, but monocyte counts return to normal within hours after the procedure ends.¹⁰⁹

In contrast, to reports of monocytosis noted above in “Inflammatory and Immune Disorders,” automated blood cell counts in large numbers of subjects find that a decreased absolute monocyte count is frequent in patients with rheumatoid arthritis¹¹⁶ or systemic lupus erythematosus,¹¹⁷ and in those with human immunodeficiency virus infection.¹¹⁸ One has to presume that these contrasting results relate to stage or activity of disease at the time of measurement.

In 2010, a disease was described in which extreme monocytopenia, and sometimes amonocytosis, was the most striking abnormality in the blood counts.¹¹⁹ It has been named the MonoMAC syndrome because of the monocytopenia (mono) and the frequency of Mycobacterium avium complex (MAC) opportunistic infections, although persistent fungal and viral infections (especially papillomavirus), also occur. Marked decreases in blood B-cell, natural killer (NK)-cell, and dendritic cell counts are characteristic.^120,121 The disease is the result of mutations in the GATA2 gene that decrease transcription of the gene message.¹²² It may present as an atypical type of MDS with a hypocellular marrow, but with striking dysmorphic megakaryocytes and micromegakaryocytes, or with acute myelogenous leukemia.¹²³ Because of the GATA2 gene product’s role in the development of the vascular and lymphatic systems, some cases may have the triad of lymphedema, monosomy 7, and myelodysplasia or acute myelogenous leukemia, designated the Emberger syndrome.^{124,125,126,127} Hematopoietic stem cell transplantation has been successful in restoring normal immunohematopoiesis in some of the patients so treated.¹²⁸

Glucocorticoid hormones produce a monocytopenia, transiently, approximately 6 hours after administration to human volunteers^129,130 or to patients.⁹⁵ Administration of interferon-α and tumor necrosis factor-α may also cause monocytopenia.¹³¹ Monocytopenia may follow radiotherapy.¹³²

Blood dendritic cells are composed of two phenotypic subtypes: myeloid-derived (HLA-DR⁺CD11c⁺CD123⁺) and lymphoid-plasmacytoid-derived (HLA-DR⁺CD11c⁻CD123⁺). The total blood dendritic cell count can be measured by flow cytometry.^133,134,135 Dendritic cells make up approximately 0.6 percent of blood cells (range: 0.15 to 1.30 percent) and represent 14 × 10⁶ cells/L (range: 3 to 30 × 10⁶ cells/L). Approximately one-third of these cells are a lymphoid-plasmacytoid–derived type and two-thirds are a myeloid-derived type.^135,136,137 Fluctuations in blood dendritic cells are often independent of changes in total blood monocyte count. Blood dendritic cell counts decrease with aging¹³⁸ and increase with surgical stress¹³⁷ (and presumably other stressful reactions) in relation to plasma cortisol levels.