What every physician needs to know about leukocytosis:
The peripheral white blood cell count (WBC) ranges from 5.0 to 10.0 x 109/L. Leukocytosis is defined as a white count above 11.0 x 109/L. Because circulating white cells include heterogeneous cell types (neutrophils [Figure 1], monocytes [Figure 2], basophils, eosinophils [Figure 3], and a variety of lymphocyte [Figure 4] subsets), the first step to take in a patient with leukocytosis is identifying which of the white cell types is over-represented.
Occasionally, the over-represented leukocytes in patients with leukocytosis will be cells that don’t belong in the peripheral blood at all (for example, myeloblasts and lymphoblasts). Such findings are often indicative of acute leukemia. So a critically important first step is to determine the “white blood cell [WBC] differential”.
Neutrophilic leukocytosis is one of the most frequent abnormalities found in any population of sick patients and is most often caused by infections, hypoxic tissue damage, trauma, inflammatory diseases, malignancy, or trauma. Even when the WBC count is high because of an excess of the more uncommon differentiated cell types, the response generally reflects responses of the marrow to environmental cues arising during the course of infections, other inflammatory processes, allergic responses, or malignancy. Therefore, the vast majority of patients with leukocytosis have a perfectly normal bone marrow that is simply responding appropriately to such challenges. Getting to the underlying cause involves a history, physical examination, appropriate imaging studies, and simple blood tests. Extremely high leukocyte counts (over 50 x 109/L) in patients who have this type of “reactive” leukocytosis are known as “leukemoid” reactions.
What features of the presentation will guide me toward possible causes and next treatment steps:
If very primitive blast forms (Figure 5) are present in the blood, or if there are both blasts and nucleated red cells seen on the blood smear, thoughts should immediately turn to the real possibility of an acute leukemic disorder and steps should be immediately taken to rule out those diseases. If the dominant white cell type is well-differentiated, chronic myeloproliferative disorders are a possibility, but it is unusual for the cause to be a primary hematologic condition.
Completing a careful history and physical examination, and determining the amount of leukocytosis and what cell types account for the increase, are essential first steps. Because neutrophils are highly effective scavengers and killers of most bacteria, an increase in their numbers and their deployment from the blood to diseased sites is, more often than not, a sign that organisms are aboard that need to be controlled.
Once the patient is initially evaluated, a focal point of diagnostic interest will likely be identified. For example, cough, pleuritic chest pain, and fever would represent indications to rule out pneumonia or other thoracic inflammatory diseases. Fever, lower abdominal pain, and pyuria would suggest something entirely different. Consequently, imaging studies and cultures need to be obtained in patients whose findings at the bedside are most consistent with acute inflammation.
If a patient with leukocytosis shows no signs or symptoms of overt inflammation, the diagnostic considerations are different. Here, it is more likely that the increase in the leukocyte count reflects a more chronic inflammatory, immune mediated, or neoplastic condition. Other clinical findings compatible with a neoplastic condition include enlarged lymph nodes, infiltrative skin lesions, hepatosplenomegaly, or abdominal masses. Once more, the complete blood count proves to be of substantial value. Lymphocytosis, monocytosis, and eosinophilia are caused by a more limited group of abnormalities but, even in these instances, can result from infectious and autoimmune diseases, as well as malignancies.
Anemia and thrombocytopenia can also occur with infectious and other inflammatory conditions so do not represent sufficient evidence of a primary hematopoietic condition (for example, leukemia). Consequently, in such cases, it is not always necessary to perform a bone marrow examination. However, “leukoerythroblastosis,” a term that describes the observation of primitive white blood cell precursors and nucleated red blood cells in the circulating peripheral blood, is an almost universal indication that a bone marrow biopsy and aspiration is warranted. While this can occur in adults and children with very brisk hemolytic anemias, for the most part it is a sign that the integrity of the bone marrow microenvironment has been compromised by some invasive disease (usually neoplastic) and is no longer capable of retaining these cells at an intramedullary site.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Other tips from the WBC differential count
The presence of eosinophils in patients with acute infections or trauma is unusual because stress-induced glucocorticosteroids very rapidly purge the circulating blood of these cells and of basophils as well. Therefore, if eosinophils are seen in the blood of such a patient there are four diagnostic possibilities to consider:
- Combined adrenal insufficiency and inflammation
- Autoimmune disorders or parasitic diseases resulting in the overproduction of both eosinophils and neutrophils
- Overproduction of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin (IL)-5 (both have eosinophilopoietic activity) by malignant epithelial cancers
- Chronic myeloproliferative disorders
What conditions can underlie leukocytosis:
Recounting the disorders that cause any kind of leukocytosis would be an exercise without end. Fortunately, because the conditions associated with high monocyte counts are not the same as those that underlie high lymphocyte or neutrophil counts, one can narrow the scope of the differential diagnostic process, simply by focusing on the specific leukocyte types increased in the peripheral blood. This is why the differential WBC is so important.
Sets of disorders linked to the overproduction of specific leukocyte types are reviewed here
Neutrophilic leukocytosis with clinical signs of inflammation
In patients with leukocytosis and signs of an infectious process, recall that the cells in the peripheral blood are using the circulatory system as a highway to get somewhere else. Your diagnostic objective is to find out where they’re going, because that is where the site of inflammation is apt to be. Once more, the history, physical examination, and imaging studies are most apt to be helpful in finding those sites. It is also true that for any given inflammatory disease, patients with higher levels of leukocytosis have more aggressive disease, more likelihood of systemic spread of infection, and in some cases, higher mortality rates.
Neutrophilia without clinical signs of inflammation or trauma
Five general explanations should be considered:
- Pharmacological or chemical agents
Pharmacological or chemical agents including lithium chloride, epinephrine, or glucocorticosteroid hormones (laboratory tests for these factors are generally not required because they are revealed or not in the history and physical exam).
The spleen contains a good number of marginated neutrophils, so splenectomized patients have higher white counts in the ground state than do patients with functioning spleens.
- Malignant neoplasms of non-hematopoietic origin
Malignant neoplasms of non-hematopoietic origin which can sometimes produce abnormally high levels of granulopoietic cytokines (for example, GM-CSF or granulocyte colony-stimulating factor [G-CSF]. Laboratory tests of relevance would depend upon the history and physical examination, but would include imaging and possibly endoscopic studies.
- Chronic myeloproliferative diseases
Chronic myeloproliferative diseases include chronic myelogenous leukemia, chronic neutrophilic leukemia, idiopathic myelofibrosis, essential thrombocytosis, and polycythemia vera. Laboratory studies of importance include genetic analyses seeking, in leukocyte DNA, evidence of the JAK2V617F mutation (for polycythemia vera or myelofibrosis), the chromosomal translocation resulting in the fusion of the BCR and ABL genes (chronic myelogenous leukemia), activating mutations of MPL or JAK2 and mutations of CALR (essential thrombocytosis) or activating mutations of CSF3R (chronic neutrophilic leukemia).
- Chronic leukocytosis
Rarely, patients who have chronic leukocytosis give histories of recurring infectious diseases (bacterial and fungal), delayed wound healing, oral ulcers and periodontal disease. These are patients with an inherited disorder, leukocyte adhesion deficiency, whose neutrophils have a defect that impairs their ability to migrate to sites of infection. This disorder is rare but is responsive to novel therapies. Common causes of neutrophilic leukocytosis are listed in Table I.
|Rheumatic and autoimmune disorders||Rheumatoid arthritis|
|Autoimmune hemolytic anemia|
|Inflammatory bowel disease|
|Neoplastic disorders||Pancreatic, gastric, bronchogenic, breast and renal cell carcinoma|
|Any cancer metastatic to the bone marrow|
|Lymphoma, especially Hodgkin’s disease|
|Chronic myeloproliferative disorders (chronic myelogenous leukemia, chronic neutrophilic leukemia, myelofibrosis with myeloid metaplasia, essential thrombocytosis, polycythemia vera)|
|Venoms (reptiles, insects, jellyfish)|
|Endocrine and metabolic disorders||Ketoacidosis|
|Hematologic disorders (non-neoplastic)||Acute hemolysis|
|Recovery from marrow failure|
|Leukocyte adhesion deficiency|
|Other disorders||Tissue necrosis|
|Granulocyte colony stimulating factor (G-CSF)|
|Granulocyte-macrophage colony stimulating factor (GM-CSF)|
Monocytosis exists when monocyte counts are in excess of 0.50 X 109/L in adults and 0.80 X 109/L in children. The cells are over-produced in the bone marrow, in response to the production of macrophage colony-stimulating factor (M-CSF) and GM-CSF by a variety of stromal, epithelial, and endothelial cells from both intramedullary and extramedullary sites. Unlike neutrophils which survive only briefly in extravascular sites, monocytes leave the circulation and can establish themselves as tissue macrophages that survive for months and can replicate in those sites.
Monocytes are the most evolutionarily conserved of the phagocytes (ancestors of which were discovered by Metchnikoff in starfish larvae in 1882). Mammalian monocytes present antigens to lymphocytes, mediate cellular cytotoxicity, participate in wound repair and bone remodeling, dispose of damaged cells and extracellular debris, and regulate the immune and hematopoietic responses by responding to cytokine cues from lymphoid cells (for example, interferons) and by producing a variety of cytokines including interleukin 1 (IL-1), tumor necrosis factor (TNF-alpha), G-CSF, other pro-inflammatory interleukins (IL-6, IL-8, IL-12, IL-18, IL-27, IL-27)-, insulin-like growth factor 1 (IGF-1) and anti-inflammatory cytokines, IL-10 and TGF-β.
Mononuclear phagocytes move more slowly toward bacteria and are somewhat less effective in killing them than are neutrophils, but they are more effective in controlling obligate intracellular parasites such as fungi, yeast, spirochetes, and viruses. These cells are critically important in controlling mycobacterial infection and they are a histological sine qua non of granulomatous inflammation. Accordingly, monocytosis is often seen in patients with tuberculosis, brucellosis, protozoal infections, some viral infections (for example, varicella), syphilis, and fungal infections as well as granulomatous colitis and sarcoidosis. Monocytosis is common in patients with a variety of solid tumors and in Hodgkin’s disease. These cells infiltrate malignant neoplasms and, in some instances, may play a role in their progression.
The highest levels of monocytes in the peripheral blood are seen in patients with primary hematopoietic malignancies, especially chronic myelomonocytic leukemia (CMML), juvenile chronic myelomonocytic leukemia (JMML), acute monocytic leukemia (AML-M5), and acute myelomonocytic leukemia (AML-M4). These are disorders associated with anemia, thrombocytopenia, and in some cases marked splenomegaly and extramedullary mucosal and cutaneous infiltrates. Many of the monocytes are primitive pro-monocytes or monoblasts in patients with the acute leukemias.
These are straightforward morphological microscopic diagnoses and warrant bone marrow examination and both molecular and cytogenetic testing, because there is substantial variation at a molecular level. For example, mutations in TET2, RUNX1, and JAK2 are commonly found in patients with CMML but are rarely seen in JMML, in which CBL, NRAS, ASXL1 and SHP2 mutations are more common. Causes of monocytosis are listed in Table II.
|Typhoid and paratyphoid|
|Recovery from acute infections|
|Viral (for example, varicella)|
|Neoplastic diseases||Hodgkin’s disease|
|Carcinoma (many varieties)|
|Acute monocytic and acute myelomonocytic leukemia|
|Juvenile chronic myelomonocytic leukemia|
|Chronic myelomonocytic leukemia|
|Myeloma and Waldenstrom’s macroglobulinemia|
|Gastrointestinal disorders||Ulcerative colitis|
|Recovery from bone marrow suppression|
This is defined as a lymphocyte count in excess of 5.0 X 109/L. If 20% or more of the lymphocytes appear morphologically “atypical” (an increase in the amount of cytoplasm and a “ballerina skirt” appearance of the plasma membrane), the term “atypical lymphocytosis” is used, a nearly universal finding in acute and subacute infectious mononucleosis. Many viral infections can cause mild (up to 12 X 109/L) lymphocytosis, but the differential diagnosis begins to narrow as the total lymphocyte count increases to higher levels. If the dominant lymphoid cell in the blood is a very primitive lymphoid precursor, a lymphoblast, the possibility of acute lymphoblastic leukemia must be entertained immediately. Causes of lymphocytosis are listed in
|HIGH (greater than 15 x 109/L)||Infectious mononucleosis|
|Acute infectious lymphocytosis|
|Chronic lymphocytic leukemia and variants thereof|
|Acute lymphocytic leukemia|
|MODERATE (less than 15 x 109/L)Viral infections||Infectious mononucleosis|
|Human immunodeficiency virus -1 (acute lymphadenopathy)|
|Other infectious diseases||Toxoplasmosis|
|Acute lymphocytic leukemia (early)|
|Chronic lymphocytic leukemia|
|Autoimmune disorders||Sjögren’s syndrome|
Lymphocytosis, moderate (less than 15 X 10/L)
Viral infections are common causes of moderate lymphocytosis, especially varicella, measles, coxsackievirus, adenovirus, mumps, cytomegalovirus, HIV-1, and Epstein-Barr virus (EBV). The history and physical examination will be very helpful in guiding the decision to obtain specific confirmatory serological studies. For example, skin lesions would be expected with measles and varicella, the stigmata of mumps are unmistakable, and pharyngitis, fever, palatal enanthem, atypical lymphocytosis, and liver function abnormalities (elevated transaminases) should strongly suggest EBV-induced infectious mononucleosis.
Acute bacterial infections rarely induce lymphocytosis. Bordetella pertussis is an important exception. In this disorder, lymphocytosis is common and is often profound (for example, lymphocyte counts of 60 X 109/L). Some cases of whooping cough have been diagnosed by hematologists to whom patients have been sent “to rule out lymphocytic leukemia.”
Lymphocytosis, high level (greater than 15 X 10/L)
Very high lymphocyte counts can be seen in patients with infectious mononucleosis (EBV), pertussis, and acute infectious lymphocytosis. In these cases, the clinical setting clearly reveals classic signs of inflammation. Absent such signs, these disorders are unlikely and thoughts must turn to lymphoid leukemias. To establish the diagnosis of one of these, tissue is generally required from lymph nodes or bone marrow. But the acuity of the disease will likely be revealed simply by examining the peripheral blood smear. If the lymphoid cells are large blast forms, acute lymphoblastic leukemia is likely and must be ruled out expeditiously with histological, cytogenetic, flow cytometric, and molecular genetic analyses of the blasts, ideally from the bone marrow. If the lymphoid cells are well differentiated small lymphocytes, the diagnosis is likely to be chronic lymphocytic leukemia or its variants.
Eosinophils are produced by progenitor cells in the marrow, largely under the influence of interleukin 5 (IL-5), a protein that also stimulates the growth and differentiation of B-lymphocytes. They are fully empowered phagocytes and efficient killers important in responding to parasitic organisms too large for any phagocyte to engulf and dispose of. They do this by attaching to such organisms then releasing highly toxic factors from their eosinophilic granules, not into the confines of a phagosome in its own cytoplasmic space (like neutrophils and monocytes do), but instead by releasing these cytotoxic factors to the extracellular environment, effectively “bombing” the parasite with cationic proteins including peroxidase (which in turn generates hypobromous acid and nitrogen dioxide highly toxic to pathogens), eosinophilic cationic protein, and neurotoxin.
Eosinophils were named for Eos the Greek goddess of the dawn because of the large bright orange red granules that fill the cytoplasm of these cells when stained with Wright-Giemsa (Figure 3). They function additionally to moderate the potentially toxic effects of mast cell degranulation in hypersensitivity reactions. Consequently, eosinophilic leukocytosis is commonly seen in parasitic infections and in allergic inflammation involving allergen specific immunoglobulin E (IgE) produced in response to environmental allergens. Eosinophil production and traffic is highly sensitive to suppression by glucocorticosteroids so hypersensitivity reactions often respond to such therapy. If eosinophilia is part of the clinical picture in any given hypersensitivity reaction, the eosinophils disappear from the peripheral blood within hours of initiating steroid treatment.
Mild, moderate, and severe eosinophilia represents peripheral counts of up to 1.5 X 109/L, from 1.5 – 5 X 109/L, and greater than 5 X 109/L, respectively. Counts in the moderate to severe range (counts that meet the standard of “hypereosinophilia”) have the potential for damaging organ systems (particularly heart, lung, and endothelial cells in a variety of sites) through the same mechanisms that allow these cells to destroy parasites under normal circumstances.
Hypereosinophilia can represent a reactive response to a particular insult (parasite or allergen) but is sometimes the result of overproduction. These primary eosinophilic syndromes are often clonal neoplasms, sometimes of myeloid origin (“chronic eosinophilic leukemia,” and “myeloid neoplasms with eosinophilia and rearrangements of the PDGFRA, PDGFRB, JAK2 or FGFR1 genes,” genes rearrangements that can also be found in some cases of acute myelogenous leukemia, myeloproliferative disorders, and myelodysplasia and sometimes neoplasms of lymphoid origin. In the latter instance, the lymphoid cells secondarily induce eosinophilia (for example, “lymphocyte variant hypereosinophilia”) by producing eosinophilopoietic factors (IL-5 for example). Absent evidence of these, a diagnosis of exclusion (“idiopathic hypereosinophilic syndrome” [HES]) is used to cover the uncategorized patients. Causes of eosinophilia are listed in Table IV.
|Metal induced (for example, nickel)|
|Chemicals (for example, trichloroethylene)|
|Drug reactions (anticonvulsants, antibiotics)|
|Allergic bronchopulmonary aspergillosis|
|Eosinophilic syndromes involving skin||Atopic dermatitis|
|Eosinophilic syndromes involving other sites||Eosinophilic pneumonia|
|Eosinophilia associated with hematologic neoplasms||Hodgkin’s disease|
|Chronic eosinophilic leukemia|
|Myeloid neoplasms associated with PDGFRA, PDGFRB, or FGFR1 gene rearrangements|
|Lymphoid neoplasms associated with PDGFRA and FGFR1 gene rearrangements|
|Chronic myelogenous leukemia|
|Systemic mastocytosis with eosinophilia|
|Other||Hyperimmunoglobulin E syndrome|
When do you need to get more aggressive tests:
Leukocytosis with blasts in the peripheral blood
If any physical sign or finding in the peripheral blood smear is compatible with an acute leukemia (for example, the presence of primitive blast forms and/or nucleated red blood cells), ruling out acute leukemia becomes an extraordinarily high priority, because the disease can be acutely life-threatening. This involves obtaining a bone marrow aspirate and biopsy. The aspirates are helpful not only morphologically (marrow smears) but also provide cells for flow cytometric, cytogenetic, and molecular genetic analyses, all of which are important in establishing a diagnosis and providing important prognostic information and, more recently, in guiding personalized therapy.
Most patients with this finding have an overt inflammatory process to which they are responding in a perfectly adaptive way. Absent signs of such processes, persistent neutrophilia should raise the following concerns:
- Asplenia (an ultrasound can rule this in or out)
- Pharmacological or chemical agents (lithium chloride levels might be helpful)
- Solid tumors that induce leukocytosis are not necessarily large (so imaging studies of the lung, abdomen, and pelvis can be helpful).
- Chronic myelogenous leukemia, chronic neutrophilic leukemia or a chronic myeloproliferative disorder. Here the signs can include basophilia, eosinophilia, thrombocytosis, or splenomegaly. The diagnoses are based on molecular genetic analyses for characteristic genomic alterations including translocations (e.g., BCR-ABL), activating point mutations (e.g., JAK2, MPL, and CSF3R, or insertions or deletions (e.g., CALR).
- Leukocyte adhesion defects generally result from inherited mutations of adhesion molecules. In the proper clinical setting (recurrent infections, slow wound healing, periodontal infections), flow cytometric analysis should be done on peripheral blood samples seeking evidence of reduced or absent levels of the surface molecules CD18 or CD15s.
With the exception of patients with early chronic lymphocytic leukemia, most patients with moderate to high level lymphocytosis have overt signs of an underlying illness involving anatomic sites other than the lymphohematopoietic system. The diagnostic approach depends simply on establishing a differential diagnosis based on the clinical picture, which in the instance of infectious etiologies can involve a battery of serological assays testing for endogenous antibodies targeting defined viral antigens.
For patients with no clear evidence of one of the more benign disorders, a tissue diagnosis can be extraordinarily helpful. Bone marrow aspiration can be helpful when lymphocytosis persists in a patient who has no evidence of acute or subacute infection or evidence of acute leukemia (from the peripheral smear and complete blood count).
If the lymphocyte count is high enough, some argue that the circulating lymphocytes can be used to obtain all of the studies necessary to firmly establish a diagnosis of chronic lymphocytic leukemia (immunophenotyping using monoclonal antibodies against definitive integral membrane proteins and immunoglobulin light chains). The light chain analysis tests the idea that the lymphocyte population is “clonal”. Clonality is presumed when the vast majority of the lymphoid cells express either lambda or kappa light chains.
Patients with hypereosinophilia are at risk of tissue damage. The heart and lungs are particularly vulnerable, and steps should be taken to firstly evaluate cardiopulmonary function quantitatively, and secondly, promptly reduce the eosinophil count. In patients for whom secondary causes have been ruled out, a bone marrow biopsy and aspiration are required for morphological analysis, conventional cytogenetic studies, fluorescent in situ hybridization(FISH)-based cytogenetics, flow cytometry, and T-cell receptor analysis for T-cell clonality.
These are critically important studies, firstly because of the threat of tissue damage, and secondly because responses to specific therapies depend entirely on the specific molecular pathogenetic lesion. For example, interferon-alpha and hydroxyurea therapy are helpful in the management of HES and glucocorticosteroids are most effective for the lymphoid variant eosinophilias. Eosinophilia associated with T-cell neoplasms require anti-lymphoma therapy. Imatinib is effective in most patients with rearrangements of PDGFRA or PDGFRB although some imatinib-responsive patients without such rearrangements have been described, so the use of this agent should not be necessarily restricted to only those with these types of molecular abnormalities.
What imaging studies (if any) will be helpful?
Neutrophilic and monocytic leukocytosis
The vast majority of patients with neutrophilia have either acute or subacute inflammatory diseases, so the use of imaging studies must be tailored to the particular clinical setting (a chest X-ray or CT scan for a patient with cough, fever, purulent sputum, and neutrophilia, for example). The same is true for patients with monocytosis. If there are clinical or laboratory indications that neutrophilia or monocytosis is the result of a leukemic disorder, imaging studies can be helpful in defining sites of extramedullary disease, adenopathy, and hepatosplenomegaly.
As is the case with neutrophilic leukocytosis, the selection of imaging studies (or for that matter whether any imaging studies are required at all) in patients with lymphocytosis should be tailored to each patient based upon their clinical setting. Likewise, if lymphocytosis is found to be a manifestation of a leukemic disorder, computed tomography (CT) scans of the chest and abdomen will help provide important information on extramedullary sites of disease, the extent of lymphadenopathy, and the presence or absence of splenomegaly or hepatomegaly.
Patients with mild eosinophilia need no pre-established set of imaging studies performed, apart from those that seem relevant for the management of the particular case. For example, chest images would be proper for a patient with cough and mild eosinophilia, but not for one with atopic dermatitis. With high levels of eosinophils (hyper-eosinophilia), two organs are at risk of serious damage, the heart and lungs. Therefore, a baseline assessment of pulmonary function studies and computed tomography (CT) scan of the chest is warranted as is electrocardiography (EKG) and echocardiographic studies. The role of cardiovascular magnetic resonance imaging may also be helpful in confirming myocardial inflammation.
What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
What other therapies are helpful for reducing complications?
What should you tell the patient and the family about prognosis?
“What if” scenarios.
Neutrophilic leukocytosis with inflammation
If there is evidence of acute or subacute inflammation, recent trauma, hemolysis, or other environmental stress, it is likely that neutrophilia is reactive and if it resolves with treatment of the underlying disease, there is nothing more to be concerned about diagnostically. If it doesn’t resolve and if recurrent inflammatory events have occurred throughout the life of the patient, a leukocyte adhesion deficiency should be considered. Otherwise, lack of resolution may indicate an underlying chronic myeloproliferative disorder.
Neutrophilic leukocytosis without “clinical” inflammation
If there is no fever or signs of an inflammatory, hemolytic, or traumatic process, other more occult inflammatory or neoplastic diseases should be considered. Sometimes morphological features of the neutrophil can indicate an inflammatory process. These include cytoplasmic vacuolization, Dohle bodies, and toxic granulation. A drugs (lithium and corticosteroids) history should be obtained.
When to consider chronic myelogenous leukemia and related myeloproliferative diseases
The co-occurrence of basophilia, thrombocytosis, myelocytosis, and splenomegaly in a patient with a high neutrophil count should represent clear indications to obtain a molecular analysis for the characteristic BCR/ABL gene translocation. Likewise, patients with erythrocytosis and/or thrombocytosis should be screened for JAK2, MPL and related mutations.
Leukoerythroblastosis is a red flag. If you see nucleated red cells and blast forms in the peripheral blood, a bone marrow aspiration and biopsy must be done, because the likelihood is that the findings stem from either a more acute form of leukemia or primary myelofibrosis (a diagnosis that requires a marrow biopsy). Bone marrow aspirates must also be analyzed by flow cytometry, conventional and FISH cytogenetics, and mutation analyses by sequencing methods. Most cancer and leukemia centers now use multigene sequencing panels for all genes currently known to be recurrently mutated in hematologic malignancies.
If a patient has persistent eosinophilia, he or she must be interviewed compulsively for any potential source of allergen or parasitic exposure. Ask about international travel. Obtain a comprehensive listing of all drugs used and any potential source of a new antigen (including new earings, piercings and tattoos). If a potential culprit is identified, discontinue the exposure if possible. If the eosinophilia is asymptomatic and resolves when the allergen is removed, one could rechallenge with the allergen to confirm that it is the real culprit if the allergen is thought to be an important therapeutic element for another disorder.
Absent such exposures, one should obtain immunoglobulin E (IgE) levels, HIV-1 testing, and both serological and stool testing for parasites. If any of these lead to a clear diagnosis, the primary disease should be treated with the expectation that eosinophilia will resolve. If no signs of secondary eosinophilia are found, primary eosinophilias have to be considered. This should involve echocardiography, CT scans of the thorax and abdomen, pulmonary function studies, and bone marrow aspirate and biopsy with searches for T-cell clonality and rearrangements of PDGFRA or FGFR1. If all of these studies are negative (apart from an increase in eosinophils in the marrow and blood), you are left with the non-specific diagnosis of the idiopathic hypereosinophilic syndrome, an outcome that is not uncommon.
In the normal inflammatory response, the neutrophil count increases in three ways. First, non-hematopoietic and well differentiated hematopoietic cells residing in inflamed sites produce inductive cytokines (e.g., IL-1) that in turn induce production of granulopoietic factors (for example, G-CSF and GM-CSF) by a variety of mesenchymal cells, including marrow stromal cells. This leads to increased production of neutrophils in the marrow. Second, the marrow releases neutrophils from a large marrow “storage pool” under the influence of adrenal glucocorticosteroid hormones. Third, epinephrine induces a rapid release of “marginated” neutrophils. These are intravascular cells adhering to vessels walls and are therefore not mechanically “counted” as circulating leukocytes. About half the intravascular neutrophils are marginated. This marginated pool is relevant when considering alterations in the neutrophil count (for example, fewer neutrophils are marginated in patients with inherited deficiencies of adhesion molecules, and in patients who have had splenectomies, more neutrophils circulate because the spleen is a site for neutrophil margination). However, when significant increases in eosinophils, basophils, lymphocytes, or monocytes are seen in clinical practice, the underlying mechanism is almost always an increase in their production.
High level production of neutrophils generally occurs in response to inflammatory stimuli, but in some cases results from mutations in stem cells (e.g., BCR-ABL translocation, activating CSF3R mutations or JAK2 V617F) that render neutrophil progenitor cells either less responsive to growth inhibitory cues or hyper-responsive to growth factors or both.
Monocytosis too occurs secondary to inflammatory or neoplastic disorders but depends upon the production of one or both of two cytokines: GM-CSF and M-CSF, both of which facilitate monocyte macrophage production, by committed granulocyte/macrophage progenitor cells. While most cases are secondary, in some instances, the production of monocytes reflects a primary hematopoietic malignancy including acute leukemia (types M4 and M5), CMML, and JMML. Here, the monocytes are progeny of a mutant stem cell clone that overproduces mononuclear phagocytes. In the case of CMML and JMML, the overproduction of monocytes results at least in part from a hypersensitivity to GM-CSF stemming from RAS mutations.
More than 50 years ago it was discovered that injecting experimental animals with media conditioned Bordetella pertussis in vitro could result in significant lymphocytosis (extreme lymphocytosis can occur in patients with whooping cough). Since then, it has become clear that a variety of factors produced by specific organisms sometimes directly or indirectly induce lymphocytosis. Notwithstanding these discoveries, the specific cytokines responsible for lymphoid expansion have not been unambiguously identified. However, a wide variety of cytokines have been implicated in the expansion of the lymphoid lineage generally. Prominent among these is IL-7 which can influence expansion of both B- and T-lymphocytes. The importance of IL-7 for B- and T-cells is clarified by studies that demonstrate immune deficiency in IL-7 deficient mice.
IL-3, IL-5, and GM-CSF can all influence the production of eosinophils. Reactive eosinophilia commonly involves the induced expression of GM-CSF by non-hematopoietic cells and/or IL-5 by T-lymphocytes. The environmental cues for these responses are numerous (see Table IV) but each is capable of inducing either one or all three of these cytokines. IL-5 plays a crucial role in not only the production but differentiation, survival, and function of eosinophils. In fact, the use of humanized anti-IL-5 immunoglobulin G (IgG) antibodies (reslizumab and mepolizumab) have shown clear-cut clinical effectiveness in the control of some of these syndromes and humanized anti-IL-5 receptor alpha antibodies (e.g., benralizumab) are also being used in clinical trials.
What other clinical manifestations may help me to diagnose leukocytosis?
Physical findings such as rash, fever, pulmonary infiltrates, lymphadenopathy, and hepatosplenomegaly can aid in pointing to a particular set of underlying disease processes. However, because every one of these findings can occur in patients with neutrophilia, monocytosis, lymphocytosis, or eosinophilia, in no way can the findings be helpful on their own. The findings must be interpreted in light of the particular cell type responsible for the leukocytosis.
What other additional laboratory studies may be ordered?
Genome sequencing is widely utilized today to help in classifying malignant hematologic diseases associated with leukocytosis. Targeted sequencing gene panels covering hundreds of genes of potential relevance vary somewhat from center to center but such studies are helpful not only in diagnosis and disease classification but in selecting proper therapy as well, at least in some cases. For example, as of October 2016 there were 72 tyrosine kinase gene translocations associated with hematopoietic neoplasms associated with eosinophilia. Therefore, while many of the recurrently mutated genes in the malignant disorders have been identified there will surely be more in the future. The use of targeted gene panels in the proper clinical setting is extraordinarily valuable. For example, imatinib treatment of patients with PDGFRA and PDGFRB rearranged neoplasms has improved the natural course of disease dramatically.
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- What every physician needs to know about leukocytosis:
- What features of the presentation will guide me toward possible causes and next treatment steps:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What conditions can underlie leukocytosis:
- Sets of disorders linked to the overproduction of specific leukocyte types are reviewed here
- Neutrophilic leukocytosis with clinical signs of inflammation
- Neutrophilia without clinical signs of inflammation or trauma
- Lymphocytosis, moderate (less than 15 X 10/L)
- Lymphocytosis, high level (greater than 15 X 10/L)
- When do you need to get more aggressive tests:
- What imaging studies (if any) will be helpful?
- What therapies should you initiate immediately and under what circumstances - even if root cause is unidentified?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- "What if" scenarios.
- What other clinical manifestations may help me to diagnose leukocytosis?
- What other additional laboratory studies may be ordered?