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Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia
Abnormalities of leukocyte number are commonly encountered in medical practice. The clinical significance of leukocytosis or leukopenia varies from none at all to being an early clue to a life-threatening process, whether that is a primary hematologic or secondary reactive process. Potential causes of leukocytosis or leukopenia are myriad. This chapter considers disorders faced by adult practitioners in hospital and outpatient clinics where the predominant hematologic abnormality is neutrophilic leukocytosis, neutropenia, monocytosis, or monocytopenia; other chapters consider lymphocytosis, lymphopenia, eosinophilia, pancytopenia, and hematologic neoplasms.
The normal range for leukocyte count in most laboratories is from about 4500/mm 3 to 11,000/mm 3 . Neutrophils (and band forms) comprise the majority of circulating leukocytes (1800 mm 3 to 7700/mm 3 ). Monocytes are about 4% of cells (mean absolute count: 300/mm 3 ). The physician should always think in terms of absolute counts of leukocyte subpopulations (total leukocyte count multiplied by the differential percentage). Thus, in a patient presenting with a normal white blood cell (WBC) count of 5000/mm 3 and an elevated lymphocyte percentage of 65%, the differential diagnosis to be considered is that of neutropenia, not lymphocytosis, because the absolute neutrophil count (ANC) is decreased but absolute lymphocytes are normal (only relatively increased).
When approaching a patient with abnormal leukocyte number, several factors impact heavily on the differential diagnosis and the vigor with which diagnosis and therapy should be pursued. Diagnostic considerations are vastly different when the abnormality first manifests in the hospital versus in the outpatient clinic . Also crucial is the degree of the abnormality , providing guidance to its likely cause and consequence. For example, agranulocytosis ( Fig. 49.1 ) is a life-threatening disorder in which neutrophils are at or near zero, has a limited spectrum of underlying causes (drug reactions being paramount), and demands immediate interventions. Duration has major implications; determining the onset of changes and whether they are stable or progressive informs as to etiology and significance. Whether the abnormality is symptomatic— for example, whether a neutropenic or monocytopenic patient has or has had infectious complications—bears on likely etiologies and need for therapy. If there are known or suspected comorbid conditions , such as autoimmune or inflammatory disorders, this can crystallize the approach; occasionally, the leukocyte abnormality may be the first sign of a previously unrecognized disorder or may provide important confirmation (e.g., neutropenia in a patient with systemic lupus erythematosus [SLE]). If the leukocyte abnormality is accompanied by additional hematologic abnormalities (unexplained abnormalities of red blood cells [RBCs], platelets, or cell morphology), this would point away from disorders considered in this chapter and often toward a primary hematologic disease. Beyond history and physical examination, the peripheral blood smear is key to establish the direction of further evaluation.
AGRANULOCYTOSIS (PURE WHITE CELL APLASIA)
(bone marrow aspirate). Virtual absence of myeloid precursors. Most often due to drug reactions, but can be due to immunologic disorders.
Neutrophilic Leukocytosis (Neutrophilia)
A high WBC count, particularly a high neutrophil count, is common with any infectious or inflammatory disorder. In the emergency department, leukocytosis is often equated with significant bacterial infection or is at least a sign of illness severe enough to warrant hospital admission rather than outpatient management. Leukocytosis can also be a prominent presenting feature of leukemias and myeloproliferative neoplasms (MPNs). The presence of increased neutrophils assures that acute leukemia is not present. When leukocytosis is extreme, it indicates chronic myeloid leukemia (CML), other MPNs, or a leukemoid reaction.
Leukemoid reaction has been defined as a reactive (nonclonal) neutrophilic leukocytosis with WBC count above 50,000/mm 3 . This must be differentiated from a neoplastic proliferation.
Leukoerythroblastosis ( Fig. 49.2 ) refers to the presence in the peripheral blood of immature myeloid cells (generally myelocytes) and nucleated RBCs, often with giant platelets as well. This is always abnormal. Patients with leukoerythroblastosis do not necessarily have leukocytosis, but they usually do. Most patients (two-thirds) with leukoerythroblastosis have an underlying myelophthisic process, such as primary or secondary myelofibrosis, metastatic tumor, necrosis, or granulomas in the bone marrow (BM). Therefore, BM examination is indicated when leukoerythroblastosis is unexplained. Teardrop poikilocytes and elliptocytes on blood smear would strengthen concerns for myelophthisis. In 20% of patients with leukoerythroblastosis, the cause is hemolytic anemia, and miscellaneous other causes consist mainly of those with shock (septic, hemorrhagic, cardiogenic, anaphylactic) when hypoperfusion of areas of BM disrupt the microenvironment and permit disorderly egress of precursor cells.
Left-shifted neutrophils refer to relative immaturity of circulating cells, often manifest as an increased percentage of band neutrophils. Marked left-shift includes less mature precursor forms, myelocytes and metamyelocytes. Left-shift is nonspecific and may occur with infection or any cause of marked neutrophilia.
Detailed directed history and physical examination are indispensable to the evaluation of neutrophilia ( Table 49.1 ). Fever and chills suggest infection (or inflammation), mandating a search for more specific symptoms that could pinpoint the focus. Examples include a sore throat, pharyngeal erythema, and exudate in pharyngitis; productive cough and abnormal lung auscultation in pneumonia; and dysuria and flank tenderness in urinary tract infection. Medication history mainly explores glucocorticoid use. With mild chronic neutrophilia, smoking habits and obesity become considerations. Recent vigorous exercise, emotional stress, burns, shock, or trauma can increase circulating neutrophils because of catecholamine-induced demargination. A positive family history may suggest hereditary neutrophilia. Often neglected are attempts to delineate the time course of the leukocyte abnormality by seeking prior medical contacts and blood count results at the time. On physical examination, care should be directed to lymph node palpation because this can be an important clue for infection or malignancy. Palpable splenomegaly may not only direct the evaluation toward hematologic disorders but can be a cardinal sign of a variety of infectious and inflammatory disorders.
Table 49.1
Causes of Neutrophilia
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CML, Chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; CNL, Chronic neutrophilic leukemia.
Blood smear should always be a part of initial evaluation when there are abnormalities of blood counts. BM aspirate or biopsy morphology may be helpful when pathophysiology and diagnosis are unclear. When appropriate, essential information can be gained by sending BM for microbiologic cultures, cytogenetic or molecular, or other ancillary studies.
Leukemoid Reaction Versus Chronic Leukemia
A relatively common reason for hematologic consultation is for very high WBC count. CML is reviewed elsewhere in this text book, as are chronic myelomonocytic leukemia (CMML) and the very rare chronic neutrophilic leukemia. Marked neutrophilic leukocytosis or overt leukemoid reaction (WBC count >50,000/mm 3 ) can represent an overly exuberant reaction to any stimulus associated with neutrophilia. Infection is the most common non-hematologic cause of leukemoid reaction. In patients with leukemoid reaction, a disproportionate number have infection with Clostridioides (formerly Clostridium) difficile (C. difficile) , an organism that elicits a vigorous neutrophil response. Leukemoid reactions may be associated with solid tumors, sometimes due to paraneoplastic production of colony-stimulating factor (e.g., granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) or other cytokines (e.g., interleukin [IL]-6 or IL-17), or due to particularly aggressive tumors with necrotic areas. The course of neutrophilia usually correlates with the course of solid cancer. The use of hematopoietic growth factors in cancer patients, cardiopulmonary distress, tissue ischemia such as bowel obstruction, gastrointestinal bleeding, major operations, pancreatitis, or splenectomy are other causes of leukemoid reaction. It is important to quickly differentiate a reactive neutrophilic leukocytosis from a clonal leukemic proliferation. The history and clinical context are usually quite different between leukemoid reaction and CML. Most patients with leukemoid reaction are encountered very ill in the hospital with obvious underlying illnesses (e.g., sepsis, organ rejection). Prior WBC counts, which are often available, demonstrate normal WBC counts until the recent onset of acute illness. This contrasts with CML, typically presenting in outpatients with hypermetabolism (weight loss, sweats, low-grade fever), symptoms referable to splenomegaly, or frequently asymptomatic. On physical examination, the spleen is palpable (occasionally massive) in the great majority of patients with CML, but splenomegaly is unusual with leukemoid reaction in the absence of comorbidities such as liver disease.
Laboratory findings reliably differentiate CML from leukemoid reaction. The total leukocyte count is commonly extremely high with CML (median 100,000/mm 3 in past series), but counts above 100,000/mm 3 are rare and above 150,000/mm 3 virtually unheard of with leukemoid reaction. Circulating myelocytes and even a few blasts are more typical of CML, but may be seen in both disorders. Similarly, changes in platelet number and morphology can be seen with both but are more characteristic of CML (especially when changes are extreme). RBC changes do not reliably separate the disorders except in a few cases with prominent teardrops, which point toward MPN. More helpful is the leukocyte differential: patients with CML almost always have some degree of absolute basophilia and eosinophilia, but infection and glucocorticoid excess induce eosinopenia. (When the leukocyte count is 100,000/mm 3 , realize that 2% to 3% basophils is a substantial absolute increase.)
The leukocyte alkaline phosphatase (LAP) score, high with leukemoid reaction and classically low with CML, has limited utility now that there are more sensitive and specific tests for CML. When CML is reasonably considered, testing should be done for the Philadelphia chromosome, t(9;22)(q34;q11.2) by chromosome G-banding, or BCR–ABL1 fusion product by fluorescence in situ hybridization or reverse-transcriptase polymerase chain reaction. When other MPNs are judged reasonably possible, JAK2 V617F mutational status may be informative. In cases with very high suspicion for MPNs but negative JAK2 V617F mutation, JAK2 exon 12, MPL , and CALR mutations can be assessed in a serial manner.
Infection
To protect against the ever-present threats to health and longevity, evolution has armed us with reactant cytokine cascades designed to increase the number of phagocytes and dispatch them to threatened locales. Neutrophilia is classically seen as a response to bacterial infection, responding to such cytokines as IL-6, tumor necrosis factor (TNF), and G-CSF. Neutrophilia is also a frequent response to other types of infections, such as fungal, parasitic, mycobacterial, and sometimes viral.
C. difficile infection should be suspected when unexplained neutrophilia is encountered in a patient with diarrhea and abdominal distension, especially with a history of recent use of antibiotics. Two large clostridial glucosylating toxins, toxin A (TcdA) and toxin B (TcdB), are primarily responsible for the colonic epithelial damage and death. These toxins also stimulate epithelial cells and tissue-resident immune cells (macrophages, dendritic cells, and mast cells) to secrete proinflammatory cytokines and neutrophil chemoattractants which recruit neutrophils and result in inflammation.
Changes in neutrophil morphology may be useful in predicting whether bacterial or other infection underlie a neutrophilic response. The authors have confirmed some published reports that prominent neutrophil vacuolization ( Fig. 49.3 ) is highly specific and moderately sensitive for serious bacterial infection, as are prominent Döhle bodies (in the absence of a primary hematologic disorder). The authors blindly assessed 125 blood smears from 50 from patients with serious bacterial infection (half bacteremic), 25 with influenza, 25 with noninfectious fever, and 25 controls. Toxic granulation of neutrophils, touted as a sign of bacterial infection, was found useless in distinguishing infections from other febrile illnesses.
Inflammation and Stress
Acute or chronic inflammation can cause neutrophilia by mechanisms similar to infection, mediated by the proinflammatory cytokines G-CSF, GM-CSF, TNF, IL-1, IL-6, IL-8, and others. Diseases such as rheumatoid arthritis (RA), vasculitis, inflammatory bowel disease, thyrotoxicosis, eclampsia, and many others are commonly accompanied by neutrophilia. Another rare but notable example is Familial Mediterranean Fever, in which an inherited MEFV mutation leads to dysfunctional pyrin and an autoinflammatory disorder with recurrent inflammatory serositis and secondary (AA) amyloidosis.
Physiologic stresses, including exercise and emotional stress, lead to endogenous catecholamine and glucocorticoid release in addition to inflammatory cytokines. This causes a rapid doubling of circulating neutrophils caused by demargination and by more rapid BM egress of maturing neutrophils. Paulsen found early peaks in M-CSF, growth hormone, and cortisol after exercise followed by increases in G-CSF, IL-6, and monocyte chemoattractant protein 1. Acute hemorrhage and hemolytic anemia are other physiologic stresses. This contributes to increased steady-state neutrophil counts recorded in patients with sickle cell anemia, and the degree of elevation correlates with pain crisis frequency, other complications, and mortality; leukocyte reduction has been postulated to be one mechanism of hydroxyurea’s beneficial actions. The stress of acute myocardial infarction is commonly accompanied by mild neutrophilia, and the early magnitude of rise has correlated with poor outcomes.
Patients with severe asthma have neutrophil-predominant lung inflammation due to formation of neutrophil extracellular traps (NETosis) and enucleated neutrophil cytoplasts, which in turn lead to T helper 17-mediated neutrophilic inflammation.
Hereditary and Congenital Neutrophilias
In newborns, neutrophilia and leukoerythroblastosis are among the hematologic abnormalities associated with trisomy 13, trisomy 18, and trisomy 21 (Down syndrome). A transient clonal MPN can be seen in children with Down syndrome and is usually self-limited, but it does put patients at increased risk for later acute megakaryoblastic leukemia.
Very rare hereditary neutrophilias are sometimes first appreciated in adults. In 1971, Herring reported a mother and three of her four children with lifelong neutrophilia (WBC: 14,000/mm 3 to 164,000/mm 3 ; granulocytes: 9000/mm 3 to 62,000/mm 3 ), unusual bleeding, thickened calvariae, and hepatosplenomegaly. They had no increase in infections. The LAP score was high, BM revealed few Gaucher-like histiocytes, karyotype was normal by routine G-banding, but chromatid breaks and gaps were increased. In 2009, French investigators identified a mutation in the CSF3R gene in a kindred with hereditary chronic neutrophilia. The point mutation led to constitutive activation of the G-CSF receptor, driving neutrophil proliferation and differentiation. One of 12 affected individuals in this kindred developed overt myelodysplastic syndrome (MDS). The frequency of this and other mutations are unknown with hereditary neutrophilias.
Smoking
Smoking has been well associated with mild neutrophilia in epidemiologic and animal studies. Perry et al. found a 27% higher WBC count in smokers. Sunyer et al. correlated the degree of leukocytosis and percentage of neutrophils with the number of cigarettes smoked. The effect can persist up to 5 years in those who stop smoking. A suggested mechanism is chronic inflammation because inflammatory markers, including C-reactive protein (CRP) and fibrinogen, are elevated. In a rodent model, cigarette smoke caused overexpression of hematopoietic growth factor genes IL-6, G-CSF, and GM-CSF. Thus, mild neutrophilia without other symptoms in a smoker could be attributed to this practice without further evaluation.
Drugs
Systemic glucocorticoids cause neutrophilia mainly by interfering with neutrophil adhesion to the capillary wall and decreasing neutrophil turnover rate. Maximal neutrophil counts occur 4 to 6 hours after dexamethasone use in normal volunteers. G-CSF increases circulating neutrophils by increasing BM production and mobilization. Epinephrine increases proinflammatory cytokines and demargination. Suggested mechanisms for lithium-induced neutrophilia are induction of G-CSF and downregulation of CXCR4 chemokine receptor, thus facilitating egress from the BM.
Malignancy
Leukocytosis is frequently associated with solid tumors without direct BM involvement. Some malignant tumors have been reported to produce G-CSF or GM-CSF, occasionally producing leukocytosis in the range of a leukemoid reaction. Recent epidemiological studies suggested that the presence of pre-treatment neutrophilia is an independent adverse prognostic factor in patients with advanced solid cancers.
Asplenia
Whereas neutrophilia is classically observed early after splenectomy, lymphocytosis predominates in the long run. Nevertheless, chronic mild neutrophilia can also be seen in functionally asplenic individuals. Furthermore, there may be an exaggerated neutrophil response to infections or other stresses. On the blood smear, Howell–Jolly bodies are a very sensitive and specific (when numerous) sign of functional asplenia.
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