Leukocytosis and Leukopenia
Authors: Mark A. Marinella, M.D., FACP
DEFINITION
The normal adult leukocyte count ranges from approximately 4,000 to 10,000 cells/mm3. Consequently, a total leukocyte count above this range constitutes the presence of leukocytosis. Furthermore, leukocytosis may be defined by the type of leukocyte that is increased in number above the normal absolute count for that particular cell type. For instance, neutrophilia exists when the absolute count of mature and immature neutrophils exceeds greater than 70% of the total leukocyte count, which is approximately 7,000 cells/mm3. Significant neutropenia is said to exist when the absolute neutrophil count (ANC=WBC (cells/microL)x(% PMNs+% bands)÷100) is less than 1,000 cells/ mm3 with the risk of bacterial infection markedly increasing with an absolute neutrophil count of less than 500 cells/mm.3 Eosinophilia is present when the absolute count exceeds 8% of the total leukocyte count, or approximately 800 cells/mm3. Eosinopenia, with often absence of cells on the differential, is very common in acute illness and typically has no significance. Basophilia, the least common type of granulocytic leukocytosis, is present when the absolute count exceeds 300 cells/mm3, or about 3% of the differential count. Basopenia is not a clinical concern since the normal basophil count is 0-3%, and the absence of basophils on the differential count is usually not considered abnormal in most patients.
Mononuclear leukocytosis is defined as an absolute lymphocyte count exceeding 4,500 cells/mm3, with a normal range of approximately 22-45% of the differential leukocyte count, or an absolute monocyte count above 1,100 cells/mm3, with a range of 4-11% of the differential count. Lymphopenia is common in acute illness, especially in the presence of neutrophilic leukocytosis. Persistent lymphopenia may occur in the normal elderly or be associated with chronic infection or malignancy. Monocytopenia may occur in stressful states and is present with an absolute count of less than 400 cells/mm.3 It must be emphasized that the absolute count of each leukocyte is what is important, since the percentages of each cell type may fluctuate and be increased, yet occur in the presence of a normal absolute count (Table 1). These are general guidelines, and a detailed discussion regarding abnormalities of each leukocyte is beyond the scope of this text.
PATHOPHYSIOLOGY
Bone Marrow Microenvironment
A common stem cell precursor (CD34 positive) gives rise to all nucleated leukocytes and erythrocytes through a complex, yet orchestrated, growth cycle. The common stem cell gradually differentiates into granulocytic and mononuclear precursors as well as erythrocytic precursors, with each division producing more mature cells, less capable of self-renewal, in contrast to the stem cell. During this maturation process, numerous cytokines and hematopoietic growth factors act on the various developing cells and influence the final phenotype. For instance, granulocyte colony stimulating factor (G-CSF) stimulates neutrophilic precursors; interleukin-5 stimulates eosinophilic precursors; and macrophage colony stimulating factor stimulates the production of monocytes. The bone marrow has an enormous capacity at cellular production, which is exemplified by the synthesis of approximately 1011 neutrophils per day.
Granulocytic marrow precursor known as myeloblasts, promyelocytes, and myelocytes constitute the proliferative or mitotic pool, with production increased in times of systemic inflammation, or the leukemias. More mature granulocytic precursors such as metamyelocytes, bands forms, and segmented granulocytes do not replicate further and serve as a non-replicative marrow reserve pool. Fully mature neutrophils may be stored in the bone marrow or marginated along the endothelium of the vasculature, ready to be released into the general circulation. Stimuli that favor the release of differentiated neutrophils include fever, tissue necrosis, elevated catecholamine levels, hypoxia, bleeding, and release of various cytokines that may be elevated in various disease states. Once granulocytes are released into the circulation, they migrate into the extravascular tissues within six to twelve hours. As such, for the leukocyte count to remain normal or elevated, a constant supply must be synthesized and released from the bone marrow at a rapid rate.
DIFFERENTIAL DIAGNOSIS AND ETIOLOGIES OF LEUKOCYTOSIS
General
Leukocytosis is a common laboratory finding encountered in hospital practice, in the emergency department or a medical or surgical setting. Generally, the vast majority of cases of leukocytosis are reactive and benign—resulting from liberation of various cytokines that stimulate the development of leukocyte precursors and release of mature cells from the marrow, endothelium, and spleen. Most reactive episodes of leukocytosis are neutrophilic in nature (“neutrophilia”) and result from a myriad of stressors (see next section).
Occasionally, the total leukocyte count will exceed 25,000 cells/mm3, with the majority of cells being polymorphonuclear leukocytes. This scenario is referred to as a leukemoid reaction, and may be difficult to differentiate from a leukemic picture, hence the name “leukemoid.” As such, in patients with leukemoid reactions, the main differential diagnostic concerns include chronic myelogenous leukemia, acute myelogenous leukemia, or other myeloproliferative disorders. A typical leukemoid reaction, however, occurs in the presence of an acutely stressful or inflammatory/infectious event, such as hemorrhage, hemolysis, febrile episodes, sepsis, trauma, pancreatitis, or Clostridium difficile infection. Clostridium difficile has the unique propensity of causing leukemoid reactions in cases of severe colitis, and likely results from liberation of cytotoxins.
The hallmark of a leukemoid reaction is the preponderance of band and mature neutrophils on the peripheral blood smear; with leukemic disease, more immature granulocytic precursors are seen (e.g., promyelocyctes, myelocytes, metamyelocytes) at times with malignant blastic cells. Absolute basophilia is suggestive of a myeloproliferative disorder. Other ways of differentiating a leukemoid blood picture with leukemia will be discussed below. The common causes of neutrophilic, eosinophilic, and basophilic leukocytosis are listed in Table 2.
Eosinophilic leukocytosis often accompanies allergic and drug reactions but may occasionally be due to hypereosinophilic syndrome or eosinophilic leukemia, both of which are rare. Basophilic leukocytosis is also rare, and may occur with allergic diseases or myeloproliferative disorders.
Mononuclear leukocytosis typically presents as lymphocytosis, and less commonly monocytosis. Most cases of lymphocytosis are reactive and commonly occur with viral infections most notably with infectious mononucleosis resulting from Epstein-Barr virus or Cytomegalovirus, although pertussis is the classic bacterial cause of acute lymphocytosis. Persistent lymphocytosis in an adult should prompt the clinician to consider chronic lymphocytic leukemia which typically presents incidentally with mature-appearing lymphocytes on the peripheral smear that are typically CD5 positive on flow cytometry. Monocytosis is typically related to viral infections, especially Varicella-zoster, but may uncommonly complicate tuberculosis, endocarditis, inflammatory bowel disease, or cancer. Recovery of neutropenia or during the convalescent period of a bacterial infection may be accompanied by monocytosis. Acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), and chronic myelomonocytic leukemia may uncommonly present with absolute monocytosis as well. Table 2 displays etiologies of mononuclear leukocytosis.
Miscellaneous Etiologies of Neutrophilia
Neutrophilia accounts for the vast majority of cases of benign leukocytosis in the clinical setting, especially among hospitalized patients. As noted, any acutely stressful event such as trauma, surgery, ischemic tissue damage, infection, hemorrhage, or drug administration can lead to an increased neutrophil count. Some of the more commonly encountered causes will be discussed, but Table 3 displays a more comprehensive list of etiologies.
Bacterial infections are among the most common causes of leukocytosis. Pneumonia, pyelonephritis, cellulitis, soft tissue infection, bacteremia, sepsis, meningitis, or endocarditis is all associated with neutrophilia, and, indeed, patients who fail to mount a significant leukocyte response to pyogenic infection have a worse prognosis. As noted above, C. difficile has a propensity to cause leukemoid reactions, at times exceeding 100,000 cells/mm3; one study revealed a 100% mortality rate in patients with this degree of leukemoid reaction complicating C. difficile colitis.
Non-infectious illnesses associated with neutrophilia include tissue necrosis (e.g., crush injury, myocardial infarction, pulmonary infarction); acute hemolysis or hemorrhage; pancreatitis; medications (e.g., corticosteroids, epinephrine, tetracycline, lithium); exercise; and surgical procedures. Table 3 displays some of the more commonly encountered causes of neutrophilia in the clinical setting.
Complications of Leukocytosis
Contrary to often popular belief, non-malignant leukocytosis, like fever, is typically not a detriment to the host. An exception to this general dictum is that patients with an entity known as the hypereosinophilic syndrome, a disease characterized by chronic eosinophilic leukocytosis, may suffer tissue damage from toxic products released by eosinophils. The heart is especially susceptible to eosinophilic-induced toxicity which can be fatal. Neutrophilic leukocytosis most often is reactive in nature in response to an infection or inflammatory process. Even total leukocyte counts of greater than 25,000 cells/mm3 (leukemoid reaction) pose no direct host threat. However, the one situation in which extreme leukocytosis (e.g., >100,000 cells/mm3) can be harmful or fatal is the hyperleukocytos-leukostasis syndrome associated with acute myeloid leukemia (AML). Briefly, this syndrome occurs mainly in patients with de novo AML or as a complication of a blast crisis which inevitably occurs in patients with chronic myelogenous leukemia. In these conditions, immature, malignant leukemic cells pathologically adhere to the microvasculature endothelium in the brain and lungs leading to microvascular occlusion and ischemic stress resulting in cerebral infarction and respiratory compromise. The leukemic cells release cytokines and toxins, further leading to local tissue damage. Unless urgently treated with leukopheresis, the leukostasis syndrome is fatal.
DIFFERENTIAL DIAGNOSIS AND ETIOLOGIES OF LEUKOPENIA
Leukopenia is a less commonly encountered problem in routine practice than is leukocytosis. Nonetheless, a busy clinician will encounter this problem not infrequently, especially in the hospital setting or the intensive care unit. For a more detailed discussion, the reader is referred to hematology texts or specialty review articles. Rather, the goal of this section is to provide a simple, yet thoughtful, approach to leukopenia.
In general, leukopenia may result from decreased marrow production of leukocytic precursors, by peripheral destruction or sequestration of circulating leukocytes, or by autoimmune celluar damage or destruction. The most common etiology of leucopenia is decreased marrow production due to a variety of disorders that damage the developing leukocyte mass in the bone marrow. For instance, cytotoxic chemotherapy damages leukocyte precursors leading to poor production and leukopenia, especially neutropenia. Many other drugs can cause marrow suppression of which include antibiotics, cardiac drugs, and anti-rheumatic drugs. Sepsis and overwhelming infection can cause bone marrow suppression and leukopenia, which is a poor prognostic sign in the setting of sepsis. Infiltration of the bone marrow by leukemia or myeloma cells as well as cancer cells can suppress normal cell production leading to various cytopenias. A clue to bone marrow infiltration with cancer, granulomas, or fibrotic tissue is the presence of circulating erythocyte and leukocyte precursors on the peripheral blood smear, a phenomenon known as a leukoerythroblastic blood picture. As such, it behooves the clinical to review the blood smear if leukopenia is prolonged or unexplained. Leukopenia may also result from the peripheral destruction of cells within the reticuloendothelial system or spleen, a typical scenario occurring in patients with portal hypertension and cirrhosis or splenomegaly associated with myelo-lymphoproliferative disorders. Patients with advanced cirrhotic liver disease can develop leukopenia, anemia, and thrombocytopenia from increased stasis, stagnation, and destruction of blood elements within the engorged spleen. Autoimmune leukopenia can occur with rheumatic diseases such as systemic lupus erythematosus from autoantibodies destroying leukocytes, most commonly the neutrophil. Felty's syndrome is an autoimmune complication of rheumatoid arthritis that consists of neutropenia and splenomegaly. Autoimmune drug reactions can cause leukopenia on occasion by directing antibodies at epitopes on developing or circulating leukocytes.
Miscellaneous Etiologies of Neutropenia
Selected etiologies of neutropenia are noted in Table 4. The clinician should approach leukopenia by one of the mechanisms noted in the above section. Examples of specific types of neutropenia are noted above as examples but many other etiologies exist. One should be aware that on average, black patients have lower neutrophil counts than whites. Appreciating this epidemiologic fact may prevent needless evaluation of a low-normal leukocyte count in an otherwise healthy black patient with normal peripheral blood smear cyto-morphology.
Often, the cause of neutropenia is obvious as in the setting of recently administered cytoxic chemotherapy, portal hypertension, leukemia, disseminated cancer, or autoimmune disease. However, occult deficiencies of vitamin B12 or folate may inhibit nuclear maturation of not only erythrocytes but also of leukocytes and may lead to leukopenia, anemia, and thrombocytopenia. Aplastic anemia due to drugs (e.g., chloramphenicol, phenylbutazone) or idiopathic cause leukopenia in the setting of pancytopenia and an acellular bone marrow. Myelodysplastic syndromes often cause leukopenia, but discussion of these disorders is beyond the scope of this text. Congenital causes of neutropenia are uncommon and are often associated with other systemic symptoms, and are also beyond the scope of this chapter.
Complications of Leukopenia
The most feared complication of leukopenia is suppression of the neutrophil cell line and subsequent neutropenia. Once the absolute neutrophil count (ANC) falls below 1,000 cells/mm,3 the risk of bacterial infection increases, but especially so when the ANC is less than 500 cells/mm.3 With ANC counts in this range, the risk of bacterial infection and sepsis is markedly increased. Patients with this degree of neutropenia typically have received cytotoxic chemotherapy, but a variety of other disease states can cause severe agranulocytosis.
Symptoms and Signs of Agranulocytosis
Patients with severe neutropenia may present with fatigue, fever, malaise, and oral ulcerations, which can be exquisitely painful. A primary site of infection may be evident if cough, dysuria, or skin lesions are present. However, the lack of circulating neutrophils may limit the degree of inflammatory reaction at the infection site leading to a paucity of localizing symptoms. Furthermore, diagnosis of bacterial infection may be limited in patients with severe neutropenia since the lack of inflammation may impede detection of pulmonary infiltrates in patients with pneumonia, pyuria in the case of a urinary tract infection, or a discrete abscess in cases of intraabdominal or soft tissue infection. A peculiar infection to consider in a patient with neutropenia and cancer is typhilitis, and infectious/inflammatory reaction involving the cecal-and appendiceal area.
DIAGNOSIS
Clinical suspicion of leukopenia may be heralded by oral ulceration and fever. Leukocytosis may be suspected in a patient with a fever or localizing signs or symptoms of infection. In the patient with acute leukemia or aplastic anemia, symptoms and signs of anemia or thrombocytopenia may predominate. For instance, anemia may be associated with dyspnea, fatigue, and pallor. Furthermore, thrombocytopenia may cause mucosal bleeding or petechiae.
Definitive diagnosis of quantitative leukocyte disorders, however, hinges upon obtaining a total leukocyte and differential count, which typically is ordered as a component of the complete blood count, or CBC. In the case of leukopenia, the total leukocyte count will be decreased; the differential count then reveals which cell line is affected. As noted, an absolute neutrophil count of less than 1,000 cells/mm3 is significant, with less than 500 cells/mm3 considered agranulocytosis. Other cells lines such as lymphopenia, monocytopenia, eosinopenia, and basopenia are not uncommon, but will not be discussed further.
An elevated total leukocyte count is usually due to an increase in circulating mature and immature neutrophils. The differential count will reveal this or abnormalities in other cell lines. In routine clinical practice, neutrophilia is the most common cause of absolute leukocytosis. However, in patients with leukemoid reactions, persistent leukocytosis, or unexpected leukocytosis, the clinician may need to consider sinister conditions such as malignancy or a primary bone marrow disorder such as leukemia or a myeloproliferative disease. In these cases, a manual differential count and blood smear should be obtained for a hematologist, oncologist, or pathologist to review. Often, the diagnosis of leukemia or an infiltrative bone marrow disease may be made if blast cells or a leukoerythroblastic blood picture are present, respectively.
As discussed earlier, a leukemoid reaction is present when the total leukocyte count exceeds 25,000 cells/mm,3 with a neutrophil predominance. Most of the time, the benign nature of the leukocytosis/neutrophilia is apparent, with clinical evidence of infection or inflammation. At times it may be difficult to delineate between a benign leukemoid reaction and leukemia, especially chronic myelogenous leukemia (CML). In this circumstance, the clinician may order a leukocyte alkaline phosphatase (LAP) score to aid in diagnosis. The LAP score is performed by the hematology laboratory after staining a dried slide of the patient’s blood and measuring the degree of staining-intensity for LAP. A low score classically is associated with CML and a high LAP score typically occurs with benign or reactive neutrophilia. Exceptions to these general rules do apply, and the interested reader is referred to subspecialty textbooks. Furthermore, specialized testing for the Philadelphia chromosome is more useful in differentiating a leukemoid reaction from CML.
Bone Marrow Biopsy
Most patients with leukopenia or leukocytosis can be evaluated with a thorough history, physical examination, and review of a CBC and peripheral blood smear. However, in some cases of leukopenia and leukocytosis, a bone marrow aspiration and biopsy may be necessary to assess for evidence of leukemia or other primary marrow disorder. Also, if the patient is pancytopenic, a bone marrow biopsy may aid in the diagnosis of aplastic anemia, infection, or granulomatous disease. A leukoeythroblastic blood picture mandates a bone marrow evaluation to rule out leukemia, lymphoma, metastatic carcinoma, marrow fibrosis, tuberculosis, fungal infection, or granulomatous disease.
The posterior iliac crest is the most widely utilized site for marrow aspiration and biopsy, although the sternum is occasionally used and, in children, the anterior tibia will provide adequate material. The posterior iliac area is typically anesthetized with lidocaine down to the periosteum. Some clinicians administer an intravenous narcotic such as morphine, which may also help with anxiety. Typically a Jamshidi needle is advanced with gentle but constant force through the bone cortex into the marrow space. The stylet is removed and a syringe is placed on the distal end of the needle and bone marrow is aspirated; this may cause pain due to the negative pressure within the marrow during aspiration. One may note bone spicules within the marrow specimen. Next, with a gentle circular, rocking type motion, the needle is removed, containing the core biopsy specimen containing the architectural marrow space along with trabecular and cortical bone. The aspirate often provides a “quick” look at the marrow cells and may be diagnostic. However, the biopsy specimen is important to assess for anatomic abnormalities, the myeloid:erythroid ratio, fibrosis, granulomas, and blasts. Bone marrow biopsy is very safe, with local bleeding, hematoma formation, and infection only occurring rarely. If the clinician utilizes intravenous narcotics or benzodiazepines, hypotension and respiratory depression must be potentially anticipated.
Role of Imaging
Generally, leukocytosis and leukopenia are diagnosed with the CBC and peripheral smear; occasional patients may require bone marrow biopsy. Nonetheless, select patients may undergo radiologic and nuclear imaging as adjunctive tests to aid in elucidating a particular cause of the leukocytosis or leukopenia.
Plain radiography has a limited role; however, adenopathy noted on a chest x-ray may occur in sarcoid or lymphoma. In a patient with a leukemoid reaction, the presence of a thickened, inflamed colon is compatible with C. difficile colitis, although lymphoma or other malignancies may present in this manner. Also, splenomegaly on computed tomography could indicate lymphoma or chronic myelogenous leukemia.
Nuclear imaging such as a gallium-67 scan, positron emission tomography (PET) scan, bone scan, or indium-labeled leukocyte scan may be helpful in certain clinical scenarios in patients with leukocytosis or leukopenia. For instance, gallium scanning may indicate lymphoma; PET scanning may help assess for malignancy or recurrence of malignancy; bone scanning may indicate osteomyelitis or metastases; and indium-labeled imaging may help locate occult infection. Even though imaging may be helpful in the diagnostic armamentarium for quantitative leukocyte disorders, these tests are no substitute for a thorough history, physical exam (including lymph nodes and spleen), and careful review of a peripheral blood smear and occasionally, the bone marrow.
EMPIRIC THERAPY
Indications for Empiric Antimicrobials Prior to Diagnosis
Often, the clinician will need to make a rather timely decision regarding the possibility of infection and the subsequent need for systemic antibiotics in patients with leukocyctosis or leukopenia. In patients with leukocytosis, the possibility of infection always exists, especially with neutrophilia and no prior documentation of leukocytosis. If the patients is febrile, has unstable vital signs (e.g., hypotension, tachycardia), looks systemically ill, or has symptoms attributable to infection, then antibiotics aimed at the most likely causes of bacterial infection should be administered.
For instance, in an elderly female nursing home patient, antibiotics directed at urosepsis should be considered. Furthermore, a community-dwelling patient with fever, cough, sputum, and fatigue should have antibiotics directed against common pneumonic pathogens.
Leukopenic patients pose a greater challenge. In the setting of fever and neutropenia (“febrile neutropenia”), the risk of bacterial infection and sepsis is increased. Often, patients with febrile neutropenia develop common bacterial infections such as pyelonephritis, pneumonia, or skin and soft tissue infections. However, the risk of aggressive and overwhelming infection and sepsis is increased due to the paucity of neutrophils. As such, patients with febrile neutropenia due to chemotherapy, drug reactions, or sometimes bone marrow disease, require prompt administration of broad-spectrum antibiotics to cover the most likely pathogens.
Role of G-CSF
Some recommend the use of filgrastim (G-CSF) to aid in neutrophil recovery. Granulocyte colony stimulating factor (G-CSF) or filgrastim, is an agent often utilized in the setting of chemotherapy administration for malignancy, in hopes to avoid the morbidity and mortality associated with neutropenia. Studies have revealed variable benefit in patients with established febrile neutropenia in hopes of raising the neutrophil count thereby increasing the phagocytic and bactericidal effects of circulating and tissue-based neutrophils.
Patient Monitoring
Meticulous supportive care should be provided to all neutropenic patients. If filgastrim is used, one should monitor the ANC and discontinue the agent when the ANC normalizes. It should be appreciated that the leukocyte count can rise dramatically, sometimes into the leukemoid reaction range. Also, monocytosis may appear as the bone marrow recovers, and is an expected finding in this situation. Patients with leukocytosis should be monitored with frequent blood counts and clinical assessment, but treatment depends on the underlying diagnosis.
REferences
1. Abramson N, Melton B. Leukocytosis: Basics of clinical assessment. Am Fam Physician 2000;62:2053-2060. [PubMed]
2. Marinella MA, Burdette SD, Markert RJ. Leukemoid reactions associated with Clostridium difficile colitis. South Med J 2004;97:59-63. [PubMed]
3. Marinella MA. Extreme leukemoid reaction associated with retroperitoneal hemorrhage. Arch Intern Med 1998;158:300-301.[PubMed]
4. Tkachuk DC, Hirschman JV. Approach to the microscopic evaluation of blood and bone marrow. In: Wintrobe’s Atlas of Clinical Hematology. In: Tkachuk DC, Hirschmann JV, eds. Philadelphia: Lippincott Williams and Wilkins, 2007, pp. 275-328.
5. Vanderdries ER, Drews RE. Drug-associated disease: hematologic dysfunction. Crit Care Clin 2006;22:347-355.[PubMed]
Table 1: Normal Ranges for Leukocytes
| Total Leukocyte Count | 4,000-10,000 cells/mm3 |
| Neutrophils | 3,500-7,000 cells/mm3 |
| Lymphocytes | 2,200-4,500 cells/mm3 |
| Monocytes | 400-1,100 cells/mm3 |
| Eosinophils | 200-400 cells/mm3 |
| Basophils | 0-300 cells/mm |
Table 2: Etiologies of Leukocytosis
| Neutrophilic leukocytosis See Table 3. |
| Eosinophilic leukocytosis
|
| Basophilic leukocytosis
|
| Lymphocytic leukocytosis
|
| Monocytic leukocytosis
|
Table
3: Etiologies of Neutrophilia
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Table 4: Etiologies of Neutropenia
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Yo CH, et al. Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis. Ann Emerg Med 2012;60:591-600.
GUIDED MEDLINE SEARCH FOR
Reviews
Ramaprasad C, Pursell K. Cytopenias after Solid Organ Transplantation.
George TI. Malignant or benign leukocytosis. Hematology Am Soc Hematol Educ Program 2012;475-484.