1. 
   

   What are the most common causes of leukocytosis in the hospital inpatient setting?

   
   
2. 
   

   Which medications can cause neutropenia and agranulocytosis?

   
   
3. 
   

   What are the most common causes of eosinophilia?

   
   
4. 
   

   What key white blood cell (WBC) findings indicate an impending medical emergency and warrant immediate action?

   
   
5. 
   

   What are the indications for a bone marrow biopsy and aspirate?

   
   
6. 
   

   What is the role of molecular testing in the diagnostic work up of common WBC disorders?

   
   
7. 
   

   What is the role for granulocyte colony-stimulating factors (GCSF) in nonmalignant hematologic disorders?

Deviation from the normal range in the leukocyte count is one of the most common laboratory abnormalities in the inpatient setting and frequently indicates the onset of clinical conditions that significantly impact hospitalized patients. Individual laboratory values may vary from day to day depending on fluid status and other factors. Hence, a “normal” white blood cell (WBC) or differential count has a typical distribution of values (Table 174-1).

A natural response to the physiologic fluctuations of the host’s hormonal and cytokine milieu, WBC counts also vary with the time of day and the season of the year. Typically, the hormonal variation associated with pregnancy will also increase the absolute WBC count due to an increase in circulating neutrophils.

There is also a significant genetic component to the ranges expressed on a WBC count, as neutrophil counts have been shown to vary considerably among ethnic groups. People of African descent, Yemenite and Ethiopian Jews, and people of Middle Eastern decent all have been shown to possess WBC counts with medians well below those established in predominantly Caucasian populations. Typically, these values do not fall below the threshold of mild neutropenia (< 1.5 × 109) for any significant period of time, and thus are not usually associated with significant infection risk. In fact, these physiologic deviations are not known to result in any clinically measurable increase in morbidity or mortality, and do not require any specific intervention once underlying pathology has been ruled out.

Recognizing abnormalities of the complete blood count (CBC) and, more specifically, the composition of the differential count are critical for formulating a differential diagnosis of disorders involving the WBC lineages. Valuable time and resources can be saved and best directed if careful attention is paid to these simple tests in the context of a good history and physical examination performed when abnormalities are first detected. As a general rule of thumb, malignant causes should always be considered in the differential diagnosis when red blood cell (RBC) or platelet lineages are also abnormal, or if there is a history of unexplained weight loss, anorexia, lymphadenopathy, or other systemic symptoms. This chapter will review each WBC lineage and the common nonmalignant conditions associated with their abnormalities. Hematologic malignancies will be addressed in Chapter 179.

In one recent large retrospective study of over 45,000 hospitalized patients, leukocytosis had a prevalence of 31.2%, and leucopenia was prevalent in 6.1%. Underlying bacterial infection is the most common reason for both leukocytosis and leukopenia in the inpatient setting, and thus the overwhelming majority of these variations in WBC counts are due to disorders involving neutrophils. Therefore, practically speaking, the terms leukocytosis and neutrophilia are commonly interchanged in the medical literature. While disorders involving other components of the WBC differential are far less common, they can represent vastly different pathological processes, and thus require different diagnostic investigation. Not all leukocytoses are neutrophilias, and thus the timely identification of the cell lineage involved in a WBC abnormality can have a significant impact on clinical outcome.

Prognosis

The WBC count can be thought of as equilibrium, with deviations above or below the normal distribution correlating with adverse outcomes in patients. Large, retrospective, population-based analysis of abnormalities in WBC magnitude have indicated that absolute WBC count correlates with all-cause mortality in an otherwise healthy population. As might be expected, this association is J-shaped, with both increasing leukopenia and increasing leukocytosis correlating with increased mortality. In hospitalized patients the presence of either abnormality has been shown to correlate with an increase in 30-day overall mortality. WBC deviations correlate with morbidity and mortality not only across patient settings, such as the intensive care unit and emergency department, but also across disease states.

Leukocystosis is a robust prognostic indicator of overall mortality in the hospitalized patient with underlying infection, such as profound sepsis, with several studies confirming that the absolute magnitude of the leukocytosis directly correlates with the overall mortality rate. Leukocytosis is also prognostic in cardiac conditions, including coronary artery disease (CAD) and acute coronary syndrome (ACS). Though it is unclear if WBC abnormalities have an active or passive role in mortality of these pathologies, it is clear that abnormalities in WBC count herald a poorer outcome in such patients.

The bulk of experience with morbidity and mortality in leukopenic patients comes from patient populations with malignancies, where there is a direct correlation between depth of neutropenia and infection and mortality rates. However, patients without malignancy or primary bone marrow pathology can also develop significant leukopenia. In this setting leukopenia may represent a myriad of pathologic mechanisms, such as direct cytokine suppression of marrow precursors or bone marrow infiltration, and is an ominous sign of profound immunocompromisation of the patient. Such patients typically require specialized clinical care as well as intensive support and monitoring. Despite the widespread availability of WBC growth factors, these medications have not shown significant efficacy in septic patients who are otherwise not immunocompromised and are not routinely recommended for septic hospitalized patients.

Neutrophillia

Infection and physiologic stress cause the overwhelming proportion of neutrophillia and, thus, leukocytosis (Table 174-2).

Common sources of infection include the pulmonary, urinary, and gastrointestinal tracts, as well as soft tissue infections. A burgeoning infective etiology in hospitalized patients in the era of widespread antibiotic use is Clostridium difficile colitis, and this diagnosis should be considered in the workup of an unexplained leukocytosis in a hospitalized patient, especially if there is a history of recent exposure to systemic antibiotic therapy.

Both pathologic and physiologic stressors can cause glucocorticoid hormone release, and the elevated circulating cortisol will liberate neutrophils from the endothelium where they are normally marginalized. Thus, any state causing stress can potentially cause an elevated neutrophil count in hospitalized patients. Common causes of the neutrophilia that is associated with stress include the presence of a hyperdynamic cardiac output state from cardiorespiratory exertion, or a prolonged state of extreme anxiety. Though initially differentiating infection from physiologic stress as a cause of neutrophilia can be challenging, a few key elements may be more suggestive of the likely cause. Stress-related neutrophilia is typically characterized by an antecedent initiating event, followed by a transient process, such as seizure, rigors, hyperthermia, or hyperemesis, that commonly reverses within hours after the initiating stimulus. In addition, stress hormone–mediated neutrophil demarginalization does not typically cause the characteristic morphologic findings of the activated neutrophil, such as toxic granulation of the cytoplasm or the presence of Dohle bodies. A history, physical examination, and review of the peripheral smear often identifies an obvious etiology and saves time and resources in the diagnostic workup.

Although less common than infection or stress, some medications frequently cause neutrophilia in the hospitalized patient. These medications include systemic corticosteroids, anesthetic agents, beta-agonists, and epinephrine. As there is often no easy way to confirm a medication-induced neutrophilia, it is a diagnosis of exclusion and should only be considered when infection has been essentially ruled out. Much like stress-induced neutrophilia, a drug-induced cause is less likely to show toxic changes to neutrophils on morphologic examination, and the presence of such changes or other concerning symptoms should lead the hospitalist to further investigate the possibility of infection as a cause.

Neutropenia

Neutropenia is often classified into mild (< 1.5 × 109/L neutrophils), moderate (< 1.0 × 109/L), or severe (< 0.5 × 109/L), with infection risk and mortality highest in the severely neutropenic patient. Such patients are at high risk of death, and specialty care and consultation with a hematologist should be sought. In contrast to the outpatient setting where primary hematologic and “unknown” causes predominate, the most common causes of acquired neutropenia in the hospitalized setting include infection (both bacterial and viral), medication, and autoimmune and systemic inflammation. From a causal standpoint, neutropenia is relatively nonspecific for bacterial infections, and is more likely a reflection of the depth of immunocompromisation rather than a reflection of any specific organism. Acute viral infections, such as with parvovirus B19, may give rise to a transient isolated neutropenia, typically associated with nonspecific viral infection symptoms and reticulocytopenia. Some chronic viral infections are also classically associated with an isolated neutropenia, including HIV and hepatitis C infection, and should be considered in the differential diagnosis of a persisting neutropenia if the history or physical examination is suggestive.

After infection, other benign causes of neutropenia are less common. A hypersplenic state can sequester neutrophils much like RBCs, causing a mild chronic neutropenia. Dietary insufficiency can cause megaloblastosis, which may initially manifest as neutropenia with classic megaloblastic changes of hypersegmented neutrophils indicating nuclear-cytoplasmic maturation dyssynchrony. Serum B12 and RBC folate levels are important to investigate if this abnormality is observed, as deficiencies in these nutrients are a common reversible cause of megaloblastosis. These findings may appear before a macrocytic anemia is present. Prevalence of B12 deficiency has been noted in the 10% to 15% range in older patients in the community, however, and perhaps as high as 30% to 40% in hospitalized patients. Metformin-related B12 deficiency is an underappreciated cause, and positively correlates with both the dose and duration of metformin therapy. In addition, common medications interfering with cellular metabolism, such as methotrexate or hydroxyurea, may also give rise to neutropenia with a megaloblastic picture, though without B12 or folate deficiency.

Acquired autoimmune neutropenia may occasionally be seen in hospitalized patients, and is associated with autoantibodies generated toward antigens on the neutrophil’s surface. In elderly hospitalized patients these antibodies are typically secondary to systemic inflammatory conditions such as systemic lupus erythematosus or rheumatoid arthritis, though they may also be associated with a recent transfusion or the presence of a thymoma. Diagnosis is largely based on supportive history, physical, and diagnostic testing for the underlying systemic diseases, as the antineutrophil antibodies are often nonspecific and haven’t been validated for diagnosis. The course may be complicated with other autoimmune phenomena such as hemolytic anemia, antiphospholipid antibody syndrome, or Felty syndrome. Patients are at risk of overwhelming infection when profoundly neutropenic and need to be closely monitored for infection, with rapid initiation of therapy should infection arise. Treatment is largely supportive and aimed at treating the underlying condition, though occasionally granulocyte colony-stimulating factor (GCSF) may be used in selected patients. It is advisable to avoid fresh unwashed fruits and vegetables or flowers during the neutropenic period due to the potential increased risk of infection associated with such exposures.

A large population-based cohort study identified several drugs that have been associated with medication-induced agranulocytosis—a failure of bone marrow to produce neutrophils. Many of these medications are commonly used in hospitalized patients (Table 174-3).

Cyclic neutropenia, chronic benign neutropenia, and congenital bone marrow failure syndrome such as Kostmann disease can also occasionally present with asymptomatic neutropenia in a hospitalized patient. These patients typically will have a history of such a condition and given the rarity of these diagnoses, should be considered only when the more common etiologies have been ruled out.

Acquired Neutrophil Dysfunction

Outside of absolute number, neutrophils can also be functionally impaired by conditions such as poorly controlled diabetes, chronic iron overload states, and chronic renal insufficiency. Typically these patients are more susceptible to bacterial infections secondary to neutrophil dysfunction, often with uncommon organisms such as Vibrio Vulnificus or Yersenia Enterocolitica as in the case of chronically iron-overloaded patients. Neutrophil dysfunction can occur as a result of the underlying condition as well as from instituted therapies, such as hemodialysis in renal failure patients. Treatment paradigms involve appropriate antimicrobial and supportive therapies, as well as control or resolution of the underlying condition if possible.