NEUTROPENIA

Neutrophils are the cellular elements of the blood, which provide a large portion of anti-bacterial immunity to the body. The risk of sepsis, fungal infections, and mucositis correlates with the severity of neutropenia.¹ Neutrophils phagocytize bacteria opsonized by either immunoglobulin or complement and kill them by means of enzymatic and oxidative mechanisms. Because neutrophils play such an important role in the killing of bacteria and fungi, neutropenic patients may succumb to severe infections caused by either. Immunity is preserved until neutrophil counts are profoundly suppressed. As with red blood cells or platelets, the absolute number of circulating neutrophils is determined by rate of production in the marrow as well as circulating half-life. Therefore absolute neutrophil count (ANC) will be influenced by processes that affect production or maturation of neutrophils in the marrow as well as conditions that shorten neutrophil survival in the periphery. Since the life span of a circulating neutrophil is on the order of hours rather than days, ANC can be an early indication of hematopoietic activity in the marrow compartment. However, there are actually two distinct populations of neutrophils in the circulation—one free in the blood and the other associated with the endothelial surface of blood vessels. Glucocorticoid steroids such as prednisone or dexamethasone have a demarginating effect on neutrophils, resulting in higher ANCs in blood samples, especially in the first hours-to-days of taking such medications. Therefore neutrophil counts can be influenced by the rate of demargination of endothelial-associated cells into the circulation.

Normal neutrophil levels vary between individuals of different races and ages; however, an ANC below 1000 cells/μL represents neutropenia. ANC, determined by total white blood cell count in the CBC as well as the percentage of cells of the neutrophilic lineage in the differential, is calculated as follows:

Thus the ANC for a person whose CBC shows a WBC of 10,000 cells/μL and a differential of 50% neutrophils, 30% lymphocytes, 10% monocytes, and 10% band forms would calculate to 6000 cells/μL. Conventionally, neutropenia is classified by the absolute number of circulating neutrophils (ANC) and is usually classified as: mild (1000–1500 cells/μL), moderate (500–1000 cells/μL), severe (<500 cells/μL), or very severe (<200 cells/μL). Generally, neutrophil counts below 1000 are abnormal and warrant further investigation.

ISOLATED NEUTROPENIA

Neutropenia, whether isolated or as part of a broader clinical scenario, may be caused by a number of different underlying conditions (Table 90-1). The epidemiology, presenting symptoms, risk of infection, clinical course, and management differ depending on the etiology. The diagnostic approach to the neutropenic patient depends on clinical context and should be guided by whether neutropenia is accompanied by other hematologic imbalances (Table 90-2). “Isolated neutropenia” implies that every other aspect of the CBC (differential, hemoglobin/hematocrit, mean corpuscular volume [MCV], and platelet count) is normal for age. Congenital forms such as Kostmann disease, cyclic neutropenia, and Shwachman-Diamond syndrome generally result in lifelong neutropenia with frequent, severe bacterial infections.² Acquired causes of neutropenia may be temporary or more long-lasting. In many cases, no identifiable diagnosis can be made at the onset, and the cause of neutropenia can only be made retrospectively or with the clarity of time.

PANCYTOPENIA

Pancytopenia is defined as inadequate numbers of more than one element of the CBC. Strictly speaking, “pancytopenia” refers to simultaneous insufficiency of all three cell lines (white blood cells, red blood cells, and platelets), with “bicytopenia” more appropriately describing patients with two lines affected instead of three. However, as their differential diagnosis, workup, and management are similar, we will simply use the more inclusive and widely-used term of pancytopenia. Pancytopenia often reflects serious pathology in the bone marrow, and many patients who eventually develop pancytopenia first present either with a single cytopenia or with partial pancytopenia. For this reason, patients with any cytopenia should be carefully followed over time, and should be referred for hematology consultation if laboratory abnormalities persist, worsen, or are accompanied by worrisome clinical findings.³ Some cases of pancytopenia may resolve, particularly if associated with viral infection or autoimmunity; however, pancytopenia in many patients will persist and worsen over time. Presenting symptoms of marrow failure depend upon the cell line(s) affected. Anemia is suspected by pallor, lethargy, and easy fatigability. Easy bruising and bleeding or the appearance of petechiae suggests thrombocytopenia. Signs/symptoms of neutropenia are discussed above.

It is important to determine if pancytopenia is caused by defective production or by peripheral destructive processes. Most of the time, destructive processes sufficiently robust enough to cause pancytopenia will be clinically evident (e.g. severe sepsis, burns, thrombotic thrombocytopenic purpura [TTP], disseminated intravascular coagulation). Red cell indices can be especially useful in distinguishing between problems of production versus destruction. Laboratory evidence of defective hematopoiesis includes a low reticulocyte count, low or normal markers of hemolysis (lactate dehydrogenase [LDH], free serum hemoglobin, bilirubin, and haptoglobin), and the absence of autoantibodies (e.g. negative Coombs testing). For this section, we focus on pancytopenia caused by marrow failure thought to be due to injury to hematopoietic stem cells themselves or marrow abnormalities that interfere with normal hematopoiesis. Bone marrow failure syndromes can be challenging to diagnose, as many share similar symptoms and signs such as pallor, petechiae, and purpurae.⁴ The differential for marrow failure is extensive (Table 90-1), but it is critical to assess children appropriately because of profound prognostic and management implications that accompany certain diagnoses.

Though marrow failure can be due to inherited causes, most cases occur in previously well children without a recognizable genetic problem, and are therefore acquired rather than inherited. Nonetheless, a detailed history including extended family medical history is imperative to rule out major causes of bone marrow failure. Physical examination should focus on signs of malignancy (especially lymphadenopathy and organomegaly), dysmorphic features, short stature, and pigmentary findings or congenital abnormalities.⁵ Certain environmental agents such as toxins, radiation, and chemicals are clearly associated with acquired bone marrow failure; however, etiologic agents are identified only in a handful of cases, and most cases of acquired bone marrow failure in children are idiopathic.⁶

Disorders of formed blood elements can be due to inherited genetic deficiencies or they can be acquired. In general, inherited causes are associated with progressive bone marrow failure, while acquired cases may either be temporary (e.g. drug- or virus-induced marrow suppression or immune-mediated cytopenias) or more permanent (e.g. aplastic anemia). In fact, the underlying cause for many cases of pediatric cytopenia is often never identified, and the clinician must determine how aggressively patients should be managed based on symptoms, duration, and degree of cytopenia.

Neutropenia can present as a laboratory abnormality in an asymptomatic child, as part of a broader disease process, or with severe, unusual, or frequent bacterial infections. One can get a good idea of the underlying etiology of neutropenia based on the frequency and severity of infections coincident with the abnormal neutrophil count. In general, children with mild or moderate neutropenia have only a minimally increased risk of infection while those with severe neutropenia have a significantly increased risk of infection.⁷ Certain causes of neutropenia (e.g. benign neutropenia of childhood) can present with profound neutropenia yet have little clinical consequence, presumably because the patient can summon neutrophils if needed to fight off infection. The most common types of infections seen in neutropenic patients are otitis media, skin infections (cellulitis and abscesses), gingivitis, pneumonia, and bacteremia or sepsis.⁸ The bacteria most commonly isolated are Staphylococcus aureus, Pseudomonas species, Escherichia coli, other enteric species, Streptococcus pyogenes, and Streptococcus pneumoniae. Fungal infections such as candidiasis or aspergillosis occur particularly if duration of neutropenia is long or in the setting of concomitant corticosteroid or immunosuppressant use. Increased susceptibility to viral pathogens is not characteristic, probably because antiviral immunity is mainly carried out by lymphocytes rather than neutrophils. In addition to infections, symptoms that suggest pathologic neutropenia include fever, oral ulcers or stomatitis, frequent paronychiae, and delayed separation of the umbilical cord in infants.