Disorders of White Blood Cells

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51 Disorders of White Blood Cells

Daniel A. Weiser

White blood cells (WBCs), or leukocytes, are an integral part of the host immune system. Their microscopic appearance after Wright-staining categorizes them as either granulocytes (neutrophils, eosinophils, and basophils) or agranulocytes (monocytes, macrophages, and lymphocytes). Each WBC has a specific function within the immune system (Figure 51-1).

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Figure 51-1 Features of white blood cells in Wright-stained blood smears.

A complete blood count (CBC) and manual differential notes the total number of WBCs per microliter of sample as well as the percentages of each subset of WBC. Absolute counts for each WBC are more clinically meaningful than percentages. Reference ranges for the WBC differential vary by age. In general, newborns have high total WBC counts (≤30,000/µL). At about 1 week of age, an infant’s total WBC decreases into the range of 5000 to 21,000/µL. Through the toddler and childhood years, the mean WBC count decreases slowly to an adult average of 7500/µL. Lymphocyte predominance is seen from 2 weeks to about 5 years of age. Then neutrophils are predominant, making up more than 50% of the differential. Monocytes, eosinophils, and basophils make up a very small percentage of the total WBC from the neonatal period through adulthood.

Etiology and Pathogenesis

WBCs derive from hematopoietic progenitor cells in the bone marrow (Figure 51-2). Their maturation is induced by colony-stimulating factors.

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Figure 51-2 Stages of hematopoiesis.

This chapter focuses on congenital and acquired neutrophil disorders with a brief discussion regarding disorders of eosinophils, basophils, and monocytes. Disorders of lymphocytes, part of the body’s acquired (adaptive) immunity, are discussed in the immunology section (see Chapter 21).

Neutrophils are part of the innate (natural) immune system. After they are released by the bone marrow, they remain in the circulation for 6 to 12 hours. They migrate to sites of infection and engulf, digest, and destroy microorganisms. A large portion of mature neutrophils reside in the bone marrow and along blood vessels in endothelial cells.

Neutropenia is defined as a decrease in the absolute neutrophil count (ANC) to less than 1500/µL. Neutropenia is considered severe if the ANC is less than 500/µL, moderate between 500/µL and 1000/µL, and mild between 1000/µL and 1500/µL. The risk of serious infection is inversely proportional to the ANC. Of note, the ANC is usually about 200 to 600/µL lower in African Americans compared with other races likely secondary to decreased neutrophil release from the bone marrow. This does not lead to a greater predisposition for infection.

Clinical Presentation and Differential Diagnosis

Congenital Disorders of Neutrophils

Because neutrophils play a key role in host defense, the primary signs and symptoms of neutropenia are related to an increased susceptibility to infection, particularly bacterial and fungal. Children with chronic neutropenia can develop cellulitis, perirectal or other deep tissue abscesses, oral ulcers, periodontal disease, pneumonia, and septicemia. Endogenous Staphylococcus aureus or gram negative organisms are frequently isolated. Clinical signs of infection, such as erythema and warmth, may be diminished secondary to a decreased neutrophil response.

There are multiple congenital neutropenias that are being further categorized as knowledge of the genetic basis of disease improves (Tables 51-1 and 51-2). These congenital disorders are exceedingly rare.

Table 51-1 Congenital Disorders of Neutrophil Development

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Table 51-2 Additional Congenital Disorders Associated with Neutropenia

Disorder Clinical Manifestations
Cartilage-hair hypoplasia Short limbs, dwarfism, abnormally fine hair
Myelokathexis with dysmyelopoiesis Marrow retention of neutrophils, recurrent bronchopulmonary infections
Dyskeratosis congenita Bone marrow failure syndrome; dystrophic changes in nails, skin (hyperpigmentation), and mucous membranes (leukoplakia)
Fanconi anemia Bone marrow failure syndrome; GU and skeletal abnormalities, increased chromosome fragility
Organic acidemias (propionic, methylmalonic) Initially well at birth, then toxic encephalopathy
Osteopetrosis Defective bone turnover with resultant hematopoietic insufficiency and bone fragility
Reticular dysgenesis (congenital aleukocytosis) Absent WBC, hypogammaglobulinemia, thymic hypoplasia, severe infection and death in infancy
Immunodeficiencies (severe combined immunodeficiency, common variable immunodeficiency, hyper-IgM) Frequent infections, failure to thrive, hepatosplenomegaly
Glycogen storage disease type 1b (von Gierke disease) and other inborn errors of metabolism Neutropenia and functional neutrophil defect, hepatosplenomegaly

GU, genitourinary; WBC, white blood cell.

Neutrophil Function Defects

Complex physiologic processes are involved in neutrophil phagocytosis of microbes. An abnormality in any of the steps—adhesion, chemotaxis, opsonization, ingestion/phagocytosis, degranulation, and oxidative metabolism (bacterial killing)—results in inadequate neutrophil functioning. Susceptibility is to bacteria and fungi, with intact resistance to viral infections.

Although very rare in general, some neutrophil function defects are relatively more common (Table 51-3). Acquired defects of chemotaxis can also occur secondary to diabetes mellitus, metabolic storage diseases, malnutrition, immaturity, and burns.

Table 51-3 Congenital Disorders of Neutrophil Function

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Acquired Disorders of Neutrophils

Acquired neutropenia, which is much more common than congenital neutropenia, is the result of decreased WBC production secondary to suppression of bone marrow synthesis or antibodies directed against neutrophils.

Infection-Associated Neutropenia

Although infection often causes a transient reactive leukocytosis, many viruses cause neutropenia within the first couple of days of illness that can last up to 1 week. The cause of neutropenia from an infection is diverse, including decreased marrow production, depleted marrow reserves, increased neutrophil margination with decreased circulating neutrophils, antibody formation with increased peripheral destruction, or a combination of multiple factors. Viruses that can cause neutropenia include HIV, parvovirus B19, Epstein-Barr virus, cytomegalovirus, hepatitis A and B, influenza A and B, malaria, respiratory syncytial virus, and varicella.

Autoimmune Neutropenia

Autoimmune neutropenia (AIN) can be primary or secondary to autoimmune diseases, drugs, infection, or immune dysregulation. Most cases of what was termed benign neutropenia of childhood are now believed to be primary AIN. Primary AIN is the most common cause of neutropenia in infancy and childhood and is usually found incidentally between the age of 2 months and 3 years. Affected infants and children may be asymptomatic or have recurrent mild infections, primarily of the upper respiratory tract or skin. It is rare to have more serious infection because the bone marrow is able to respond to stressors and increase granulocyte output two to three times. Because monocytosis precedes a brisk neutrophil response, it is not unusual to see an increased monocyte count in children with AIN. Antineutrophil IgG antibodies may also be identified. The prognosis is excellent with a self-limited course within 2 years in 95% of affected children. Secondary AIN will resolve when the underlying cause is treated.

Isoimmune or Alloimmune Neonatal Neutropenia

Within the first 2 weeks of life, neonates can develop neutropenia secondary to transplacental transfer of maternal antineutrophil IgG antibodies. This is similar to how Rh disease affects a newborn; however, isoimmune neonatal neutropenia is much more rare (one in 1000 neonates) and self-resolves within 4 to 6 months. The diagnosis is made by detecting antineutrophil alloantibodies in the maternal serum. Depending on the degree of neutropenia and the extent of other risk factors, neonates may present with infection as the first sign of this diagnosis. More often it is found incidentally.

Drug-Induced Neutropenia

Cytotoxic agents for the treatment of malignancies are known to cause severe neutropenia, anemia, and thrombocytopenia. Other more routine medications may be implicated in causing neutropenia (Table 51-4). Neutropenia is caused either by decreasing bone marrow synthesis or by evoking production of antineutrophil antibodies. Spontaneous resolution typically occurs after discontinuation of the offending drug.

Table 51-4 Drugs Associated with Neutropenia*

Drug Class Drugs
Antimicrobials Trimethoprim–sulfamethoxazole, sulfonamides, macrolides, vancomycin, cephalosporins, semisynthetic penicillins (vancomycin), quinine, chloroquine, amphotericin B
Antiinflammatory drugs NSAIDs (ibuprofen, others)
Psychotropic drugs Clozapine, phenytoin
Gastrointestinal drugs Histamine H2 receptor antagonists (ranitidine)
Antithyroid drugs Methimazole, propylthiouracil
Cardiovascular Antiarrhythmics, diuretics
Toxins Benzene
Chemotherapeutic agents Cytotoxic drugs

NSAID, nonsteroidal antiinflammatory drug.

* This is a partial list only of the more commonly prescribed medications for children.

Other Causes of Acquired Neutropenia

Malignancies and marrow infiltrative processes do not usually cause an isolated neutropenia; multiple cell lines are more commonly affected (Table 51-5). Additionally, splenomegaly affects all cell lines because blood products get trapped in the enlarged spleen.

Table 51-5 Other Causes of Acquired Neutropenia

Malignancies and bone marrow failure Leukemia, lymphoma, preleukemic states, myelodysplastic syndromes, aplastic anemia
Nutritional deficiency Vitamin B12, folate, copper or starvation
Other Splenomegaly, complement activation (e.g., hemodialysis)

Leukocytosis

If a higher number of WBCs than expected are in the peripheral circulation, an underlying systemic process is likely. In the majority of children with leukocytosis, it is a reactive process to infection and subsides with resolution of the acute event. It can also occur in chronic inflammatory states such as autoimmune disease, rheumatologic disorders (systemic lupus erythematosus [SLE], juvenile idiopathic arthritis [JIA], inflammatory bowel disease [IBD], Kawasaki disease), and oncologic processes (leukemia, lymphomas, neuroblastoma). When the WBC is greater than 100k/µL, there should be a suspicion for a marrow infiltrative process such as leukemia. A history and physical examination may reveal lymphadenopathy or hepatosplenomegaly. A peripheral smear evaluation and manual differential count will note atypical lymphocytes (suggestive of a viral process) or blasts (premature WBCs suggestive of leukemia).

Neutrophilia

An elevated neutrophil count can result from increased bone marrow production, increased movement of neutrophils out of the marrow and into the circulation, or possibly from decreased peripheral destruction if the spleen is not functioning. There are many causes of neutrophilia, some acute and some chronic in nature (Table 51-6).

Table 51-6 Causes of Neutrophilia

Infectious Bacterial and viral
Rheumatologic JIA, Kawasaki disease
Asplenia Surgical or functional
Gastrointestinal Liver failure, IBD
Endocrine Diabetic ketoacidosis
Neutrophil function disorders CGD, LAD (see Neutrophil Function Defects above)
Drugs Corticosteroids (release neutrophils from marrow, slow egress from circulation into tissues, postpone apoptotic cell death), epinephrine (release of the marginating pool into circulation)
Stressors Shock, trauma, emotional, burns, surgery, hemorrhage, hypoxia
Malignancy Clonal expansion, especially if WBC >100,000/µL; leukemia, myeloproliferative disorders (note H&P, other cell lines, peripheral blasts)
Trisomy 21 (Down syndrome) Defective proliferation and maturation of myeloid cells

CGD, chronic granulomatous disease; H&P, history and physical; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; LAD, leukocyte adhesion deficiency; WBC, white blood cell.

Monocytosis

Monocytes develop much more rapidly than neutrophils in the bone marrow, and they give rise to macrophages. After bone marrow recovery from myelosuppressive chemotherapy, monocytes are the first to reappear in the circulation; the reactive monocytosis is transient. An increased monocyte count is seen in particular infections such as tuberculosis, syphilis, typhoid, and brucellosis. Also, in chronic inflammatory states such as rheumatologic disorders (SLE, JIA), IBD, and Langerhans cell histiocytosis, a monocytosis can be present.

Basophilia

Basophils are a nonspecific sign of a variety of disorders. Basophils are involved in immediate hypersensitivity diseases and may play a role in the defense against bacterial infections. An absolute value greater than 120 cells/µL is considered elevated, and this can occur in hypersensitivity reactions as well as chronic inflammatory states, particularly JIA, chronic sinusitis, IBD, and oncologic processes.

Eosinophilia

Eosinophils have a role in both immunoenhancing and suppressive functions. They are very efficient in the destruction of invasive metazoan parasites, and they inactivate inflammatory mediators in immediate hypersensitivity reactions. Eosinophilia is characterized by the total eosinophil count. Mild eosinophilia, with an absolute count 600 to 1500/µL, is fairly common and usually transient. It most frequently results from allergies and resolves with control of the underlying disease process. Moderately severe eosinophilia is defined as an absolute count of 1500 to 5000/µL. Severe eosinophilia is greater than 5000/µL with the most common reason being visceral larva migrans (toxocariasis). The cause of eosinophilia is diverse; a history of fever, allergies, atopy, asthma, recent travel, diarrhea, environmental exposures, medication, or exposure to pets may help differentiate causes of eosinophilia (Figure 51-3).

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Figure 51-3 Causes of eosinophilia.

Evaluation and Management

If isolated neutropenia is discovered incidentally on a routine screening CBC, a thorough history and physical examination should be completed. Recent fevers, upper respiratory infection symptoms, or diarrhea may point toward a preceding viral illness. If frequent infections are reported, a full understanding of the infection type and frequency is important to delineate. In the history, recent medication exposures should be reviewed. A diet history may elicit nutritional deficiencies as in vitamin B12 or folate. Family history of early unexplained deaths and parental blood counts can help to narrow down otherwise unrecognized inherited disorders. A comprehensive physical examination should identify phenotypic abnormalities that are associated with particular disorders. The clinician should carefully assess for hepatosplenomegaly or lymphadenopathy. If the child is otherwise healthy with normal examination results, a repeat CBC should be obtained in 2 to 3 weeks.

Neutropenia on three separate occasions over 8 weeks in an otherwise well child should prompt a more extensive workup. Discontinue drugs known to be associated with neutropenia. More specific testing should be guided by the patient’s age, physical examination, and clinical presentation.

It is prudent to anticipate infection in patients with persistent severe neutropenia. Fever may be the first and only sign of a potentially life-threatening systemic infection. Fever is defined as a temperature greater than 101.5°F. Rectal thermometers should be avoided because of the lack of hygiene in the region. A blood culture and a CBC with differential should be drawn at the time of the fever. A urine culture should be added for infants and young children. Further infectious workup should be guided by the physical examination results. Fever with severe neutropenia (ANC < 500/µL) should be managed with empiric broad-spectrum antibiotics in a hospital setting for at least 24 hours. If a treatable organism is identified, antibiotic coverage can be narrowed. A well-appearing febrile patient with mild or moderate neutropenia can usually be managed as an outpatient with or without antibiotics depending on whether an infectious source has been identified.

Recombinant granulocyte colony-stimulating factor (GCSF) is readily available and often effective at increasing neutrophil counts and thereby decreasing infectious complications. GCSF is the standard treatment for patients with severe congenital neutropenia, for some patients with cyclic neutropenia, and for certain disorders if infectious complications are severe. Therapy should be tailored as necessary for specific WBC disorders as outlined in previous sections. Hematopoietic stem cell transplantation may be curative for some disorders.

Treatment of patients’ neutrophil function disorders varies, although prophylactic antibiotics and prompt supportive care with fever is universal. Specifically, trimethoprim–sulfamethoxazole may enhance the bactericidal activity of neutrophils, and interferon-γ decreases the frequency and severity of infections in chronic granulomatous disease. Patients with Chediak-Higashi syndrome may improve clinically when given ascorbic acid. Because the outcomes after bone marrow transplantation have improved, transplant may be a viable therapeutic option with the goal of reconstitution of normal neutrophil function.

Future Directions

Additional neutrophil function disorders continue to be described as a more elaborate understanding of the molecular basis for disease is elucidated. This will allow for improved diagnosis and targeted therapeutics. Increasingly, functional disorders of the hematopoietic system are being partially, or even fully, treated through hematopoietic stem cell transplantation.

Suggested Readings

Kyono W, Coates TD. A practical approach to neutrophil disorders. Pediatr Clin North Am. 2002;49(5):929.

Lekstrom-Himes JA, Gallin JI. Immunodeficiency caused by defects in phagocytes. N Engl J Med. 2002;343(23):1703.

Schwartzberg LS. Neutropenia: etiology and pathogenesis. Clin Cornerstone. 2006;8(suppl 5):S5.

Segel GB, Halterman JS. Neutropenia in pediatric practice. Pediatr Rev. 2008;29:12-24.

Serwint JR, Dias MM, Chang H, et al. Outcomes of febrile children presumed to be immunocompetent who present with leukopenia or neutropenia to an ambulatory setting. Clin Pediatr. 2006;44(7):593.

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