Neutrophil Abnormalities

After completing this article, readers should be able to: The differential diagnosis for a patient presenting with recurrent infections is challenging, given the complexity of the immune system. Similarities in the clinical presentation of neutrophil, antibody, and complement disorders can prove difficult for the physician attempting to establish a diagnosis. Infants and children who are brought to the pediatrician for “repeated infections” must be evaluated carefully. Often these patients ultimately have no identifiable underlying disease, but frequently they have respiratory allergy or other risks for recurrent infection (Table 1). Most patients who have recurrent infections do not have an identifiable phagocyte defect or immunodeficiency. Given the low probability of identifying a discreet immune defect, the physician faces the difficult decision of which patients merit a complete evaluation.In general, evaluations should be initiated for those who have had at least one of the following clinical features within a 1-year period: 1) more than two systemic bacterial infections (eg, sepsis, meningitis, osteomyelitis); 2) serious respiratory infections (eg, pneumonia, sinusitis); 3) bacterial infections (eg, cellulitis, draining otitis media, lymphadenitis); 4) the presence of an infection at an unusual site (eg, hepatic or brain abscess); 5) infections caused by unusual pathogens (eg, Aspergillus pneumonia, disseminated candidiasis, infection with Serratia marcescens, Nocardia sp, Burkholderia cepacia); 6) infections of unusual severity; and 7) chronic gingivitis and recurring aphthous ulcers.Once the decision is reached that a phagocyte evaluation is warranted, a thorough clinical history, physical examination, and laboratory testing for immunodeficiency (Table 2) should provide the diagnosis and help to formulate an appropriate therapeutic plan.Absolute neutrophil counts (ANCs) vary widely in healthy individuals. The relative proportion of neutrophils and lymphocytes in the blood changes with age. Neutrophils predominate at birth, but decrease rapidly in the first few days of life. During infancy, they constitute 20% to 30% of the circulating leukocyte populations. Approximately equal numbers of neutrophils and lymphocytes are found in the peripheral circulation by the time the child reaches about 5 years of age, and the characteristic 70% predominance of neutrophils that occurs in adulthood usually is attained at puberty. In healthy children, therefore, 20% to 70% of the total circulating white blood cells may be neutrophils.Neutropenia is defined as a decrease in the absolute numbers of circulating segmented neutrophils and bands in the blood. Obtaining a complete blood count (CBC) and differential count identifies this condition. The ANC is determined by multiplying the total white blood cell count by the percentage of segmented and band forms. The ANC for the general population normally ranges between 1.5 and 8.0 × 103/mcL (1.5 and 8.0 × 109/L) for Caucasian children older than 6 years of age. As much as 30% of the African-American population may have ANC levels as low as 1.0 × 103/mcL (1.0 × 109/L). Individual patients may be characterized as having mild neutropenia when the ANC is 1.0 to 1.5 × 103/mcL (1.0 to 1.5 × 109/L), moderate neutropenia when the ANC is 0.5 to 1.0 × 103/mcL (0.5 to 1.0 × 109/L), and severe neutropenia when the ANC is less than 0.5 × 103/mcL (0.5 × 109/L). This classification is useful for predicting the risk associated with pyogenic infections among patients who have sustained neutropenia over 2 to 3 months. It also is useful in counseling families because generally only those patients who have chronic severe neutropenia are likely to develop a life-threatening illness.Patients who have neutropenia are infected most frequently with endogenous flora. Colonization with various nosocomial organisms often is observed. Susceptibility to bacterial infections, even in the presence of severe neutropenia, varies. Some patients who have chronic neutropenia and an ANC of less than 0.2 × 103/mcL (0.2 × 109/L) do not experience serious infection, but they commonly experience gingivitis, probably because other parts of their immune system remain intact. In contrast, patients receiving immunosuppressive drugs, particularly in conjunction with malignancies, who develop neutropenia are more likely to develop serious bacterial infections than those whose neutropenia is isolated because immune suppression compromises both function and numbers of lymphocyte and monocytes.The types of pyogenic infections occurring most frequently among patients who have profound neutropenia are cutaneous cellulitis and abscesses or furunculosis, pneumonia, and septicemia. Stomatitis, gingivitis, perirectal inflammation, and otitis media are also common. In contrast, isolated neutropenia does not predispose patients to parasitic, viral, or fungal infections or to bacterial meningitis. The most common pathogens isolated from patients who have neutropenia are Staphylococcus and gram-negative organisms. Often, the signs and symptoms of local infections and inflammations, such as exudate, abscess formation, and regional lymphopathy, are less evident in patients who have neutropenia than in those who do not because there is a paucity of neutrophils to mediate the inflammatory response. Other signs and symptoms, such as redness, pain, tenderness, and warmth accompanied by fever, generally are present.A large number of acquired conditions may be associated with neutropenia (Table 3). Infectious diseases are among the most common causes of neutropenia in children. Viral infection is the major cause of acute neutropenia in childhood. Viruses commonly causing neutropenia include respiratory syncytial virus, varicella, influenza A and B, measles, and rubella. Neutropenia often occurs during the first 24 to 48 hours of illness and usually persists for 3 to 8 days, which corresponds to the period of acute viremia. Significant neutropenias also may be associated with bacterial, protozoal, rickettsial, and severe fungal infections.The mechanisms responsible for neutropenia in acute bacterial and viral infections include: 1) redistribution of neutrophils from the peripheral blood circulating pool to the marginating pool following release of cytokines that increase expression of the protein’s intracellular adhesion molecule (ICAM)-1 and -2 on endothelium, 2) increased use of neutrophils at sites of infection, and in some cases, 3) decreased production of neutrophils. Sepsis is a particularly serious cause of neutropenia, especially among young infants and children. Neonates are especially prone to exhausting their marrow reserve pool of segmented neutrophils and bands and succumbing rapidly to bacterial sepsis. In contrast, marrow reserves in older children and adults can increase by a log during infection.Drugs can induce severe neutropenia by immunologic, toxic, and hypersensitivity-mediated mechanisms (Table 4). This form of neutropenia must be distinguished from that seen with viral infections and from the severe neutropenia that accompanies administration of large doses of cytotoxic drugs or following radiation therapy. Once neutropenia occurs, the most effective therapeutic measure is withdrawal of all drugs that are not essential, particularly drugs suspected of being myeloid-toxic. Bacterial infections should be treated with antibiotics. Often the neutropenia will respond to withdrawal of the offending drug. If the neutropenia fails to respond to drug withdrawal and the patient subsequently experiences signs and symptoms related to severe neutropenia, subcutaneous administration of 5 mcg/kg recombinant human granulocyte-colony stimulating factor (rhG-CSF) should be considered.Immune neutropenias are associated with the presence of circulating antineutrophil antibodies. The antibodies are directed against specific neutrophil antigens that are genetically controlled independent of the human leukocyte antigen (HLA) system. The antibodies mediate neutrophil destruction by complement-mediated lysis or splenic phagocytosis of opsonized neutrophils. The assays employed most commonly to detect neutrophil antibodies are indirect or direct immunofluorescence to identify surface antigens on the neutrophil and microcapillary agglutination assays, which evaluate the ability of the antibody to clump neutrophils. Usually a combination of immunofluorescence and microcapillary agglutination assays is employed along with a panel of neutrophils that have different known antigen specificity to assure identification of the antineutrophil antibodies.This form of neonatal neutropenia occurs after transplacental transfer of maternal alloantibodies directed against an antigen of the infant’s neutrophils. It is present in 0.3% of pregnancies. Prenatal sensitization induces maternal immunoglobulin G (IgG) antibodies to neutrophil antigens of the fetal cells. Symptomatic infants may present with delayed separation of the umbilical cord, mild skin infections, fever, and pneumonia within the first 2 weeks after birth; these resolve with antibiotic therapy. The neutropenia often is severe and associated with fever and infection due to the usual microbes that cause neonatal disease. By 7 weeks after birth, the infant’s neutrophil count generally returns to normal, reflecting the duration of survival of the maternal antibody in the infant’s circulation. Treatment consists of supportive care and appropriate antibiotics for clinical infections.Primary autoimmune neutropenia (AIN) is observed most commonly in infants and is caused by granulocyte-specific autoantibodies. For many patients, AIN is diagnosed only after an expensive and burdening investigation and unnecessary treatment with rhG-CSF because AIN is not well known among physicians. Primary AIN typically is diagnosed in infants between the ages of 5 and 15 months. In 90% of infants, AIN is not associated with an increased risk of repeated pyogenic infections, even in the presence of severe neutropenia. In the past, many of these patients were categorized as having chronic benign neutropenia of childhood. Typically, 95% of infants undergo spontaneous remission within 7 to 24 months. Often screening must be repeated for antibodies several times until the antibodies are detected because they are not always observed in the serum. The bone marrow typically is normocellular or hypercellular and usually contains a reduced number of segmented neutrophils. Symptomatic treatment with antibiotics is satisfactory in most infants. Among patients treated for severe infection or for surgical preparation with rhG-CSF, neutrophil counts can be increased. When combined with the detection of neutrophil-specific antibodies, most patients can be diagnosed readily without burdening investigations, including a need for bone marrow aspiration.The isolated disorders of proliferation and maturation of myeloid stem cells are rare (Table 3). Affected patients frequently benefit from rhG-CSF therapy. Congenital disorders that have severe neutropenia as a clinical feature include the severe combined immunodeficiency syndromes, hyper IgM syndrome, common variable immune deficiencies, glycogen storage disease type 1b, Shwachman-Diamond syndrome, cyclic neutropenia, and severe congenital neutropenia.Cyclic neutropenia is a rare congenital granulopoietic disorder. The mode of inheritance is autosomal dominant, and it is characterized by regular, periodic oscillations, with the number of peripheral neutrophils ranging from normal to neutropenic values. The mean oscillatory period is 21±4 days. The estimated frequency of this condition is approximately 1 per 1 million population.Clinically, patients may suffer from oral ulcers, stomatitis, or cutaneous infections associated with lymph node enlargement during the neutropenic phase. Serious infections occur occasionally and may lead to pneumonia or recurrent ulcerations in the oral, vaginal, and rectal mucosa. Approximately 10% of patients who had cyclic neutropenia prior to the availability of rhG-CSF developed fatal Clostridium perfringens infection, likely arising from dissemination of organisms from ulcers in the gastrointestinal tract. Cyclic neutropenia frequently is called cyclic hematopoiesis because of the cycling of other blood cells, such as platelets and reticulocytes. Monocytes also cycle, but in a reciprocal fashion to the neutrophils.Cyclic neutropenia is diagnosed by obtaining blood counts two to three times per week for 2 months. The diagnosis can be confirmed with molecular genetic studies demonstrating mutations in the elastase gene. Once affected patients are treated with daily rhG-CSF, their cycle changes from a 21-day interval to a 9- to 11-day interval. Such patients no longer are at risk for fatal infections with clostridia, and antibiotic use associated with inflammatory disease is diminished.Severe congenital neutropenia (SCN), also known as Kostmann disease, is characterized by an arrest in myeloid maturation at the promyelocyte stage of the bone marrow, resulting in an ANC of less than 0.2 × 103/mcL (0.2 × 109/L). This disorder occurs sporadically.Patients who have SCN experience a predictable pattern of infection and inflammation. Mouth ulcers, gingivitis, otitis media, respiratory infections, cellulitis, and skin abscesses are the most common conditions. Pneumonia and deep-tissue abscesses occur frequently and are life-threatening. The most common causes of infection are S aureus and Streptococcus present on the body surfaces.The onset of mouth ulcers and gingivitis occurs in early childhood. Mild hepatosplenomegaly is common. Evidence for gingivitis is the most frequent finding. SCN is diagnosed by an ANC of less than 0.2 × 103/mcL (0.2 × 109/L) on at least three separate occasions over a 1-month period. Peripheral blood eosinophilia and monocytosis and a bone marrow reflecting arrest of promyelocyte cell maturation are associated with the profound neutropenia. The platelet count often is mildly elevated, and patients have anemia associated with chronic inflammatory disease. In the past, two thirds of patients died from fatal infections before reaching adolescence. Prior to the availability of rhG-CSF, leukemic transformation occurred in patients who had SCN and Shwachman-Diamond syndrome. The use of rhG-CSF has had a major impact on the management of SCN. After 11 years of clinical use, it has been documented that approximately 10% of patients who are diagnosed with SCN convert to myelodysplasia/acute myelogenous leukemia (MDS/AML).The onset of MDS can be insidious, with patients developing thrombocytopenia, anemia, or an increase or decrease in the dose of rhG-CSF required to maintain the target ANC. Cytogenetic analysis of unstimulated bone marrow cells frequently documents loss of entire chromosome homolog (monosomy 7) or a partial deletion involving the long arm. Some patients have trisomy 21. After development of MDS/AML, activating ras oncogene mutations have been identified retrospectively. In 80% of patients who have MDS/AML, point mutations in the gene for the G-CSF receptor occur, resulting in a truncated cytoplasmic region of the receptor. The mutations eliminate a crucial portion of the receptor involved in myeloid maturation signaling. The receptor mutations are acquired and are not the cause of congenital neutropenia.In contrast, patients who have SCN may have existing mutations in the neutrophil elastase gene (60% to 80%). Three-dimensional molecular modeling has suggested that most, if not all, of the mutations associated with cyclic neutropenia occur in proximity to the active site of the elastase gene and binding pocket for the enzyme’s natural inhibitors. The mutations responsible for SCN would be predicted to alter molecular folding. these the storage of neutrophil elastase in of the neutrophil and may to of myeloid found in the bone marrow of both of more than 90% of patients respond to rhG-CSF at mcg/kg per in two doses at resulting in a in their ANC. the 10% of patients who do not respond to G-CSF with an increase in ANC and mcg/kg per or more of the should be as for stem cell from an It is to point that no of have occurred in other cell of congenital neutropenia patients other than those who have SCN or Shwachman-Diamond syndrome. cell has to be the only treatment SCN patients convert to with of neutropenia to of neutrophil counts per age. If patients have 1.0 × 103/mcL (1.0 × 109/L), a differential count should be to or neutrophils are present in the peripheral which a response. 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For the who the of neutropenia, studies should be initiated to the contains antineutrophil marrow usually is not in the patient who has neutropenia, is not more than the usual bacterial infections, and does not have a of chronic gingivitis or recurrent mouth contrast, children who have a clinical with infections due to chronic neutropenia, such as gingivitis in infancy, more should be for 6 weeks to establish there is a cycle of 21±4 days, which cyclic neutropenia from severe congenital neutropenia. marrow and bone marrow are required to evaluate the risk for as well as to and the of myeloid cell who present with a with and neutropenia should be evaluated for Shwachman-Diamond syndrome. patients studies to evaluate and evaluation to the of children who have chronic neutropenia associated with recurrent infections should have to evaluate the of recurrent infections on and antibody cell and levels are for patients in disease and deficiencies, are evaluation is for patients suspected of having a presenting with a bone marrow and to in the diagnosis and to bone marrow marrow including and for leukemia and other are required in of other laboratory is determined by the duration and of the neutropenia and by the on the physical are particularly in the and of the respiratory and gastrointestinal As they form the first of against During the to period after by cells must at the site of if infection is to be If the resulting infection to a local or dissemination the be effective and at the site of inflammation, cells must to the the in the the site to and the offending and in intracellular is by two 1) of and often of molecular by an known as the respiratory and 2) the microbes of antibiotics and within several types of whose neutrophils have in adhesion and generally develop cutaneous abscesses with common pathogens such as S aureus or have caused by such as or oral bacterial flora. 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