Types of Severe Chronic Neutropenia

Information provide below by: E.L. Sievers, D.C. Dale

Audrey Anna Bolyard, R.N., B.S., Tammy Cottle, Carole Edards, R.G.N./R.S.C.N. Bsc., Sally Kinsey, M.D., Beate Schwinzer, Ph.D., Cornelia Zeidler, M.D.

Severe chronic neutropenia can exist from birth (congenital neutropenia) or cn occur an any time through life (acquired neutropenia). It may develop by itself or as an accompanying symptom of a different underlying disease. The following list gives you examples of the different types of chronic neutropenias.

• Neutropenias present at birth:
  • Severe congenital neutropenia (Kostmann syndrome)
  • Cyclic neutropenia
• Metabolic diseases associated with neutropenia
  • Shwachman-Diamond syndrome
  • Glycogen-storage disease type 1b
• Neutropenias that are acquired during life
  • Idiopathic neutropenia
  • Autoimmune neutropenia

Introduction
To meet normal physiologic needs, a healthy adult produces roughly 60 billion neutrophils each day. While neutrophils are produced by the bone marrow at a prodigious rate, their blood half-life is short - on the order of approximately 8 hours in a normal individual. Hence, erythrocytes, with a far longer lifespan, vastly outnumber neutrophils by a ratio of about one thousand to one in the peripheral blood. Under normal physiologic conditions, as stable equilibrium exists between marrow neutrophil production and peripheral utilization. When the production of neutrophils by the bone marrow is outspaced by utilization in the periphery, the number of circulating neutrophils in the peripheral blood decreases and Neutropenia results.

Normal neutrophil levels vary with age and race. In general, these counts range from 1.8 to 7.0 x 109 /L, with a mean of approximately 4.0 x 109 /L. Infants between 2 weeks and 1 year of age have neutrophil counts that are normally somewhat lower than older individuals. Additionally, people of African origin have normal neutrophil counts that are slightly lower than those seen in Caucasians. When a patient is found to be neutropenic, the peripheral blood neutrophil count serves as a rough guide to the relative seriousness of the disorder. This degree of Neutropenia can be "mild" (1.0 - 1.8 x 109 /L), "moderate" (0.5 - 1.0 x 109 /L), or "severe" (less than 0.5 x 109 /L). It should be emphasized, however, that the duration of Neutropenia, the function of neutrophils and other host defenses, and the capacity of the bone marrow to respond also contribute considerably to the relative susceptibility of a patient to infection.

Patients with severe Neutropenia, and particularly those with neutrophil levels less than 0.2 x 109 /L, have a significantly increased risk of infection due to invasion of surface bacteria in the mouth, intestinal tract or skin. Such patients frequently demonstrate mucosal inflammation, particularly of the gingival and perirectal areas and often manifest cellulitis, abscesses, furunculosis, pneumonia or septicemia. Unlike normal individuals, infections in these individuals often lack the fluctuance, induration, and exudate that typically accompany a normal inflammatory response. While superficial infections cause substantial morbidity in these patients, deep-tissue infections of the sinuses, lungs, liver and blood pose the greatest risk. Resistant organisms caused by the repeated use of broad spectrum antibiotics often complicate treatment.

Acquired non-malignant Neutropenia occurs much more commonly than chronic Neutropenia. In children, the acute forms are most frequently seen in association with viral infection. Neutropenia in this setting usually develops over one to two days and can persist for up to a week without serious sequelae. Since concomitant diminution of other cell lines in this setting is unusual, evaluation for malignancy should be considered if the red cell or platelet compartment are also significantly decreased. In the seriously ill patient - particularly the neonate - sepsis can cause acute Neutropenia. Since such patients can deplete their neutrophil reserves during an overwhelming infection, granulocyte transfusions may be life-saving.

Acute Non-Malignant Neutropenia

Infection

Table 1 : Causes of non-malignant Neutropenia

Isoimmune neonatal Neutropenia
Analogous to Rh hemolytic disease of the newborn, isoimmune neonatal Neutropenia results following maternal sensitization to fetal neutrophil antiogens during estation. Antibodies freely cross the placenta, destroy infant neutrophils, and predispose these affected children to serious infection. Commonly cutaneous infections are seen but, occasionally, respiratory tract or urinary tract infections occur. Bone marrow evaluation usually shows a relative myeloid hyperplasia, with an unusually decreased number of mature neutrophils. Often, a specific maternal neutrophil antibody is identified that reacts with the father's neutrophils. Most commonly, antibody is directed against paternal NA1 or NA2 which is inherited by the fetus. Since the half-life of circulating maternal IgG is approximately 7 weeks, the child's Neutropenia usually resolves by about 2 months of age. Antibiotics serve as the foundation of treatment of this disorder. In seriously ill neonates, transfusion of maternal granulocytes might be considered.

Autoimmune Neutropenia
(Presence of neutrophil-specific antibodies)

Severe acute Neutropenia discovered in older children and adults unassociated with an acute viral syndrome may represent autoimmune Neutropenia. However, demonstration of neutrophil antibodies is required to differentiate this disorder from benign chronic idiopathic Neutropenia. Presence of neutrophil-specific antibodies can result in increased destruction of the body's own blood neutrophils. Physical examination in these patients is usually unremarkable, but occasionally splenomegaly is noted. Marrow finding generally reflect that of "bone marrow arrest" - where adeuate numbers of early myeloid cells can be identified, but more mature myeloid elements appear lacking. The level of this "arrest" seems to vary between patients, and may reflect patient variability with regard to the myeloid antigen (early versus late) target by autoantibodies. Since young patients with autoimmune Neutropenia are likely to have a relatively benign course, most do not appear to require treatment of any kind. In some children where severe infections occur, treatment with G-CSF is indicated. In most children the blood counts normalise during the first 2 - 3 years. In patients with recurrent infections, treatment with corticosteroids results in improved neutrophil counts in about half of patients. The majority of patients less than 2 years of age spontaneously achieve a durable remission within 3 years of their initial diagnosis. In contrast, adults and children over the age of 2 tend to have accompanying immunologic abnormalities and appear less likely to improve spontaneously over time. Similarly, older patients appear more resistant to therapeutic interventions including corticosteroids, intravenous immune globulin, and splenectomy. Two patients have acheived clinical improvement with cyclosporine.

Drug-induced Neutropenia
This grave and unpredictable disorder is characterized by severe Neutropenia caused by an idiosyncratic reaction reaction to a drug that results in either direct suppression or immune destruction of neutrophils or myeloid precursors. Historically, women and older individuals experience these reactions more commonly than men and younger patients. In addition, genetic factors appear to influence a particular individual's tendency to develop this type of reaction. Typically, Neutropenia becomes evident 1 - 2 weeks following an initial exposure to a drug, or swiftly following a recent re-exposure to any offending agent. Treatment consists of rapid withdrawal of any drug suspected of causing the idiosyncratic reaction. Unfortunately, therapy with cortcosteroids has not shown significant efficacy. A partial list of drugs that have been associated with drug-induced Neutropenia is provided in Table 2.

Table 2

Severe Chronic Neutropenia
Severe chronic Neutropenia (SCN) is a global, descriptive term for several disorders in which neutrophil levels are consistently or recurrently at levels less than 0.5 x 109 /L. As congestive heart failure has varied etiologies, SCN describes a group of diseases with multiple causes. Despite this heterogeneity of origin, administration of exogenous myeloid growth factors to individuals with SCN results in an increase in neutrophil counts in most patients. Hence treatment of this group of disorders will be considered as a separate topic at the end of this section.

Congenital Neutropenia
Congenital Neutropenia, or Kostmann's syndrome, is a form of SCN. Kostmann, a Swedish physician who described a large family with several severely affected members, originally described this disease entity in 1956. Inherited in both an autosomal dominant and recessive manner, this syndrome is most often recognized at birth or shortly thereafter because of significant fever and infection. Oomphalatis, cellulitis, and perirectal abscesses are particularly common. Morphologic examination of bone marrow from these patients usually reveals almost no evidence of developing neutrophils beyond the promyelocyte stage. However, formation of monocytes and eosinophils usually remains normal. In vitro cultures demonstrate adequate numbers of colony forming cells (CFCGM), in which normal maturation of progenitor cells into mature neutrophils variably occurs. Upon the exposure to supraphysiologic levels of recombinant human granulocyte colony stimulating factor (rHuGCSF), however, these CFC-GM often form mature neutrophils. While this observation might suggest impaired synthesis of G-CSF in these patients, biologically active levels of this cytokine are usually elevated or normal. Hence, the G-CSF receptor somehow fails to transduce its signal appropriately.

G-CSF receptors appear normal in number and binding affinity in almost all patients evaluated. However, occasional children with Kostmann's syndrome - almost all in transition to AML - have been shown to manifest abnormalities of the receptor for G-CSF. In these rare cases, somatic mutation in one of the two alleles prevents function of the receptor encoded by the remaining normal allele. This mutated receptor appears to disrupt the normal regulation of myeloid growth, and might facilitate the evolution of leukemic subpopulations. It should be emphasized, however, that for the large majority of patients with Kostmann's syndrome, no obvious defect has been detected - suggesting a postreceptor problem.

Cyclic Neutropenia
This rare congenital disorder is characterized by remarkably regular oscillations of the blood neutrophil count. Usually with a periodicity of approximately 21 days. Frequently, cells of all hematopoietic lineages cycle as well. Periods of Neutropenia usually last for 3 - 6 days. During this time, there are usually no identifiable mature neutrophils present in the peripheral blood. Patients usually anticipate these periods of Neutropenia because they notice increasing anorexia and malaise. They often complain of headaches and myalgia when the neutrophil counts nadir and pharyngitis and oral ulcerations are common physical findings. While some patients occasionally develop severe, life-threatening infections, most adapt well to these periods of illness and experience relatively few chronic problems. Usually, when the neutrophil counts return to levels greater that 0.5 x 109 /L, patients report an improved sense of well-being, an increased appetite and the appearance of a yellowwhite exudate over the ulcers of the mouth and tongue.

While a third of patients appear to inherit the disorder in an autosomal dominant pattern, the majority of cases seem to occur sporadically. Most patients experience the onset of symptoms in infancy or childhood, but in 3 individuals, the initial diagnosis notably occurred late in life. Two features are necessary to confidently make a diagnosis of cyclic Neutropenia: (1) regular, cyclic fluctuations in peripheral blood neutrophil counts with a period ranging from 19 to 21 days and (2) documentation of neutrophil counts of less than 0.2 x 109 /L during periods of Neutropenia. In instances where the fluctuations do not appear regular, and severe Neutropenia is absent, it is best to regard the diagnosis as idiopathic or obtain additional clinical and laboratory data. At a minimum, 3 complete blood counts with differentials should be observed weekly for 6 - 8 weeks to discern the characteristic cycling and severe Neutropenia seen with this disorder.

Chronic Idiopathic Neutropenia
The term "idiopathic" neutropenia describes various types of neutropenia that may occur an any point in life for unknow reasons. Therefore, onset of idiopathic neutropenia is possible in both children and adults.

This heterogeneous diagnostic category is one of exclusion. It includes patients with a normal past history, generally including a previously normal complete blood count. These patients cannot carry the diagnosis or have received treatment for a malignant or premalignant hematologic disease, or a recognized infectious or immunologic disease. Often, the Neutropenia is identified on routine blood counts without accompanying symptoms or signs suggestive of infection. However, skin, perirectal, and oral infections can be reported in the history as well. Normal numbers of platelets and red blood cells are present, but these patients often demonstrate a moderate increase in their monocyte count. While morphologic examination of the marrow aspirate demonstrates variable findings, this procedure is recommended for the purpose of evaluating for malignancy. The diagnosis of chronic idiopathic Neutropenia in children merits special mention. This disorder tends to follow a remarkably benign course and often resolves spontaneously. However, it is particularly important to exclude autoimmune diseases and myelodysplastic syndromes in these patients. While demonstration of neutrophil antibody suggest an immunologic mechanism for Neutropenia, these tests have not been shown to predict clinical outcome, nor whether a patient will respond to cytokine therapy. Since this entity usually follows a benign course, it is not clear whether cytokine therapy should be routinely instituted in these patients. On balance, children experiencing multiple infections during periods of Neutropenia would appear to benefit from chronic administration of rHuG-CSF. Conversely, rHuG-CSF therapy might be avoided in healthy children with chronic Neutropenia until insights regarding the potential risks of prolonged therapy are gleaned.

Most patients respond well to G-CSF treatment but require long-term treatment.

Shwachman's Syndrome
Severe Neutropenia also occurs in Shwachman's syndrome (Neutropenia associated with exocrine pancreatic insufficiency, metaphyseal chondrodysplasia, and dwarfism). This rare disorder is inherited in an autosomal recessive fashion and usually presents in the neonatal period. Neutrophil counts vary from 200 to 400 per ul. A paucity of maturing neutrophils is usually noted on morphologic evaluation of the marrow aspirate. Often confused with cystic fibrosis, these patients do not typically demonstrate abnormal pulmonary findings. Some patients with Shwachman syndrome have developed severe aplastic anemia and rarely, leukemia.

Glycogen-Storage Disease Type 1B
Glycogen-storage disease type 1b is a rare metabolic disorder, which affects the glucose-6-phosphate metabolism. The liver, spleen, and other tissues accumulate glycogen. Patients present with an enlarged liver and spleen, failure to thrive, kidney problems, hypoglycaemia (low blood sugar) and recurrent infections. The presence of an enlarged spleen can be associated with low red blood cells causing anaemia and thrombocytopenia whereas neutropenia is always present. Chronic neutropenia in these patients is accompanied by a defective function of the cells that are responsible for the killing of bacteria. Patients respond to treatment with G-CSF not only with an increas in ANC but also with improvement of the activity of their neutrophils.

Myelokathexis Syndrome
Myelokathexis syndrome is an extremely rare disease characterized by chronic moderate Neutropenia and an increased incidence of infections. The diagnosis of this disorder is based upon the identification of hypersegmented nuclei and cytoplasmic vacuoles in mature neutrophils and marked hyperplastic changes seen in the bone marrow. Characteristically, the marrow demonstrates degenerating granulocytes suggesting an increased intramedullary obliteration of neutrophils as one possible mechanism for Neutropenia.

Congenital Immunologic Deficiency Syndromes
Various rare congenital immunologic deficiency syndromes are associated with Neutropenia. Usually these patients have a coexisting T-cell deficiency as well. Reticular dysgenesis is an extremely uncommon hematopoietic stem-cell disorder that results in an absence of cells of lymphoid and myeloid lineage. If instituted early, bone marrow transplant has successfully corrected this disorder.

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