CHAPTER 31 APLASTIC ANEMIA
CHAPTER 31 APLASTIC ANEMIA
RICHARD K. SHADDUCK
Definition and History
Etiology and Pathogenesis
Stem Cells, Microenvironment, Cytokines
Hereditary Aplastic Anemia
Signs and Symptoms
Plasma and Urine Findings
Course and Prognosis
The term aplastic anemia describes a clinical syndrome in which there is a deficiency of red cells, neutrophils, and monocytes, and platelets without morphologic evidence of another marrow disorder. Marrow examination shows a near absence of hematopoietic precursor cells and fatty replacement. The disorder can be induced by toxic chemicals (e.g., benzene), specific viruses (e.g., Epstein-Barr virus), or can be inherited (e.g., Fanconi’s anemia). Most cases occur without an evident incitant and are the result of autoreactive T lymphocytes that suppress or destroy hematopoietic cells. The disease may be ameliorated or sometimes cured by immunosuppressive therapy, especially antithymocyte globulin. For those with a suitable donor, allogeneic stem cell therapy is often curative. The disease, even after successful treatment with immunosuppressive agents, has a propensity to evolve into a clonal hematopoietic disorder such as paroxysmal nocturnal hemoglobinuria, oligoblastic or acute myelogenous leukemia.
Acronyms and abbreviations that appear in this chapter include: ALG, antilymphocyte globulin; ALS, antilymphocyte serum; ATG, antithymocyte globulin; BFU–E, erythroid burst-forming units; CFU-GM, granulocyte-macrophage colony-forming units; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpes virus; HIV, human immunodeficiency virus; IL, interleukin; NMRI, nuclear magnetic resonance imaging; PNH, paroxysmal nocturnal hemoglobinuria; SCF, stem cell factor.
DEFINITION AND HISTORY
Aplastic anemia results from a failure of blood cell production in the marrow. This results in a markedly hypocellular marrow and varying degrees of anemia, granulocytopenia, and thrombocytopenia. Most cases of aplastic anemia are acquired. The decrease in hematopoiesis may be secondary to toxic effects of offending agents on marrow stem cells; in many cases, however, the pathogenesis is the suppression of blood cell progenitor proliferation and maturation by autoreactive lymphocytes. The disease also may occur as the result of an inherited disorder, especially Fanconi anemia. A close association also exists between the clonal hemopathy, PNH, and aplastic anemia.
Aplastic anemia was first recognized by Ehrlich in 1888.1 He described a young pregnant woman who died of severe anemia and neutropenia; autopsy examination revealed a fatty marrow with essentially no hematopoiesis. The name aplastic anemia was subsequently applied to this disease in 1904.2 Over the next 30 years many conditions that caused pancytopenia were confused with aplastic anemia based on incomplete or inadequate histologic study of the patient’s marrow. Marrow biopsies are required to document that a hypocellular marrow aspirate represents hypoplasia or aplasia and to exclude other conditions that may infiltrate, replace, or suppress normal marrow cells.3
ETIOLOGY AND PATHOGENESIS
It is unclear why some individuals who are exposed repeatedly to potential marrow toxins sustain severe and often irreversible marrow injury, whereas most have no untoward effects. It has been postulated that there is a genetic predisposition based on a high incidence of HLA class II antigens DR24 and DPw35 in patients with marrow aplasia. The disease may result from the accumulated effects of multiple noxious exposures on pluripotential stem cells. Ultimately, all stem cells sustain sufficient damage to hinder their ability to replicate. Alternatively, such exposures may induce a single abnormal cell to proliferate in a clonal fashion and to somehow hinder the growth of normal stem cells. The result in the first case would be aplastic anemia from a polyclonal injury (classical aplastic anemia) to stem cells and/or very early multipotential progenitor cells and in the latter injury to a single stem cell resulting in a monoclonal disorder (e.g., paroxysmal nocturnal hemoglobinuria—aplastic anemia syndrome). Although classic aplastic anemia and paroxysmal nocturnal hemoglobinuria are thought to be distinct clinical entities, studies suggest an overlap in these conditions. As many as 40 percent of patients with otherwise typical aplastic anemia have evidence of glycosyl-phosphatidylinositol molecule defects in leukocytes and red cells as judged by flow cytometry, analogous to that seen in PNH.6,7 and 8 Aplastic anemia, hypoplastic myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria each may eventually evolve into acute myelogenous leukemia.9,10,11,12 and 13
STEM CELLS, MICROENVIRONMENT, CYTOKINES
Potential mechanisms responsible for acquired marrow cell failure include induced defects in hematopoietic stem cells, failure of the stromal microenvironment of the marrow, impaired production or release of hemopoietic growth factors, and cellular or humoral immune suppression of the marrow. Several pathogenic abnormalities have been found in patients with aplastic anemia14,15,16,17 and 18; however, it is unclear whether these are inciting events or represent epiphenomena secondary to the disease. Although it is not possible to assess human totipotential stem cells in culture, their progeny are easily identified by clonal growth in vitro. The number of CFU-GM and BFU–E are reduced markedly in patients with aplastic anemia.19,20,21,22,23,24 and 25 The more immature long-term culture initiating cells are also reduced to about 1 percent of normal values.26 CD34-positive hematopoietic cells, in which fraction the hematopoietic stem cells reside, are also correspondingly low.27,28 These findings suggest that reduced hematopoietic stem cells are the primary defect in the abnormal hematopoiesis. Stem cell inhibition may, however, occur by a T-cell–mediated suppressor effect. Early studies showed inhibition of colony growth by autologous marrow lymphocytes or by blood or marrow mononuclear cells from patients with aplastic anemia when cocultured with normal marrow.20,23,29,30 and 31 In many cases the inhibition was thought to result from transfusion sensitization rather than autoimmunity.32,33 However, culture studies in patients with aplastic anemia prior to transfusion34 or before and after successful treatment35,36 are highly suggestive of a T-cell–mediated suppressor cell phenomenon. Alternatively, injured hemopoietic stem cells may present neoantigens that serve as a stimulus for secondary T-cell–mediated suppression, which serves to worsen the aplasia.
Based on studies in rats, a theory of “seed” (stem cells) versus “soil” (microenvironment) abnormality was established.37 Modest doses of irradiation to a limb lead to transient aplasia, with recovery secondary to ingress of circulating stem cells. With doses of 20 Gy (2000 rad) and greater, there is similar aplasia and recovery; however, permanent aplasia develops in this limb several months later. This appears to result from late damage to the marrow microenvironment, which may also occur in certain cases of aplastic anemia.
Pathogenetic studies have been conducted of the residual marrow damage in mice that receive busulfan.38,39 Although blood counts are usually normal, both marrow progenitor cells and stem cells are decreased substantially. Some animals progress to chronic hypoplastic marrow failure, whereas others retain relatively normal blood counts.38 When treated with chloramphenicol, animals exposed to busulfan have a marked decrease in progenitor cells, whereas controls are unaffected.39 Perhaps similar repeated exposures with different agents may be necessary to induce aplastic anemia in humans.
The hematopoietic defects, macrocytic anemia, and mild hypoplasia occur in two strains of mice (WWv and Sl/Sld). WWv anemia is cured by lethal irradiation and infusion of stem cells from nonaffected litter mates, whereas the Steel (Sl) defect is not corrected by stem cell transplantation because it is the result of an abnormal microenvironment.40 WWv cells are deficient in the proto-oncogene kit,41 which encodes a tyrosine kinase receptor for the hemopoietic growth factor kit ligand42 (see Chap. 14). Sl/Sld mice do not produce kit ligand, also called stem cell factor (SCF). Similar defects have not been observed in patients with aplastic anemia. Serum levels of SCF have been either moderately low or normal in several studies of aplastic anemia.43,44 and 45 Although SCF augments the growth of hemopoietic colonies from aplastic marrows,46 its use in patients has not led to clinical remissions. Another early acting growth factor, Flt-3 ligand, is 30- to 100-fold elevated in the serum of patients with aplastic anemia.47 Short-term clonal assays for marrow stromal cells have shown variable defects in stromal cell function. Fibroblasts grown from patients with severe aplastic anemia have subnormal cytokine production. However, serum levels of granulocyte colony-stimulating factor,48 erythropoietin,49 and thrombopoietin50 are usually high. Synthesis of IL-1, an early stimulator of hemopoiesis, is decreased in mononuclear cells from patients with aplastic anemia, but it is produced normally by cells from patients with myelodysplastic syndrome.51 Levels of cytokines with inhibitory effects on hemopoiesis are increased in most patients with severe aplastic anemia. Increased mononuclear cell production of interferon-g,52,53 IL-2,54 and tumor necrosis factor-a55,56 has been noted spontaneously or in response to certain mitogens. Elevated serum levels of interferon-g have been found in 30 percent of patients with aplastic anemia, and interferon-g expression has been detected in the marrow of most patients with acquired aplastic anemia.57 Moreover, addition of antibodies to interferon enhances in vitro colony growth of marrow cells from affected patients.52 This suggests a potential role for interferon-g in either the initiation or propagation of the defect in aplastic anemia.
Studies of the microenvironment have shown relatively normal stromal cell proliferation and growth factor production.58,59 and 60 These findings, coupled with the limited response of patients with aplastic anemia to the known growth factors, suggest that cytokine deficiency is not the etiologic problem in most cases.
Potential causes for aplastic anemia are shown in Table 31-1. The disorder may follow exposure to various chemicals, drugs, radiation, or viruses. In addition, connective tissue disorders and pregnancy may be associated with marrow aplasia. Constitutional forms, particularly Fanconi anemia, develop in the setting of an underlying genetic defect. As many as 65 percent of cases of aplastic anemia, however, are idiopathic.
TABLE 31-1 ETIOLOGIC CLASSIFICATION OF APLASTIC ANEMIA
Benzene was the first chemical linked to aplastic anemia, based on studies in factory workers before the twentieth century.61 Despite its known properties as a marrow toxin, benzene is still used widely as a solvent and is employed in the manufacture of chemicals, drugs, dyes, and explosives. It has been a vital chemical in the manufacture of rubber and leather goods and has been used widely in the shoe industry, leading to an increased risk for aplastic anemia and leukemia in workers in all these industries.62,63,64,65 and 66 In China, where benzene is still used widely in industry, benzene poisoning was found in 0.5 percent of the workers; aplastic anemia among workers was sixfold higher than in the general population.67
The U.S. Occupational Safety and Health Administration has lowered the permissible exposure limit to benzene to 1 ppm,68 after it was shown that exposure to 100 ppm was associated with leukopenia in about one-third of workers.69 Other hematologic abnormalities have been observed in patients exposed to benzene, including hemolytic anemia, marrow hyperplasia, myeloid metaplasia, and acute myelogenous leukemia.62,63,64,65,66 and 67,70
There appears to be a relationship between the use of insecticides related to benzene and aplastic anemia. Chlorinated hydrocarbons and organophosphate compounds have been implicated in 280 cases reported in the literature.71 DDT (chlorophenothane), lindane, and chlordane appear to be the most common insecticides involved. Aplastic anemia was reported following the use of lindane in home vaporizers for disinfection. This practice continued until the 1970s, when over 30 case reports of aplastic anemia led to its curtailment.72 Occasional cases still occur following heavy exposure at industrial plants or after its use as a pesticide.73 Lindane is metabolized in part to pentachlorophenol (PCP), another toxic chlorinated hydrocarbon that is manufactured for use as a wood preservative. Many cases of aplastic anemia and related blood disorders have been attributed to PCP over the past 25 years.72,73,74 and 75 Prolonged exposures to petroleum distillates in the form of Stoddard solvent76 and acute exposure of toluene through the practice of glue sniffing77 have also been reported to cause aplasia. Trinitrotoluene (TNT), an explosive used extensively during World Wars I and II, is absorbed readily by inhalation and through the skin. Many fatal cases of aplastic anemia were observed in munitions workers exposed to TNT in Great Britain from 1940 to 1946.78
Chloramphenicol is a nitrobenzene compound with broad-spectrum antibiotic activity. It was introduced in 1948 and used widely during the 1950s and 1960s by various routes of administration, often for trivial indications. Reports of an association with aplastic anemia began early after its introduction.79,80 and 81 Indiscriminant use of the drug continued, however, despite warnings to limit its use to infections caused by organisms that were resistant to other agents or for which no other drugs were available.82 The risk of developing aplastic anemia in patients treated with chloramphenicol is about 1 in 20,000, or 10 to 50 times that of the general population.83,84 and 85 Unfortunately, reports of fatal aplastic anemia continue to appear with topical or systemic use of the drug.86,87
Two adverse hematopoietic responses to the drug occur. Suppression of marrow function occurs in many individuals receiving the drug, with reduced erythroid cell production characterized by a rise in serum iron, accumulation of iron in the mitochondria, and vacuolization of marrow erythroid precursor cells.88,89,90 and 91 Reticulocytes decrease and the hematocrit declines as inhibition of red cell production continues. Mild decreases in circulating neutrophils and platelets are also observed in some patients. These effects are probably the result of inhibition of mitochondrial protein synthesis and are reversible after discontinuation of the drug. There appears to be no relationship between this common, temporary inhibition of hematopoiesis and the rare, but devastating, severe aplastic anemia that ensues in a small proportion of patients. This latter reaction may occur weeks to months after treatment and does not appear related to the total drug exposure nor to the route of administration. Based on the nearly simultaneous development of aplastic anemia in identical twins given this agent,92 it was postulated that there is a genetic defect that predisposes to this severe reaction to the drug.
With chloramphenicol, the many cases of aplastic anemia strongly established the potential for toxic effects with this drug. Owing to a lower incidence of aplastic anemia with many other drugs, however, it has often been difficult to isolate the single offending agent. Perhaps the only drug for which there is good statistical information is quinacrine (Atabrine).93 This drug was administered to all U.S. troops in the South Pacific and Asiatic theaters of operations as prophylaxis for malaria during 1943 and 1944. The incidence of aplastic anemia was compared to army personnel in the United States and Europe who did not receive quinacrine. The incidence of aplastic anemia was 7 to 28 cases per 1,000,000 personnel per year in the prophylaxis zones, whereas nontreated soldiers had 1 to 2 cases per 1,000,000 personnel per year. In contrast to other drugs, the aplasia occurred during administration of the offending agent and was preceded by a characteristic rash in nearly half the cases.
Many other drugs have been implicated in sporadic cases of aplastic anemia, but owing to limited reporting of information, it is possible that the spectrum of drug-induced aplastic anemia is not fully appreciated. A list of drugs that have been implicated is shown in Table 31-2. Antineoplastic drugs such as alkylating agents, antimetabolites, and certain cytotoxic antibiotics all have the potential for producing marrow aplasia. In general, this is transient, is an extension of their pharmacologic action, and resolves within several weeks of completing chemotherapy. Although unusual, severe hypoplasia can follow use of the alkylating agent busulfan and may persist for extended intervals. Patients may develop marrow aplasia 2 to 5 years after discontinuation of alkylating agent therapy. These cases often evolve into hypoplastic myelodysplastic syndromes.
TABLE 31-2 DRUGS ASSOCIATED WITH APLASTIC ANEMIA
Other types of drugs may be associated with occasional cases of aplastic anemia. These include analgesics as well as antiarthritic and anti-inflammatory agents. The most serious offenders in the latter group include gold salts, penicillamine, and the butazone compounds. Many nonsteroidal analgesics have been associated with sporadic cases of marrow aplasia. Anticonvulsant medications, particularly carbamazepine, are marrow suppressants. The sulfonamides and their derivatives, which include diuretics and oral hypoglycemic agents, have been associated with cases of aplastic anemia. Many of these drugs are known to induce selective cytopenias, such as agranulocytosis, which are usually reversible after discontinuation of the offending agent. These reversible reactions are not correlated with the risk of aplastic anemia, casting doubt on the effectiveness of routine monitoring of blood counts as a strategy to avoid aplastic anemia.
Since aplastic anemia remains a rare event, it may occur because of an underlying metabolic predisposition in susceptible individuals. In the case of phenylbutazone-associated aplasia, there is delayed oxidation and clearance of a related compound, acetanilide, as compared to either normal controls or those with aplastic anemia due to other causes.94 This suggests excess accumulation of the drug as a potential mechanism for the aplasia. In some cases drug interactions or synergy may be required to induce aplasia. Cimetidine, a histamine H2-receptor antagonist, is occasionally implicated in cytopenias and in causing aplastic anemia, perhaps owing to a direct effect on hematopoietic stem cells.95,96 This drug accentuates the marrow-suppressive effects of the chemotherapy drug carmustine97 and in several instances has been reported as a possible cause of aplasia when given with chloramphenicol.87
Chronic exposure to low doses of radiation or use of localized radiation for ankylosing spondylitis is associated with an increased, but delayed, risk of developing aplastic anemia and acute leukemia.98,99 Patients who were given thorium dioxide (Thorotrast) as an intravenous contrast medium suffered numerous late complications, including malignant liver tumors, acute leukemia, and chronic aplastic anemia.100 Chronic radium poisoning with osteitis of the jaw, osteogenic sarcoma, and aplastic anemia was seen in workers who painted watch dials with luminous paint when they moistened the brushes orally.101
Acute exposures to large doses of radiation are associated with the development of marrow aplasia and a gastrointestinal syndrome.102,103 Total body exposure to between 1 and 2.5 Gy (100 to 250 rad) leads to gastrointestinal symptoms and depression of leukocyte counts, but most patients recover. A dose of 4.5 Gy leads to death in half the individuals (LD50) owing to marrow failure. Higher doses in the range of 10 Gy are universally fatal unless the patient receives extensive supportive care followed by marrow transplantation. Aplastic anemia associated with nuclear accidents was seen after the disaster that occurred at the Chernobyl nuclear power station in the Ukraine in 1986.104,105,106 and 107
A striking relationship between hepatitis and the subsequent development of aplastic anemia has been the subject of a number of case reports; this association was emphasized by two major reviews in the 1970s.108,109 In the aggregate, these reports summarized findings in over 200 cases. In many instances, the hepatitis was improving or had resolved when the aplastic anemia was noted 4 to 12 weeks later. Approximately 10 percent of cases occurred more than 1 year after the initial diagnosis of hepatitis. Most patients were young (18 to 20 years), two-thirds were male, and their survival was short (10 weeks). Although hepatitis A and B have been implicated in aplastic anemia in a small number of cases, most cases are related to non-A, non-B hepatitis.110,111 Severe aplastic anemia developed in 9 of 31 patients who underwent liver transplantation for non-A, non-B hepatitis but in none of 1463 patients transplanted for other indications.112 Several lines of evidence indicate there is no association with hepatitis C virus, suggesting that a hitherto unknown viral agent is involved.113,114 and 115
EBV has been implicated in the pathogenesis of aplastic anemia.116,117 The onset usually occurs within 4 to 6 weeks of infection. In some cases infectious mononucleosis is subclinical, with a finding of atypical lymphocytes in the blood film and serological results consistent with a recent infection. EBV has been detected in marrow cells,118 but it is uncertain whether aplasia results from a direct effect or an immunologic response by the host. Some patients have recovered following therapy with antithymocyte globulin.113,116,118
A number of other viruses have been implicated in the pathogenesis of marrow failure. B-19 parvovirus, the cause of fifth disease, leads to transient erythroid aplasia but is not known to induce aplastic anemia.113,119 HHV-6 has caused severe marrow aplasia subsequent to bone marrow transplantation for other disorders.120 HIV infection is frequently associated with varying degrees of cytopenia. The marrow is often cellular, but occasional cases of aplastic anemia have been noted.121,122 and 123 In these patients, marrow hypoplasia may result both from viral suppression and from the many drugs used to control viral replication in this disorder.
Rheumatoid arthritis is not ordinarily associated with severe aplastic anemia, but an epidemiologic study in France revealed a sevenfold increase in the incidence of aplastic anemia in patients with this disorder.124 It is uncertain whether the aplastic anemia is related directly to rheumatoid arthritis or to the various drugs used to treat the condition (gold salts, D-penicillamine, and nonsteroidal agents). Occasional cases of aplastic anemia are seen in conjunction with systemic lupus erythematosus.125 In vitro studies have suggested the presence of an antibody126,127 or suppressor cell128,129 directed against hematopoietic progenitor cells. Patients have recovered after plasmapheresis,126,127 glucocorticoids,129 or cyclophosphamide therapy,128,130 suggesting a possible immune etiology.
Eosinophilic fasciitis, an uncommon connective tissue disorder with painful swelling and induration of the skin and subcutaneous tissue, has been associated with aplastic anemia on at least 14 occasions.131,132,133 and 134 Although it may be antibody-mediated in some cases, it has been largely unresponsive to therapy. One patient improved with immunosuppressive therapy using ATG and cyclosporine.133 In another case, a partial remission was achieved following therapy with ATG.
There are a number of reports of pregnancy-associated aplastic anemia, but the relationship between the two conditions is not clear.135,136,137,138,139,140 and 141 In some patients, preexisting aplastic anemia is exacerbated with pregnancy, only to improve following termination of the pregnancy.136,139,140 In other cases, the aplasia develops during pregnancy with recurrences during subsequent pregnancies.136,140,141 Termination of pregnancy or delivery may improve the marrow function, but the disease may progress to a fatal outcome even after delivery.135,136,137,138,139,140 and 141 Therapy may include elective termination of early pregnancy, supportive care, immunosuppressive therapy, or marrow transplantation after delivery.
HEREDITARY APLASTIC ANEMIA
The most common form of constitutional aplastic anemia was described in three brothers by Fanconi in 1927.142 Since that time nearly 800 cases have been recorded, either by reports in the literature or through an International Fanconi Anemia Registry.143,144,145 and 146
Fanconi anemia is inherited as an autosomal recessive condition. It is estimated to be present in one in a million individuals, although it is more frequent in Afrikaners of European descent and in southern Italy.
At least eight gene mutations have been associated with the development of Fanconi anemia. The genes have been designated FAA through FAH. The great majority of patients have mutations of FAA or FAC. It has been proposed that the A and C gene products, which are cytoplasmic proteins, form a complex with the products of genes B, E, F, and G, which are adaptors or phosphorylators; the complex translocates to the nucleus, where it subserves its normal function. In the presence of a mutant gene product, normal function is disturbed leading to effects in sensitive tissues, including hematopoietic cells. Mutation of the D product appears to effect tissue cells through a different mechanism, perhaps downstream from the complex.147,148
Blood counts and marrow cellularity are often normal until 5 to 10 years of age, when pancytopenia develops gradually over an extended interval. Thrombocytopenia may precede the development of granulocytopenia and anemia. The marrow becomes hypocellular, and in vitro colony assays reveal a decrease in CFU-GM and BFU–E.145 It is often associated with abnormal skin pigmentation typical of café-au-lait lesions. Growth retardation results in short stature. Skeletal anomalies, especially dysplastic radii and thumbs, occur in half the patients. Heart, kidney, and eye defects may be present. Microcephaly and mental retardation may be present. Hypogonadism occurs. Hematologic and visceral manifestations are combined in more than a third of patients, but some may have anemia and inconspicuous somatic changes whereas others may have the anomalies with little hematopoietic disorder. A few may be virtually unaffected.145,146 and 147 In the past, children with a similar onset of aplastic anemia without congenital abnormalities were thought to have a different disorder termed Estren-Dameshek syndrome.149 These children, whose lymphocytes show sensitivity to diepoxybutane, have the same inherited disorder without skeletal abnormalities.144
Random chromatid breaks are present in myeloid cells, lymphocytes, and chorionic villus preparations. This chromosome damage is intensified after exposure to DNA cross-linking agents such as mitomycin C or diepoxybutane. The hypersensitivity of the chromosomes of marrow cells or lymphocytes to the latter agent is used as a diagnostic test for this condition. Cell-cycle progression is prolonged at the G2 to M transition phase of the cell mitotic cycle, and the cells are more susceptible to oxygen toxicity when cultured in vitro.147 It is important to test the lymphocytes from pediatric patients with aplastic anemia for sensitivity to diepoxybutane, since therapy for Fanconi anemia differs from that used for idiopathic aplastic anemia.
Most patients with Fanconi anemia do not respond to ATG or cyclosporine but do improve with androgen preparations, often for as long as several years. Relapses occur gradually, with eventual death by age 10 to 20 years from progressive marrow failure or from conversion to acute myelogenous leukemia (approximately 10 percent of patients). Allogeneic stem cell transplantation is curative for this disorder.150,277 A marked reduction in dosage of the marrow-conditioning regimen of cyclophosphamide and radiation is necessary owing to the undue sensitivity of the tissues to alkylating agents.150
DYSKERATOSIS CONGENITA AND SCHWACHMAN-DIAMOND SYNDROME
Dyskeratosis congenita and Schwachman-Diamond syndrome (pancreatic insufficiency with neutropenia) are two rare disorders that may also evolve into aplastic anemia. Dyskeratosis is usually inherited as a recessive X-chromosome–linked disorder although rare cases are autosomal. The disease is reflected in reticulate skin pigmentation, leukoplakia, and dystrophic nails. A variety of noncutaneous anomalies have also been observed. The skin and mucosal lesions appear in adolescence, and aplastic anemia usually develops in early adulthood.151 Schwachman-Diamond syndrome is manifest by pancreatic insufficiency and steatorrhea. Neutropenia is present in virtually all patients and granulocytopenia and thrombocytopenia in about one-third to one-half. Thus a substantial plurality of patients have bi- or tricytopenia with hypoplastic marrows. There is a significant risk of progression to myelogenous leukemia.152,278 Severe hematopoietic dysfunction can be treated successfully with allogeneic stem cell transplantation.
The incidence of aplastic anemia is estimated to be 2 to 5 cases per 1,000,000 population per year based on retrospective studies.83 The incidence rates in Sweden (13 cases per 1,000,000 per year),153 Israel (8 cases per 1,000,000 per year),84 and the United States (5 to 12 new cases per 1,000,000 per year)154,155 suggest that the rate in industrialized countries is about 5 to 10 cases per 1,000,000 per year.
SIGNS AND SYMPTOMS
The onset of aplastic anemia may be insidious, with a gradual fall in red cells leading to pallor, weakness, and fatigue, or it may be more dramatic with fever, chills, and pharyngitis or other infections resulting from neutropenia. Dependent petechiae, bruising, and bleeding secondary to thrombocytopenia are seen often and may be the initial clue to the underlying marrow disorder.
Physical examination is generally unrevealing except for evidence of infection or bleeding. Oral purpuric lesions (wet purpura) suggest a platelet count of less than 10,000/µl (10 × 109/liter), which portends a higher risk for cerebral hemorrhage. Retinal hemorrhages may be seen with severe anemia or thrombocytopenia. Lymphadenopathy or splenomegaly are not ordinarily found in aplastic anemia; such findings suggest recent infection or an alternative diagnosis such as leukemia or lymphoma.
Patients with aplastic anemia have varying degrees of pancytopenia. Anemia is associated with a low reticulocyte index.156 The reticulocyte count is usually less than 1.0 percent and may be zero. Macrocytosis may result from the high levels of erythropoietin,157 stimulating the few residual erythroblasts to mature more rapidly,158 or from an abnormal clone of erythroid cells, such as is seen in myelodysplasia or paroxysmal nocturnal hemoglobinuria.10,11,12 and 13 The total leukocyte count is low; the differential cell count reveals a marked decrease in neutrophils. The absolute neutrophil count is the most important prognostic feature, with a count of less than 500/µl (0.5 × 109/liter) associated with increased risk of infections and less than 200/µl (0.2 × 109/liter) associated with a dire prognosis. Lymphocyte production is thought to be normal, but patients may have mild lymphopenia. Platelets are reduced, but they function normally. On occasion, only one cell line is depressed initially, which may lead to an early diagnosis of red cell aplasia or amegakaryocytic thrombocytopenia. In such patients, other cell lines will fail shortly thereafter (days to weeks) and permit a definitive diagnosis.
The marrow aspirate typically contains numerous spicules with empty fatty spaces and relatively few hematopoietic cells. Lymphocytes, plasma cells, macrophages, and mast cells may be prominent, but this probably reflects a lack of other cells rather than an increase in these elements. On occasion, some spicules are cellular or even hypercellular, but megakaryocytes are usually reduced. These areas of residual hematopoiesis do not appear to be of prognostic significance. Residual granulocytic cells generally appear normal, but it is not unusual to see mild dysplastic or megaloblastoid features in the erythroid cells. At times they are macrocytic or macronormoblastic, presumably due to the high levels of erythropoietin. Marrow biopsy is essential to confirm the overall hypocellularity (Fig. 31-1), since a poor yield of cells is seen on marrow aspirates in a number of other hematologic disorders.
FIGURE 31-1 Marrow biopsy in aplastic anemia. The marrow is devoid of hematopoietic cells and contains only scattered lymphocytes and stromal cells.
Severe aplastic anemia has been defined by the International Aplastic Anemia Study Group159 as a marrow of less than 25 percent cellularity, or less than 50 percent cellularity with less than 30 percent hematopoietic cells, with at least two of the following: neutrophil count less than 500/µl (0.5 × 109/liter), platelet count less than 20,000/µl (20 × 109/liter), and anemia with a corrected reticulocyte index of less than 1 percent. Those patients with a neutrophil count less than 200/µl (0.2 × 109/liter) have an extremely poor prognosis and are characterized as having very severe aplastic anemia.160
If a lymphocytosis is noted in the marrow or blood, a tartrate-resistant acid phosphatase determination as well as immunophenotyping should be done to exclude early cases of hairy-cell leukemia161 or acute lymphocytic leukemia.162
PROGENITOR CELL GROWTH
In vitro granulocytic-monocytic (CFU-GM) and erythroid (BFU–E) colony assays reveal a marked reduction in progenitor cells.19,20,21,22,23,24 and 25,29,30,31,32,33,34 and 35 In some instances, improvement in colony growth after incubation with anti-T-cell monoclonal antibodies may predict improvement after immunosuppressive therapy163; this has not, however, been a universal finding.
Cytogenetic analysis may be difficult to perform owing to low cellularity; thus, multiple aspirates may be required to provide sufficient cells for study. The results are often normal in aplastic anemia and abnormal in myelodysplastic syndromes; one study, however, suggested that 4 percent of patients with otherwise typical aplastic anemia had abnormalities usually seen in myelodysplasia.164 Two of three patients with aplastic anemia and cytogenetic abnormalities who did not have marrow transplants progressed to a myelodysplastic syndrome, suggesting that the cytogenetic abnormalities of such patients represent or will soon evolve into a clonal (neoplastic) disorder.
NMRI can be used to distinguish between marrow fat and hematopoietic cells.165 This may provide a better overall estimate of marrow aplasia than morphologic techniques and may differentiate hypoplastic myelodysplastic syndrome from aplastic anemia.166,167
PLASMA AND URINE FINDINGS
Studies should include assessment of antibodies to hepatitis A, B, and C; hepatitis B antigen; heterophile determination; and antibodies to EBV. A sucrose hemolysis test and leukocyte and red cell immunophenotyping6,7 and 8 should be done prior to transfusions to exclude paroxysmal nocturnal hemoglobinuria (see Chap. 36).
The serum has high levels of hematopoietic growth factors, including erythropoietin, thrombopoietin, and myeloid colony-stimulating factors.48,49 and 50
Serum iron values are usually high, and 59Fe clearance is prolonged, with decreased incorporation into circulating red cells.168 Ferrokinetic studies or marrow scanning following injection of technetium sulfur colloid or indium chloride may be required to assess overall marrow cellularity and function.
Both marrow aspirate and biopsy are essential to show the overall marked hypocellularity and to exclude other causes of pancytopenia. Several disorders may be confused with severe aplastic anemia at the initial presentation. Approximately 10 percent of patients with myelodysplastic syndromes present with hypoplasia rather than a hypercellular marrow. This possibility is suspected if there is abnormal blood film morphology, as seen with myelodysplasia (see Chap. 92). Marrow erythroid precursors in myelodysplasia have both megaloblastoid and dysplastic features, with dumbbell and cloverleaf nuclei, Howell-Jolly bodies, and increased siderotic granules. Granulocyte precursors have reduced granulation, with abnormal blue cytoplasm in the promyelocytes and acquired Pelger-Huüet anomalies in the mature cells. Megakaryocytes may have hyperlobulation or may have a single nucleus in a small cell (unilobular micromegakaryocytes). Cytogenetic abnormalities are often found but are not essential for the diagnosis of myelodysplastic syndromes. MRI studies may be useful in differentiating severe aplastic anemia from myelodysplastic syndromes by showing a diffuse cellular pattern in the latter disorders.165,166 and 167 Paroxysmal nocturnal hemoglobinuria is usually identified by a positive sucrose hemolysis test, or abnormal CD59 red cell membrane proteins as detected by flow cytometry.6,7 and 8
Acute lymphocytic leukemia may initially have a hypoplastic phase, but even then clumps of lymphocytic cells are often seen.162 Less often, hairy-cell leukemia may be preceded by a hypoplastic phase.161 Both conditions can be differentiated from severe aplastic anemia by use of special stains such as tartrate-resistant acid phosphatase for hairy-cell leukemia and by immunophenotyping using flow cytometry for acute lymphocytic leukemia.
The median survival of untreated patients with aplastic anemia [neutrophil count <500/µl (0.5 × 109/liter)] is 3 to 6 months, with only 20 percent surviving beyond a year.169 Very severe aplastic anemia [neutrophils <200/µl (0.2 × 109/liter)] has an extremely poor prognosis.160 Those patients with less severe disease [i.e., neutrophils >1000/µl (1.0 × 109/liter)], who do not require red cell or platelet transfusions, may be treated conservatively with supportive care, as there are occasional cases of spontaneous recovery.
Prompt and aggressive therapy is usually indicated for most patients with severe disease. The major curative approach is allogeneic marrow transplantation.170 and 171 This treatment modality is described in Chap. 18. Only one-third of all patients have compatible donors. Many transplants have been performed using partially matched siblings or unrelated histocompatible donors recruited through the National Marrow Donor Program or similar organizations in other countries.172 Umbilical cord blood may evolve as an alternative source of unrelated donors for transplantation.173
ANTILYMPHOCYTE AND ANTITHYMOCYTE GLOBULIN
Many cases of aplastic anemia may be mediated by a cellular immune reaction directed against hematopoietic stem or progenitor cells. The recovery of their own cells was observed in some recipients of mismatched allogeneic transplants after treatment with ALG.174 Improvement occurred in benzene- or 32P-induced aplastic anemia in rabbits after ALG treatment and transplantation with mismatched marrow cells.175,176 The requirement for high-dose immunosuppressive treatment to allow engraftment in half the syngeneic transplants170,177 also supports the concept of a cellular immune reaction. Subsequently, many investigators found evidence of T-cell–mediated suppressor mechanisms by in vitro marrow culture studies.20,23,29,31,32,33,34,35 and 36 Some of these observations were undoubtedly due to transfusion sensitization, but a number of studies supported the notion of an active immune (T-lymphocyte–mediated) suppressor mechanism being responsible for the aplasia. Although ALS and ATG appear to act by reducing cytotoxic T cells, these preparations also release hematopoietic growth factors from certain T cells.178,179
There is about a 50 percent response rate with ALS or ATG.180,181,182,183 and 184 Therapy is given for 4 to 10 days with doses of 15 to 40 mg/kg daily. Since the antisera are prepared in horses, it is important to perform skin tests against horse serum prior to administration.185 If positive, pretreatment with glucocorticoids for 24 h lessens reactions. Fever and chills are common during the first day of treatment; these can be reduced with oral prednisone, 20 mg, daily. During treatment, accelerated platelet destruction is often seen. This leads to an increase in transfusion requirements over the 10-day treatment interval. Serum sickness occurs commonly 7 to 10 days from the first dose. This is characterized by spiking fevers, skin rashes, and arthralgias. The clinical manifestations of serum sickness can be prevented by increasing prednisone to 60 to 80 mg daily, from day 10 to day 17 of the treatment course.
Marrow recovery can occur after very high doses of glucocorticoids.186,187 Methylprednisolone in the range of 500 to 1000 mg daily for 3 to 14 days has been successful, but the side effects can be severe. These include marked glycosuria, electrolyte disturbances, gastric distress, psychosis, increased infections, and aseptic necrosis of the hips.
Repeated responses to immunosuppressive therapy have been observed. As shown in Fig. 31-2, a 45-year-old woman with severe aplastic anemia responded completely to ATG and remained well for nearly 9 months. At relapse, she received a second course of ATG and recovered for another 6 months. She developed an anaphylactic reaction with a third exposure to ATG. There were several subsequent responses to 14-day infusions of methylprednisolone (1 g/day), but no appreciable responses to nandrolone decanoate, cyclosporine, or goat antilymphocyte globulin; she became refractory to therapy and died of fungal sepsis.
FIGURE 31-2 Responses to repeated cycles of immunosuppressive therapy. A 45-year-old woman with severe aplastic anemia had two complete responses following treatment with horse antithymocyte globulin (ATG). After an anaphylactic reaction on the third exposure, she received 1 g of methylprednisolone (MP), intravenously daily for 14 days. This led to a partial response on three occasions. She was essentially unresponsive to further treatment with nandrolone decanoate (DECA), cyclosporine (CSA), or goat antilymphocyte globulin (ALG).
Another approach to immunosuppressive therapy uses cyclosporine, a cyclic polypeptide that inhibits IL-2 production by T lymphocytes and prevents expansion of cytotoxic T cells in response to IL-2. After the initial report in 1984 of its ability to induce remission,188 many groups have utilized cyclosporine as primary treatment,189,190,191 and 192 in patients refractory to ATG or glucocorticoids,190,191,192,193,194 and 195 in combination with granulocyte colony-stimulating factors,196,197 or in varying combinations with other modes of therapy.198 Cyclosporine is administered orally at 3 to 7 mg/kg per day for at least 4 to 6 months. Dosage adjustments may be required to maintain trough blood levels of 300 to 500 ng/ml. Renal impairment is common and may require increased hydration or dose adjustments to keep creatinine values below 2 mg/dl. Responses are usually seen by 3 months and may range from achieving transfusion independence to complete remission. Approximately 25 percent of patients respond to this agent, but the response rate has ranged from 0 to 80 percent in various reports.198
Although immunosuppression with ALG or ATG has the longest experience and a seemingly better response rate, there are certain advantages to cyclosporine. This drug does not require hospitalization or use of central venous catheters. Fewer platelet transfusions are required during the first few weeks of therapy, where accelerated platelet needs are seen in patients receiving ALG or ATG. It is unclear whether cyclosporine should be considered primary therapy for most patients, with views ranging from cautious optimism to marked reservation concerning its effectiveness. A French cooperative trial showed equal effectiveness of ATG plus prednisone compared to cyclosporine.199 In this crossover study of newly diagnosed patients, survivals of about 65 percent were observed 12 months after diagnosis. Improved in vitro tests to predict responsiveness may help tailor specific therapy for each patient in the future.194
Both low-dose and high-dose methylprednisolone have been used in combination with ATG and oxymethylone.200,201 Responses and survival were similar in both groups of patients. Androgens have been used in conjunction with immunosuppressive agents in randomized trials with both negative202 and positive results.201,203 Nonrandomized trials suggest that coadministration of androgens with ATG or ALG improves the response rate.204 At this time, it is unclear whether androgen preparations should be added to primary therapy; their use should be avoided in patients with posthepatitis aplastic anemia or in those with abnormal liver function tests.
Several trials have examined the effect of adding cyclosporine to basic regimens of ALG and glucocorticoids. Overall response rates increased from 47 percent to 70 percent in one study205 and from 39 percent to 65 percent in another.206 With combined therapy a 67 percent response rate was noted at 3 months, which improved to 78 percent at 1 year.207 Although granulocyte colony-stimulating factor alone may be detrimental,208 its addition to ALG, glucocorticoids, and cyclosporine appeared to improve response rates.209 Eighty-three percent of 40 patients with very severe aplastic anemia had trilineage reconstitution and became transfusion independent within 4 months of therapy.
These encouraging results with immunosuppressive therapy are in some instances equal to the results after marrow transplantation.210,211 and 212 The results from UCLA indicated a 49 percent survival for 146 patients treated with ATG alone.210 This did not differ from the survival of age-matched patients that underwent bone marrow transplantation during the same time interval. However, the survival after transplants improved after 1984, from 43 percent to 72 percent, indicating better results with improved transplant protocols. Similar results were seen in Seattle,211 where 227 patients were treated with ATG alone, and 168 received bone marrow transplants. The actuarial survival at 15 years was 38 percent following ATG therapy and 69 percent after bone marrow transplant. However, later results with combination immunosuppressive therapy showed better results. Forty-eight children treated at Memorial Sloan-Kettering between 1983 and 1992 had a 10-year survival of 76 percent for bone marrow transplantation and 74 percent for combined immunosuppressive therapy.212 Thus, immunosuppression may be preferable for patients who are greater than 30 to 40 years of age and who may experience delay in finding a suitable donor. Marrow transplants are, however, curative for aplastic anemia, whereas many long-term sequelae have been found after immunosuppressive therapy.213,214 and 215 Several surveys have shown a substantial rate of relapse or conversion to other stem cell disorders. Of 358 patients responding to immunosuppressive therapy, 74 relapsed after a mean of 2.1 years. The actuarial incidence was 35 percent at 10 years.216 In the Swiss experience,217 29 of 129 patients treated with ALG developed myelodysplasia, leukemia, paroxysmal nocturnal hemoglobinuria, or combined disorders. This tendency to relapse and to develop clonal hematologic disorders has been reviewed by the European Cooperative Group for Bone Marrow Transplantation in 468 patients, most of whom received ATG.218 The risk of a hematologic complication increased continuously and reached 57 percent at 8 years after immunosuppressive therapy. A further survey indicated 42 malignancies in 860 patients treated with immunosuppression, whereas only 9 malignancies were seen in 748 patients who received marrow transplants.219 Careful morphologic review of the blood and marrow before and after therapy may distinguish those patients at risk for late hematologic complications.220
High-dose cyclophosphamide has been used as a unique form of immunosuppression.221 Although it would seem inappropriate to administer high doses of chemotherapy to patients with severe marrow aplasia, this approach was based on observations of autologous recovery after preparative therapy for allogeneic transplants.221 Ten patients received cyclophosphamide at 45 mg/kg per day intravenously for 4 days with or without cyclosporine for an additional 100 days. Gradual neutrophil and platelet recovery ensued over 3 months. Seven patients responded completely and remain in remission 11 years after treatment.
A variety of androgenic and anabolic steroids have been used for aplastic anemia. Testosterone, methyltestosterone, testosterone enanthate, fluoxymesterone, norethandrolone, oxymetholone, nandrolone decanoate, danazol, and etiocholanolone have all been employed. These agents stimulate the production of erythropoietin, and their metabolites stimulate erythropoiesis when added to marrow cultures in vitro.222
Randomized trials have not shown efficacy when androgens were used as primary therapy for severe or moderately severe aplastic anemia.159,202 However, a French study showed that high doses of androgens were superior to low doses in patients with only moderately severe aplasia.223 Large series of patients were reported in which survival seemed improved as compared with historical controls,224 but this could equally be attributed to better supportive care. Many physicians use androgens in those patients with moderate degrees of marrow aplasia who have failed initial treatment with immunosuppressive agents. The response of one patient who was resistant to fluoxymesterone, ATG, and cyclosporine is shown in Fig. 31-3. There was progressive marrow recovery after 5 months of treatment with etiocholanolone and nandrolone decanoate.225
FIGURE 31-3 Response to etiocholanolone and nandrolone decanoate. A 62-year-old woman with severe aplastic anemia failed to improve after treatment with fluoxymesterone (Halotestin)(1¯, ×5 months), methylprednisolone (M Pred)(2
, 14 days), antithymocyte globulin (ATG) (3¯, 10 days), or cyclosporine (CYS)(4
, ×1 month). Marrow recovery occurred during therapy with 3-b-etiocholanolone and nandrolone decanoate. (Reproduced from Seewald et al,225 with permission.)
Androgens should be continued for at least 3 to 6 months, since responses may require prolonged treatment. Nandrolone decanoate, 400 mg intramuscularly per week, is a good initial drug. Concerns about local hematomas are usually obviated by firm local pressure for 30 min following injection. Long-term survivors after androgen therapy have essentially the same progression to clonal hematologic disorders as patients treated with immunosuppressive agents.224
Despite their effectiveness in accelerating recovery from chemotherapy, these agents have been far less effective in achieving long-term benefits in patients with severe aplastic anemia. Daily treatment with granulocyte-macrophage colony-stimulating factor226,227 and 228 or granulocyte colony-stimulating factor229 has improved marrow cellularity and increased neutrophil counts approximately 1.5- to 10-fold. Unfortunately, in nearly all patients, the blood counts return to baseline within several days of cessation of therapy. Although occasional patients show evidence of trilineage marrow recovery with long-term therapy,229,230,231 and 231 the vast majority do not respond. In fact, physicians have been cautioned not to use hemopoietic growth factors as primary therapy.208 Repeated transfusions of blood and platelets while awaiting definitive therapy by bone marrow transplant or immunosuppression can reduce the chances of responding to such therapy. Therapy with myeloid growth factors is probably best reserved for instances of proved infections or as a preventive measure prior to dental work or other procedures that would compromise mucosal barriers. Doses of 250 to 300 µg daily by subcutaneous injection are easiest to administer and seem to be associated with the fewest side effects.
IL-1, a potent stimulator of marrow stromal cell production of other cytokines, and IL-3 have been ineffective in small numbers of patients with severe aplastic anemia.233,234 These disappointing results with cytokines are not unexpected, as previous work has suggested high serum levels of growth factors in patients with aplastic anemia. Moreover, the majority of patients appear to have a stem cell defect, which may be unresponsive to factors that act on more mature progenitor cells.
High doses of intravenous gamma globulin have been given to small numbers of patients with severe aplastic anemia235,236 and 237 because of its success in treating certain cases of antibody-mediated pure red cell aplasia. Some improvement was noted in four of six patients treated. Other treatments that are occasionally successful include lymphocytapheresis238,239 and acyclovir240 (perhaps owing to a viral etiology in some cases).
Removal of the spleen does not increase hematopoiesis but may increase neutrophil and platelet counts two- to threefold and improve survival of transfused red cells or platelets in highly sensitized individuals.241 The surgical morbidity and mortality in patients with virtually no platelets makes this a questionable therapeutic procedure.
All patients should have immediate HLA typing performed.242 Where marrow transplant is a consideration, HLA typing of all siblings should be performed as soon as possible. Blood and platelet transfusions should be used sparingly, if at all, in potential transplant recipients to minimize sensitization. Most young adults can tolerate hemoglobin levels of 7 to 8 g/dl; platelets need to be given only for active hemorrhage or severe thrombocytopenia with platelet counts less than 10,000/µl (10 × 109/liter). It is important not to transfuse patients with red cells or platelets from family members, since this may sensitize patients to minor histocompatibility antigens, increasing the risk of graft rejection after marrow transplantation. Following a marrow transplant, or in those individuals in whom transplantation is not a consideration, family members may be ideal donors for platelet apheresis products.
It is important to assess the risk of bleeding in each individual patient and not to transfuse solely on the basis of platelet counts. Some patients tolerate platelet counts of 8000 to 10,000/µl (8 to 10 × 109/liter) without undue bruising or bleeding.243 In some cases, administration of 4 to 12 g daily of e-aminocaproic acid seems to reduce the bleeding tendency and to avoid transfusion requirements without influencing the platelet counts.244 Pooled random-donor platelets may be used until sensitization ensues, although it is preferable to use single-donor platelets from the onset to minimize sensitization to HLA or platelet antigens. Subsequently, single-donor apheresis products or HLA-matched platelets may be required.
Platelet refractoriness has been a major problem with long-term transfusion support. This may occur transiently, with fever or infection, or as a lasting problem secondary to HLA sensitization. In the past, this occurred in approximately 50 percent of patients after 8 to 10 weeks of transfusion support. Filtration of blood and platelet concentrates to remove leukocytes reduces this problem to approximately 15 to 20 percent of patients receiving chronic transfusions.245 In some patients who are refractory to platelets, this problem can be overcome by administering high-dose intravenous gamma globulin246,247 or by immunoabsorbent pheresis, using a column to remove circulating IgG complexes.248
Packed red cells are usually given to alleviate symptoms of anemia; transfusions are often indicated at hemoglobin values below 7 to 8 g/dl. These products should also be given through leukocyte-removal filters to lessen leukocyte and platelet sensitization and to reduce subsequent transfusion reactions. Since each unit of red cells provides approximately 200 to 250 mg of iron, there are long-term consequences of transfusion-induced hemosiderosis. This is not usually a major problem in patients who respond to transplantation or immunosuppressive therapy but is an issue in nonresponders who require continued support. Consideration should be given to chelation therapy with deferoxamine to avoid or reduce severe iron overload.249
CMV antibody titers should be obtained on admission; until these results are available, only CMV-negative blood products should be given to potential transplant recipients to minimize problems with CMV infections after transplantation. Once a patient is shown to be CMV-positive, this restriction is no longer necessary. Leukocyte-depletion filters will also decrease the risk of transmitting CMV.
Neutropenic precautions should be applied to hospitalized patients with neutrophil counts less than 1000/µl (1 × 109/liter). Precautions vary widely from institution to institution. One approach is to use private rooms, with requirements for face masks and hand-washing with antiseptic soap. Fresh fruits and vegetables should be avoided to prevent bacterial colonization or infection. When patients with aplastic anemia become febrile, cultures should be obtained from the blood, urine, and any suspicious lesions. Broad-spectrum antibiotics should be initiated promptly, without awaiting culture results (see Chap. 17). The choice of antibiotics depends on local practices; major organisms of concern include Staphylococcus aureus, S. epidermidis (in patients with venous access devices), and gram-negative organisms. Patients with persistent culture-negative fevers should receive antifungal treatment with fluconazole, itraconazole, or amphotericin.
In the past, leukocyte transfusions were used on a daily basis to reduce the short-term mortality from infections. Approximately 1010 leukocytes were obtained from normal donors by apheresis. However, there was generally a high proportion of mononuclear cells rather than neutrophils in these products. With a 1- to 2-h half-life in febrile patients, it was unusual to detect more than 100 to 200 neutrophils per microliter for more than a few hours after transfusion. The yield of neutrophils can be increased by administering GM-CSF or G-CSF to the donor,250 but most physicians avoid using white cell products since present-day antibiotics are usually sufficient to carry a patient through an episode of sepsis. Notable exceptions include documented invasive aspergillosis unresponsive to amphotericin (particularly in the post-transplant setting) and infections with organisms resistant to all known antibiotics.
COURSE AND PROGNOSIS
Before marrow transplantation and immunosuppressive therapy, more than 25 percent of the patients died within 4 months of diagnosis; half succumbed within 1 year.169,251,252 Marrow transplantation is highly successful and curative for 75 to 85 percent of untransfused patients and for 55 to 60 percent of those with multiple previous transfusions. Unfortunately, as many as 20 to 30 percent of transplant survivors suffer the deleterious consequences of severe graft-versus-host disease. Immunosuppressive therapy leads to a marked improvement in about 50 to 70 percent of the patients; some are hematologically normal, but many continue with moderate anemia or thrombocytopenia. Relapse occurs in about 15 percent of patients, and indeed the underlying stem cell defect may progress over 10 years to paroxysmal nocturnal hemoglobinuria, a myelodysplastic syndrome, or acute myelogenous leukemia in as many as 40 percent of initial responders to immunosuppressive therapy.213,214,215,216,217,218 and 219
At diagnosis, the prognosis is largely related to the absolute neutrophil count and platelet count. In the past, the prognosis appeared worse when the disease followed hepatitis.108,109,253 Recent results with immunosuppression254 or bone marrow transplant255 are equivalent to that seen with idiopathic or drug-induced cases. Children appear to respond better than adults, both with transplantation and with androgen therapy, especially those with mild or moderate disease. Constitutional aplastic anemia responds temporarily to androgens and glucocorticoids but is invariably fatal unless treated by transplantation.145,150
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn