Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027947 (neutropenia)
17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma.
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PMID:An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. 1018 30

Research in chronic lymphocytic leukemia (CLL) has undergone a resurgence of interest in the last decade. While it is obvious that most patients with CLL have typical mature B cells, a number of variants such as splenic lymphoma villous lymphocytes, mantle cell leukemia, and prolymphocytic leukemia need to be considered in the differential diagnosis. This can be established by immunophenotype studies and morphology. Cytogenetic abnormalities are emerging as being of interest, with abnormalities in chromosomes 11 and 17 having major prognostic significance. Immune disregulation is complicated in that along with hypergammaglobulinemia and T-cell dysfunction, the emergence of antibodies directed against hematopoietic cells causes autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. A number of prognostic factors are emerging as being more influential in prognosis and stage, such as serum beta2-microglobulin and soluble CD23. Apoptosis dysregulation is a major feature of CLL, and while no clear pattern has emerged, abnormal levels of bcl2 are common in CLL and bcl2 to bax ratios are also commonly disturbed. Bcl1 levels are commonly increased. Treatment has changed radically. The purine analogs have been demonstrated to be the most active group of drugs in CLL. Combinations of purine analogs, such a fludarabine or 2-chlorodeoxyadenosine, with alkylating agents are emerging as new treatments. The most recent development has been the emergence of two monoclonal antibodies, rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA; directed against CD20) and Campath-1H (directed against CD52 in CLL). The activity of rituximab in lymphoma has been less prominent in small lymphocytic lymphoma (the lymphomatous counterpart of CLL) and this has led to dose escalation studies in CLL with a good level of response. Campath-1H is emerging as another major antibody with marked effect against disease, particularly in the blood and bone marrow. Autologous, allogeneic, and mini-transplant are also being explored extensively. The prognosis for patients with CLL is changing as these new treatments become available.
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PMID:Chronic lymphocytic leukemia. 1056 Oct 25

Over the last few decades many biological factors have been discovered. Among these immunoglobulins are currently being used for large number of indications. Initially it was used for primary and secondary immunodeficiency states. Subsequently, intravenous immunoglobulins are being used for variety of immunohematological, autoimmune, and immunopathological disorders. In the present communication besides it basic structure, pharmacology and immunoregulation, its use in various hematological disorders is being reviewed. Currently, it is the preferred treatment for conditions such as immune mediated thrombocytopenic purpura, neutropenia, and autoimmune hemolytic anemia.
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PMID:Immunoglobulin therapy in immunohematological disorders. 1077 23

The past year's literature shows that little progress has been achieved in the laboratory diagnosis of autoimmune hemolytic anemia. The direct antiglobulin test is the only diagnostic test for autoimmune hemolytic anemia. Advantages of new techniques, such as the gel test, have to be determined. Today, cephalosporins are known to cause both drug-dependent and -independent autoantibodies. The diagnosis of idiopathic thrombocytopenic purpura is a clinical one. The new assays that measure antibodies against specific glycoproteins offer improved specificity. New laboratory advancements and accumulation of data on granulocytes' antigens and antibodies enabled us to recommend guidelines for the laboratory investigation of autoimmune neutropenia.
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PMID:Laboratory diagnosis of autoimmune cytopenias. 1105 17

The newer purine nucleoside analogues (PNA), fludarabine (FAMP) and cladribine (2-chlorodeoxyadenosine, 2-CdA) have been synthesized recently and introduced into the treatment of chronic lymphocytic leukemia (CLL). The results of large phase II studies indicate that FAMP and 2-CdA are similarly active in CLL. Unfortunately, no prospective randomized study comparing the results of the treatment of CLL patients with FAMP and 2-CdA has been published so far. Significantly higher overall response (OR) and complete remission (CR) in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens has been recently confirmed in five prospective multicentre randomized trials. These studies have also shown longer response duration in patients treated with PNA than with conventional chemotherapy. Overall survival progression free and events free survival were similar in patients treated with PNA and with chlorambucil or other alkylating agent based regimens. However, the majority of randomized trials were designed as cross over studies and most patients, treated with conventional chemotherapy were given PNA when refractory or in early relapse, which may influence the survival time. The results of a randomized study have shown a higher incidence of neutropenia and infections in patients treated with PNA than with chlorambucil. However. the frequency of autoimmune hemolytic anemia, pure red cell aplasia, secondary neoplasms and Richter's syndrome seems to be similar in patients treated with PNA and standard alkylating agents based chemotherapy. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. They are in general safe, given on an out patients basis and significantly cheaper than PNA. PNA should be routinely used as second line treatment, and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.
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PMID:The role of nucleoside analogues in the treatment of chronic lymphocytic leukemia-lessons learned from prospective randomized trials. 1200 57

The aim of the study was to determine the effectiveness and toxicity of cladribine (2-CdA) used alone or in combination with prednisone (P) or cyclophosphamide and mitoxantrone in re-treatment of patients with progressive B-cell chronic lymphocytic leukemia (B-CLL). We analyzed treatment outcome in 40 patients who had responded to previous treatment with 2-CdA-based regimens. Criteria for re-treatment were the same as for the first treatment. The patients were retreated with the same agents if they responded to the first treatment and then relapsed with progressive disease not earlier than 3 months after achieving the first response. Eight patients received 2-CdA alone (0.12 mg kg(-1) d(-1)) i.v. for 5 d, and 21 patients additionally were given P (30 mg m(-2) d(-1)) orally, also for 5 d. Eleven patients received 2-CdA for 3 d combined with cyclophosphamide (650 mg m(-2)) i.v. and mitoxantrone (10 mg m(-2)) i.v. on day 1 (CMC regimen). The cycles were repeated usually at 4 wk intervals or longer if severe myelosuppression or infections occurred. The therapy was finished if complete remission (CR) was achieved or until maximum of six courses. Overall response (OR) in re-treatment was obtained in 16 out of 40 (40%) patients (95% CI 16-64), including 62% after 2-CdA, 33% after 2-CdA +P and 36% after CMC. CR was obtained in four (10%) patients. Residual disease evaluated in the patients with CR by surface immunophenotyping had been demonstrated in 5 out of 16 (31%) patients after the first treatment and in one out of four (25%) patients after re-treatment. The median progression-free survival (PFS) was 16 months (range 3-39) for the first treatment and 9.5 months (range 3-18) for re-treatment (P=0.34). Grade III or IV neutropenia was observed in 20% patients during the first treatment and in 35% patients during re-treatment (P=0.1). 2-CdA-induced thrombocytopenia occurred in 20% and 42% of the patients, respectively (P=0.05). Anemia was also more frequent during re-treatment (35%) than during the first treatment (7%) (P=0.007). Autoimmune hemolytic anemia developed in four (10%) of the patients during or after re-treatment. Severe infections, including pneumonia and herpes reactivation, occurred in 11 patients during the first treatment and in 10 patients during re-treatment. Twelve (30%) patients died during the study. Infections were the cause of death in six and AIHA in two patients. In conclusion, 2-CdA applied in monotherapy or in combination with prednisone or cyclophosphamide and mitoxantrone has therapeutic activity in some B-CLL patients in whom these drugs induced earlier complete or partial remission. However, since the second response is usually shorter and myelotoxicity more pronounced than during the first therapy, more clinical trials to find other therapeutical approaches are necessary.
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PMID:Re-treatment with cladribine-based regimens in relapsed patients with B-cell chronic lymphocytic leukemia. Efficacy and toxicity in comparison with previous treatment. 1227 59

To determine the clinical characteristics and outcome of patients with chronic hepatitis C virus (HCV) infection presenting severe autoimmune cytopenia unrelated to interferon alpha therapy, we analyzed characteristics and outcomes of 35 patients with HCV (16 from our departments and 19 from the literature). We considered active autoimmune hemolytic anemia (AHA) as a decrease of at least 2 g/dL in hemoglobin levels, an increase of at least 0.6 mg/dL in the serum unconjugated bilirubin level, a reticulocyte count >5%, and a positive direct Coombs test. Severe neutropenia was defined as a neutrophil count <0.5 x 10(9)/L, and severe thrombocytopenia as a platelet count <30 x 10(9)/L. We identified the following cytopenias: AHA (17 cases), severe thrombocytopenia (16 cases), aplastic anemia (2 cases), severe neutropenia (1 case), refractory sideroblastic anemia (1 case), and pure red cell aplasia (1 case). Three patients simultaneously presented 2 types of severe cytopenias. Twenty-seven patients (77%) were female and 8 (23%) male, with a mean age at diagnosis of cytopenia of 51.7 years (range, 18-84 yr). Immunologic markers were detected in 19 (68%) of 28 patients, the most frequent being hypocomplementemia in 16 (57%), cryoglobulins in 15 (54%), antinuclear antibodies in 12 (43%), and rheumatoid factor in 5 (18%). Other associated processes were autoimmune diseases in 14 (50%) of 28 and human immunodeficiency virus (HIV) coinfection in 3 (9%) of 32. We found clinical and immunologic differences between HCV patients with AHA and those with severe thrombocytopenia. Patients with HCV-related AHA showed a higher prevalence of associated autoimmune diseases (71%), cryoglobulins (67%), and cirrhosis (59%). All had a good response to corticosteroids, but a poor prognosis (47% mortality). In contrast, patients with HCV-related severe thrombocytopenia had a lower prevalence of associated autoimmune diseases (11%), a poorer response to corticosteroids (55%), and lower mortality (6%), with HIV/HBV coinfections in some patients. The 35 cases presented demonstrate that different types of immune-mediated cytopenias may be severe and clinically significant in patients with HCV infection. Hemolytic anemia and severe thrombocytopenia were the most frequent cytopenias observed. Most patients responded well to corticosteroids, although a higher rate of mortality was observed in those with liver cirrhosis.
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PMID:Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 35 cases. 1264 Jan 85

Warm, active antibody adult autoimmune hemolytic anemia is the most common form of hemolytic anemia not related to drug therapy. Mortality in adult autoimmune hemolytic anemia is related to the inability to successfully treat patients' underlying disease, or the infectious complications of splenectomy and prolonged steroid therapy. Predisposing factors for invasive aspergillosis are neutropenia and steroid therapy. We present a fatal case of aspergillosis complicating a nonneutropenic case of warm active antibody adult autoimmune hemolytic anemia treated with prolonged steroid therapy.
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PMID:Pulmonary aspergillosis and central nervous system hemorrhage as complications of autoimmune hemolytic anemia treated with corticosteroids. 1293 87

Although advances in immunosuppressive therapy have allowed prolonged patient survival, immune dysregulation observed in these patients has increased. We report an 11-year-old female heart transplant recipient in whom Glanzmann thrombasthenia was identified as part of a "multiple autoantibody syndrome" manifesting sequentially as autoimmune hemolytic anemia, thrombocytopenia, and neutropenia.
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PMID:Acquired Glanzmann's thrombasthenia as part of multiple-autoantibody syndrome in a pediatric heart transplant patient. 1512 12

To describe the main characteristics and outcome of autoimmune thrombocytopenic purpura (AITP) in patients with common variable immunodeficiency (CVID), we analyzed data from 21 patients and reviewed additional cases from the literature. To be included in this study, patients had to have CVID and a previous history of AITP with a platelet count < or = 50 x 10(9)/L at onset. A complete response to treatment was defined by a platelet count > or = 150 x 10(9)/L, and a partial response by a platelet count >>50 x 10(9)/L with an increase of at least twofold the initial level. The median platelet count at AITP diagnosis was 20 x 10(9)/L (range, 2-50 x 10(9)/L). The median age at AITP diagnosis was 23 years (range, 1-51 yr), whereas the median age at CVID diagnosis was 27 years (range, 10-74 yr). CVID was diagnosed before the onset of AITP in only 4 patients (19%), 3 of whom were being treated with intravenous immunoglobulin (i.v.Ig) replacement therapy. CVID was diagnosed more than 6 months after AITP in 13 cases (62%), and the 2 conditions were diagnosed concomitantly in 4 cases. Eleven patients (52%) had at least 1 autoimmune manifestation other than AITP, among which autoimmune hemolytic anemia (7 cases) and autoimmune neutropenia (5 cases) were preeminent. Seventeen of the 21 patients (80%) received at least 1 treatment for AITP; 13 patients received corticosteroids alone and 7 (54%) achieved at least a partial response; 8 patients received i.v.Ig at 1-2 g/kg alone or in combination with steroids, leading to a short-term response rate of 50%. Four patients underwent a splenectomy (2 complete responses, 2 failures); 2 additional splenectomies were performed for associated autoimmune hemolytic anemia. With a mean follow-up of 5.6 years after the surgical procedure, none of the 6 splenectomized patients had a life-threatening infection. With a median follow-up after AITP onset of 12 years, 13/21 patients (62%) were in treatment-free remission (7 complete responses, 6 partial responses), 7 patients (23%) were in remission while on prednisone < or = 20 mg/day with or without azathioprine, and only 1 patient still had a platelet count <50 x 10(9)/L. Five patients had died at the time of the analysis; none of the deaths was related to a hemorrhage. Severe infections including 3 fatal bacterial infections and 2 opportunistic infections occurred in 6 patients during or after treatment of AITP. In conclusion, AITP, alone or in combination with autoimmune hemolytic anemia (Evans syndrome) and/or autoimmune neutropenia, is frequent in patients with CVID, and is not prevented by i.v.Ig substitutive therapy. Since AITP frequently precedes the diagnosis of CVID, testing for immunoglobulin levels should be performed in every patient diagnosed with AITP. Steroids and splenectomy seem to have the same efficacy as in idiopathic AITP, but the increased risk of severe infections must be taken into consideration.
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PMID:Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. 1523 13


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