Drug-induced Agranulocytosis Research Articles

2 - Drug-induced Agranulocytosis

2 - Drug-induced Agranulocytosis

Drug-induced agranulocytosis

Drug-induced agranulocytosis

Drug-Induced Agranulocytosis: In Vitro Evidence for Immune Suppression of Granulopoiesis and a Cross-Reacting Lymphocyte Antibody

Two patients with agranulocytosis associated with diphenylhydantoin (DPH) therapy and clinical data suggesting suppression of granulopoiesis were investigated using in vitro culture techniques for committed granulocyte/macrophage precursors. Addition of DPH to cultures containing the patients' sera resulted in significant suppression of colony growth. Extensive studies on the acute serum from one patient revealed the drug-dependent inhibitory activity to be nondialyzable, resistant to chloroform extraction, heat stable, active in the presence of heat-inactivated fetal bovine serum, active against autologous as well as allogeneic cells, and absent from convalescent sera. Drug-dependent bone marrow colony-suppressing activity was removed by absorption on an antiimmunoglobulin-Sepharose column but not by IgG-Sepha-rose. The serum showed non-drug dependent suppression of oxygen consumption by normal polymorphonuclear leukocytes engaged in phagocytosis and also showed evidence of ability to opsonize these cells. When the serum was incubated with mitogen-stimulated lymphocytes, suppression of 3H-thymidine uptake by autologous but not allogeneic cells was noted. Similarly, the serum suppressed short-term 3H-thymidine uptake by autologous but not allogeneic bone marrow. Absorption of the patients' sera with allogeneic polymorphonuclear leukocytes, autologous polymorphonuclear leukocytes, or autologous lymphocytes removed the drug-dependent inhibitory activity, but absorption with allogeneic lymphocytes did not. These data are most consistent with the presence of a noncomplement dependent antibody capable of suppressing granulopoiesis, mediating peripheral destruction of polymorphonuclear leukocytes, and cross-reacting with a lymphocyte antigen of limited population distribution.

Drug-induced agranulocytosis: in vitro evidence for immune suppression of granulopoiesis and a cross-reacting lymphocyte antibody

Two patients with agranulocytosis associated with diphenylhydantoin (DPH) therapy and clinical data suggesting suppression of granulopoiesis were investigated using in vitro culture techniques for committed granulocyte/macrophage precursors. Addition of DPH to cultures containing the patients' sera resulted in significant suppression of colony growth. Extensive studies on the acute serum from one patient revealed the drug-dependent inhibitory activity to be nondialyzable, resistant to chloroform extraction, heat stable, active in the presence of heat-inactivated fetal bovine serum, active against autologous as well as allogeneic cells, and absent from convalescent sera. Drug-dependent bone marrow colony-suppressing activity was removed by absorption on an antiimmunoglobulin-Sepharose column but not by IgG-Sepharose. The serum show non-drug dependent suppression of oxygen consumption by normal polymorphonuclear leukocytes engaged in phagocytosis and also showed evidence of ability to opsonize these cells. When the serum was incubated with mitogen-stimulated lymphocytes, suppression of 3H-thymidine uptake by autologous but not allogeneic cells was noted. Similarly, the serum suppressed short-term 3H-thymidine uptake by autologous but not allogeneic bone marrow. Absorption of the patients' sera with allogeneic polymorphonuclear leukocytes, autologous polymorphonuclear leukocytes, or autologous lymphocytes removed the drug-dependent inhibitory activity, but absorption with allogeneic lymphocytes did not. These data are most consistent with the presence of a noncomplement dependent antibody capable of suppressing granulopoiesis, mediating peripheral destruction of polymorphonuclear leukocytes, and cross-reacting with a lymphocyte antigen of limited population distribution.

Candida-Coxitis

Following drug-induced agranulocytosis and antibiotic and steroid treatment, sepsis due to candida albicans together with bilateral fungal coxitis developed in a 41-year-old female patient. Satisfactory eradication of the inflammatory process was achieved with combined treatment with amphotericin B and 5-fluorocytosine, so that mobilisation was possible after surgical fitting of bilateral total endoprothesis.

Drug‐Induced Blood Dyscrasias

Drug-induced dyscrasias (agranulocytosis, aplastic anemia, hemolytic anemia and thrombocytopenia) in Sweden during a 10-year period (1966-75) have been analyzed. The overall occurrence is remarkably constant, although marked changes have occurred with regard to offending drugs. Drug-induced thrombocytopenia and agranulocytosis are about twice as common as hemolytic anemia, which in turn is twice as common as aplastic anemia. There is a marked increase with age in the incidence of all drug-induced cytopenias. Women predominate and make up close to 70% of the material. With regard to responsible drugs, the most remarkable finding is the high frequency with which sulfonamides appear as responsible for all types of drug-induced cytopenia.

HLA-B27, antinuclear antibodies and drug-induced agranulocytosis

Eight female patients with drug-induced agranulocytosis (five patients with definite seropositive rheumatoid arthritis (RA), three patients with upper respiratory infections) were studied for the presence of HLA-B27 and antinuclear antibodies (ANA). Five of eight patients were found to be HLA-B27 positive and all RA patients had ANA in their serum. The frequency of HLA-B27 and ANA was found to be significantly different from control groups. It is concluded that the occurrence of HLA-B27 and ANA was found to be significantly different from control groups. It is concluded that the occurrence of HLA-B27 in female patients with seropositive RA (especially in those with ANA) and of HLA-B27 alone in other individuals could reflect an increased risk for drug-induced agranulocytosis.

Drug-Induced Agranulocytosis

An unexpected precipitous fall in peripheral leucocyte count may occur during treatment of certain sensitised individuals with drugs usually well tolerated by most people. Three basic mechanisms for drug sensitivity have been found. One is characterised by sudden destruction of large numbers of leucocytes in peripheral blood by antibodies elicited in response to drug sensitivity. A prototype for this type of reaction is aminopyrine. A second mechanism involves the production of a lupus-like syndrome followed by leucopenia in response to sensitisation to drugs such as procainamide. A third type involves development of agranulocytosis following a latent period during which a sensitive patient is treated with large amounts of chlorpromazine. This type of reaction is associated with production of bone marrow insufficiency in a patient who is believed to have a limited proliferative potential of bone marrow cells, which limit compensatory bone marrow response during treatment with a drug (e.g. chlorpromazine) that has limited bone marrow toxicity.

Acute drug-induced agranulocytosis: comparison between openward treatment and antimicrobial decontamination in a plastic isolation bed system (retrospective study of 30 cases) (author's transl)

Thirty patients with severe drug-induced agranulocytosis were admitted to the Ulm University Hospital between January, 1968 and October, 1976. All of 13 already infected patients treated with antimicrobial decontamination in a plastic isolation bed system survived. But nine of 17 patients treated in the open ward died. The cases were not randomised and there was a difference in age between the two groups, but nevertheless the results suggest that antimicrobial decontamination and isolation is superior to treatment in an open ward.

Adjuvant Protection against Bacterial Infection in Granulocytopenic Mice

The hypothesis that the induction of nonspecific resistance to infection by immunostimulation prior to drug-induced granulocytopenia would afford increased protection to subsequent bacterial challenge was tested in a murine model of infection with Pseudomonas aeruginosa or Staphylococcus aureus in mice rendered granulocytopenic with cyclophosphamide. Prior intraperitoneal immunostimulation of mice with complete Freund's adjuvant (CFA) or Mycobacterium bovis (Bacille Calmette-Guèrin; BCG) increased the 50% lethal dose in mice challenged subcutaneously with P. aeruginosa, but only CFA protected against challenge with S. aureus. The degree of protection was 1-2 log 10. Corynebacterium parvum provided no protection against infection with P. aeruginosa. The protective effect observed with CFA and BCG substantiates our hypothesis and indicates that nonspecific immunostimulation may be of value in protection of granulocytopenic patients from opportunistic infections.

Cryopreserved autologous marrow infusion following high dose cancer chemotherapy

Seventeen patients with advanced malignancies received escalating doses of chemotherapy with adriamycin and cyclophosphamide. Sixty-five per cent of the courses produced circulating granulocyte counts of 500 cells/mm 3 or less. Febrile episodes occurred in only 15% of courses and were seen only with doses of chemotherapy that produced granulocyte nadirs of less than 200 cells/mm 3 . There were no episodes of septicaemia. Ten of the 17 patients received an intensive dose followed by reinfusion of cryopreserved, autologous bone marrow. In 5 of these patients, recovery to 500 granulocytes/mm 3 was more rapid following the intensive, marrow-supported course by comparison with the prior, less intensive, unsupported course. We conclude that higher doses of adriamycin and cyclophosphamide than are conventionally used can be given without serious toxicity. Autologous bone marrow reinfusion may have a role in reducing the period of drug-induced granulocytopenia, but effective storage and recovery of human bone marrow remains a major problem.

"Pseudoleukemia" in Alcoholism

To the Editor.— The existence of hematologic abnormalities secondary to alcoholism has been well documented. 1 Hematologic abnormalities secondary to septicemia are also known to occur, and when sepsis has occurred in chronic alcoholics, an especially severe form of leukopenia has been reported. 2 Bone marrow examination in these patients showed virtual absence of any granulocyte precursors except promyelocytes and myelocytes. With treatment of the infection, subsequent bone marrow examination showed rapid recovery of the granulocyte elements. A not dissimilar bone marrow picture has been described in patients recovering from drug-induced agranulocytosis, wherein the descriptive term pseudoleukemia was applied to the clinical situation because of the initial differential problem in a patient with anemia, thrombocytopenia, and severe leukopenia. 3 Because we feel that this term could be extended to include the picture of the alcoholic patient with sepsis, we report here the case of an alcoholic patient with overwhelming pneumococcal

Study of granulocytopoiesis in drug-induced agranulocytosis using 3HTdR autoradiography.

Autoradiographic study of granulocytopoiesis was carried out in 6 patients with acute drug‐induced agranulocytosis (5 induced by pyrazolone derivatives, and one by gold salt) by in vitro bone marrow labelling with 3HTdR. During the days preceding the normalisation of blood granulocyte count, 11 bone marrow samples were analysed when the marrow was promyelocytic‐myelocytic (or myeloblastic‐promyelocytic). The finding of an increased number of cells synthesizing DNA can be explained by the increase of the growth fraction of myelocytes close to one. Calculation of proliferation parameters on the basis of: DNA synthesis time equalling 12 h (Stryckmans et a1 1966) demonstrates an increased birth rate of cells in the proliferative compartment of granulocytopoiesis and, consequently, an increased outflow into the maturation compartment at the rate 2.2‐2.7 times the original amount. A higher mitotic index in the same bone marrow samples gives proof of an increased mitotic activity. The results presented confirm the findings from cytological analysis, i. e. that promyelocytic‐myelocytic (and also myeloblastic‐promyelocytic) marrow (a morphologic pattern erroneously termed ‘maturation arrest’) reflects a proliferative push in the regenerative phase of granulocytopoiesis in acute agranulocytosis.

Granulocyte-Monocyte Colony-forming Capacity of Human Marrow: A Clinical Study

Abstract A modification of the in vitro culture of marrow cells in soft agar to form granulocyte-monocyte colonies has been applied to human marrow using a constant stimulus of colony-stimulating factor (CSF) in the form of pooled serum from endotoxin-treated C57BL mice (EMS). With this system reproducible increments in colony formation were observed between two concentrations of EMS. The results indicate that the incremental response to two doses of CSF (CSF response ratio) combined with an observation of the number of colonies formed provide a more reliable measurement of colony-forming cells (CFC) than colony counts at a single dose level of CSF. The CSF response ratio in 43 marrow cultures from 34 patients with no obvious disturbance in granulopoiesis was found to be 1.65 (± 0.17 SD). Hodgkin’s disease with normal marrow showed a mean CSF response ratio of 2.04. Two subjects recovering from drug-induced agranulocytosis showed increased CSF response at a time when the blood was still neutropenic and the marrow showed hyperplasia and immaturity of the granulocytic tissue. In contrast, patients with sustained neutropenia and impaired marrow granulopoiesis showed CSF response ratios of less than 1.65. CSF response ratios in chronic myelogenous leukemia averaged 1.72, often with extremely high numbers of colonies per plate. Patients with untreated acute leukemia and marrows replaced by blasts did not form colonies. However, with partial leukemic marrow replacement, lymphoblastic leukemia marrow formed more colonies than did that of myeloblastic leukemia.

Drug-induced blood dyscrasias in Sweden.

Cases of drug-induced aplastic anaemia, haemolytic anaemia, thrombocytopenia, and agranulocytosis reported to the Swedish Adverse Drug Reaction Committee during the five-year period 1966-70 have been analysed and compared with cases of the same cytopenias from "all" causes. Oral diuretics were a dominant cause of drug-induced thrombocytopenia, methyldopa of haemolytic anaemia, and oxyphenbutazone of aplastic anaemia. Computer systems should help such studies, particularly in showing a changing pattern of complications and causes.

Treatment of psychosis subsequent to phenothiazine-induced agranulocytosis

Most psychiatric patients receive phenothiazine preparations for the amelioration of psychopathological symptoms. During the course of phenothiazine treatment, agranulocytosis or granulocytopenia and severe leukopenia are not infrequent. In the face of unrelenting psychopathology and occurrence of agranulocytosis, this complication has to be treated first. Subsequently, the unabated psychopathology can be treated by various therapeutic techniques; withdrawal of medication, rechallenging with the same medication with caution, substitutions with the same medication with caution, substitutions with another phenothiazine preparation or butyrophenone or thioxanthine, and administration of ECT. The particular therapeutic technique depends on the circumstances and drug history of the individual patient. The treatment of patients with unrelenting psychopathology after drug-induced agranulocytosis is described in this paper.

Drug-induced agranulocytosis, with special reference to aminophenazone. IV. Children.

Abstract Thirteen cases of agranulocytosis in children under 15 years have been diagnosed in Finland during 1966–67. This is an incidence of 1: 185 000. In children under 5 years the incidence was 1: 86 000. These frequencies correspond well with those for adults in Finland, but remarkably exceed estimates accepted in other countries. Twelve episodes occurring in ten patients were analysed in detail. The use of drugs suspected of causing agranulocytosis was found in ten episodes, aminophenazone and sulfonamides being the most common. The fatality rate was surprisingly high (50%), probably caused, at least in some cases, by administration of the causative drug after symptoms of agranulocytosis had appeared. Our results indicate that drug‐induced agranulocytosis is as common among children as among adults and, therefore, that the same or more caution should be applied to the administration of these suspected drugs to children as to adults.

Chronic neutropenia in siblings: the effect of steroids.

Excerpt The literature is replete with articles on the use of steroids in the treatment of drug-induced agranulocytosis but not with articles on nondrug-induced, non-cyclic, nonsplenic neutropenia....