M. Arning

SEPTICEMIA DUE TO STREPTOCOCCUS MITIS IN NEUTROPENIC PATIENTS WITH ACUTE LEUKEMIA

SummaryEight neutropenic patients with acute lymphocytic or nonlymphocytic leukemia had septicemia due to different strains ofStreptococcus mitis (St. mitis), a microorganism not commonly recognized as a special pathogen in leukemic patients. Four of the patients had been treated with high-dose cytosine arabinoside as part of the cytostatic regimen, six had a central venous line and four patients had oral lesions prior to the infection. Selective gut decontamination consisted of co-trimoxazole/colistin in five patients and quinolones in three patients. The first three patients died, either due to interstitial pneumonia with the adult respiratory distress syndrome (ARDS), or due to infection-triggered disseminated intravascular coagulation despite prompt empiric antibiotic therapy including vancomycin. The other patients improved after empiric supplementation of penicillin G (30 Mega/day) to the antibiotic regimen. Beginning ARDS in two of these patients dramatically responded to high-dose steriods. We conclude thatSt. mitis is a major pathogen in neutropenic leukemic patients. Infection appears to occur independently of acute leukemic cell type, regimen of selective gut decontamination, venous access, visible oral lesions or treatment with highdose cytosine arabinoside. The clinical course of our patients raises questions about the value of commonly recommended empiric antibiotic regimens, which were clearly ineffective to control infections withSt. mitis in this patient group. Our data indicate that immediate antibiotic therapy with penicillin G is indicated and may be life-saving for suspectedSt. mitis infections in neutropenic leukemic patients.

Serum erythropoietin concentrations in patients with myelodysplastic syndromes.

Medullary dyserythropoiesis with reduced production of erythrocytes is an early and consistent feature of myelodysplastic syndromes (MDS). The mechanism underlying the disturbed red cell proliferation and maturation is presently unknown. In order to study the role of erythropoietic growth factors, we determined by radioimmunoassay the serum concentrations of immunoreactive erythropoietin (Epo) in 42 non-transfused patients with primary and secondary MDS. Their median hemoglobin concentration at the time of Epo measurement was 9.1 g/dl (range, 5.7-14.6). Compared with the control group, 83% of the MDS patients had increased serum Epo levels, ranging from 26-4530 mU/ml. Although in the entire patient population an inverse relationship between serum Epo and hemoglobin concentrations was noted (r = -0.35; p = 0.02), Epo titers differed markedly between patients at comparable degrees of anemia. In 7 patients presenting with a hemoglobin concentration between 5.9 and 11.9 g/dl, excessive elevations of Epo levels (greater than 500 mU/ml) were found. In contrast to previous observations, serum Epo concentrations were not shown to correlate with the percentage of erythroblasts in the bone marrow. There was, however, a significant relationship between the Epo activity and the degree of medullary dyserythropoiesis, as assessed by morphological criteria (p less than 0.01). From these data we conclude that the anemia in MDS is not due to an endogenous Epo deficiency. The marked variability of Epo production in these disorders is not fully explained by the degree of anemia, but may also reflect inherent abnormalities of the myelodysplastic erythropoiesis.

GM-CSF therapy and capillary-leak syndrome

In the October issue in 1990, Emminger and coworkers report the occurrence of a capillary-leak syndrome during low-dose-granulocyte-macrophage-colony-stimulating factor (GM-CSF) therapy in a patient with a continuing febrile state after bone-marrow transplantation. Although their data are convincing, one might argue that the aggressive conditioning regimen could have been a predisposing causative factor for the development of a capillary-leak syndrome. Therefore, we would like to emphasize these findings by reporting our own observation in a patient with myelodysplasia who was treated with low-dose cytosine-arabinoside, complicated by pulmonary aspergillosis. Our 50-year-old patient had a 3-year history of refractory anemia with ring sideroblasts. The patient was admitted to our hospital and treated with low-dose ara-C (25 mg/day via continuing intravenous infusion) for 3 weeks. On day 16, however, the therapy had to be discontinued because of beginning pneumonia. The resulting fever did not respond to broad-spectrum antibiotics and, therefore, empiric amphotericin B and flucytosine treatment was started. Along with the worsening clinical condition and after informed consent of the patient, low-dose rh GM-CSF therapy (250/zg/m z daily as continuous infusion) was added to accelerate the recovery of neutrophils. Within 1 week of treatment the patient developed a capillary-leak syndrome with a weight gain of more than 10~ body

Influence of Infusion Time on the Acute Toxicity of Amphotericin B: Results of a Randomized Double-Blind Study

Despite the development of several new antifungal drugs, intravenous amphotericin B (amB) is still considered the drug of choice for the treatment of severe systemic fungal infections in immunocompromised patients. However, therapy is often limited by various side effects (Table 1). From the patients’ point of view, the acute toxic reactions (fever, chills, nausea and vomiting) induced by the drug are particularly troublesome.

Granulocyte colony-stimulating factor (G-CSF) treatment in a neutropenic leukemia patient with diffuse interstitial pulmonary infiltrates

SummaryAdult respiratory distress syndrome (ARDS) in patients suffering from acute leukemia usually occurs during chemotherapy-induced neutropenia. In addition, intensified chemotherapy with high-dose cytosine arabinoside and mediastinal irradiation may contribute to the development of ARDS. This complication is usually refractory to conservative treatement with antibiotics, steroids, and mechanical ventilation. In this report, we describe a 25-year-old patient with acute lymphoblastic leukemia who developed ARDS during the phase of chemotherapy-induced neutropenia. Subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) at doses of 300–600 μg/day led to a prompt increase of peripheral granulocyte counts. With resolution of neutropenia, respiratory function gradually improved, and mechanical ventilatory support was stopped after 2 weeks. From this observation we surmise that the application of G-CSF may be an effective therapeutic approach for preventing the fatal outcome of ARDS in leukemia patients with bone marrow aplasia.

Increases of sICAM-1 during neutropenic pneumonia in leukemic patients.

Aggressive chemotherapy of leukemia increases the risk of severe infections during treatment-induced myelosuppression. However, the assessment of an infectious origin of neutropenic fever is often difficult. Leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are involved in early inflammatory response. We studied plasma concentrations of their soluble isoforms during 48 treatment courses with myeloablative chemotherapy in 32 leukemic patients. There were 35 febrile episodes during neutropenia. Pneumonia was clinically and microbiologically documented in 15 cases, six had proven infections but normal chest radiograph, and 14 were classified as fever of unknown origin. Longitudinal studies revealed a sustained increase of sICAM-1 plasma levels associated with pneumonia. Increase of sICAM-1 plasma levels distinguished patients with pneumonia from those with fever not related to pneumonia (positive predictive value 0.87, negative predictive value 0.94). Plasma levels of sICAM-1 were elevated in both, fungal and non-fungal pneumonia. Increases of sICAM-1 paralleled first radiographic evidence of pulmonary infiltrations in most cases. In contrast, no elevation of sVCAM-1 or sE-selectin was documented during febrile events prior to recovery of leukocyte counts.

Neutrophilic dermal infiltrates in granulocytopenic patients with acute leukemia.

Acute febrile neutrophilic dermatosis (AFND, Sweets syndrome) is clinically characterized by fever, neutrophilic leukocytosis, and tender dermal plaques. Histological examination typically reveals infiltration of the dermis by neutrophils. In three patients (2 female, 1 male, 54–59 years) with acute leukemia (2 myelogenous, 1 lymphoblastic) dermal plaques developed during febrile episodes in chemotherapy-induced pancytopenia. The clinical appearance was compatible with AFND. The diagnosis was substantiated by skin biopsies which showed dense neutrophilic dermal infiltrates without leukemic cells. Leukocytoclastic vasculitis was considered as differential diagnosis. Plasma levels of soluble adhesion molecules ICAM-1, VCAM-1, and E-selectin regulating leukocyte transendothelial migration were in the normal range. Systemic glucocorticoids were avoided because of the high risk of infection during prolonged bone marrow aplasia. The lesions were treated with topical steroids and resolved without scarring within 1–5 weeks. AFND has been reported in association with acute leukemia at normal or elevated white blood cell counts. Although implausible from a pathophysiological point of view, similar neutrophilic dermal infiltrates were found in three patients during chemotherapy-induced pancytopenia with white blood cell counts distinctly below 1×109/l.

Preliminary Results of Treatment with Itraconazole in Patients with Systemic Fungal Infections

Patients with acute leukemias undergo a high risk of lethal systemic fungal infections during prolonged periods of granulocytopenia. While amphotericin B is still the most effective antimycotic drug, its use is limited by anaphylactoid, hepatotoxic and/or nephrotoxic side effects. Imidazole antimycotics, such as miconazole and ketoconazole, lack activity against aspergillus infections [1]. The new triazole derivative itraconazole has shown its efficacy in treatment of fungal infections due to Candida and Aspergillus species [2, 3, 6]. Here we report our experiences with itraconazole in six patients aged 24 to 47 years suffering from acute myelogenous (n = 5) or acute lymphoblastic leukemias (n = 1), and microbiologically proven (n = 4) or clinically suspected (n = 2) systemic aspergillus or Candida infections.

Incidence and Severity of Amphotericin B-induced Acute Toxicity in Leukemic Patients After Treatment with Three Different Formulations (Amphotericin B, AmBisome and Amphotericin B/lntralipid) — A Pilot Study

Intravenous amphotericin B (AmB) is the most potent drug for treatment of systemic fungal infections in leukemic patients. However, use of this drug is often limited by renal side effects and acute toxicity (fever, chills, nausea, vomiting). A far better tolerance has been reported with the use of AmBisome, a liposomal preparation of AmB, but this formulation is extremely expensive. In search of a cheaper AmB preparation with a better tolerance than conventional AmB, french scientists recently reported that AmB mixed in fat emulsion (Intralipid) has a significantly better tolerance profile compared to conventional AmB (Caillot et al., 1992, Chavanet et al., 1992). Our pilot study was performed to get information about the tolerance of the three different AmB preparations in individual patients.

Regulation of Erythropoietin Production in Patients with Myelodysplastic Syndromes

Preleukemic syndromes or myelodysplastic syndromes (MDS) comprise a heterogeneous group of acquired bone marrow disorders, probably resulting from malignant transformation of a multipotent hematopoietic stem cell [1, 2]. In the elderly they are rather common diseases. Analysis of our own data referring to the population of Dusseldorf (Germany) yields an age-specific incidence rate of about 25/100 per year in people over the age of 70 [3]. Hallmarks of MDS include ineffective hematopoiesis, hypercellular bone marrow, and peripheral blood cytopenias [4]. In the majority of cases the etiology remains unkown.