Infusion-related toxicity of three different amphotericin B formulations and its relation to cytokine plasma levels.

A prospective study was performed to compare the infusion-associated toxicity of three different amphotericin B preparations and to correlate acute side-effects with plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1-RA) during and after the infusions. Six adult neutropenic patients with acute leukaemia suffering from suspected or documented systemic fungal infections were treated on three consecutive days with conventional amphotericin B (AmB), liposomal AmB (AmBisome) and AmB mixed in lipid emulsion (AmB/lipid). Drugs were given over 1-2 h. Drug-induced toxicity was monitored every 30 min for 4 h. Plasma levels of the three cytokines were determined using commercially available enzyme-linked immunosorbent assay (ELISA) techniques. Four of six patients showed toxicity after AmB and AmB/lipid infusions; only one patient reacted to liposomal AmB. Clinical toxicity was associated with increases in TNF-alpha plasma levels during two of four infusions of AmB and three of four infusions of AmB/lipid. Major increases in IL-6 occurred during three of four infusions of AmB and during all four AmB/lipid infusions associated with clinical toxicity. Three of four AmB infusions and all four AmB/lipid infusions accompanied by clinical toxicity were associated with major increases in IL-1-RA plasma concentrations. Liposomal AmB was better tolerated than AmB and AmB/lipid. This formulation also caused the lowest liberation of all three cytokines tested. The severity of clinical symptoms did not correlate closely with absolute cytokine plasma levels. The findings provide further evidence that expression of TNF-alpha, IL-6 and IL-1-RA plays an important role in mediating AmB-related acute toxicity in vivo.

Neutrophilic dermal infiltrates in granulocytopenic patients with acute leukemia.

Acute febrile neutrophilic dermatosis (AFND, Sweet's 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 x 10(9)/l.

Pulmonary toxicity during infusion of liposomal amphotericin B in two patients with acute leukemia.

Pulmonary toxicity with acute dyspnea occurred during infusion of a liposomal amphotericin B preparation (AmBisome) in two adult leukemic patients. The preparation was administered as a one hour infusion at a dose of 3 mg/kg body weight. Within 15 min after starting the infusion, both patients experienced sudden onset of dyspnea and chest tightness. Physical examination showed the patients to be anxious and restless with tachycardia and orthopnea but without other cardiopulmonary findings. No elevation of body temperature, rigors or chills were recorded. Symptoms disappeared within minutes after discontinuing the infusion. At present, the pathophysiologic mechanisms underlying these side effects are unknown.