[Pure leukopenias and agranulocytoses].
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We report fatal reticular dysgenesis in a premature infant presenting with severely decreased blood and bone marrow granulocytes and lymphocytes, an absent thymic shadow by x-ray film, and generalized lymphoid hypoplasia. Immunologic and electron microscopic evaluation of his white blood cells demonstrated that, despite extremely low cell numbers, cells from all stages of both granulocytic and lymphocytic development were present. Immature bone marrow cells of both myeloid and lymphoid lineages were found in much greater proportions than were mature cells; pre-B cells outnumbered B cells by more than tenfold. Megakaryocytes and erythroid cells appeared to be present in normal numbers, and tritiated-thymidine incorporation by bone marrow nucleated cells was also normal, although it may have largely occurred in erythroblasts. These data suggest that the primary defect in reticular dysgenesis is not failure in initiation of stem cell differentiation along lymphoid and myelomonocytic lines but rather an, as yet, undefined abnormality that interferes with normal growth and maturation of immune cells committed to these differentiation pathways.
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BACKGROUND: Serious infections constitute a major problem for patients with cancer, and new approaches must be found in dealing with these. The pathophysiology of neutropenic infection is not well understood, although there is some evidence that, as in sepsis in the primarily immunocompetent host, a pro- and an antiinflammatory phase can be discriminated. In the recent literature is described a series of nonneutropenic patients with sepsis in whom interferon-gamma was successfully administered during the immunoparalytic phase, a concept that might possibly be extended to immunocompromised hosts. PROCEDURE: A 14-year-old patient with RAEB-T/hypoplastic M2 and chemothera py-induced neutropenia developed a severe infection and continued to deteriorate clinically despite maximum supportive measures, including broad antibacterial and antifungal coverage. On the basis of monocyte de-activation this patient was considered to be in the immunoparalytic phase of sepsis and consequently treated with 60 microg/m(2) of interferon-gamma per day for 10 days. RESULTS: The patient made a rapid clinical recovery, and biochemical markers of infection improved promptly. At the same time, the fraction of activated monocytes normalized rapidly and stably. We hypothesize that treatment with interferon-gamma effected this rapid restoral of monocyte activation and that monocyte reactivation might have contributed to the patient's prompt recovery from his severe infection. Interferon-gamma treatment was well tolerated. CONCLUSIONS: Immunostimulation with interferon-gamma might prove to be a valuable adjuvant treatment for patients with chemotherapy-induced neutropenia during the rare scenario of infection with immunoparalysis.
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Although the semisynthetic broad-spectrum acylureido-penicillin, azlocillin has been demonstrated to have significant antibiotic activity in leukemic patients, its role in combination therapy of febrile granulocytopenic patients with chemotherapy-treated solid tumors has not been clearly delineated. Thirty-five solid tumor patients with chemotherapy-induced absolute granulocytopenia (less than 1000 granulocytes/ml) associated with fever (greater than 38.3 degrees C) were treated on a prospective study with a combination of azlocillin 4 g intravenously (IV) every 6 hours, cephalothin 2 g IV every 6 hours, and tobramycin 80 to 100 mg IV every 8 to 12 hours. Prior chemotherapy included doxorubicin combinations in 18 patients and other combinations in 17 patients. Granulocyte counts preantibiotic therapy were greater than 100 granulocyte/ml in 14 patients, 100 to 499 in nine patients, and 500 to 1000 in 12 patients. Granulocyte nadirs were less than 100 in 20 patients, 100 to 499 in nine patients, and 500 to 1000 in six patients. Times for granulocytes to rise towards normal were 1 to 3 days in eight patients, 4 to 6 days in 18 patients, and 7 or more days in nine patients. Tobramycin levels were primarily in the peak range of 3 to 6 micrograms/ml and trough range of 0 to 1.9 micrograms/ml. The site and pathogen were identified in nine patients, the infection site clinically documented without isolated pathogen in three patients, and no site or pathogen identified in 23 patients. Of the 35 patients, 34 had good responses to the antibiotic combination (complete disappearance of fever and other evidence of infection). Serum creatinine rose 0.4 to 0.6 mg/dl in nine patients, 0.7 to 1.5 in four patients, and 1.5 in one patient (obstructive uropathy). The only other noted antibiotic-related side effect was hypokalemia. This antibiotic combination had little toxicity with marked efficacy.
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The absolute granulocyte count (AGC) in 125 blood samples from patients with total white blood cell counts of less than 1,000/microliter was estimated using three different methods, which were then compared for efficiency and accuracy. The three methods were 25 cell differential counts using Wright's-stained blood smears, granulocyte percentage estimates from WBC counting chambers, and combined narrow- and wide-angle light-scatter characteristics determined on a flow cytometer. A survey of clinical laboratories at University Hospital Cancer Centers revealed that the smear differential was the most-often-used method in those laboratories even when less than 25 cells could be counted. Consequently the data obtained from the counting chamber and flow cytometer methods were compared to the smear differential "standard" using linear regression, and outliers were identified. There was good correlation between AGC determined by smear differential and WBC counting chamber (correlation coefficient .911) and excellent correlation between the AGC determined by smear differential and the flow cytometer method (correlation coefficient .970). The flow cytometer method used in this investigation required minimal specimen preparation, and test results were available at a rate of 60 seconds/sample. The ease of sample preparation, speed, and statistical reliability of test results makes the flow cytometer an attractive alternate method of determining granulocyte counts on leukopenic patients as compared to the stained blood smear differential.
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