Treatment of severe sepsis in bone marrow transplant recipients with teicoplanin in combination with β-lactams and aminoglycosides

Summary We evaluated teicoplanin for suspected gram-positive infections after inadequate response to initial empiric beta-lactam and aminoglycoside combination therapy. All 20 patients included in this study received either an allogeneic (8 patients) or an autologous (12 patients) bone marrow transplant for acute myeloid leucaemia (AML), non-Hodgkin's-lymphoma (NHL, high grade) or other malignant diseases. All patients developing primary septicaemia of unknown origin (18 patients) or catheter-related septicaemia (2 patients) were treated with 400 mg teicoplanin, administered i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g i.v., t.i.d.; netilmicin 400 mg once daily). All patients responded to therapy, 19 patients were clinically cured and one patient improved under therapy. The therapeutic regimen was well tolerated; only one adverse drug reaction was observed. We did not observe any delayed take or prolonged neutropenia or thrombocytopenia with this therapeutic regimen when our patients were compared to other bone marrow transplant patients (who did not receive this antimicrobial therapy). Our results suggest that teicoplanin is a potentially effective and well tolerated antimicrobial agent in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides.

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Teicoplanin in Kombination mit -Laktamen und Aminoglykosiden bei Knochenmarktransplantatempfängern mit schwerer Sepsis

Zusammenfassung Wir untersuchten Teicoplanin bei vermuteten grampositiven Infektionen nach ungenügendem Ansprechen auf die anfängliche Kombinationstherapie von -Laktam-Antibiotika und Aminoglykosiden. Alle 20 in dieser Studie erfaßten Patienten wurden entweder allogen (8 Patienten) oder autolog (12 Patienten) transplantiert mit folgenden Grundkrankheiten: akute myeloische Leukämie (AML), Non-Hodgkin-Lymphom (NHL) oder andere maligne Erkrankungen. Alle Patienten, die eine primäre Septikämie unbekannten Ursprungs entwickelten (18 Patienten) oder unter einer Katheter-bedingten Septikämie (2 Patienten) litten, wurden mit 400 mg Teicoplanin behandelt. Die Verabreichung von Teicoplanin erfolgte einmal täglich intravenös in Kombination mit einem Cephalosporin und einem Aminoglykosid (Ceftazidim 2 g i.v., 3 ×/die, Netilmicin 400 mg, 1 ×/die). Alle behandelten Patienten sprachen auf diese Therapie an. 19 Patienten wurden klinische geheilt, ein Patient besserte sich unter dieser Therapie. Die Kombinationstherapie wurde gut vertragen, unerwünschte Arzneimittelwirkungen traten während der Studie nicht auf. Wir beobachteten kein verzögertes Angehen des Knochenmarks oder eine Verlängerung der Thrombozytopenie unter dieser Behandlung im Vergleich zu anderen knochenmarktransplantierten Patienten, die diese antimikrobielle Behandlung nicht erhielten. Unsere Ergebnisse zeigen, daß Teicoplanin ein wirksames und gut verträgliches Antibiotikum für knochenmarktransplantierte Patienten ist, die primär nicht auf die Kombinationstherapie mit -Laktam-Antibiotika und Aminoglykosiden ansprechen.

     

Oral ciprofloxacin as antibacterial prophylaxis after allogeneic bone marrow transplantation: a reappraisal

The efficacy of ciprofloxacin as antibacterial prophylaxis for allogeneic bone marrow transplantation has been well documented, and it virtually eliminated bacteremias caused by gram-negative pathogens in early reports. Ciprofloxacin was therefore incorporated into the prophylactic antibiotic regimen during allogeneic bone marrow or peripheral blood stem cell transplantation at Veterans General Hospital, Kaohsiung from February 1997. In 12 consecutive patients receiving allogeneic bone marrow or peripheral blood stem cell transplantation, ciprofloxacin-resistant Escherichia coli bacteremia developed in three (25%). In addition to our data, increasing evidence suggests that the widespread use of a fluoroquinolone is associated with the emergence of resistant isolates as well as documented infections caused by these resistant strains. The incidence of Escherichia coli bacteremia in our transplant patients was 25%, which was similar to that in patients not receiving preventive therapy or in those receiving trimethoprim-sulfamethoxazole prophylaxis. The prophylactic efficacy of ciprofloxacin in allogeneic bone marrow transplant or peripheral blood stem cell transplant recipients should therefore be reassessed.     

A randomized clinical trial of ceftriaxone and teicoplanin versus ceftazidime and teicoplanin as antibiotic therapy in febrile neutropenic cancer patients and bone marrow transplant recipients

Summary A prospective, randomized clinical trial comparing combination therapy with ceftriaxone and teicoplanin versus ceftazidime and teicoplanin in the treatment of febrile episodes in neutropenic cancer patients and bone marrow transplant recipients was performed. One hundred and two patients were randomized, but two patients were considered unevaluable for efficacy, and three patients were withdrawn due to incorrect randomization. Of the remaining 97 patients, infection resolved without modification of therapy in 31/49 (63%) patients treated with ceftriaxone/teicoplanin versus 27/48 (56%) patients treated with ceftazidime/teicoplanin (P=0.48). Of all 97 patients treated therapy was modified in 18/49 (36%) with ceftriaxone/teicoplanin and 21/48 (43%) with ceftazidime/teicoplanin. Nineteen patients treated with ceftriaxone/teicoplanin received netilmicin and 21 patients treated with ceftazidime/teicoplanin also received netilmicin according to the study design (escalation therapy). When netilmicin was added infection resolved in 78% of patients treated with ceftriaxone/teicoplanin versus 84% of those treated with ceftazidime/teicoplanin. It was concluded that combination therapy with ceftriaxone/teicoplanin is an alternative to combination therapy with ceftazidime/teicoplanin, and has the advantage of once daily administration.

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Antibiotische Therapie der febrilen Neutropenie von Tumor- und Knochenmarktransplantationspatienten. Eine randomisierte Studie mit Ceftriaxon und Teicoplanin im Vergleich mit Ceftazidim und Teicoplanin

Zusammenfassung In einer prospektiven, randomisierten klinischen Studie wurde die Kombinationstherapie mit Ceftriaxon und Teicoplanin gegen die Kombinationspartner Ceftazidim und Teicoplanin bei neutropenischen Patienten oder Patienten nach Knochenmarktransplantation verglichen. Insgesamt wurden 101 Patienten in die Studie eingebracht, davon waren 97 Patienten auswertbar. In der Ceftriaxon/Teicoplanin-Gruppe waren 63% der Patienten geheilt, gegenüber 56% der Patienten in der Ceftazidim/Teicoplanin-Gruppe. Dieses Ergebnis war ohne Modifikation der Studien-Medikamente erreicht worden. Bei 18 von 49 Patienten in der Ceftriaxon/Teicoplanin-Gruppe und 21 von 48 Patienten in der Ceftazidim/Teicoplanin-Gruppe wurde von der Studienmedikation abgegangen und zusätzlich Netilmicin (Eskalationstherapie) gegeben. Durch die zusätzliche Gabe von Netilmicin waren 78% der Patienten in der Ceftriaxon/Teicoplanin-Gruppe und 84% in der Ceftazidim/Teicoplanin-Gruppe geheilt. Diese Daten deuten darauf hin, daß die Kombinationstherapie mit Ceftriaxon/Teicoplanin eine Alternative zur Kombinationstherapie mit Ceftazidim und Teicoplanin darstellt, zumal die Gabe von Ceftriaxon und Teicoplanin den Vorteil hat, daß diese Medikamente nur einmal pro Tag gegeben werden müssen.

     

Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma

This study compares the probability of disease progression, progression-free survival, and overall survival between patients undergoing an allogeneic or autologous transplant for multiple myeloma using an identical preparative regimen. Patients received a preparative regimen of TBI, busulfan, and cyclophosphamide followed by an allogeneic or autologous transplant. In the allogeneic group (n = 21), six patients received bone marrow and 15 received G-CSF mobilized PBSC; all autologous patients (n = 35) received PBSC mobilized with cyclophosphamide and G-CSF. Allogeneic donors were HLA-identical (n = 20) or one-antigen mismatched (n = 1) siblings. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (n = 10), tacrolimus/methotrexate (n = 6), cyclosporine/methotrexate (n = 4), or cyclosporine (n = 1). The groups were evenly matched for gender, pretransplant therapy, disease status at time of transplant, myeloma subtype, and time from diagnosis to transplant. The median age was significantly lower in the allogeneic group (48 vs 55 years, P < 0.01). In the allogeneic group the probabilities of developing acute GVHD grade II-IV and chronic GVHD were 55% and 82%, respectively. The Kaplan-Meier probability of disease progression was significantly lower in the allogeneic group (11% vs 64%, P < 0.001) compared to the autologous group. Although progression-free (60% vs 30%, P = 0.19) and overall survival at 2 years (60% vs 42%, P = 0.39) favored the allogeneic group, this did not reach statistical significance. Within the allogeneic transplant group, patients age 50 years or under had a 3-year overall survival significantly higher when compared to older patients (79% vs 29%, P = 0.03). Using identical preparative regimens, allogeneic transplantation reduced disease progression compared to autologous transplantation for myeloma. This suggests that allogeneic transplantation induces a graft-versus-myeloma (GVM) effect.     

Teicoplanin in the treatment of Gram-positive bacteraemia in neutropenic patients

S ummary The increasing incidence of bacteraemia caused by Gram-positive bacteria in neutropenic patients prompted the authors to evaluate, in a prospective trial, the role of teicoplanin in the treatment of this infection. Over a 15-month period. 76 cases of bacteraemia (out of 265 evaluable episodes of fever) were observed at the Division of Haematology. University La Sapienza. Kome. Of the 76 cases studied, 46 (60%) were caused by Gram-positive bacteria and 28 (37%) were caused by Gram-negative bacilli. All febrile episodes were treated randomly and empirically with piperacillin plus amikacin with or without teicoplanin. Overall, 41 (54%) of the 76 cases of bacteraemia responded to the initial antibiotic regimen: with subsequent modifications the response rate rose to 96%.
In the treatment of Gram-positive bacteraemia. first-line administration of teicoplanin was found to be associated with early defervescence and with a significantly higher rate of success without modification of treatment (P < 0.01). Addition of teicoplanin as second-line therapy produced a favourable outcome in 12 (70%) out of 17 cases of bacteraemia unresponsive to the initial piperacillin + amikacin regimen. No cases of Gram-positive bacteraemia associated with septic shock or adult respiratory distress syndrome were observed in either treatment group. Only two late deaths were observed, and these occurred in patients with streptococcal septicaemia who were not receiving early teicoplanin.
The above data do not endorse the use of glycopeptide antibiotics in the early treatment of fever in neutropenic patients: rather, these compounds should be reserved for proven or presumed Gram-positive infections which do not respond to initial beta-lactam/aminoglycoside treatment.     

Allogeneic bone marrow transplantation in patients with lymphoma relapsing after autologous marrow transplantation

Two patients who underwent autologous bone marrow transplantation for recurrent non-Hodgkin's lymphoma relapsed at 46 and 28 days after the transplant. Both patients had an HLA-identical sibling and were treated with high-dose chemotherapy and allogeneic marrow transplantation. One patient is now 24 months after the allogeneic transplant without evidence of disease. The second patient died on day 7 with interstitial pneumonia. We conclude that high-dose therapy and allogeneic bone marrow transplantation after failure of autologous transplantation for non-Hodgkin's lymphoma is feasible and should be considered in young patients with HLA-identical siblings.     

Efficacy of teicoplanin for enterococcal infections: 63 cases and review.

Sixty-three cases of monomicrobial enterococcal infections treated with teicoplanin in two open clinical studies in Europe from 1982 to 1989 are presented. Infections were documented as endocarditis (n = 18); septicemia (n = 8); and urinary tract (n = 29), skin/soft-tissue (n = 6), or bone/joint (n = 2) infections. A total of 63 enterococcal strains were isolated; all of 29 strains tested were susceptible to teicoplanin (geometric mean MIC, 0.16 micrograms/mL; range, 0.06-0.5 micrograms/mL). Forty-eight patients were treated with teicoplanin alone and 15 were treated with teicoplanin in combination with an aminoglycoside. The rate of clinical cure was 84.1%; 4.8% of patients clinically improved, 7.9% had clinical recurrence, and 3.2% did not respond to therapy. Bacteriologic eradication was observed in 87.2% of patients; persistence, in 3.2%; recurrence, in 3.2%; and reinfection, in 4.8%. One case was not evaluable bacteriologically. Of 18 patients with endocarditis, 15 were cured with a mean daily dose of 5.4 mg/kg--six with monotherapy and nine with combination therapy. All patients with urinary tract infections were treated with monotherapy, and 89.7% were cured (mean daily dose, 4.6 mg/kg). Lower rates of clinical cure and bacteriologic eradication were observed in septicemic patients without endocarditis (62.5%). This study demonstrated a good efficacy of teicoplanin for the treatment of enterococcal infections due to susceptible strains, but further clinical studies would be useful for establishing optimal dosage and the indications for combination therapy, especially for severe infections.     

Tuberculosis among allogeneic bone marrow transplant recipients in India.

Allogeneic bone marrow transplant recipients have severe impairment of cell-mediated immunity and hence a higher incidence of mycobacterial infections might be expected in regions where tuberculosis is common. We reviewed the case records of 217 patients who underwent allogeneic bone marrow transplantation during the period 1986-1999 at our center in India. Mycobacterial infections were diagnosed in three patients (1.38%). All patients presented with extrapulmonary disease. Two patients had disseminated tuberculosis with one of these being diagnosed on autopsy studies. The third patient had tuberculosis involving the cervical lymph node and dorsal spine. Two patients treated with antituberculous therapy are well. Infection with Mycobacterium tuberculosis is not a common problem in allogeneic bone marrow recipients even in an endemic area, but when it occurs, it is usually disseminated with predominantly extrapulmonary involvement.     

Bone marrow transplantation for adult poor prognosis lymphoblastic lymphoma in first complete remission

Twenty-five adult patients, 19 males, six females, age 16-43 years (median 23), with lymphoblastic lymphoma received allogeneic or autologous bone marrow transplantation in first complete remission. Twelve patients were Murphy stage IV with bone marrow and/or CNS involvement and 13 were stage III of whom nine had thoracic involvement. Complete remission was achieved with an intensive anthracycline containing multiagent chemotherapy protocol. Twelve patients with an HLA identical sibling received an allogeneic marrow and 13 without a donor received their own marrow harvested a median of 2 months (0-4 months) after complete remission and purged in vitro with either mafosfamide (eight patients) or anti T-cell monoclonal antibodies and complement (three patients). Bone marrow transplantation was performed 1-7 months (median 3 months) after achieving first complete remission. The conditioning regimen consisted of cyclophosphamide or high dose melphalan and total body irradiation. The actuarial 4-year disease-free survival is 68% (+/- 9% SE). The actuarial probability of relapse was 26% (+/- 3% SE) with a median follow up to 22 months. There was no difference between allogeneic and autologous transplantation with eight out of 12 allo patients in first continuous complete remission 26-45 months after transplant and nine out of 13 auto in continuous complete remission 15-75 months after transplant. These results compare favourably with those achieved with the best chemotherapeutic regimen used for such patients.     

Fetal erythropoiesis following bone marrow transplantation

"Fetal" erythrocytes are present in older children and certain adults with hematologic disorders. To determine if regenerating bone marrow produces such cells, we examined the blood of seven allogeneic bone marrow transplant recipients. Six patients were engrafted with donor cells, while on e patients recovered autologous bone marrow after rejection of a marrow transplant. All seven patients had fetal hemoglobin levels of up to 10% by 100 days after transplant. In three patients, the Ggamma to Agamma ratio in the fetal hemoglobin was "newborn", while in one it was "adult". Gamma chain synthesis in blood and bone marrow never exceeded 20% of total non-alpha globin synthesis. The fetal hemoglobin was heterogeneously distributed in the cells. High titer i antigen also appeared. All fetal characteristics declined by 200 days. Erythropoiesis during bone marrow recovery appears to be associated with an accelerated, albeit partial, recapitulation of ontogeny.     

Serum erythropoietin changes in autologous and allogeneic bone marrow transplant patients

Sequential changes in serum erythropoietin (sEPO) levels were measured by radioimmunoassay in six patients receiving autologous rescue (AR) and 11 patients receiving an allogeneic bone marrow transplant (BMT) for malignant disease. Longitudinal studies showed an inverse relationship between sEPO and haemoglobin levels in the autologous rescue and allogeneic transplant patients throughout the 130 d post-transplant study period. Early post-conditioning EPO responses were normal for the haemoglobin level in both groups, but after day 14 post-transplant, erythropoietin production in response to anaemia became impaired in one autologous rescue patient and eight of the 11 allogeneic transplant patients. There was no clear association between late impairment of sEPO production and conditioning therapy, infection, graft-versus-host disease, immunosuppressive therapy or serum creatinine. Blood transfusion requirements were similar for both groups in the first month after transplantation, but from days 31 to 90 post-transplant, BMT patients required an average of 5.5 units per patient compared with 1 unit per patient for the autologous group. Marrow transplant procedures do not affect early EPO responses but may diminish late responses. The potential value of exogenous rHuEPO in hastening engraftment and decreasing transfusion requirements, particularly for those patients who appear to have impaired EPO responses, remains to be shown by clinical trials.     

Longitudinal study of bacterial, viral, and fungal infections in adult recipients of bone marrow transplants.

The epidemiology of infections was studied in a retrospective cohort of 446 recipients of bone marrow transplants (BMTs; 92 of which were allogeneic and 354 of which were autologous) during 1993--1996. Infections that were microbiologically documented in 274 recipients included bacteremia, urinary tract infections, cytomegalovirus viremia, fungemia, invasive aspergillosis, and catheter-related infections. During the period of neutropenia, no differences were found between recipients of allogeneic BMTs and recipients of autologous BMTs with regard to the incidence and the nature of infection. After patients underwent engraftment, bacteremia, cytomegalovirus viremia, and invasive aspergillosis were significantly more common in recipients of allogeneic BMTs than in recipients of autologous BMTs. Deaths caused by infection were uncommon and were mainly the result of invasive aspergillosis. Therefore, empirical antimicrobial therapy should be the same for recipients of both allogeneic and autologous BMTs during the period of neutropenia; after engraftment, more attention should be paid to the risk of infection in allogeneic BMT recipients, particularly with regard to detection and prevention of invasive aspergillosis.     

Abnormal liver function tests following bone marrow transplantation: aetiology and role of liver biopsy

INTRODUCTION: Liver dysfunction is common in bone marrow transplant recipients. Common causes are graft-versus-host disease, drugs, veno-occlusive disease, sepsis and iron overload. We studied the prevalence and aetiology of abnormal liver function tests following bone marrow transplantation and the role of liver biopsy. METHODS: All allogeneic and autologous bone marrow transplantations undertaken in our institution over a 2-year period were studied. Subsequent liver function tests, the use and timing of liver biopsy and the final cause of liver dysfunction were determined in each case. RESULTS: We studied 121 patients (58 allogeneic, 63 autologous). Abnormal liver function tests were found in 52% of bone marrow transplant recipients (72% allogeneic and 33% autologous; P = 0.015). The most common causes of liver dysfunction were graft-versus-host disease, drugs and iron overload in the allogeneic group, and drugs and sepsis in the autologous group. Nineteen patients (16%; 18 allogeneic) underwent liver biopsy. The majority of liver biopsies were carried out in the late post-transplant period to exclude or confirm graft-versus-host disease, although only one case was confirmed. Sixteen of the 19 patients who underwent biopsy had significant hepatic iron overload, but no biopsy revealed evidence of fibrosis or cirrhosis. CONCLUSION: Liver dysfunction following bone marrow transplantation is common and most diagnoses can be ascertained without resorting to liver biopsy. In our series, hepatic iron overload was the most common finding in those who underwent liver biopsy.     

High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group

Relapse is a major cause of treatment failure following allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). To reduce the risk of relapse following BMT for patients with hematologic malignancy, our group developed a novel preparative regimen which combines high-dose etoposide with cyclophosphamide and total body irradiation (VPCyTBI). We now report the outcome of therapy with VPCyTBI followed by allogeneic BMT for 40 patients with AML in untreated first relapse. With the exception of increased stomatitis, the toxicity of this regimen was similar to that reported by others for CyTBI. Forty-four months after transplant the actuarial probabilities of disease-free survival (DFS), persistent or recurrent leukemia, and transplant related mortality were .29, .44, and .47 respectively. DFS was improved (P < .01) and risk of persistent or recurrent leukemia reduced (P = .005) among patients with significant (grade > or = 2) acute GVHD. Patients with 30% or more blasts on pre-BMT bone marrow examination were not at increased risk for persistent or recurrent leukemia. We conclude that VPCyTBI with allogeneic BMT is effective therapy for AML in untreated first relapse and that a randomized trial comparing this regimen with CyTBI is warranted.     

Respiratory viral infections after bone marrow/peripheral stem-cell transplantation: the Christie hospital experience

Respiratory virus infections are an important cause of morbidity and mortality in bone marrow transplant patients. A retrospective study was performed on the bone marrow transplant unit at the Christie Hospital Manchester. The aim of this study was to determine the frequency, clinical presentation, laboratory diagnosis, types of intervention (eg antiviral agents used) and the outcome of such infections in this cohort of transplant recipients. Data were collected from a total of 626 adult patients and showed 27 patients with 29 confirmed episodes of viral respiratory tract infections. The viruses present were rhinovirus (40%), respiratory syncytial virus (RSV) (22.2%), influenza A (18.5%), parainfluenza (PIV) (14.8%) and enteroviruses (7.4%). The overall frequency of documented respiratory virus infections was 4.3% during the 5-year period of the study. The prevalence of respiratory viral infections was 7.8% among allogeneic and 2.3% among autologous transplant recipients. The frequency of lower respiratory tract infection (LRTI) was 3.0% among allogeneic and 1.3% among autologous transplant recipients. Eight patients died (seven had allogeneic transplants). Three of these deaths were directly attributable to a respiratory viral infection (two rhinoviruses; one PIV 3). This study further supports the role played by human respiratory viruses in transplant-associated morbidity and mortality, and particularly highlights the significance of rhinovirus infections.     

Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but Fluconazole was significantly better tolerated.     

Functional asplenia after bone marrow transplantation. A late complication related to extensive chronic graft-versus-host disease

STUDY OBJECTIVE: To evaluate splenic function in bone marrow transplant recipients, with relation to chronic graft-versus-host disease and infections. DESIGN: Survey, outpatients geographically accessible for voluntary participation. SETTING: Bone marrow transplantation referral center. PATIENTS: Fifteen bone marrow graft recipients (13 allogeneic, 2 autologous), out of a total of 33 patients who received transplants at the center and survived more than 6 months after grafting. MEASUREMENTS AND MAIN RESULTS: In 6 of 15 patients impaired splenic function (functional asplenia) was indicated by the presence of Howell-Jolly bodies in peripheral blood smears, reduced spleen size (P less than 0.001), higher platelet counts (P less than 0.01), higher indium-111 labeled autologous platelet recovery (P less than 0.005), reduced splenic blood flow (P less than 0.001), and reduced accumulation of radioactivity at the splenic site (P less than 0.001). All patients with functional asplenia but only 2 patients without functional asplenia had extensive chronic graft-versus-host disease. The incidence of bacterial infections was four times higher in patients with impaired splenic function. CONCLUSIONS: Functional asplenia is a late complication after allogeneic bone marrow transplantation and contributes to the high susceptibility to bacterial infections in patients with extensive chronic graft-versus-host disease.     

Use of recombinant human granulocyte-macrophage colony-stimulating factor in graft failure after bone marrow transplantation

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was evaluated in 37 patients with marrow graft failure after allogeneic (n = 15), autologous (n = 21), or syngeneic (n = 1) bone marrow transplantation. rhGM-CSF was administered by 2-hour infusion at doses between 60 and 1,000 micrograms/m2/d for 14 or 21 days. At doses of less than 500 micrograms/m2, rhGM-CSF was well-tolerated and did not exacerbate graft-versus-host disease in allogeneic transplant recipients. No patient with myelogenous leukemia relapsed while receiving rhGM-CSF. Twenty-one patients reached an absolute neutrophil count (ANC) greater than or equal to 0.5 x 10(9)/L within 2 weeks of starting therapy while 16 did not. None of seven patients who received chemically purged autologous marrow grafts responded to rhGM-CSF. The survival rates of GM-CSF-treated patients were significantly better than those of a historical control group.     

Varicella-zoster virus infections after autologous bone marrow transplantation in children

We report a retrospective analysis of children who underwent autologous bone marrow transplantation (ABMT) and subsequently developed a varicella-zoster virus (VZV) infection. Among 236 patients transplanted between January 1979 and December 1987, 54 (23%) aged 2 to 18.5 years (mean 7.2) developed 60 VZV infections (25%); there were 10 cases of chicken-pox in 10 patients, 43 zoster infections in 41 patients and seven disseminated zoster infections in seven patients. Eighty-seven percent of VZV infections occurred within the first 6 months after bone marrow transplantation, with a mean interval of 89 days. No significant risk factors for the development of zoster infections were identified. The incidence of VZV infections following ABMT was similar to that observed after allogeneic bone marrow transplant but the onset was earlier after ABMT (3 vs 5 months) and there were fewer complications (2 vs 18%). Acyclovir and/or adenine arabinoside were administered to 46 patients. One child who had had chicken-pox died of interstitial pneumonitis due to VZV despite antiviral therapy. No other symptomatic visceral dissemination was observed.     

Clinical benefits of granulocyte colony-stimulating factor therapy after hematopoietic stem cell transplant in children: results of a prospective randomized trial

BACKGROUND AND OBJECTIVES: Hematopoietic stem cell transplantation (HSCT) is associated with profound neutropenia and significant morbidity and mortality. To evaluate the safety and efficacy of non-glycosylated recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in accelerating myeloid recovery and its influence on infections, supportive therapy, and transplant-related mortality we carried out a randomized study in pediatric patients receiving HSCT. DESIGN AND METHODS: Two hundred and twenty-one consecutive children, recipients of an allogeneic or autologous bone marrow (BM) or peripheral blood progenitor cell (PBPC) transplant, were randomized to either receive rHuG-CSF 10 mg/kg (n=110) or not (n=111). RESULTS: Myeloid engraftment was faster in the treated arm (14 vs 20 days, p=0.0001). Neutrophil recovery was accelerated both in the BM subgroups (allogeneic and autologous, p=0.002) and in the PBPC group (p=0.0005). All the other evaluated variables showed an advantage in favor of rHuG-CSF treated patients that was significant for platelet transfusion independence and time to discharge (p=0.02 and p=0.04, respectively) only in the BM subgroup. INTERPRETATION AND CONCLUSIONS: We conclude that faster neutrophil recovery in BM recipients receiving rHuG-CSF led to clinical benefits, while, in the PBPC subgroup, it did not translate into clinical advantages.