Antimicrobial prophylaxis in neutropenic patients after bone marrow transplantation

Summary Fourty-one patients with haematological malignancies or severe aplastic anaemia underwent allogeneic or syngeneic bone marrow transplantation and received one of two forms of infection prophylaxis while granulocytopenic: total decontamination in strict reverse isolation (ITD, 26 patients) or selective decontamination of the digestive tract with barrier nursing (SD, 15 patients). The patients were evaluated for infection acquisition, fever days, days on systemic antibiotics and granulocyte transfusions from 48 hours after the beginning of the decontamination procedure until 1,000 granulocytes/µl have been reached. Ten of 26 patients of the ITD group remained free of febrile episodes and infections, whereas all patients of the SD group acquired infections (p < 0.001). During granulocytopenia patients of the ITD group had fewer fever days, were less frequently on systemic antibiotics and received fewer granulocyte transfusions as compared with the SD group. Both methods were obviously very effective in preventing gram-negative infections, infections caused byStaphylococcus aureus and infections due to yeasts or fungi. No death due to infection occurred in either group. However, the data of this study provide evidence that ITD is a more effective antimicrobial prophylaxis in bone marrow transplant recipients than SD.

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Antimikrobielle Prophylaxe bei neutropenischen Patienten nach Knochenmarktransplantation

Zusammenfassung 41 Patienten mit malignen hämatologischen Systemerkrankungen oder schwerer Panmyelopathie wurden mit einer allogenen oder syngenen Knochenmarktransplantation behandelt und erhielten zur Infektprophylaxe während der Phase der Granulozytopenie entweder eine totale Dekontamination in strikt reverser Isolation (ITD, 26 Patienten) oder eine selektive Dekontamination des Gastrointestinaltraktes mit barrier nursing (SD, 15 Patienten). Die Patienten wurden ausgewertet bezüglich erworbener Infektionen, Fiebertagen, Tagen unter antibiotischer Therapie und dem Bedarf an Granulozytentransfusionen 48 Stunden nach Beginn der Dekontamination bis zum Erreichen von 1000 Granulozyten/µl. Zehn von 26 Patienten mit ITD blieben frei von Fieberepisoden und Infektionen, während alle Patienten mit SD Infektionen entwickelten (p < 0.001). Während der Phase der Granulozytopenie hatten Patienten der Gruppe ITD weniger Fiebertage, waren seltener unter systemischer Antibiotikatherapie und erhielten weniger häufig Granulozytentransfusionen im Vergleich zu Patienten der Gruppe SD. Beide Methoden waren sehr effektiv in der Prophylaxe gramnegativer Infektionen, Infektionen durchStaphylococcus aureus und Pilzinfektionen. In keiner Gruppe trat eine tödliche Infektion auf. Die Ergebnisse dieser Studie zeigen, daß mit ITD im Vergleich zu SD eine effizientere antimikrobielle Prophylaxe bei Patienten mit Knochenmarktransplantation möglich ist.

     

Outcomes of antiemetic prophylaxis in children undergoing bone marrow transplantation

A prospective survey of the control of acute and delayed antineoplastic and radiation-induced nausea and vomiting was undertaken in children undergoing bone marrow transplantation (BMT) at The Hospital for Sick Children. Prior administration of antineoplastic agents or irradiation, presence of anticipatory nausea or vomiting prior to starting the conditioning regimen, antiemetic use within 24 h of conditioning, the prescribed antineoplastic and/or radiation ablative regimen, and prescribed antiemetic regimens were recorded. Emetic episodes, dietary intake, administration of conditioning agents and antiemetics, and adverse effects were monitored on each day of the conditioning regimen and for 96 h thereafter. Children older than 3 years of age assessed their nausea on each study day. Twenty-five children were followed for 258 patient days. Children did not vomit or retch on 73% and 43% of patient days, in the acute and delayed phases, respectively. Nausea data were evaluable for 21 children on 200 patient days. Nausea was absent on 55% and 26% of patient days in the acute and delayed phases, respectively. Five children never had an emetic episode during the entire study period. One child was completely free from nausea and vomiting throughout the study period. Antineoplastic and radiation-induced nausea and vomiting can be successfully prevented in the majority of children undergoing BMT. However, effective treatment strategies must be developed in the event of antiemetic failure and for effective prophylaxis in children who cannot tolerate dexamethasone.     

Norfloxacin prophylaxis for neutropenic patients undergoing bone marrow transplantation

To prevent bacterial infections in the neutropenic post-transplant period, norfloxacin 400mg twice daily was administered as oral prophylaxis to 44 marrow recipients isolated in laminar airflow rooms (LAFRs). Patients had a mean age of 30 years (8-50) and a male/female ratio of 29/15. The mean duration of prophylaxis was of 41 days (20-80), that of neutropenia (PMN less than 1000 x 10(6)/l) of 31 days (6-76) and that of severe neutropenia (PMN less than 100 x 10(6)/l) of 19 days (10-55). All but two patients developed one or more febrile episodes (total episodes: 71), 33 of which were documented infections. Eighteen bacteraemias occurred and all were caused by Gram-positive cocci: five by coagulase-negative staphylococci (three methicillin resistant), four by coagulase-positive (one methicillin resistant), seven by streptococci (four S. sanguis, one S. milleri, one group B, one group C), and two by enterococci. All streptococcal and enterococcal strains, but only one MR coagulase-positive staphylococcus, proved to be resistant to norfloxacin. Norfloxacin was well tolerated and no prophylactic course had to be interrupted because of side effects. In conclusion, norfloxacin adequately prevents infections caused by Gram-negative bacilli in bone marrow recipients isolated in LAFRs, but Gram-positive infections still remain a problem in these patients indicating the need for improving this prophylactic regimen.     

Is aciclovir prophylaxis necessary after bone marrow transplantation?

Summary To assess the cost-effect relationship of aciclovir prophylaxis versus early treatment, we performed a retrospective study in 44 allogeneic bone marrow transplant recipients, who had only received aciclovir for therapeutic purposes. After bone marrow transplantation 18 herpes simplex infections occurred in 15 of the 33 patients who were seropositive for herpes simplex virus. In ten patients without clinical signs, routine viral cultures yielded herpes simplex virus. Aciclovir was given intravenously to the patients with mucocutaneous herpes infection. All infections responded rapidly. It can be calculated that restricting the drug to therapeutic use reduced the amount of aciclovir used, which in turn diminished the cost of treatment and the risk of aciclovir resistance.

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Ist nach Knochenmarkstransplantation eine Aciclovir-Prophylaxe nötig?

Zusammenfassung Bei 44 Empfängern von allogenen Knochenmarkstransplantaten, die Aciclovir ausschließlich therapeutisch erhalten hatten, wurde eine retrospektive Studie durchgeführt, um die Kosten-Nutzen-Beziehung für die Prophylaxe im Vergleich zur Frühtherapie zu bestimmen. Bei 15 der 33 Herpes-simplex-Virus-seropositiven Patienten traten nach Knochenmarkstransplantation 18 Herpes-simplex-Virus-Infektionen auf. Bei zehn klinisch symptomfreien Patienten wurde in Routinekulturen Herpes-simplex-Virus nachgewiesen. Patienten mit mukokutaner Herpesinfektion erhielten Aciclovir intravenös appliziert. Alle Infektionen sprachen rasch auf die Therapie an. Es läßt sich errechnen, daß eine Beschränkung auf den therapeutischen Einsatz des Medikamentes den Verbrauch von Aciclovir vermindert und somit die Behandlungskosten und das Risiko der Resistenzentwicklung gegen Aciclovir erniedrigt.

     

Safety and efficacy of jet anesthesia for bone marrow aspirations.

Aspirations or Jamshidi needle biopsies (n = 287) of bone marrow were performed on children and adolescents with acute leukemia or other malignant disease following the use of a spring-loaded instrument that delivered local anesthetic in a jet spray; 89% of the patients were receiving chemotherapy, 12% were thrombocytopenic, and 23% of the 269 patients who were afebrile at the time of the procedure were severely neutropenic. None of these patients had an infection or a hemorrhage as a complication of the procedure. We conclude that not only is this procedure safe, but it is also much less painful than the traditional method of local anesthetic infiltration using a syringe and needle.     

Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells.

BACKGROUND: There have been a number of recent reports on the use of autologous bone marrow implantation (BMI) in the treatment of peripheral arterial disease, with a clinical response rate of approximately 70%. However, the factors that influence efficacy have not yet been clarified. We have analyzed the relationship between the number of implanted bone marrow cells and the clinical efficacy of BMI. METHODS AND RESULTS: Eight patients with arteriosclerosis obliterans were treated with BMI. Bone marrow was aspirated from the ilium (500-1,000 ml), the mononuclear cells were separated and then were implanted. The clinical effectiveness of BMI was evaluated by assessing changes in the ankle-brachial pressure index (ABI) and the transcutaneous oxygen pressure (TcO2) between the pre-treatment baseline, with follow-up testing at 4 weeks. These changes were defined as DeltaABI and DeltaTcO2. The mean number of CD34-positive cells was 1.04+/-0.60 x10(6) /kg body weight. There was a strong correlation between the number of CD34-positive cells and DeltaABI (r=0.754, p=0.028). CONCLUSIONS: It is likely that the number of implanted CD34-positive cells is one of the primary factors that influence the clinical efficacy of BMI.     

Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow.

Using multidimensional flow cytometry we have defined and quantified the human T-cell differentiation pathway, focusing on those events occurring among the most immature thymocytes and putative bone marrow (BM) T-precursors. Early thymocytes were found to express the CD34 antigen and consisted of a mean 1.2% of cells within human pediatric (n = 9) and 2.0% in fetal thymi (n = 4). All CD34+ thymocytes were atypical blast by morphology, expressed intracytoplasmatic, but not cell surface, CD3, and were cell surface CD2+, CD5+, CD7+, CD38+, CD45+, CD45RA+, CD49d+, and LECAM-1(Leu8)high. CD34high thymocytes lacked surface expression of CD4 and CD8, but as CD34 expression diminished there was a coordinate increase in CD4 levels, followed by the appearance of CD8. The expression of CD1 and CD10 also increased concomitant with the loss of CD34, whereas expression of LECAM-1 diminished with CD34 downregulation. The differential expression of these antigens on early thymocytes (as well as the number of thymocytes displaying these patterns) was highly reproducible among the nine pediatric and four fetal specimens examined, suggesting a precise, stereotyped regulation of early differentiation events. Cell populations with antigen expression patterns suggestive of pluripotent stem cell (CD34high, CD38-), or non-T-lineage committed stem cells (CD34+, CD33+ or CD34+, CD19+) were not identified in either fetal or pediatric thymi (sensitivity = 1/10(4)). The presence of cells with the antigenic profile of the earliest CD34+ thymocytes was explored in human BM. Putative BM T-cell precursors with the appropriate phenotype (CD34+, CD7+, CD5+, CD2+, LECAM-1high) were readily identified in fetal specimens (constituting +/- 2% of the CD34+ population), but could not be reliably detected in adults. In contrast with thymi, only 13% of these cells expressed cytoplasmatic CD3, suggesting the presence of the immediate precursor of the putative prothymocyte population. This was further supported by the detection of CD34bright, CD7+, CD2-, CD5-, LECAM-1moderate cells in fetal specimens. Our results document the flow of cell surface differentiation during T-lymphopoiesis and suggest that T-lineage features are first acquired in the BM. The ability to reproducibly identify and isolate T-cell precursor populations of precisely defined maturational stage in marrow and thymus by multiparameter flow cytometry will facilitate characterization of the molecular events controlling T-lineage differentiation.     

Dynamic assessment of quality of life after autologous bone marrow transplantation.

To determine the quality of life in adult patients after autologous bone marrow transplantation (BMT), we administered a questionnaire to a cohort of patients seen at a single referral-based center. The sample included adults 18 years and older during the 1 year following an autologous BMT. Both disease-free patients and those who relapsed with 1-year of follow-up data available were included. Of 59 eligible patients, 58 (98%) responded to the questionnaire. Patients completed a telephone questionnaire administered by a nurse specialist in the field of BMT approximately every 90 days. At the time of initial contact on day +90, the mean quality of life was 7.8 (range, 1 to 10) on a scale of 1 to 10, with 10 being the best. By the end of the first year of follow-up, the mean quality of life was 8.9 (range, 3 to 10). Seventy-eight percent of the patients were employed. Twenty-one percent lost weight during the first year, with the majority reporting voluntary weight loss. Fourteen percent reported difficulties with sexual activity. Only 5% reported difficulty with sleeping or with frequent colds. One patient felt that her appearance was worse, and none of the patients reported a poor appetite. Eighty-eight percent of surviving adult patients reported an above-average to excellent quality of life 1 year following autologous BMT. This outcome is encouraging and suggests that this procedure is not associated with long-term morbidity in the surviving adult patient.     

Proliferation-based T-cell selection for immunotherapy and graft-versus-host-disease prophylaxis in the context of bone marrow transplantation

Graft-versus-host disease (GvHD) caused by alloreactive T cells within the graft is a major drawback of allogeneic BMT, but depletion of T cells leads to higher rates of relapse, opportunistic infections and graft failure. Therefore, selective removal of GvHD-inducing alloreactive T cells might be beneficial. We describe here the separation of alloresponsive T cells, based on carboxyfluorescein succimidyl ester labeling, in vitro allostimulation and FACS-sorting. In vivo effects of the separated cell populations were investigated in the context of allogeneic BMT in murine models: in vitro resting T cells were shown to survive in the allogeneic host and retain immunoreactivity against 'third-party' antigens. As demonstrated in two different transplantation models, elimination of proliferating cells significantly reduces GvHD but offers no advantages to using T-cell-depleted bone marrow alone concerning engraftment and tumor control. Transplanting T cells that proliferate in response to tumor antigens in vitro may narrow down the spectrum of antigens recognized by T cells and therefore reduce GvHD while maintaining graft-facilitating function and tumor control. Therefore, selecting tumor-reactive T cells on the basis of their proliferative response in vitro may be beneficial for the recipient, less time consuming than T-cell cloning and still reduce the extent of GvHD.     

Polyploidy of the bone marrow.

In a consecutive series of 841 patients whose bone marrows were cytogenetically investigated because of verified or suspected haematological disease, 11 patients were found to have at least 10% polyploid bone marrow mitoses. The chromosome numbers varied greatly between the cells of the same patients and between the patients. In 4 cases, the number was nearly or exactly tetraploid and in 1 patient a prevalent octaploid line was seen. Structurally abnormal marker chromosomes were seen in 8 of the patients. A total of 31 bone marrow chromosome counts were performed on a young woman with acute myelomonocytic leukaemia who had had several drug-induced remissions during the 3 1/2 years of disease. The results were related to the clinical findings. On several occasions a clear-cut correlation was noted between high proportions (nearly 100%) of polyploid cells and relapse on the one hand and low proportions (as low as 0%) of polyploids and remission on the other. Of the 11 patients, 2 had chronic myeloid leukaemia, 3 acute myelomonocytic leukaemia, 3 acute myeloid leukaemia and a further 3 some other malignant haematological disorders. We conclude that polyploidy is a feature associated with rare cases of leukaemia and other malignant diseases. It is often a sign of a poor prognosis.     

Immunohistochemical assessment of ferritin in bone marrow trephine biopsies: correlation with marrow hemosiderin

In 340 bone marrow biopsies we compared ferritin, stained with an immunoperoxidase method, with hemosiderin, stained with Perls' reaction. Ferritin and hemosiderin showed the same distribution in reticuloendothelial cells. All the Perls-positive cases (n = 177) were ferritin-positive too. None of the ferritin-negative cases (n = 13) were Perls-positive. Of 163 cases with negative Perls' reaction in bone marrow, 13 (12.5%) were also ferritin-negative: these patients were mainly affected by polycythemia vera or by untreated iron deficiency anemia. Thus, immunohistochemical assessment of bone marrow ferritin can be a more sensitive tool for the evaluation of body iron stores in iron deficiency than Perls' reaction.     

Alcohol-induced bone marrow damage. A bone marrow study in alcohol-dependent individuals

Bone marrow biopsies from 30 alcohol-dependent individuals hospitalized for detoxification were investigated. Typical alcohol-induced bone marrow changes were found and served to define alcohol-induced bone marrow damage as a nosological entity. The findings took the form of heightened ineffective erythropoiesis associated with impaired iron utilization, vacuolated proerythroblasts, multinuclear erythroblasts, megaloblasts and iron-containing plasma cells as well as vacuolated precursor cells of the granulocytopoietic series. In the differential diagnosis, alcohol-induced bone marrow damage is to be distinguished from the myelodysplastic syndrome of the RA and RARS form. Alcohol-induced bone marrow damage is reversible. Bone marrow cell cultures performed in our cases are normal, showing that the toxic defect probably does not reside in the stem cell but is more peripheral. Normal bone marrow cell culture may be a typical feature of alcohol-induced bone marrow damage.     

An overview of the Welsh bone marrow donor registry: 10 years of bone marrow donor provision

The Welsh Bone Marrow Donor Registry (WBMDR) is in its 11th year of operation and its 4th year as an International 'Hub' participating in Bone Marrow Donors Worldwide. It is operated by the Welsh Regional Tissue Typing Laboratory which is accredited by Clinical Pathology Accreditation (UK) Ltd, and the European Federation for Immunogenetics and, together with the Welsh Blood Service, its donor centre, is ISO 9001 Registered. The active donor panel of over 21 000 regular blood donors are all HLA-A, B, DR, DQ typed (over 95% to the split specificity level or higher). All HLA-DR, DQ and over 50% of HLA-A, B typing has been performed by DNA-based methods. CMV antibody status, now tested on all donors, is known on over 70% of subjects. The WBMDR has over 80% success at obtaining Confirmatory Typing samples and operates a rapid Expanded Typing service on stored donor material. It has provided 174 bone marrow donations (140 for UK and 34 for overseas patients), and 11 lymphocyte donations, since its inception in 1989.     

Cytomegalovirus pneumonia in allogeneic bone marrow transplantation. An immunopathologic process?

Recent literature suggests that CMV pneumonia is an immunopathologic process. This case report summarizes the clinical course of a patient which supports this hypothesis. The patient is the recipient of an allogeneic BMT who recovered from an episode of CMV pneumonia that occurred about two months after the transplant. Despite recovery from the viral infection, follow-up BALs revealed persistent lymphocytosis in an apparent asymptomatic patient. He subsequently developed BOOP about four months after the initial CMV infection. These observations suggest that the viral infection may have resulted in the activation of the host's cell-mediated response and provides evidence to support the hypothesis that CMV pneumonia is an immune-mediated process.