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Infectious Complications During Neutropenia Subsequent to Peripheral Blood Stem Cell Transplantation

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Infectious Complications During Neutropenia Subsequent to Peripheral Blood Stem Cell Transplantation Bone Marrow Transplantation, (1997) 19, 143–147 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 Infectious complications during neutropenia subsequent to peripheral blood stem cell transplantation K Kolbe1, D Domkin1, HG Derigs1, S Bhakdi2, C Huber1 and WE Aulitzky1,3 1Division of Hematology, IIIrd Department of Medicine and 2Department of Microbiology, Johannes Gutenberg University Hospital, Germany Summary: diagnostic procedures further decrease the natural resist- ance to infection. Finally, granulocytopenia compromises Type, severity and incidence of infection during the neu- the first line of defense against bacterial, fungal and para- tropenic period after peripheral blood stem cell trans- sitic pathogens. Fever of unknown origin, bacteremia and plantation (PBSCT) for treatment of malignant disease pneumonia are the most frequent clinical manifestations of were studied in 66 patients treated at a single insti- infection in patients after chemotherapy.3 Infections with tution. Data of 34 female and 32 male patients with a both gram-positive and gram-negative bacteria as well as median age of 43 years suffering from leukemia (12), fungi are common in these patients. In particular, staphylo- lymphoma (35), multiple myeloma (six) or solid tumors cocci, streptococci, E.coli, klebsiella, pseudomonas, can- (13) were retrospectively analyzed. All patients had dida and aspergillus species are frequently isolated from received at least 2.5 3 106 CD34-positive cells for stem infectious sites in granulocytopenic patients. cell rescue after high-dose chemotherapy. Ninety-four Chemotherapeutic agents display a dose–response percent of the patients experienced at least one febrile relationship in vivo and in vitro.4,5 However, the application episode during their post-transplant course. The of high-dose chemotherapy is limited by its toxic effects, patients recovered quickly and defervesced after a in particular on the hematopoietic system. Stem cell rescue median of 4 days. The incidence of bacteremia was 39% by autologous bone marrow transplantation has been and gram-positive cocci were the predominant patho- applied to circumvent the dose-limiting hematopoietic tox- gens. In contrast, severe organ infections were rare. icities.6–8 Myeloablative therapies with autologous bone Only 5% of the patients suffered from lung infiltrates. marrow transplantation, however, cause prolonged marrow No invasive fungal infections were observed. No trans- aplasia accompanied by severe infectious complications. plant-related deaths occurred in the 66 patients studied. Autologous bone marrow transplantation caused a trans- We conclude that the severe, but shortlasting neutro- plant-related mortality consistently in the range of penia after peripheral blood stem cell transplantation is 5–10%.6–8 Mobilization of peripheral hematopoietic stem associated with a high incidence of bacterial infection. cells by chemotherapy and growth factors and leukapher- The severity of the majority of these infections is moder- esis yields higher numbers of hematopoietic stem cells than ate. With appropriate anti-infective therapies these bone marrow harvesting.9,10 Numerous reports have mean- infections can be managed and life-threatening infec- while confirmed the feasibility and effectiveness of trans- tious complications, in particular fungal infections, are plantation with peripheral blood stem cells (PBSCT) to rare. Empirical anti-infective regimens specifically mitigate the hematotoxic effects of myeloablative ther- designed for this clinical situation should be explored. apies.11–16 Most of these studies demonstrated a shortening Keywords: infection; neutropenia; autologous peripheral of the time to leukocyte and thrombocyte recovery when blood stem cell transplantation compared to autologous bone marrow transplantation or growth factor therapy. Very few reports, however, have focused on the type and severity of infectious complications observed in severely leukopenic patients after high-dose Infections are the leading cause of morbidity and mortality therapy and peripheral stem cell transplantation.17,18 This 1,2 in patients treated with aggressive chemotherapy. A var- study aims to analyze frequency, type and severity of infec- iety of factors contribute to the pathogenesis in these tions during the aplastic phase after peripheral stem cell patients. Direct damage of the skin and mucous membrane transplantation in a cohort of unselected patients treated at barrier facilitates the entry of pathogens. In addition, iatro- a single institution with PBSCT. genic disruption of the skin by central venous catheters or Patients, material and methods Correspondence: K Kolbe, Division of Hematology, IIIrd Department of Medicine, Johannes Gutenberg University Hospital, Langenbeckstr. 1, All patients treated at the Medical School of the Johannes 55101 Mainz, Germany 3Current address: Division of Hematology/Oncology/Immunology, Robert Gutenberg University in the years 1993 to 1995 were retro- Bosch Hospital, Auerbachtrabe 110, 70376 Stuttgart, Germany spectively analyzed. Sixty-six patients underwent high-dose Received 7 May 1996; accepted 18 September 1996 chemotherapy and autologous transplantation of peripheral Infectious complications during PBSCT K Kolbe et al 144 blood stem cells during this period. The clinical character- at least once daily in case of elevated body temperature istics of the study patients are summarized in Table 1. .38.0°C. The diagnosis of a documented bacterial infec- Thirty-four female and 32 male patients suffered from acute tion was based on the occurrence of at least one positive myelogenous leukemia (AML), chronic myelogenous leu- culture in the face of appropriate clinical findings. All kemia (CML), non-Hodgkin’s lymphoma, Hodgkin’s dis- medication was applied through central venous catheters ease, acute lymphoblastic leukemia (ALL), breast cancer, throughout the in-patient period. Platelet transfusions were mutliple myeloma and testicular cancer. Only patients with administered in the case of thrombocytopenia less than an age of less than 60 years and preserved function of all 10/nl in asymptomatic patients, ,20/nl in febrile patients vital organs were treated with high-dose chemotherapy or in the case of hemorrhagic diathesis being present. and PBSCT. Leukocyte-depleted erythrocyte concentrates were given to All patients had received chemotherapy for mobilization patients with a hemoglobin concentration ,8 g/dl. of stem cells. Fifty-six patients received G-CSF at a dose In febrile patients a thorough physical examination and of 5–10 mg/kg, nine patients received sequential treatment chest X-ray were performed. All patients received i.v. anti- with interleukin-3 5 mg/kg plus G-CSF 10 mg/kg for mobil- biotics after one measurement of an elevated body tempera- ization of stem cells. Peripheral blood stem cells were ture .38.3°C or two times body temperature .38.0°C. obtained by repeated leukaphereses. Leukaphereses were Empiric antibiotic therapy was performed according to pre- started after a rise of leukocytes to above 0.8/nl and more viously published guidelines.19 In 58 patients, antimicrobial than 0.5% CD34-positive cells in the peripheral blood and treatment was started with a triple combination with b- were repeated until a minimum number of 2.5 3 106 CD34- lactam, aminoglycoside and glycopeptide. One patient positive cells/kg was harvested. Different conditioning regi- received a b-lactam with aminoglycoside, three patients mens were applied according to diagnosis and disease were started with b-lactam monotherapy. Antibiotic treat- status (Table 1). Peripheral stem cells were infused intra- ment was continued until disappearance of all clinical venously 1–3 days after discontinuation of chemotherapy. and/or microbiological evidence for infection and granulo- During PBSCT procedure patients were kept in single cyte counts above 0.5/nl. In case of persistent fever, i.v. rooms under reverse isolation. Rooms were not equipped amphotericin B was added 2–5 days after start of antibiotic with high-efficiency air filters. All patients received anti- treatment. Modifications of the antibiotic regimen were per- biotic prophylaxis with ofloxacin 2 3 200 mg per day and formed, if appropriate, according to microbiologic results. antimycotic prophylaxis with fluconazole 2 3 200 mg per Thirty-seven patients received 5 mg G-CSF s.c. beginning day. Appropriate clinical examinations were performed day 2 after peripheral stem cell transplantation, whereas the once daily and body temperature was measured at least remaining patients were not treated with recombinant three times daily. Routine cultures from stool, urine and growth factors during the post-transplant period. No differ- mouth swabs were examined twice weekly for contaminat- ences regarding leukocyte recovery, thrombocyte recovery ing pathogens. In addition, two blood cultures were drawn and incidence of infection were observed between these two patient groups. All data were analyzed with descriptive statistical Table 1 Clinical characteristics of PBSCT patients methods. Statistical significance of differences between diagnostic groups was calculated using x2 test. Probability No. 66 Age of events (onset of fever, leukocyte recovery, response to Median 43 (range 18–59) antibiotics) were analyzed using Kaplan–Meier product limit estimates and groups were compared applying the log Sex Female 34 (51%) rank test. Male 32 (49%) Diagnosis AML 8 Results ALL 2 NHL 31 Breast cancer 12 Hematopoietic
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