Patients' experience of ambulatory self-administration of pamidronate in multiple myeloma.

The aim was to explore ambulatory self-administration of Pamidronate (Self-A-Pam) from a patient perspective in patients with multiple myeloma. Pamidronate is normally administered once a month as an intravenous infusion over 2 to 4 hours. Twenty-one patients were included, of whom 13 (6 women, 7 men) with a median age of 56 years (range 37-70) completed the educational program and subsequent ambulatory Self-A-Pam. An RN at the hospital initiated the Pamidronate therapy (90 mg). The patients then left hospital and later, on completion, they disconnected the infusion, either alone or with the assistance of a relative or significant other. Interviews were used to collect information about the experiences during the course of the Self-A-Pam. In total, 12 patients were interviewed after 3 doses of Self-A-Pam. One patient declined to participate in the interview. A qualitative analysis of the textual data was performed. Five main categories were identified: decision concerning Self-A-Pam, information and education, sources of practical help or support, effects of Self-A-Pam, and feelings and activities in relation to place (hospital, home, or public place). All 13 patients who started on Self-A-Pam went through 3 courses of Self-A-Pam during the study period. Many patients reported a gain in feelings of freedom/independence and time saving. However, some patients reported insufficient education and feelings of anxiety associated with the responsibility of handling the venous access device.

Human cytomegalovirus, human herpesvirus-6 and human herpesvirus-7 in neutropenic patients with fever of unknown origin.

OBJECTIVE: To investigate the appearance of cytomegalovirus (CMV) DNA, human herpesvirus-6 (HHV-6) DNA and human herpesvirus-7 (HHV-7) DNA in plasma as a sign of reactivation and possible causes of fever of unknown origin (FUO) during neutropenia. METHODS: From 134 patients with febrile neutropenia following cytotoxic chemotherapy during the years 1996-2000, 20 severely neutropenic patients (granulocyte count < 0.1 x 109/L) were selected. Ten were patients with bacteremia and ten were patients with FUO. Five samples from each patient were selected at the start of chemotherapy, at the time of blood culture and fever, after 24 and 48 hours of fever, and, finally, after two to three days without fever. Virus DNA was detected by real-time quantitative and nested polymerase chain reaction (PCR). RESULTS: CMV-DNA was detected in two out of ten FUO-patients in all samples drawn during fever. From another FUO and during two bacteremia episodes, CMV-DNA was detected after 48 hours of fever. DNA from HHV-6 and HHV-7 was not detected in any of the 20 febrile episodes. CONCLUSIONS: HHV-6 and HHV-7 as a possible explanation for FUO in severely neutropenic patients treated with cytotoxic chemotherapy seems not be very likely. However, CMV was identified in 5/20 patients and the febrile episodes in the two FUO-patients with constant DNA-emia may have been caused by a reactivation of CMV. This implies that CMV infection can be expected not only in transplant patients but also in chemotherapy-treated neutropenic patients.

Fibrosis regression induced by intravenous gammaglobulin treatment.

OBJECTIVES: To review case histories of patients in whom fibrosis played a significant role in the pathogenesis of their disease, and to determine whether intravenous gammaglobulin (IVIg) contributed to the regression of their fibrotic condition. METHODS: Eight patients with excess fibrotic reaction in the course of diverse diseases were analysed; a tendency that reverted with different IVIg treatment options. Myelofibrosis was predominant in three patients (a patient with a myeloproliferative syndrome, one with systemic lupus erythematosus, and one with Sjögren's syndrome). Three patients had scleroderma as their main feature, one patient had hepatitis C cirrhosis, and one had idiopathic thrombocytopenic purpura. RESULTS: Fibrotic excess was reduced in all the patients by IVIg treatment. In five patients the disease as a whole benefited from the infusion of immunoglobulins. CONCLUSION: IVIg may enhance resorption of fibrosis and promote healing in patients with fibrotic associated disorders.

Liposomal amphotericin B and surgery in the successful treatment of invasive pulmonary mucormycosis in a patient with acute T-lymphoblastic leukemia.

Pulmonary mucormycosis is a usually fatal opportunistic infection in immunocompromised patients. We describe the first case of an adult patient with hematological malignancy and profound neutropenia to survive a disseminated pulmonary Rhizomucor pusillus infection. Early diagnostic procedures combined with high doses of liposomal amphotericin B and surgical resection may have contributed to the successful outcome.

Outpatient parenteral antibiotic therapy in patients with haematological malignancies. A pilot study of an early discharge strategy.

The objectives of this study were to estimate the feasibility of a self-administration outpatient parenteral antibiotic therapy (OPAT) model. to record the complication rate and to estimate patient acceptance during the OPAT period in patients with acute leukaemia (AL) or aggressive non-Hodgkin lymphoma (NHL). Patients were trained to administer the antibiotic infusions themselves, via their central venous access device, according to a checklist and step-by-step instructions. Study-specific questionnaires were used to evaluate patient acceptance. Eleven patients [AL (n=8) and NHL (n=3), median age 51 years, range 29-661 participated in the education programme and subsequent OPAT during ten episodes of documented infection and six episodes of fever of unknown aetiology. All patients had assessment of the infectious episode and initial parenteral antibiotic therapy in the hospital before they continued self-administration at home. The median education time was 3 h (range 0.75-4.5). The patients could stay at home for 4 days (median, range; 1-12) with ongoing intravenous antibiotic therapy instead of being hospitalised. None of the patients developed recurrent fever. All patients reported that OPAT was of great value and they would favour OPAT again during subsequent antibiotic therapy. In conclusion, the results of this pilot series suggest that OPAT, in this setting, is a safe alternative during the last days of an episode of fever / infection. All patients were satisfied overall, and none was readmitted.

Increased incidence of bacteraemia due to viridans streptococci in an unselected population of patients with acute myeloid leukaemia.

The aetiology, clinical characteristics and outcome of bacteraemia in patients with acute myeloid leukaemia were studied. All positive blood cultures collected at a haematological ward during 2 7-y periods were evaluated. Altogether, 274 episodes of bacteraemia in 152 patients were recorded, 80 episodes during 1980-86 and 194 during 1990-96. During the 2 periods, trimethoprim-sulfamethoxazol in combination with amikacin was the first-line empirical therapy in patients with neutropaenia and fever. In 1990, antimicrobial prophylaxis with ciprofloxacin and fluconazole was introduced. The incidence of bacteraemia due to viridans streptococci or coagulase-negative staphylococci increased from the first period to the second, whereas the incidence of Enterobacteriaceae decreased. In granulocytopaenic patients during 1990-96, viridans streptococci accounted for 21% of the isolates and in patients treated prophylactically with fluoroquinolone, viridans streptococci accounted for 31%. All viridans streptococci were sensitive to penicillin. At the time of the positive blood cultures, the patients of the second period were granulocytopaenic in 83% of the episodes. The mortality related to septicaemia during the later period was 13% and only 1 of 33 (3%) of the patients with viridans streptococci died. Eight patients (9%) died in relation to septicaemia following curative antileukaemic therapy.

Vascular access devices used during harvest of peripheral blood stem cells: high complication rate in patients with a long-term dialysis central venous catheter.

PBSC harvesting requires good quality venous access. The efficacy and complication rate of the venous access devices used during stem cell harvest in 101 consecutive patients were examined. Four different categories of venous access were used: (1) long-term dialysis central venous catheter (dCVC), (2) short-term dCVC, (3) peripheral venous cannulae (PVC), and (4) PVC and conventional central venous catheter. The number of harvest occasions per patient or harvest days per occasion were similar between the various categories of access. Complications during harvest occurred in 13 out of 48 (27%) occasions using a long-term dCVC compared to six out of 97 (6%) in the other three categories pooled together (P < 0.01). Forty-two of the 101 patients received a long-term dCVC to facilitate the harvest. The long-term dCVC was planned to stay in place and also be used as a conventional i.v. line during the following high-dose treatment. Twenty-one (50%) of the long-term dCVCs were removed due to complication. Thirteen (31%) of the long-term dCVCs were usable throughout the entire treatment period. In conclusion, we recommend that PBSC harvesting is performed through peripheral venous catheters when practically possible, otherwise via short-term dCVC.

Cefepime as empirical monotherapy in febrile patients with hematological malignancies and neutropenia: a randomized, single-center phase II trial.

The purpose of this phase II trial was to evaluate the efficacy and safety of cefepime monotherapy in patients with neutropenia expected to last more than 7 days. Sixty-nine patients with neutropenia (<0.5 x 10(9)/1) were randomized during 94 episodes of fever to receive either cefepime monotherapy (n=76) or combination therapy with trimethoprim/sulfamethoxazole plus amikacin (TMP/SMZ plus AMI, n=18). A successful response to cefepime was seen in 31/76 (41%) episodes, with 10/36 (28%) in microbiologically documented infections, 3/4 (75%) in clinically documented infections and 18/36 (50%) in fever of unknown origin. No patient in either treatment group died due to the presenting infection. One patient in the cefepime group discontinued treatment due to a rash. Susceptibility testing of blood isolates by E-test strip showed low MIC values to cefepime for most isolates. It is concluded that cefepime monotherapy appeared both safe and effective as empirical therapy in patients with febrile neutropenia.

PBSC harvests individually optimized by using pre-collection CD34(+) values and on-line flow cytometric analysis of the mononuclear cell enrichment.

BACKGROUND: We have investigated how the amount of blood processed during collection of PBSC affects the yield of CD34 cells. METHODS: We first established a method of significantly increasing the enrichment of mononuclear cells (MNC), CD34(+) cells and granulocyte-macrophage progenitors (GM-CFU) by on-line flow cytometric (FCM) analysis of the leukocyte populations in the collect line. A total of 166 PBSC collections from 94 patients, were devided into five groups according to the blood volume processed: < 12 L of processed blood, 12-13L, 13-14L, 14-15L and > 15L. RESULTS: When the yield of CD34(+) cells war compared between these groups, a positive correlation was seen (r=0.97) between the processed blood volume and the yield, expressed as a ratio between total number of CD34(+) cells in the harvest and the CD34(+) cell concentration in blood. This correlation can be used to estimate the volume that must be processed to exceed a specific target number of CD34(+) cells. The implications of these results on the need for one, two or more leukapheresis procedures in order to collect a sufficient amount of stem and progenitor cells for a given patient are discussed, i n relation to clinical logistics and the benefits for the patients. DISCUSSION: PBSC harvest can be improved by individually-adjusted leukapheresis according to on-line FCM analysis and pre-harvest levels of CD34(+) cells and the processed blood volume can be used to predict the CD34(+) yield.

Alterations in adhesion molecule (CD11b/CD18 and CD62L) expression on granulocytes after chemotherapy.

BACKGROUND: Infections during chemotherapy-induced granulocytopenia constitute a major threat to patients with malignant disorders. The aim of this study was to evaluate whether circulating granulocytes after chemotherapy have a normal expression of adhesion molecules or if the granulocytes, in addition to being present in low number, also present signs of qualitative alterations. METHODS: We have investigated the time course of adhesion molecule expression (CD11b/CD18 and CD62L) and in vitro mobilization [responsiveness against N-formyl-methionyl-leucyl-phenylalanine (fMLP) for CD11b/CD18] by flow cytometry in circulating granulocytes after chemotherapy in 12 patients with haematological malignancies. Blood samples for analysis were drawn before chemotherapy and at time points when granulocyte counts were < 0.5, 0.5-1.0 and > 1.0 x 109 L-1. RESULTS: The quantitative level, expressed as mean fluorescence intensity (MFI), of CD11b/CD18 was significantly higher and of CD62L significantly lower at granulocyte nadir than before chemotherapy. The in vitro responsiveness to fMLP was significantly reduced at the same time point. These alterations were restored to pretreatment values at the time of granulocyte count recovery. Granulocytes from patients with bacteraemia (n = 6) exhibited lower CD11b/CD18 MFI values after fMLP stimulation than non-bacteraemic patients after granulocyte count recovery. In addition, the MFI of CD62L was significantly lower both before chemotherapy and after granulocyte recovery in the bacteraemic group. CONCLUSION: Chemotherapy induces qualitative alterations in circulating granulocytes with respect to adhesion molecule expression and mobilization, and these alterations are more pronounced in patients with accompanying bacteraemia.

Low incidence of candidaemia among neutropenic patients treated for haematological diseases.

Candida colonization and haematogenous infection were studied retrospectively in 277 patients with haematological diseases by reviewing the microbiological reports of fungal surveillance and blood cultures over a 4-year period. Most patients (83%) were colonized by Candida and in the majority (68%) the same Candida species was isolated from at least 2 body sites. However, candidaemia was diagnosed in only 3 patients. During the same period invasive aspergillosis was diagnosed in 7 patients. Possible causes for the low incidence of candidaemia were fluconazole prophylaxis, empirical amphotericin B and strict indication for antibacterial therapy.

Endotoxemia in febrile patients with hematological malignancies. Relationship of type of bacteremia, clinical findings and serum cytokine pattern.

The relation between gram-negative bacteremia, endotoxemia and cytokinemia in patients with hematological malignancies was studied. Serum endotoxin and cytokines (tumor necrosis factor-alpha, interleukin-1 receptor antagonist, interferon-gamma, interleukin-6 and interleukin-10) were determined in 24 patients with hematological malignancies. Patients were included at start of fever (n = 18) or during a temperature peak during continuous fever (n = 6; time = 0). Blood was drawn for cultures at time of inclusion. Additional samples were obtained and grouped in two time intervals (1-5 h and 6-12 h after inclusion). Endotoxin was detected in eight patients. Endotoxemia was more common among patients with bacteremia than among non-bacteremic patients (7/12 versus 1/12; p < 0.05). All studied cytokines showed a tendency to higher mean values at time 0 in patients with endotoxemia than in patients without endotoxemia. Significantly higher mean endotoxin values were seen at time 1-5 h in patients with gram-negative bacteremia (n = 6) than in patients without gram-negative bacteremia, and at time 0 in patients with chills (n = 6) compared to those without chills.

Imipenem/cilastatin monotherapy as salvage treatment in febrile neutropenic patients.

Imipenem/cilastatin (I/C) monotherapy was used as salvage treatment in 55 neutropenic patients (58 fever episodes) after treatment failure on first-line antibiotic therapy. Successful antibiotic treatment was defined as eradication of all signs, symptoms and microbiologic evidence of infection on I/C monotherapy alone. Twenty-five out of the 58 episodes (43%) were classified as success, 6 episodes (10%) as initial response but the regimen had to be modified (amphotericin B was added) and 27 episodes (47%) as failures. In episodes with documented infections 9 out of 23 (39%) were classified as success. All patients survived during the first 72 hours after change to I/C therapy. One patient had to discontinue I/C due to a skin rash. In conclusion, the use of a treatment algorithm with I/C monotherapy as second-line treatment was safe and effective. Other antimicrobial agents, most often vancomycin and/or amphotericin B, had to be added in half of the patients.

Autologous peripheral blood stem cells: collection and processing.

The rapid development in the area of collecting and processing autologous peripheral blood stem cells (PBSC) is reflected by the escalating number of patients treated with PBSC, and by the increasing amount of literature on the subject. Clinical experience suggests that among the variables with a negative influence on mobilization of PBSC, the most important may be the amount of previous stem cell toxic chemotherapy. In selecting patients suitable for autologous PBSC support, the requirement of an adequate anti-tumor therapy has to be weighed against the risk of chemotherapy related stem cell toxicity which will result in inability to collect a sufficient amount of PBSC. The general consensus is that a sufficient PBSC-autograft should contain 2-5 x 10(6) CD34+/kg body weight, but attempts to provide a recommended optimal or threshold level are hampered by the lack of standardized methods for CD34+ cell enumeration. In addition, the time to haematological recovery depends both on the dose of infused CD34+ cells and also on the amount of previous chemotherapy, which affects both the quality of the graft and the supportive microenvironment of the host. The quality of the autograft may also be contaminated by malignant cells, even if the biological significance of tumor cell detection in the PBSC graft has not yet been established. Recent development of methods for in vitro purging and selection of CD34+ cells for clinical use have provided the means to avoid or reduce reinfusion of malignant cells. Future directions of clinical research include the ability to define and enumerate the proportion of stem cells versus committed progenitor cells among the CD34+ cells in a PBSC collection, which will be important to ensure rapid engraftment as well as long term haematopoiesis.

Infections in neutropenic patients. II: Management.

Improvement in supportive care including the introduction of new antibiotics, antiviral and antifungal agents and haematopoietic growth factors have all contributed to a decreased chemotherapy-related mortality and morbidity in cancer patients. However, infection during neutropenia is still a major complication and a great concern for the clinician responsible for the patient. Management of infectious complications in the neutropenic patient is reviewed.

Trimethoprim-sulfamethoxazole plus amikacin versus ceftazidime monotherapy as empirical treatment in patients with neutropenia and fever.

In a prospective randomized comparison, 217 episodes of fever (oral temperature > 38.5 degrees C on 1, or 38.0 degrees C on 2 occasions with a minimum interval of 4 h between recordings) during neutropenia (neutrophil count < 0.5 x 10(9)/I), patients were empirically treated with trimethoprim-sulfamethoxazole plus amikacin (TMP/SMZ plus AMI) or ceftazidime. Successful antibiotic treatment was defined as eradication of all signs, symptoms and microbiological evidence of infection on the primary therapy alone. The overall success rate did not differ between the 2 treatment groups: 31/102 (30%; 21-39%, 95% confidence interval, CI) for TMP/SMZ plus AMI and 41/115 (36%; 27-44%) for ceftazidime (difference 0.06 +/- 0.13, 95% CI). The corresponding numbers for documented infections were 12/50 (24%; 12-36%) and 14/60 (23%; 12-35%), respectively (difference 0.01 +/- 0.16). One patient in the TMP/SMZ plus AMI group and 2 patients in the ceftazidime group died from Gram-negative bacteraemias within 72 h. No other early deaths were observed. Antibiotics were changed due to adverse events in 2 episodes of each treatment group. In conclusion, this study demonstrates that TMP/SMZ plus AMI combination is comparable (i.e. a difference of < 20%) to ceftazidime monotherapy with regard to efficacy and safety in haematological patients with severe neutropenia. Both regimens require frequent modifications, particularly in bacteraemic fever episodes. However, in centres with a low frequency of isolation of Pseudomonas and especially of multi-resistent Pseudomonas strains, TMP/SMZ plus AMI offers an inexpensive alternative for the empirical treatment of febrile neutropenia.

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia.

Serum concentrations of tumour necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr-) bacteraemias after 2 h (TNF-alpha, IL-1ra and IFN-gamma), 4 h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-alpha value was higher in the Gr- group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr+, 14 pg/ml; range 7-60 pg/ml; P < 0.05) and blood culture negative episodes (BCN, 8 pg/ml; range 0-87 pg/ml; P < 0.05). Furthermore, the peak values of TNF-alpha, IL-1ra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the Gr- group in comparison to the Gr+ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.

Infections in neutropenic patients I: aetiology.

Improvement in supportive care including the introduction of new antibiotics, antiviral and antifungal agents and haematopoietic growth factors have all contributed to a decreased chemotherapy-related mortality and morbidity in cancer patients. However, infections/septic shock during neutropenia still constitutes a major threat to these patients. Most patients develop fever during neutropenia and in 20-40% a manifest bacteremia is documented. In patients with prolonged neutropenia, the risk for fungal infections is increased. The spectrum of bacterial, fungal and viral infections in the neutropenic patient is reviewed.

Increase of monocytes predicts mobilization of peripheral stem and progenitor cells after chemotherapy followed by G-CSF administration.

Mobilization of primitive haematopoietic cells to the peripheral blood was studied in 25 patients with haematological malignancies. The optimal level of peripheral stem cells (PSC), defined by their surface expression of CD34, was significantly higher after mobilization with G-CSF, either following chemotherapy or alone (median: 123 x 10(6)/l and 143 x 10(6)/l of CD34+ cells respectively) than without administration of G-CSF subsequent to chemotherapy (median: 27 x 10(6)/l of CD34+ cells). An individual variation in when optimal mobilization of CD34+ cells and myeloid progenitors occurs after chemotherapy and G-CSF administration was noted (median: day 12, range 7-24 days), which makes it difficult to predict when PSC collections in a given patient should be performed. In this study, chemotherapy followed by G-CSF administration resulted in a short lasting (2-3 days) peak appearance of CD34+ cells that could predicted by a 2-fold increase in absolute numbers of monocytes, as compared to the previous day. After the peak level of CD34+ cells in the blood was reached, no further increase in monocytes was seen. The identification of an increase in monocytes, to be used as a predictive variable for when optimal mobilization of PSC will occur in a given patient, may be particularly useful in the individual timing of PSC collections from non-hospitalized patients.