Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection.

Ganciclovir-resistant cytomegalovirus (CMV) infection is an emerging problem in transplant recipients. Foscarnet resistance and cidofovir resistance have also been described, but no previous reports have suggested treatment regimens for patients with CMV refractory to all three of these drugs. Leflunomide, an immunosuppressive drug used in rheumatoid arthritis and in rejection in solid-organ transplantation, has been reported to have novel anti-CMV activity. However, its clinical utility in CMV treatment has not been described previously. We report an allogeneic bone marrow transplant recipient who developed CMV infection refractory to sequential therapy with ganciclovir, foscarnet, and cidofovir. The patient was ultimately treated with a combination of leflunomide and foscarnet. Both phenotypic and genotypic virologic analysis was performed on sequential CMV isolates. The patient's high CMV-DNA viral load became undetectable on leflunomide and foscarnet, but the patient, who had severe graft-versus-host disease (GVHD) of the liver, expired with progressive liver failure and other complications. We concluded that leflunomide is a new immunosuppressive agent with anti-CMV activity, which may be useful in the treatment of multiresistant CMV. However, the toxicity profile of leflunomide in patients with underlying GVHD remains to be defined.

The efficacy of prophylactic outpatient antibiotics for the prevention of neutropenic fever associated with high-dose etoposide (VP-16) for stem cell mobilization.

High-dose etoposide (2 g/m(2)) plus G-CSF is a very effective regimen for peripheral blood progenitor cell (PBPC) mobilization. Unfortunately, neutropenia is common. The infectious complications associated with high-dose etoposide have not been previously described. After noting a high incidence of hospitalizations for neutropenic fever, we began a vigorous prophylactic antibiotic regimen for patients receiving high-dose etoposide plus G-CSF, attempting to reduce infectious complications. Ninety-eight patients underwent etoposide mobilization between December 1997 and June 2000. Three chronological patient groups received: (1) no specific antibiotic prophylaxis (n = 44); (2) vancomycin i.v., cefepime i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27); and (3) vancomycin i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27). The patients not receiving antibiotic prophylaxis had a 68% incidence of hospitalization for neutropenic fever. In the patients receiving prophylaxis, the incidence was reduced to 26% and 15% respectively, for an overall incidence of 20% (P < 0.001 for comparison between prophylaxed and unprophylaxed groups). We conclude that etoposide mobilization is associated with a significant incidence of neutropenic fever, which can be substantially reduced by a vigorous antimicrobial prophylactic program.

Clinical characteristics of 13 solid organ transplant recipients with ganciclovir-resistant cytomegalovirus infection.

BACKGROUND: Ganciclovir-resistant (GCV-R) cytomegalovirus (CMV) is now being reported with increasing frequency in solid organ transplant recipients. OBJECTIVE: To describe the clinical characteristics and outcomes of all solid organ transplant patients with GCV-R CMV seen between 1990 and 2000 at a single center. METHODS: Patients with clinically suspected GCV resistance had viral isolates subjected to phenotypic analysis by plaque reduction assay, and also genotypic analysis. Medical records of the 13 patients with GCV-R CMV were reviewed for demographic, microbiologic, clinical, and pathologic data. RESULTS: Thirteen patients were identified, including 5 kidney, 1 heart, and 7 lung transplant recipients. All but one patient (92%) were CMV donor seropositive, recipient negative (D+/R-), and 11/13 (85%) had tissue-invasive CMV. CMV viremia was recurrent in 9/13 (69%); in 2 others, the first CMV episode was fatal. Overall, 9/13 (69%) of patients have died, all of CMV or its complications. Of the 10 who received foscarnet, only one survived. All patients had received GCV-based prophylactic regimens; 8/13 patients (62%) had received CMV hyperimmune globulin (CMVIG) as part of prophylaxis, 6/13 (46%) had received oral ganciclovir, and 5/13 (38%) had received intermittent (3 x/week) IV ganciclovir for prophylaxis. CONCLUSIONS: GCV-R CMV is associated with CMV D+/R- status, tissue-invasive disease, and high mortality even with foscarnet therapy. Exposure to less than fully therapeutic levels of GCV, in the form of oral or intermittent IV GCV, is common. The use of CMVIG in prophylaxis does not appear to prevent resistance. Further work remains to be done to elucidate the risk factors and optimal mode of prophylaxis and treatment for GCV-R CMV.

The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants.

BACKGROUND: Invasive aspergillosis (IA) is associated with significant morbidity and mortality in solid organ transplant recipients but data on the incidence rates stratified by type of solid organ are limited. OBJECTIVE: To describe the attack rates and incidence of IA in solid organ transplant recipients, and the impact of universal Aspergillus prophylaxis (aerosolized amphotericin B or oral itraconazole) in lung transplant recipients. PATIENTS: The 2,046 patients who received solid organ transplants at the Cleveland Clinic Foundation from January 1990 through 1999 were studied. METHODS: Cases were ascertained through computerized records of microbiology, cytology, and pathology reports. Definite IA was defined as a positive culture and pathology showing septate hyphae. Probable IA was clinical disease and either a positive culture or histopathology. Disseminated IA was defined as involvement of two or more noncontiguous anatomic sites. RESULTS: We identified 33 cases of IA (28% disseminated) in 2,046 patients (attack rate = 1.6%) for an incidence of 4.8 cases per 1,000 patient-years (33 cases/6,813 pt-years). Both the attack and the incidence rates were significantly higher for lung transplant recipients vs. other transplant recipients: lung 12.8% (24 cases/188 patients) or 40.5 cases/1,000-pt year vs. heart 0.4% (3/686) or 1.4 per 1,000-pt year vs. liver 0.7% (3/439) or 2.1 per 1,000-pt year vs. renal 0.4% (3/733) or 1.2 per 1,000-pt year (P < 0.01). The incidence of IA was highest during the first year after transplantation for all categories, but cases occurred after the first year of transplantation only in lung transplant recipients. The attack rate of IA in lung transplant recipients was significantly lower after institution of routine Aspergillus prophylaxis (4.9% vs. 18.2%, P < 0.05). CONCLUSIONS: The highest incidence and attack rate of invasive aspergillosis among solid organ transplant recipients occurs in lung transplant recipients and supports the routine use of Aspergillus prophylaxis for at least one year after transplantation in this group.

Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond.

This review presents evidence-based guidelines for the prevention of infection after blood and marrow transplantation. Recommendations apply to all myeloablative transplants regardless of recipient (adult or child), type (allogeneic or autologous) or source (peripheral blood, marrow or cord blood) of transplant. In Section I, Dr. Dykewicz describes the methods used to rate the strength and quality of published evidence supporting these recommendations and details the two dozen scholarly societies and federal agencies involved in the genesis and review of the guidelines. In Section II, Dr. Longworth presents recommendations for hospital infection control. Hand hygiene, room ventilation, health care worker and visitor policies are detailed along with guidelines for control of specific nosocomial and community-acquired pathogens. In Section III, Dr. Boeckh details effective practices to prevent viral diseases. Leukocyte-depleted blood is recommended for cytomegalovirus (CMV) seronegative allografts, while ganciclovir given as prophylaxis or preemptive therapy based on pp65 antigenemia or DNA assays is advised for individuals at risk for CMV. Guidelines for preventing varicella-zoster virus (VZV), herpes simplex virus (HSV) and community respiratory virus infections are also presented. In Section IV, Drs. Baden and Rubin review means to prevent invasive fungal infections. Hospital design and policy can reduce exposure to air contaminated with fungal spores and fluconazole prophylaxis at 400 mg/day reduces invasive yeast infection. In Section V, Dr. Sepkowitz details effective clinical practices to reduce or prevent bacterial or protozoal disease after transplantation. In Section VI, Dr. Sullivan reviews vaccine-preventable infections and guidelines for active and passive immunizations for stem cell transplant recipients, family members and health care workers.

Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation.

Nonmyeloablative peripheral blood stem cell transplantation (PBSCT) is a novel therapeutic strategy for patients with malignant and non-malignant hematologic diseases. Infectious complications of this procedure have not been previously well described. Data on 12 patients transplanted at a tertiary care center were collected prospectively and verified retrospectively. Neutropenia developed in a third of patients, lasting for a median of 5 days. All patients developed some degree of graft-versus-host disease, as intended. Most patients achieved full chimerism by week 5. Bacterial infections occurred in two patients (17%). Cytomegalovirus (CMV) viremia occurred in five patients (42%) at a median of 80 days; none had received CMV prophylaxis. Viremia was associated with fever and fatigue in three patients, possible gastrointestinal involvement in one patient and was asymptomatic in one patient. All viremic patients responded to intravenous ganciclovir therapy. No fungal infections were documented. No patients died as a result of infection. The incidence of CMV viremia in our patients was high, but the incidence of invasive disease due to CMV was low. The best strategy to prevent CMV in patients undergoing nonmyeloablative PBSCT remains to be determined, but strategies employed in traditional allogeneic bone marrow transplantation should be considered in these patients.

Microbial drug resistance and the roles of the new antibiotics.

Physicians should be cautious in prescribing broad-spectrum antibiotics, particularly vancomycin and the fluoroquinolones, because widespread use of these drugs is promoting antibiotic resistance. Resistance is now found in many organisms, including staphylococci, enterococci, streptococci, pneumococci, and Pseudomonas aeruginosa. Some resistant strains can be treated with alternative narrower-spectrum antibiotics. In addition, five newly licensed antibiotics are available, but they should be used judiciously because of their side effects, high cost, and ability to promote additional resistance.

Infectious complications of advanced cancer.

We present a retrospective study of the frequency, pattern, and management of infections in advanced cancer. Three hundred ninety-three patients were admitted to an acute care palliative medicine unit in an 8-month period for evaluation and palliation of cancer-related symptoms and complications. One hundred fifteen had at least one positive bacteriological culture, and 100 of these patients were evaluable. One hundred fifty-two infections and 192 isolates were identified. Sixty-eight patients had polymicrobial infections. Sixty-six patients had urinary tract infections. Forty-one were found to have multisystemic infections. Eighty-one had invasive devices; 32 had more than one invasive device. Fifty-three were taking corticosteroids at the time of infection. Only 3 were neutropenic. Urinary tract infections were significantly more common in those taking corticosteroids. The median duration of antibiotic treatment was 11 days and the median hospital stay, 14 days. Twenty-eight patients died in the hospital; 10 of those who died had lung cancer, which was a statistically significant observation. In conclusion, infections are an underrecognized but common complication in nonneutropenic hospitalized patients with advanced solid tumors. Urinary tract infections appear to be associated with the use of corticosteroids. Lung cancer patients are at greater risk for fatal infections. Infections increase morbidity in debilitated patients with solid tumors, are a frequent cause of hospital admission, and are associated with significant mortality.

Diagnosis and management of infections involving implantable electrophysiologic cardiac devices.

BACKGROUND: Optimal treatment of infections related to implantable electrophysiologic cardiac devices is poorly defined. OBJECTIVE: To describe the clinical presentation, treatment, and outcome of patients with such infections. DESIGN: Retrospective case series. SETTING: The Cleveland Clinic Foundation, Cleveland, Ohio. PATIENTS: 123 patients with infections involving implantable cardiac electrophysiologic devices. MEASUREMENTS: Demographic characteristics, clinical manifestations, time to diagnosis, management, and outcome. RESULTS: 87 patients with permanent pacemakers and 36 patients with implantable cardioverter defibrillators had infections. The most common signs and symptoms were pocket erythema and local pain. The most common pathogens were coagulase-negative staphylococci (68%) and Staphylococcus aureus (23%). In 117 patients (95%), all equipment was extracted and antibiotic therapy lasted a median of 28 days. Operative mortality was zero. Follow-up showed crude mortality and relapse rates of 8% and 3%, respectively. CONCLUSION: For infections related to implantable electrophysiologic devices, complete device removal and antimicrobial therapy allow timely, successful reimplantation at a remote anatomic site without substantial risk for operative mortality or recurrent infection.

A survey of allogeneic bone marrow transplant programs in the United States regarding cytomegalovirus prophylaxis and pre-emptive therapy.

Despite an extensive literature, no consensus has emerged regarding the optimal preventive strategy for CMV in allogeneic bone marrow transplantation (BMT). No survey of CMV prevention in BMT centers in the United States has yet been published. A questionnaire was sent to all allogeneic BMT programs in the United States, as listed in the November 1998 National Marrow Donor Program (NMDP) address roster. Questions included whether universal prophylaxis, pre-emptive therapy, or some other strategy was used for CMV prevention, and which CMV diagnostic tests were utilized. Eighty-one of 96 programs (86%) responded to the survey. Of these, 46 (56%) utilize a pre-emptive ganciclovir strategy, whereas 17 (21%) utilize universal prophylaxis, and 15 (19%) utilize a hybrid strategy based on risk stratification. The most commonly utilized CMV diagnostic tests are CMV-DNA by PCR (55 centers), shell vial centrifugation culture (52), tissue culture (42), pp65 antigenemia assay (38), and CMV-DNA by Digene hybrid capture (14). Of these, the CMV-DNA by PCR, pp65 antigenemia assay, and shell vial culture are the most frequently utilized as triggers for pre-emptive therapy. Quantitative assays are common (PCR 42%, Digene 64%). We conclude that centers currently performing allogeneic BMT in the United States employ a variety of strategies for CMV prevention, and differ in their diagnostic tests of choice for CMV monitoring. These results emphasize the need for large-scale studies to identify optimal diagnostic and management protocols. Bone Marrow Transplantation (2000) 26, 763-767.

Early onset prosthetic valve endocarditis: the Cleveland Clinic experience 1992-1997.

BACKGROUND: We reviewed all cases of early onset prosthetic valve endocarditis (EO-PVE) occurring less than 12 months after valve operation among 7,043 patients undergoing heart valve replacements or repairs at The Cleveland Clinic between 1992 and 1997. METHODS: Cases were defined by the Duke criteria and identified through prospective surveillance. RESULTS: Seventy-seven cases of EO-PVE were identified (1 per 100 procedures), and during the study period the incidence of EO-PVE decreased from 1.5% (1992 to 1994) to 0.7% (1995 to 1997) (p < 0.01). The incidence of EO-PVE for rings (0.2%; 4 of 1,992) was significantly lower than for mechanical (1.6%; 28 of 1,731) and bioprosthetic valves (1.1%; 41 of 3,320) (p < 0.001). The incidence of EO-PVE was also significantly lower for mitral valve versus aortic valve surgeries (0.6% versus 1.4%, p < 0.001). The most common pathogens causing EO-PVE were coagulase-negative staphylococci (52%), fungi (13%), Staphylococcus aureus (10%), and enterococci (8%). Patients undergoing combined surgical and medical treatment of EO-PVE had a significantly higher 30-day, 2-year, and 3-year survival than medically treated patients, although patients judged to be too ill to survive surgery accounted for two-thirds of the patients treated medically. CONCLUSIONS: There is a 1% incidence rate of EO-PVE among patients undergoing valve operations at our institution, usually caused by coagulase-negative staphylococci, and combined surgical and medical treatment is associated with improved survival compared with medical treatment alone.

Successful lecturing: a prospective study to validate attributes of the effective medical lecture.

OBJECTIVE: In a study conducted over 3 large symposia on intensive review of internal medicine, we previously assessed the features that were most important to course participants in evaluating the quality of a lecture. In this study, we attempt to validate these observations by assessing prospectively the extent to which ratings of specific lecture features would predict the overall evaluation of lectures. MEASUREMENTS AND MAIN RESULTS: After each lecture, 143 to 355 course participants rated the overall lecture quality of 69 speakers involved in a large symposium on intensive review of internal medicine. In addition, 7 selected participants and the course directors rated specific lecture features and overall quality for each speaker. The relations among the variables were assessed through Pearson correlation coefficients and cluster analysis. Regression analysis was performed to determine which features would predict the overall lecture quality ratings. The features that most highly correlated with ratings of overall lecture quality were the speaker's abilities to identify key points (r =.797) and be engaging (r =.782), the lecture clarity (r =.754), and the slide comprehensibility (r =.691) and format (r =.660). The three lecture features of engaging the audience, lecture clarity, and using a case-based format were identified through regression as the strongest predictors of overall lecture quality ratings (R2 = 0.67, P = 0.0001). CONCLUSIONS: We have identified core lecture features that positively affect the success of the lecture. We believe our findings are useful for lecturers wanting to improve their effectiveness and for educators who design continuing medical education curricula.

Antiphospholipid antibody syndrome in a patient with neurosarcoidosis.

The case of a 56-year-old woman who developed neurosarcoidosis and was discovered to have inferior vena cava and lower extremity thromboses is described. She was found to have anticardiolipin antibodies. This newly described association of antiphospholipid antibody syndrome with sarcoidosis is discussed and the relevant literature reviewed.

Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued?

Solid organ transplant recipients are at risk for Pneumocystis carinii pneumonia (PCP), but the risk of PCP beyond 1 year is poorly defined. We identified 25 cases of PCP in 1,299 patients undergoing solid organ transplantation between 1987 and 1996 at The Cleveland Clinic Foundation (4.8 cases per 1,000 person transplant-years [PTY]). Ten (36%) of 28 PCP cases (transplantation was performed before 1987 in three cases) occurred > or = 1 year after transplantation, and no patient developed PCP while receiving prophylaxis for PCP. The incidence of PCP during the first year following transplantation was eight times higher than that during subsequent years. The highest rate occurred among lung transplant recipients (22 cases per 1,000 PTY), for whom the incidence did not decline beyond the first year of transplantation. We conclude that the incidence of PCP is highest during the first year after transplantation and differs by type of solid organ transplant. Extending the duration of PCP prophylaxis beyond 1 year may be warranted for lung transplant recipients.

Evolving concepts in the management of patients with neutropenia and fever.

Much has changed in the treatment of patients with fever and neutropenia, including the patterns of microbial flora and drug resistance and the drugs used. More patients now have indwelling central venous catheters, exposing them to new types of infections. This article reviews the recent treatment guidelines published by the Infectious Diseases Society of America.

Routine cultures of bone marrow and peripheral stem cell harvests: clinical impact, cost analysis, and review.

The American Association of Blood Banks requires routine culture of hematopoietic progenitor cells prior to bone marrow transplantation. We sought to evaluate the cost of that requirement and the incidence and clinical significance of positive cultures. We performed a retrospective analysis of transplant recipients at our institution. Of the 605 patients for whom 1,934 consecutive cultures of harvests were done between December 1992 and February 1996, 11 had positive cultures. Six patients received a culture-positive harvest with no adverse effects. The total cost of cultures was $35,660 (U.S. $). In North America and worldwide in 1995, routine culture of harvests would have prevented 7.9 and 18.9 cases of bacteremia, respectively, at a cost of $95,000 per bacteremia prevented. We conclude that routine culture of hematopoietic progenitor cells yields low rates of positivity and that infusion of contaminated harvests rarely results in clinically adverse outcomes.