Diagnostic efficacy and safety of computed tomography-guided transthoracic needle biopsy in patients with hematologic malignancies.

RATIONALE AND OBJECTIVES: The role of transthoracic needle biopsy (TTNB) in patients with hematologic malignancies, particularly in discriminating between malignant and benign etiologies, has not been well studied. Hence, the diagnostic efficacy and safety of computed tomography-guided TTNB were retrospectively evaluated in this population. MATERIALS AND METHODS: The records of 53 patients with hematologic malignancies who underwent TTNB from August 1, 1999, to July 31, 2007, were reviewed. Potential factors for increased diagnostic yield and risk for complications were collected and analyzed, including the status of neutropenia, thrombocytopenia, chemotherapy, and transplant as well as lesion size and location. Both cytopathologic and microbiologic results were assessed. RESULTS: The most common underlying hematologic malignancy was non-Hodgkin lymphoma, in 20 patients (37.7%). Lesions were most frequently located in the left upper lobe (16 [30.2%]); 33 lesions were pleural based (63.5%), and nine had cavitation (17.0%). TTNB established specific diagnoses in 22 patients (41.5%): malignancies was found in 12 (22.6%) and infections in 10 (18.9%). Sensitivity for detecting malignancy was 50.0%, and sensitivity for the detection of a specific infection was 40.0%. There were no false-positive results. Complications occurred in nine patients (17.0%): self-limited small-volume hemoptysis in one patient (1.9%) and pneumothorax in eight patients (15.1%), one requiring chest tube placement. The results of TTNB led to changes in antimicrobial therapy for eight of the 22 patients with specific diagnoses (36.4%). CONCLUSIONS: TTNB is a safe diagnostic procedure in patients with hematologic malignancies and has the potential of making specific diagnoses with minimal morbidity.

The pathogenesis and clinical management of cytomegalovirus infection in the organ transplant recipient: the end of the 'silo hypothesis'.

PURPOSE OF REVIEW: Cytomegalovirus infection is initiated when tumor necrosis factor binds to the cytomegalovirus receptors of latently infected cells, resulting in the reactivation of the virus and the production of clinical disease of two types: direct infection causing pneumonia, mononucleosis, colitis and other viral-related syndromes, and indirect infection in which an array of cytokines are released by the host that produce much the same effect as does the rejection process. RECENT FINDINGS: These effects fall into three categories: allograft injury, an increase in superinfection with opportunistic pathogens and an increase in the incidence of B cell lymphoproliferative disease. Other factors that modulate the clinical impact of reactivated cytomegalovirus in the transplant patient include the past experience of the host with the virus (primary infection, donor seropositive and recipient seronegative), the degree of major histocompatibility complex mismatch, the viral burden and the amount of calcineurin inhibitor the patient receives. SUMMARY: Optimal therapy for diagnosing, treating and preventing these indirect effects still remains to be defined; the direct effects, in contrast, are well managed with valganciclovir.

Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign.

BACKGROUND: Computed tomography (CT) of the chest may be used to identify the halo sign, a macronodule surrounded by a perimeter of ground-glass opacity, which is an early sign of invasive pulmonary aspergillosis (IPA). This study analyzed chest CT findings at presentation from a large series of patients with IPA, to assess the prevalence of these imaging findings and to evaluate the clinical utility of the halo sign for early identification of this potentially life-threatening infection. METHODS: Baseline chest CT imaging findings from 235 patients with IPA who participated in a previously published study were systematically analyzed. To evaluate the clinical utility of the halo sign for the early identification and treatment of IPA, we compared response to treatment and survival after 12 weeks of treatment in 143 patients who presented with a halo sign and in 79 patients with other imaging findings. RESULTS: At presentation, most patients (94%) had > or =1 macronodules, and many (61%) also had halo signs. Other imaging findings at presentation, including consolidations (30%), infarct-shaped nodules (27%), cavitary lesions (20%), and air-crescent signs (10%), were less common. Patients presenting with a halo sign had significantly better responses to treatment (52% vs. 29%; P<.001) and greater survival to 84 days (71% vs. 53%; P<.01) than did patients who presented with other imaging findings. CONCLUSIONS: Most patients presented with a halo sign and/or a macronodule in this large imaging study of IPA. Initiation of antifungal treatment on the basis of the identification of a halo sign by chest CT is associated with a significantly better response to treatment and improved survival.

Surgical wound infection: epidemiology, pathogenesis, diagnosis and management.

Surgical wound infection remains a significant problem following an operation, although surveillance for such infections remains a challenge exacerbated by early discharge and outpatient surgery. The risk of such infections is determined by technical problems with the operation, particularly bleeding, the amount of devitalized tissue created, and the need for drains within the wound, as well as such metabolic factors as obesity and diabetes. Perioperative antibiotic prophylaxis can decrease the incidence of such infections further, but a technically perfect operation is even more important.

Opportunities and challenges for clinical and cardiovascular research in Latin America.

Latin America in the past two decades has increasingly become a significant contributor of clinical research. The future capacity of clinical and specifically cardiovascular research has the potential to positively affect human health in the region and foster economic growth. However, the challenges of conducting clinical research in Latin America include a need for logistical support from local governments, continued commitment to education of physicians and ethics committees, and creation of oversight bodies to guarantee the highest quality of research. Bibliometric analyses were conducted to assess trends in clinical research. Latin American investigators demonstrated a tendency to publish clinical results in local and regional journals. The region offers many opportunities for clinical research including large treatment-naive patient populations and most importantly motivated investigators capable of producing high-quality results. Strategies to foster clinical research in Latin America must be based on development of a positive regulatory environment, leveraged protection of intellectual property, creation of alliances between private and public sectors with incentives for investment in science and technology, and finally focus on areas of clinical expertise such as cardiovascular disease, epidemiology, gastroenterology, and infectious diseases. Fostering the creation of research alliances across and between continents will help in establishing the supportive environment for dissemination of important ethical clinical research in the region.

The prevention of infection post-transplant: the role of prophylaxis, preemptive and empiric therapy.

The close linkage of infection with the nature and intensity of the transplant immunosuppressive program has led to the concept of the therapeutic prescription. This has two components: an immunosuppressive one to prevent or treat rejection and graft-versus-host disease and an antimicrobial one to make it safe. This review provides a conceptual framework to approach the risk and risk periods for infection in solid organ and hematopoietic stem cell transplant recipients as well as an approach to antimicrobial use in this population.

Strategy of following voriconazole versus amphotericin B therapy with other licensed antifungal therapy for primary treatment of invasive aspergillosis: impact of other therapies on outcome.

BACKGROUND: In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis. METHODS: Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed. RESULTS: Fewer patients in the voriconazole group (52 [36%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P<.001). CONCLUSIONS: This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis.

The hepatotoxicity of antifungal medications in bone marrow transplant recipients.

BACKGROUND: Systemic antifungal medications can be lifesaving but can also have important toxicities. With a number of new antifungal drugs being introduced, there is a compelling need to define the toxicities associated with existing therapies. METHODS: We identified cases of hepatotoxicity among patients who underwent bone marrow transplantation and selected matched control subjects from the same population. Multivariable logistic regression modeling was used to control for patient characteristics in evaluating the relationship between hepatotoxicity and exposure to antifungal medications. Follow-up analyses were performed for patients who continued receiving antifungal medications after developing hepatotoxicity. RESULTS: The unadjusted incidence of hepatotoxicity was 0.78 cases per 100 patient-days of exposure to amphotericin deoxycholate, 0.98 for fluconazole, and 1.50 for liposomal amphotericin B. Case-control analyses found that liposomal amphotericin B was associated with a substantial increase in the risk of hepatotoxicity in these patients (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.61-6.88); a smaller increase in risk was found for fluconazole (OR, 1.99; 95% CI, 1.21-3.26). There was no statistically significant association between amphotericin B deoxycholate and the development of hepatotoxicity. Patients had greater elevations of serum transaminase values associated with exposure to larger cumulative doses of liposomal amphotericin B. In the follow-up analysis of patients who developed hepatotoxicity and who continued receiving antifungal medication, one-third of those receiving liposomal amphotericin B had marked increases in bilirubin levels, as opposed to 8% of patients treated with fluconazole. CONCLUSIONS: In these bone marrow transplant recipients, liposomal amphotericin B and fluconazole were both associated with increased risk of hepatotoxicity, independent of other treatments received or patient characteristics; the magnitude of the risk was larger for liposomal amphotericin B. Patients who develop hepatotoxicity appear to tolerate continued therapy with fluconazole, but a large fraction of those who received liposomal amphotericin B have worsening conditions with continued treatment.

Prevention and treatment of cytomegalovirus infection in solid organ transplant recipients.

PURPOSE OF REVIEW: Cytomegalovirus remains the single most important pathogen affecting solid organ transplant recipients. Its importance lies both in its effects and as a model for deciphering the clinical impact and management of other agents such as hepatitis C virus and other herpes viruses such as human herpes virus-6 and 7. The effects of cytomegalovirus infection in these patients can be divided into two categories: the direct causation of a wide variety of infectious disease syndromes; and the indirect effects, which include contributing to the net state of immunosuppression, allograft injury, and potentiating posttransplant lymphoproliferative disease. RECENT FINDINGS: The advent of valganciclovir, with its excellent oral bioavailability, combined with intravenous ganciclovir have provided powerful tools for controlling the direct effects of cytomegalovirus, particularly with the recognition that the intensity of the antiviral therapy has to be linked to the intensity of the immunosuppression required.Unfortunately, far less is known about the efficacy of antiviral therapy in managing the indirect effects of cytomegalovirus. Preliminary data suggest antiviral prophylaxis protects against acute allograft injury, as well as decreasing the incidence of some opportunistic infection. SUMMARY: A great deal of progress has been made in the prevention and treatment of the infectious disease syndromes caused by cytomegalovirus, with the development of the concept of the therapeutic prescription. This has two components: an immunosuppressive component to prevent and treat rejection and an antimicrobial component to make it safe. Much more information, however, is required.

Preparation and pharmacokinetics of 11C labeled stavudine (d4T).

Stavudine, a potent antiviral agent for treating human immunodeficiency virus (HIV) infections, was radiolabeled with (11)C by methylation of a specifically designed precursor, 5'-O-(2-tetrahydropyranyl)-5-bromo-2',3'-didehydro-3'-deoxythymidine, with (11)C H(3)I. The radiolabeled drug was isolated by reverse phase HPLC. A total time of approximately 45 minutes was required for synthesis, purification and isolation of (11)C stavudine with chemical and radiochemical purities of greater than 98%. (11)C stavudine was combined with unlabeled drug (2.0 mg/kg) and used to study its pharmacokinetics in rats by measurement of radioactivity in excised tissues. In this species, there was rapid accumulation of drug in all tissue. In all tissues, with the exceptions of testis and brain, highest concentrations of drug were detected at 5 minutes after injection and decreased monotonically thereafter. The peak concentration (microg/g) of stavudine in blood was 1.78 +/- 0.16 and similar levels were achieved in most other tissues; heart 1.66 +/- 0.11, lung 1.60 +/- 0.15, liver 2.13 +/- 0.17, spleen 1.61 +/- 0.15, adrenal 1.47 +/- 0.20, stomach 1.40 +/- 0.11, GI tract 1.44 +/- 0.14, skeletal muscle 1.38 +/- 0.15 and bone 1.30 +/- 0.16. Much higher peak concentrations were achieved in kidney; 7.23 +/- 0.57 microg/g. Concentrations in testis were lower and remained relatively constant over 1 hour; peak 0.62 +/- 0.14 microg/g at 15 min Brain concentrations were low but increased monotonically over time; peak 0.26 +/- 0.02 microg/g at 60 min. Future PET studies with this radiopharmaceutical will allow in vivo measurements of the pharmacokinetics of stavudine in both animal models and human subjects.

A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Smallpox vaccination and the patient with an organ transplant.

Organ transplant recipients are vulnerable to a variety of infections because of the immunosuppressed state required to prevent organ rejection. We review the recommendations of the Centers for Disease Control and Prevention (Atlanta, Georgia) for smallpox vaccination and the possible complications of vaccination in the population with organ transplants. The risk of these complications is presumably dependent on the extent of deficient cell-mediated immunity.

Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.

BACKGROUND: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. METHODS: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. RESULTS: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients). CONCLUSIONS: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B.