Lepromatous leprosy masquerading as acute sarcoidosis: a case report and literature review.

Leprosy is uncommon in North America. Because it has a prolonged incubation period and can masquerade with a variety of manifestations, many patients with leprosy experience a significant delay in diagnosis and treatment. Lepra reactions are of 2 types: reversal (type 1) and erythema nodosum leprosum (ENL) (type 2). Type 1 or reversal reactions represent an increase in cell-mediated immunity, whereas type 2 or ENL is caused by antigen-antibody complex formation and deposition after antigen release from dying lepra bacilli. This article describes the diagnostic challenges presented by a Minnesota patient eventually found to have lepromatous leprosy. That challenge was compounded by the fact that the clinical scenario closely mimicked connective tissue/immune complex disease and by the fact that the patient presented in a location where the incidence and prevalence of leprosy is extremely low.

A scheme for defining cause of death and its application in the T cell depletion trial.

The primary cause of death (COD) provides important information in many studies of hematopoietic stem cell transplantation (HSCT). A panel of experts critically assessed the CODs submitted by 15 transplantation centers for 281 patients who died in a randomized multicenter trial of unrelated HSCT. The panel reviewed the CODs reported by the transplantation centers, which used the Center for International Blood and Marrow Transplant Research and National Marrow Donor Program COD reporting form. The panel determined that the existing criteria for primary and contributing CODs lacked sufficient stringency for uniform interpretation. A hierarchy was developed and applied to the T cell depletion project. Using its scheme, the panel reclassified 157 CODs (56%) reported by the transplantation centers. The changes resulted in increased recognition of graft-versus-host disease as the primary COD and a concomitant decrease in attribution of the primary COD to infection. This algorithm promotes consistent assignment of primary and contributing CODs for patients with leukemia or lymphoma who expire after myeloablative allogeneic HSCT.

Higher risk of cytomegalovirus and aspergillus infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious complications in patients treated with T cell depletion versus immunosuppressive therapy to prevent graft-versus-host disease.

Serious infections are a major obstacle limiting the usefulness of unrelated donor marrow transplantation. Graft-versus-host disease (GVHD) and its therapy are associated with a high risk of opportunistic infection. In this study, patients were randomized to receive 1 of 2 GVHD prophylaxis strategies, marrow T cell depletion, and cyclosporine (TCD) or methotrexate/cyclosporine (M/C) after transplantation. The patients underwent transplantation between March 1995 and October 2000 as part of a multicenter randomized trial. As a secondary analysis, we analyzed infections in this study cohort. Among the 404 patients who underwent transplantation, a total of 1598 infections were reported. The rates of serious and fatal infections did not differ between the TCD and M/C groups. Bacterial infections accounted for 1/3 of serious infections in each treatment arm. A significantly higher incidence of severe cytomegalovirus (CMV) and life-threatening or fatal aspergillus infections was observed in the patients receiving TCD (CMV, 28% vs 17% [P = .02]; aspergillosis, 16% vs 7% [P < .01]). The only independent risk factor for serious infection was the development of grade III-IV acute GVHD (aGVHD; hazard ratio = 1.41; 95% confidence interval = 1.03-1.91). Strategies to speed immune recovery, even in the absence of GVHD, are needed to overcome the risk of infection after unrelated donor transplantation.

Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources.

Cytomegalovirus (CMV) infection is an important complication following allogeneic hematopoietic stem cell transplant (HSCT), but the natural history in the cord blood setting has not been well studied. We assessed CMV infection episodes in 753 consecutive allogeneic HSCT recipients at the University of Minnesota between January 1, 1998 and December 31, 2003. The 6-month cumulative incidence of viremia/antigenemia was 22% by day +182: 21% (95% confidence interval 16%-26%) in cord blood recipients (UCB), 24% (20%-28%) in marrow (BM), and 22% (16%-28%) using peripheral blood grafts (PBSC). CMV disease incidence was 6% (2%-10%) in UCB, 8% (5%-11%) in BM, and 9% (6%-12%) in PBSC. In multivariate analysis, CMV infection (viremia/antigenemia and disease) was significantly more likely in patients who were seropositive to CMV, in those with acute graft versus host disease, and in those receiving T cell-depleted grafts. Graft source did not independently contribute to the risk of CMV infection and did not impact survival after CMV infection. These data confirm that recipient CMV serostatus remains the dominant risk factor for CMV infection. Recipients of UCB have similar risks of CMV infection, responses to antiviral therapy, and survival following CMV infection as recipients of either marrow or PBSC.

Galactomannan antigen enzyme-linked immunosorbent assay for diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation.

Invasive aspergillosis is difficult to diagnose in patients undergoing hematopoietic stem cell transplantation (HSCT). In 2003, a serum enzyme-linked immunosorbent assay (ELISA) test for the detection of galactomannan (a glycoprotein found on the Aspergillus cell wall) became available in the United States. In 2004, patients undergoing HSCT were screened biweekly with the galactomannan ELISA at our institution. We performed a retrospective chart review of 121 SCT patients who underwent galactomannan testing. Thirteen of the patients (10.7%) had at least 1 positive galactomannan ELISA, and 4 had multiple positive tests. When calculated in reference to a proved or probable diagnosis of aspergillosis, the galactomannan ELISA had a sensitivity of 0.50 and a specificity of 0.94. The positive predictive value was 0.46, and the negative predictive value was 0.94. Galactomannan ELISA had fewer false-positive and false-negative results in pediatric patients than in adult patients. In 4 of the 12 cases of invasive aspergillosis, the galactomannan ELISA was positive before other microbiologic evidence of aspergillosis was available. In these cases, a positive ELISA predated culture and cytologic evidence of invasive aspergillosis by a mean of 5 days (range, 1-8 days). Our findings indicate that a biweekly serum galactomannan ELISA is a highly specific diagnostic tool for detecting invasive aspergillosis in patients undergoing HSCT. When used regularly, the ELISA may allow for earlier diagnosis of invasive aspergillosis in some patients. The test is troubled by a low sensitivity and high frequency of false-negative tests.

Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial.

BACKGROUND: Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. RESULTS: Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. CONCLUSIONS: Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation.

Umbilical cord blood (UCB) is increasingly used as an alternative source of hematopoietic stem cells for transplantation for patients who lack a suitable sibling donor. Despite concerns about a possible increased risk of Epstein-Barr virus (EBV) posttransplantation lymphoproliferative disorder (PTLD) after UCB transplantation, early reports documented rates of PTLD comparable to those reported after HLA-matched unrelated marrow myeloablative (MA) transplantations. To further investigate the incidence of EBV PTLD after UCB transplantation and potential risk factors, we evaluated the incidence of EBV-related complications in 335 patients undergoing UCB transplantation with an MA or nonmyeloablative (NMA) preparative regimen. The incidence of EBV-related complications was a 4.5% overall, 3.3% for MA transplantations, and 7% for NMA transplantations. However, the incidence of EBV-related complications was significantly higher in a subset of patients treated with an NMA preparative regimen that included antithymocyte globulin (ATG) versus those that did not (21% vs 2%; P < .01). Nine of 11 patients who developed EBV PTLD were treated with rituximab (anti-CD20 antibody), with the 5 responders being alive and disease free at a median of 26 months. Use of ATG in recipients of an NMA preparative regimen warrants close monitoring for evidence of EBV reactivation and potentially preemptive therapy with rituximab.

Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.

BACKGROUND: Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA). METHODS: A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel. RESULTS: Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA. CONCLUSIONS: Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups.

Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases.

To evaluate the activity of posaconazole for treatment of zygomycosis, a disease for which therapeutic options are limited, we conducted a retrospective study including 91 patients with zygomycosis (proven zygomycosis, 69 patients; probable zygomycosis, 22 patients). Patients had infection that was refractory to prior antifungal treatment (n=81) or were intolerant of such treatment (n=10) and participated in the compassionate-use posaconazole (800 mg/day) program. The rate of success (i.e., either complete or partial response) at 12 weeks after treatment initiation was 60%, and 21% of patients had stable disease. The overall high success and survival rates reported here provide encouraging data regarding posaconazole as an alternative therapy for zygomycosis.

Role of new antifungal agents in prophylaxis of mycoses in high risk patients.

PURPOSE OF REVIEW: For pancreas, liver, and hematopoietic stem cell transplant recipients, no antifungal prophylaxis led to a high rate of and high morbidity from fungal infection. With the use of fluconazole as prophylaxis since the early 1990s, there have been shifts in the types of infecting fungal pathogens, documentation of resistance among fungal organisms, and changes in transplant practices. The aim of this article is to review recent clinical trials regarding antifungal chemoprophylaxis among several populations of high risk patients. RECENT FINDINGS: Itraconazole, micafungin, and posaconazole have been studied as alternatives to fluconazole prophylaxis. Itraconazole showed no dramatic improvement over fluconazole as prophylaxis during liver and hematopoietic stem cell transplantation, primarily due to gastrointestinal side effects. In addition, detrimental changes to cyclophosphamide metabolism were noted for hematopoietic stem cell transplant recipients. Micafungin was superior to fluconazole during the pre-engraftment period of hematopoietic stem cell transplantation, because it was able to prevent mold infections, required less switches to empirical antifungal therapy, and functioned as well as fluconazole in preventing yeast infections. Posaconazole was compared to fluconazole during a 16-week prophylaxis period during graft-versus-host disease, but results of this study are still forthcoming. Aerosolized amphotericin products appear to be safe for lung transplant recipients. SUMMARY: Fluconazole remains the standard agent for prophylaxis against invasive fungal infections for pancreas, liver, and hematopoietic stem cell transplant recipients. Micafungin is superior to fluconazole with minimal toxicity for use in the pre-engraftment period of hematopoietic stem cell transplantation. The optimal agent for prophylaxis later following transplant, if mold coverage is desired during prolonged immunosuppression, has not been determined.

HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial.

OBJECTIVES: We sought to evaluate the effectiveness of HspE7, a recombinant fusion protein of Hsp65 from Mycobacterium bovis BCG and E7 protein from human papillomavirus 16, to improve the clinical course of pediatric patients with recurrent respiratory papillomatosis. METHODS: An open-label, single-arm intervention study was conducted in 8 university-affiliated medical centers. Twenty-seven male and female patients with recurrent respiratory papillomatosis, ages 2 to 18 years, were enrolled and followed up to 60 weeks. Before enrollment, these patients required surgery on average every 55 days. After a baseline debulking surgery, the patients received HspE7 500 microg subcutaneously monthly, for 3 doses over 60 days. The primary end point was the length of the interval from the last surgery during the treatment period until the first debulking surgery in the posttreatment period, compared with the median intersurgical interval (ISI) of the 4 surgeries before the treatment. RESULTS: The mean of the first posttreatment ISI increased 93% (from 55 days to 106 days; p < .02). The median ISI for all surgeries after treatment was similarly prolonged (mean, 107 days; p < .02), indicating a sustained treatment effect, and was associated with a significant decrease in the number of required surgeries (p < .003). Unexpectedly, the treatment effect was most striking in the 13 female patients, who had statistically significant increases in both the first posttreatment ISI (142%; p < .03) and the median ISI (147%; p < .03). The most common adverse events were mild-to-moderate injection site reactions. CONCLUSIONS: Treatment with HspE7 appears to significantly improve the clinical course in pediatric patients with RRP insofar as it reduces the frequency of required surgeries. These results warrant a confirmatory phase III trial.

Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source.

How the infection risks compare after umbilical cord blood (UCB) and bone marrow (BM) transplantation is not known. Therefore, we compared serious infections in the 2 years after pediatric myeloablative unrelated donor transplantation with unmanipulated BM (n = 52), T cell-depleted (TCD) BM (n = 24), or UCB (n = 60) for the treatment of hematologic malignancy. Overall, the cumulative incidence of 1 or more serious infections was comparable between groups (BM, 81%; TCD, 83%; UCB, 90%; P = .12). Furthermore, by taking all serious infections into account and using multivariate techniques with unmanipulated BM as the reference, there were also no significant differences between groups (TCD relative risk [RR], 1.6; P = .10; UCB RR, 1.0; P = .84). Within the time periods days 0 to 42, days 43 to 100, and days 101 to 180, the only difference was a greater risk of viral infections from days 0 to 42 in TCD recipients (RR, 3.5; P = .02). Notably, after day 180, TCD recipients had a significantly increased infection risk (RR, 3.1; P = .03), whereas the risk in UCB recipients (RR, 0.5; P = .23) was comparable to that in BM recipients. Other factors associated with an increased infection risk in the 2 years after transplantation were age > or = 8 years, graft failure, and severe acute graft-versus-host disease. These data suggest that the risk of serious infection after pediatric UCB transplantation is comparable to that with unmanipulated BM.

Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation.

We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm [difference, 6.5%]; 95% confidence interval, 0.9%-12%; P=.03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.

Genetic diversity of human pathogenic members of the Fusarium oxysporum complex inferred from multilocus DNA sequence data and amplified fragment length polymorphism analyses: evidence for the recent dispersion of a geographically widespread clonal lineage and nosocomial origin.

Fusarium oxysporum is a phylogenetically diverse monophyletic complex of filamentous ascomycetous fungi that are responsible for localized and disseminated life-threatening opportunistic infections in immunocompetent and severely neutropenic patients, respectively. Although members of this complex were isolated from patients during a pseudoepidemic in San Antonio, Tex., and from patients and the water system in a Houston, Tex., hospital during the 1990s, little is known about their genetic relatedness and population structure. This study was conducted to investigate the global genetic diversity and population biology of a comprehensive set of clinically important members of the F. oxysporum complex, focusing on the 33 isolates from patients at the San Antonio hospital and on strains isolated in the United States from the water systems of geographically distant hospitals in Texas, Maryland, and Washington, which were suspected as reservoirs of nosocomial fusariosis. In all, 18 environmental isolates and 88 isolates from patients spanning four continents were genotyped. The major finding of this study, based on concordant results from phylogenetic analyses of multilocus DNA sequence data and amplified fragment length polymorphisms, is that a recently dispersed, geographically widespread clonal lineage is responsible for over 70% of all clinical isolates investigated, including all of those associated with the pseudoepidemic in San Antonio. Moreover, strains of the clonal lineage recovered from patients were conclusively shown to genetically match those isolated from the hospital water systems of three U.S. hospitals, providing support for the hypothesis that hospitals may serve as a reservoir for nosocomial fusarial infections.

Specific detection of human BK polyomavirus in urine samples of immunocompromised patients.

A semiquantitative PCR assay for the detection of BK virus in urine was developed using primers for BK virus that specifically amplified BK but not JC virus. DNA was extracted from urine through treatment with proteinase K followed by DNA precipitation with sodium acetate. Semiquantitation was achieved by amplifying serial dilutions (1:1, 1:10, 1:100, and 1:1,000) of the urine specimens. Each assay included both positive (stock BK virus and previously positive patient urine) and negative (no template) controls. A urine sample was interpreted as positive if any of the serial dilutions showed amplification of the DNA fragment of the expected size. For some patient-derived samples, amplification of the expected-size fragment was achieved with a dilute template whereas no amplification was achieved with a concentrated template. This was attributed to interfering substances in the urine. PCR results were compared with urine cytology and shown to be more sensitive. Validation studies were performed at the University of Nebraska Medical Center, utilizing a separate qualitative PCR assay that detects both BK and JC virus and distinguishes between them by restriction enzyme digestion patterns. Of 46 urine samples analyzed using both methods, 22 were positive by both assays, 18 were negative by both assays, 5 were positive only by the Nebraska method, and 1 was positive only by our method. In comparison with the Nebraska PCR, our PCR assay had a sensitivity of 81% and specificity of 95%. For twenty-one (43%) of 49 immunocompromised patients, tests were positive when specimens were submitted because of clinical suspicion of BK virus infection.