Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

Modulation of Tumor-Treating Fields by Cerebral Edema from Brain Tumors.

Purpose: Cerebral edema is an important component of brain metastasis, and its presence may alter the distribution of tumor-treating fields (TTFields). We therefore performed a computational study to model the extent of this alteration according to various edema conditions associated with the metastasis. Methods and Materials: Postacquisition magnetic resonance imaging data sets were obtained from 2 patients with solitary brain metastases from non-small cell lung cancer. After delineation of various anatomies, a 3-dimensional finite element mesh model was generated and then solved for the distribution of applied electric fields, rate of energy deposition, and current density at the gross tumor volume (GTV), edema, and other cranial structures. Electric field-volume histograms, specific absorption rate-volume histograms, and current density-volume histograms were generated, by which plan quality metrics were derived from and used to evaluate relative differences in field coverage between models under various conditions. Results: Changes in the conductivity of cerebral edema altered the electric fields, rate of energy deposition, and current density at the GTV region. At the cerebral edema region, increasing electric conductivity of the edema only decreased the electric fields and rate of energy deposition while the current density increased. The ratio of edema-to-tumor is also important because the plan quality metrics increased linearly when the edema-to-GTV ratio decreased, and increased vice versa. Furthermore, a conductive necrotic core additionally altered the distribution of TTFields according to the plan quality metrics. Conclusions: Our modeling study demonstrated that cerebral edema alters the distribution of applied TTFields in patients. Personalized treatment planning will need to take into account the modulating effects of cerebral edema on TTFields as well as additional effects from a necrotic core inside the GTV.

Low incidence of invasive fungal disease following CD19 chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma.

CAR T-cell therapy has revolutionized the treatment of hematologic malignancies, although its use may be complicated by toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Invasive fungal disease (IFD) has been reported after CAR T-cell therapy, but the incidence in the absence of antifungal prophylaxis is unknown. Optimal prophylaxis strategies are widely debated. We performed a single-center retrospective study of 280 adults receiving CD19 CAR T-cell therapy for non-Hodgkin lymphoma (NHL) from December 2017 through September 2021. Patients did not receive routine antiyeast or antimold prophylaxis. IFD was identified between day of cell infusion and last follow-up. Cumulative incidence functions were calculated at 100 days and 18 months based on time to IFD, using dates of IFD-free death, initiation of salvage treatment, and hematopoietic cell transplantation as competing risks. Eight patients (2.9%) developed IFD, including 3 Pneumocystis jirovecii pneumonia, 3 invasive mold infections (IMIs), and 2 invasive yeast infections (IYIs). The 100-day cumulative incidence of IFD accounting for competing risks was 1.8% (95% confidence interval [CI], 0.8% to 4.4%). Among the 280 patients, early toxicities including CRS (85%) and ICANS (55%) and late toxicities after day 30 including grades 3 and 4 neutropenia (41%) and low CD4 T-cell count (20%) were common. IFD was rare among patients who received CD19 CAR T-cell therapy for NHL in the absence of routine antifungal prophylaxis, despite frequent toxicities. These results suggest that, in settings with low institutional rates of IFD, routine antifungal prophylaxis may not be indicated.

Somatic GATA2 mutations define a subgroup of myeloid malignancy patients at high risk for invasive fungal disease.

Invasive fungal disease (IFD) can be a severe treatment complication in patients with myeloid malignancies, but current risk models do not incorporate disease-specific factors, such as somatic gene mutations. Germline GATA2 deficiency is associated with a susceptibility to IFD. To determine whether myeloid gene mutations were associated with IFD risk, we identified 2 complementary cohorts of patients with myeloid malignancy, based on (1) the diagnosis of invasive aspergillosis (IA), or (2) the presence of GATA2 mutations identified during standard clinical sequencing. We found somatic GATA2 mutations in 5 of 27 consecutive patients who had myeloid malignancy and developed IA. Among 51 consecutive patients with GATA2 mutations identified in the evaluation of myeloid malignancy, we found that IFD was diagnosed and treated in 21 (41%), all of whom had received chemotherapy or had undergone an allogeneic stem cell transplant. Pulmonary infections and disseminated candidiasis were most common. The 90-day mortality was 52% among patients with IFD. Our results indicate that patients with somatic GATA2 mutations are a vulnerable subgroup of patients with myeloid malignancy who have high risk for treatment-associated IFD and suggest that a focused approach to antifungal prophylaxis be considered.

Clinical experience with a novel assay measuring cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity by flow cytometry and intracellular cytokine staining to predict clinically significant CMV events.

BACKGROUND: Cytomegalovirus (CMV) infection is one of the most common opportunistic infections following organ transplantation, despite administration of CMV prophylaxis. CMV-specific T-cell immunity (TCI) has been associated with reduced rates of CMV infection. We describe for the first time clinical experience using the CMV T-Cell Immunity Panel (CMV-TCIP), a commercially available assay which measures CMV-specific CD4+ and CD8+ T-cell responses, to predict clinically significant CMV events. METHODS: Adult (> 18-year-old) patients with CMV-TCIP results and ≥ 1 subsequent assessment for CMV DNAemia were included at Brown University and the University of Maryland Medical Center-affiliated hospitals between 4/2017 and 5/2019. A clinically significant CMV event was defined as CMV DNAemia prompting initiation of treatment. We excluded indeterminate results, mostly due to background positivity, allogeneic hematopoetic cell transplant (HCT) recipients, or patients who were continued on antiviral therapy against CMV irrespective of the CMV-TCIP result, because ongoing antiviral therapy could prevent a CMV event. RESULTS: We analyzed 44 samples from 37 patients: 31 were solid organ transplant recipients, 4 had hematologic malignancies, 2 had autoimmune disorders. The CMV-protection receiver operating characteristic (ROC) area under the curve (AUC) was significant for %CMV-specific CD4+ (AUC: 0.78, P < 0.001) and borderline for CD8+ (AUC: 0.66, P = 0.064) T-cells. At a cut-off value of 0.22% CMV-specific CD4+ T-cells, positive predictive value (PPV) for protection against CMV was 85% (95%CI 65-96%), and negative predictive value (NPV) was 67% (95%CI 41-87%). CONCLUSIONS: The CMV-TCIP, in particular %CMV-specific CD4+ T-cells, showed good diagnostic performance to predict CMV events. The CMV-TCIP may be a useful test in clinical practice, and merits further validation in larger prospective studies.

Increased Risk of Infectious Complications in Older Patients With Indolent Non-Hodgkin Lymphoma Exposed to Bendamustine.

Background: Bendamustine is a potent chemotherapy agent increasingly used to treat indolent non-Hodgkin lymphoma (iNHL). While effective, it causes significant T-cell lymphopenia, which may increase risk of infection. We examined infectious complications associated with bendamustine-containing regimens among older patients with iNHL. Methods: For this Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort study, we identified 9395 patients with iNHL (follicular, marginal zone, Waldenström macroglobulinemia) treated with chemotherapy from 2006 to 2013. Thirteen percent received bendamustine-containing regimens. We compared baseline characteristics and infection incidence rates between patients treated with and without bendamustine. We conducted multivariate Cox proportional hazards regression (adjusting for demographics, comorbidities, disease and treatment characteristics, risk factors for infection, and antimicrobial prophylaxis) to determine infectious risks associated with bendamustine. Results: Bendamustine was associated with an increased risk of both common infections such as bacterial pneumonia (hazard ratio [HR], 1.50 [95% confidence interval {CI}, 1.21-4.85]) and opportunistic infections such as cytomegalovirus (HR, 3.98 [95% CI, 1.40-11.26]), varicella zoster virus (HR, 1.49 [95% CI, 1.18-1.89]), histoplasmosis (HR, 3.55 [95% CI, 1.10-11.42]), and Pneumocystis jirovecii pneumonia (when administered as third-line therapy: HR, 3.32 [95% CI, 1.00-11.11]). Risk of infections was more prominent in patients receiving bendamustine as part of later (third-line and above) regimens, and independently associated with well-established factors such as neutropenia and corticosteroid exposure. Conclusions: Bendamustine is associated with an increased risk of common and opportunistic infections in patients with iNHL. Further prospective investigation into the potential role of antimicrobial prophylaxis is needed in these patients.

False positive bronchoalveolar lavage galactomannan: Effect of host and cut-off value.

OBJECTIVES: Bronchoalveolar lavage galactomannan (BAL-GM) is a mycological criterion for diagnosis of probable invasive aspergillosis (IA) per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORT-MSG) consensus criteria, but its real-world positive predictive value (PPV) has not been well-studied. Our aim was to estimate the PPV of BAL-GM in a contemporary cohort of patients with positive BAL-GM. METHODS: We identified consecutive patients with ≥1 positive BAL-GM value (index ≥ 0.5) at Brigham and Women's Hospital from 11/2009 to 3/2016. We classified patients as having no, possible, probable, or proven IA, excluding BAL-GM as mycological criterion. RESULTS: We studied 134 patients: 54% had hematologic malignancy (HM), and 10% were solid organ transplant (SOT) recipients. A total of 42% of positive (≥0.5) BAL-GM results were falsely positive (PPV 58%). The number of probable IA cases was increased by 23% using positive BAL-GM as mycologic criterion alone. PPV was higher in patients with HM or SOT (P < 0.001) and with use of higher thresholds for positivity (BAL-GM ≥ 1 vs 1-0.8 vs 0.8-0.5: P = 0.002). CONCLUSIONS: 42% of positive BAL-GM values were falsely positive. We propose a critical reassessment of BAL-GM cutoff values in different patient populations. Accurate noninvasive tests for diagnosis of IA are urgently needed.

Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab.

Importance: Powassan virus is a rare but increasingly recognized cause of severe neurological disease. Objective: To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. Design, Setting, and Participants: Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. Exposure: Infection with Powassan virus. Main Outcomes and Measures: Results of individual assays compared retrospectively. Results: In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. Conclusions and Relevance: Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

Dasatinib Use and Risk of Cytomegalovirus Reactivation After Allogeneic Hematopoietic-Cell Transplantation.

Viral infections have been reported with dasatinib use, but its cytomegalovirus risk after hematopoietic-cell transplantation (HCT) is not known. We found that post-HCT dasatinib use increased the risk of cytomegalovirus reactivation (adjusted hazard ratio, 7.65; 95% confidence interval, 1.84-31.7), controlling for acute graft-versus-host disease, in 109 patients with Philadelphia-chromosome-positive malignancies.

Prophylactic Antibiotics and Postoperative Complications of Radical Cystectomy: A Population Based Analysis in the United States.

PURPOSE: Infectious, wound and soft tissue events contribute to the morbidity of radical cystectomy but the association between these events and antibiotic prophylaxis is not clear. We sought to describe the contemporary use of antibiotic prophylaxis in radical cystectomy and adherence to published guidelines, and identify regimens with the lowest rates of infectious events. MATERIALS AND METHODS: We identified the intraoperative antibiotic prophylaxis regimen in a population based, retrospective cohort study of patients who underwent radical cystectomy across the United States between 2003 and 2013. Multivariable regression was done to evaluate 90-day infectious events and length of stay. RESULTS: In a weighted cohort of 52,349 patients there were 579 unique antibiotic prophylaxis regimens. Cefazolin was the most commonly used antibiotic (16% of cases). The overall infectious event rate was 25%. Only 15% of patients received antibiotic prophylaxis based on guidelines. Of guideline based antibiotic prophylaxis ampicillin/sulbactam had the lowest odds of infectious events (OR 0.34, p <0.001). In 2.7% of patients a penicillin based regimen with a ß-lactamase inhibitor was associated with a prominent reduction in the odds of infectious events (OR 0.45, p = 0.001) and decreased length of stay (-1.3 days, p = 0.016). CONCLUSIONS: Antibiotic prophylaxis practices are highly heterogeneous in radical cystectomy. There is a lack of adherence to published guidelines. We observed decreased infectious event rates and shorter length of stay with regimens that included broad coverage of common skin, genitourinary and gastrointestinal flora. The ideal antibiotic regimen requires further study to optimize perioperative outcomes.

Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia.

BACKGROUND: Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. METHODS: We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. RESULTS: Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. CONCLUSIONS: Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.

Risk factors for invasive fungal disease in heart transplant recipients.

BACKGROUND: Heart transplant (HT) recipients are at risk for invasive fungal disease (IFD), a morbid and potentially fatal complication. METHODS: We performed a retrospective cohort study to evaluate the incidence and risk factors for IFD in HT recipients from 1995 to 2012 at a single center. IFD cases were classified as proven or probable IFD according to current consensus definitions of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. We calculated IFD incidence rates and used Cox proportional hazards models to determine IFD risk factors. RESULTS: Three hundred sixty patients underwent HT during the study period. The most common indications were dilated (39%) and ischemic (37%) cardiomyopathy. There were 23 (6.4%) cases of proven (21) or probable (2) IFD, for a cumulative incidence rate of 1.23 per 100 person-years (95% CI 0.78 to 1.84). Candida (11) and Aspergillus (5) were the most common etiologic fungi. Thirteen cases (56%) occurred within 3 months of HT, with a 3-month incidence of 3.8% (95% CI 2.2 to 6.4). Delayed chest closure (HR 3.3, 95% CI 1.4 to 7.6, p = 0.01) and the addition of OKT3, anti-thymocyte globulin or daclizumab to standard corticosteroid induction therapy (HR 2.7, 95% CI 1.1 to 6.2, p = 0.02) were independently associated with an increased risk of IFD. CONCLUSIONS: IFD incidence was greatest within the first 3 months post-HT, largely reflecting early surgical-site and nosocomial Candida and Aspergillus infections. Patients receiving additional induction immunosuppression or delayed chest closure were at increased risk for IFD. Peri-transplant anti-fungal prophylaxis should be considered in this subset of HT recipients.

A breath fungal secondary metabolite signature to diagnose invasive aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection. METHODS: Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples. RESULTS: The monoterpenes camphene, α- and ß-pinene, and limonene, and the sesquiterpene compounds α- and ß-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, ß-trans-bergamotene, a ß-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%). CONCLUSIONS: In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.

Green herring syndrome: bacterial infection in patients with mucormycosis cavitary lung disease.

Mucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease.

Marital status and survival in patients with cancer.

PURPOSE: To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States. METHODS: We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available. RESULTS: Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy. CONCLUSION: Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival.

Safety of posaconazole and sirolimus coadministration in allogeneic hematopoietic stem cell transplants.

Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient's sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.

Cord-blood hematopoietic stem cell transplant confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis.

Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease.

Invasive Mycoleptodiscus fungal cellulitis and myositis.

We report progressive necrotizing fungal cellulitis and myositis in the leg of a patient with glioblastoma multiforme treated with temozolomide and corticosteroids. While the morphologic appearance of the isolate and its ability to grow at temperatures greater than 32°C were suggestive of Mycoleptodiscus indicus, some of the conidia were atypical for this species in that they had single septa and occasional lateral appendages. Furthermore, the isolate was different from M. indicus based on the sequencing analysis of two rDNA regions. This is the first case of Mycoleptodiscus invasive fungal disease in which the causative agent could not be resolved at the species level because of inconsistencies between morphological and molecular data.