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1.  Detection of Cytomegalovirus DNA in Plasma as an Adjunct Diagnostic for Gastrointestinal Tract Disease in Kidney and Liver Transplant Recipients 
Quantitative polymerase chain reaction for cytomegalovirus (CMV) DNA in plasma has good sensitivity and excellent specificity for the diagnosis of CMV gastrointestinal disease in kidney and liver transplant recipients presenting with gastrointestinal symptoms.
Background. Cytomegalovirus (CMV) disease is the most common infectious complication after solid organ transplantation, frequently affecting the gastrointestinal (GI) tract. There are limited data on quantitative polymerase chain reaction (qPCR) for plasma CMV DNA as an adjunct diagnostic method for GI tract disease in kidney and liver transplant recipients.
Methods. We reviewed all records of adult kidney and liver transplant recipients with a GI tract biopsy and plasma CMV qPCR result within 15 days of biopsy during a 6.5-year period at our center. CMV GI tract disease was defined as histopathologic evidence of CMV on biopsy by immunohistochemistry or visualization of inclusion bodies.
Results. GI tract biopsy and qPCR results were available for 81 kidney and liver transplant recipients; 20 cases of confirmed CMV GI tract disease were identified. Overall, the sensitivity of qPCR for diagnosing CMV GI tract disease was 85% (95% confidence interval [CI], 61%–96%), and the specificity was 95% (95% CI, 85%–99%). For CMV-seronegative recipients (R−) with CMV-seropositive donors (D+), the sensitivity of qPCR was 100% (95% CI, 59%–99%), and the specificity was 80% (95% CI, 30%–99%). The lowest sensitivity was observed in CMV D+/R+ cases (72.7%; 95% CI, 39%–93%). The mean plasma CMV copy number in patients with GI tract disease was 3.84 log10 (38 334 copies/mL).
Conclusions. Plasma CMV qPCR had good sensitivity and excellent specificity for CMV GI tract disease in kidney and liver transplant recipients. Its sensitivity was 100% in CMV D+/R− cases but 72.7% in CMV D+/R+ cases. This variation in assay performance according to host serostatus may reflect differences in disease pathogenesis.
PMCID: PMC3814823  PMID: 23956167
CMV; viremia; colitis; kidney and liver transplant recipients
2.  Epidemiology of Candida kefyr in Patients with Hematologic Malignancies 
Journal of Clinical Microbiology  2014;52(6):1830-1837.
Candida kefyr is an emerging pathogen among patients with hematologic malignancies (HM). We performed a retrospective study at Johns Hopkins Hospital to evaluate the epidemiology of C. kefyr colonization and infection in HM patients between 2004 and 2010. Eighty-three patients were colonized and/or infected with C. kefyr, with 8 (9.6%) having invasive candidiasis (IC). The yearly incidence of C. kefyr colonization and candidemia increased over the study period (P < 0.01), particularly after 2009. In 2010, C. kefyr caused 16.7% of candidemia episodes. The monthly incidence of C. kefyr was higher during the summer throughout the study. In a cohort of patients with acute myelogenic leukemia receiving induction chemotherapy, risks for C. kefyr colonization included the summer season (odds ratio [OR], 3.1; P = 0.03); administration of an azole (OR, 0.06; P < 0.001) or amphotericin B (OR, 0.35; P = 0.05) was protective. Fingerprinting of 16 isolates by repetitive sequence-based PCR showed that all were different genotypes. The epidemiology of C. kefyr candidemia was evaluated in another hospital in Montreal, Canada; data confirmed higher rates of C. kefyr infection in the summer. C. kefyr appears to be increasing in HM patients, with prominent summer seasonality. These findings raise questions about the effect of antifungal agents and health care exposures (e.g., yogurt) on the epidemiology of this yeast.
PMCID: PMC4042816  PMID: 24622105
3.  Invasive fungal infections in solid organ transplant recipients 
Future microbiology  2012;7(5):639-655.
Invasive fungal infections are a major problem in solid organ transplant (SOT) recipients. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Development of invasive disease hinges on the interplay between host factors (e.g., integrity of anatomical barriers, innate and acquired immunity) and fungal factors (e.g., exposure, virulence and resistance to prophylaxis). In this article, we describe the epidemiology and clinical features of the most common fungal infections in organ transplantation. Within this context, we review recent advances in diagnostic modalities and antifungal chemotherapy, and their impact on evolving prophylaxis and treatment paradigms.
PMCID: PMC4222063  PMID: 22568718
antifungal; aspergillosis; candidiasis; cryptococcosis; fungal; galactomannan; kidney transplant; liver transplant; lung transplant; transplant
4.  Clostridium difficile infection among hematopoietic stem cell transplant recipients: beyond colitis 
Purpose of review
To review the most recent data regarding the epidemiology, risks factors, and outcomes among hematopoietic stem cell transplant recipients with Clostridium difficile infection (CDI).
Recent findings
With the emergence of an epidemic strain of C. difficile known as NAP1 in the early 2000s, rates of this infection have escalated globally. Hematopoietic stem cell transplant recipients appear to be one of the most vulnerable populations for the development of CDI. Traditional risk factors for CDI including antimicrobial exposure and older age are likely only a piece of the overall risk profile, with recent study results also emphasizing other factors such as transplant type, conditioning regimen, and graft-versus-host disease (GVHD). The relationship between CDI and subsequent development of GVHD, particularly of the gastrointestinal tract, is of specific interest. A bidirectional relationship of association has been highlighted in a number of recent studies and underscores the need for further prospective studies to address the potential indirect effects of alloreactivity induced by CDI.
CDI has emerged as one of the most common infections in the early transplant period. Recent studies have begun to address the epidemiology of disease, risk factors for, and outcomes after infection in the stem cell transplant. However, more research is needed to unravel the observed relationship between CDI and GVHD.
PMCID: PMC4222064  PMID: 23806895
Clostridium difficile; colitis; graft-versus-host disease; hematopoietic stem cell transplant
5.  Clostridium difficile infection after adult autologous stem cell transplantation: A multicenter study of epidemiology and risk factors 
We sought to describe the epidemiology of Clostridium difficile infection (CDI) among adult recipients of autologous hematopoietic stem cell transplantation (auto HSCT) within the first year after HSCT in centers with variable epidemiology of hyper-toxigenic strains. A multicenter, retrospective nested case-control study was conducted among 873 auto HSCT recipients at Johns Hopkins Hospital (JHH, Baltimore, MD) and Hôpital Maisonneuve-Rosemont (HMR, Montreal, Canada) between 1/2003-12/2008. Despite center differences in the prevalence of NAP-1 strains over the time period (21-43% JHH; 80-84% HMR), the 1-year incidence of CDI was similar (6.2% JHH; 5.7% HMR). The median time to infection was 11 days (interquartile range [IQR] 1 to 27). In case control analysis, the following were predictors for CDI: grade 2 or higher mucositis (odds ratio [OR]: 3.00, P=0.02) and receipt of a 4th generation cephalosporin (OR: 2.76, P=0.04). Mucositis was the strongest predictor of risk for CDI in multivariate analysis (adjusted OR [AOR]: 2.77; P=0.03). CDI is a common and early complication of auto HSCT. Treatment-related gastrointestinal mucosal damage, in addition to the potentially modifiable risk of antimicrobial exposure, influence risk for CDI early post-auto HSCT.
PMCID: PMC3806308  PMID: 23916741
Clostridium difficile; stem cell transplantation; mucositis; antibiotics; NAP-1
6.  Antiviral Immune Response Following Live Yellow Fever Vaccination of a Kidney Transplant Recipient Treated with IVIG 
Transplantation  2013;95(9):e59-e61.
PMCID: PMC3647227  PMID: 23648410
yellow fever; kidney transplantation; intravenous immunoglobulin; vaccination
7.  Cost-effectiveness Analysis of Voriconazole Compared With Fluconazole for Prevention of Invasive Fungal Infection in Patients Receiving Allogeneic Hematopoietic Cell Transplants 
Cost-effectiveness analysis of voriconazole compared with fluconazole, both with galactomannan monitoring, for prevention of invasive fungal infections (IFI) in patients receiving allogeneic hematopoietic cell transplantation (HCT)
A decision analytic economic model was developed to estimate the drug costs associated with planned prophylaxis, supplemental prophylaxis, and empirical therapy and costs associated with treatment of suspected or documented IFI. We estimated incremental cost-effectiveness ratios (ICERs) at 6 months, 12 months, and lifetime. A bootstrap analysis was conducted to estimate the uncertainty of the clinical trial results.
At 12 months, mean total fungal-infection-related costs were not significantly different for voriconazole prophylaxis than for fluconazole prophylaxis for a subpopulation with acute myeloid leukemia (AML) but were significantly higher for voriconazole prophylaxis for the study population and in a subpopulation of those with other underlying diseases. The cost per IFI avoided ($66,919) and the cost per life-year gained (LYG) ($5,453) were also lower for the AML subgroup than for the complete trial population ($812,990/IFI avoided; and dominated for cost/LYG). ICERs were more favorable for voriconazole at 6 months and when the generic price was used for oral voriconazole. Bootstrap analysis results for the cost per LYG showed that the probability of voriconazole being cost-effective is 33% for the complete study population and 85% for the AML subpopulation, for a maximum willingness to pay for 1 year of life gained of $50,000.
Voriconazole prophylaxis was significantly more costly than fluconazole for the complete study population but may be cost-effective for those undergoing an allogeneic HCT for AML. Use of generic oral voriconazole will have a favorable impact on the costs and cost-effectiveness of prophylaxis with voriconazole compared with fluconazole for all undergoing allogeneic HCT.
PMCID: PMC4019750  PMID: 23943184
8.  Epidemiology, outcomes, and risk factors of invasive fungal infections in adult patients with acute myelogenous leukemia after induction chemotherapy☆,☆☆,★,★★ 
This is a retrospective, single-center study of adult patients with newly diagnosed acute myelogenous leukemia (AML), who received intensive induction timed sequential chemotherapy from 1/2005 to 6/2010. Among 254 consecutive AML patients, 123 (48.4%) developed an invasive fungal infection (IFI): 14 (5.5%) patients with invasive candidiasis (IC) and 108 (42.5%) patients with invasive mould infections (IMI). Among 108 IMI identified, 4 (3.7%) were proven, 1 (0.9%) probable, and 103 (95.4%) were possible, using current definitions. Overall, 6-month mortality was 23.7% (27/114) and 20.6% (26/126) for patients with and without an IFI, respectively. Older age (≥50 years; hazard ratio [HR]: 2.5, P < 0.001), female gender (HR: 1.7, P = 0.006), and baseline renal and/or liver dysfunction (HR: 2.4, P < 0.001) were the strongest mortality predictors. We report relatively low rates of IC despite lack of routine primary antifungal prophylaxis, albeit associated with poor long-term survival. High rates of IMI, the vast majority with a possible diagnosis, were observed. Host-related variables (demographics and baseline organ dysfunction) were identified as the most significant risk factors for IFI and mortality predictors in this series.
PMCID: PMC3986043  PMID: 23142166
Invasive fungal infections; Acute myeloid leukemia; Epidemiology; Risk factors; Survival
9.  Cerebrospinal Fluid (1,3)-β-d-Glucan Detection as an Aid for Diagnosis of Iatrogenic Fungal Meningitis 
Journal of Clinical Microbiology  2013;51(4):1285-1287.
This case series highlights our experience with use of the Fungitell assay for quantifying (1,3)-β-d-glucan in cerebrospinal fluid during the current U.S. outbreak of fungal meningitis related to contaminated methylprednisolone acetate. This test may prove a useful adjunct in diagnosis and management of exposed patients.
PMCID: PMC3666821  PMID: 23363831
10.  Fluconazole Coadministration Concurrent with Cyclophosphamide Conditioning May Reduce Regimen-Related Toxicity Post-myeloablative Hematopoietic Cell Transplantation 
In a previous study comparing fluconazole and itraconazole administered as antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients, we found that fluconazole administration concurrent with cyclophosphamide (CY)-based conditioning was associated with fewer early toxicities compared to itraconazole. Fluconazole inhibits cytochrome P450 2C9, which is involved with the activation of CY, and so might provide protection from CY-related toxicities.
To investigate this further, we compared CY and CY-metabolite data from patients who received fluconazole (n=56) concurrent with CY-containing conditioning in patients who did not (n=17). The fluconazole group had greater exposure to CY, and lower peak serum concentration of CY-metabolite 4-hydroxycyclophosphamide. In a separate cohort, we examined outcomes in patients randomized to receive either fluconazole (n=152) or placebo (n=147) concurrent with CY-containing conditioning in a prior randomized trial. Patients who received fluconazole experienced less hepatic and renal toxicity, and had lower mortality. No difference in relapsed malignancy was apparent. These data support the hypothesis that fluconazole, when co-administered with CY, decreases CY-related toxicities by inhibiting cytochrome P450 2C9 metabolism.
PMCID: PMC3690587  PMID: 17580253
11.  Galactomannan Antigen Testing for Diagnosis of Invasive Aspergillosis in Pediatric Hematology Patients 
Invasive aspergillosis (IA) can cause significant morbidity and mortality in immunocompromised children. The galactomannan (GM) enzyme immunoassay (EIA) has been shown in adult studies to be a useful adjunct in diagnosing IA. Data on this assay in children are limited by small sample sizes and conflicting results; false-positive assays were a concern in historical studies. We sought to evaluate the GM EIA in a large cohort of children who received intensive chemotherapy and/or hematopoietic stem cell transplant. A focus was placed on evaluating the assay specificity, and the potential of measuring GM antigen in urine.
A multicenter prospective observational study in children with anticipated prolonged neutropenia was performed. Serum specimens were collected twice weekly, and urine was collected once weekly during neutropenic periods. Operating characteristics were calculated using the GM EIA optical density index cutoffs of 0.5 and 1.0 for both serum and urine specimens.
At least one serum or urine specimen was tested from 198 patients. Ten patients had one or more repeatedly positive serum specimens, while 37 patients had one or more repeatedly positive urine specimens. The specificity of serum and urine testing was 95% and 80%, respectively. Although the urine test resulted in a higher false positivity rate, it successfully identified the only case of probable IA.
Data suggest that the serum GM EIA does not provide frequent false-positive results as previously reported. Screening for galactomannan, or a related antigen in urine, needs to be further evaluated as it may be amenable to development of surveillance strategies.
PMCID: PMC3656552  PMID: 23687575
12.  Epidemiology and Outcomes of Clostridium difficile Infections in Hematopoietic Stem Cell Transplant Recipients 
Clostridium difficile is a major early infectious complication of hematopoietic stem cell transplantation (HSCT). Infections are related to antimicrobial use, underlying host variables, and acute graft-versus-host disease (GVHD). C. difficile infection is associated with gastrointestinal GVHD after allogeneic HSCT.
Background. Clostridium difficile is the leading cause of infectious diarrhea among hospitalized patients and is a major concern for patients undergoing hematopoietic stem cell transplantation (HSCT). Risk factors and the natural history of C. difficile infection (CDI) are poorly understood in this population.
Methods. We performed a retrospective nested case-control study to describe the epidemiology, timing, and risk factors for CDI among adult patients who received HSCTs at our center from January 2003 through December 2008.
Results. The overall 1-year incidence of CDI was 9.2% among HSCTs performed (n = 999). The median time to diagnosis of CDI was short among both autologous and allogeneic HSCT recipients (6.5 days and 33 days, respectively). Risk factors for CDI in allogeneic HSCT recipients included receipt of chemotherapy prior to conditioning for HSCT, broad-spectrum antimicrobial use, and acute graft-versus-host disease (GVHD; adjusted odds ratio [AOR], 4.45; 95% confidence interval [CI], 1.54–12.84; P = .006). There was a strong relationship between early CDI and subsequent development of gastrointestinal tract GVHD in the year following allogeneic HSCT (P < .001). Gastrointestinal GVHD was also strongly associated with an increased risk for recurrent CDI (AOR, 4.23 [95% CI, 1.20–14.86]; P = .02).
Conclusions. These results highlight the high incidence and early timing of CDI after HSCT. Early timing, coupled with the noted risk of pretransplant chemotherapy, suggests that the natural history of disease in some patients may involve colonization prior to HSCT. A potentially important interplay between CDI and GVHD involving the gastrointestinal tract was observed.
PMCID: PMC3309884  PMID: 22412059
13.  Cryptococcus gattii as an important fungal pathogen of western North America 
Cryptococcus gattii, a pathogenic fungus historically appreciated to be endemic to tropical regions, was recognized to emerge in a more temperate zone of North America in the 1990s. Early reports focused on an outbreak that was first apparent on Vancouver Island (BC, Canada), involving both the veterinary and human population. More recently, it has been recognized that this organism is endemic to a wider geography in western North America, with recognized disease caused by unique molecular subtypes in both healthy and immunosuppressed human hosts and a variety of domestic and wild animals. A number of cases of disease caused by C. gattii isolates that are unrelated to the Vancouver Island–Pacific Northwest outbreak strains have also been recognized in different parts of the USA. As microbiology laboratories have historically not identified these organisms to the species level, our current understanding of the scope of this infection is probably an underestimate. Ongoing public health epidemiologic efforts will be facilitated by increased attention towards culture-confirmed diagnosis and species identification in clinical microbiology laboratories. Early experience presents a strong rationale for increasing diagnostic attention, with multiple clinical features that are unique to this infection, including variability in antifungal susceptibilities and a heightened need for aggressive management of inflammatory responses. Larger prospective studies to evaluate and optimize clinical management are needed.
PMCID: PMC3500029  PMID: 22734955
cryptococcosis; Cryptococcus gattii; North America
14.  Detection of Urinary Excreted Fungal Galactomannan-like Antigens for Diagnosis of Invasive Aspergillosis 
PLoS ONE  2012;7(8):e42736.
Mortality associated with invasive aspergillosis (IA) remains high, partly because of delayed diagnosis. Detection of microbial exoantigens, released in serum and other body fluids during infection, may help timely diagnosis. In course of IA, Aspergillus galactomannan (GM), a well established polysaccharide biomarker, is released in body fluids including urine. Urine is an abundant, safely collected specimen, well-suited for point-of-care (POC) testing, which could play an increasing role in screening for early disease. Our main objective was to demonstrate GM antigenuria as a clinically relevant biological phenomenon in IA and establish proof-of-concept that it could be translated to POC diagnosis. Utilizing a novel IgM monoclonal antibody (MAb476) that recognizes GM-like antigens from Aspergillus and other molds, we demonstrated antigenuria in an experimental animal IA model (guinea pig), as well as in human patients. In addition, we investigated the chemical nature of the urinary excreted antigen in human samples, characterized antigen detection in urine by immunoassays, described a putative assay inhibitor in urine, and indicated means of alleviation of the inhibition. We also designed and used a lateral flow immunochromatographic assay to detect urinary excreted antigen in a limited number of IA patient urine samples. In this study, we establish that POC diagnosis of IA based on urinary GM detection is feasible. Prospective studies will be necessary to establish the performance characteristics of an optimized device and define its optimal clinical use.
PMCID: PMC3416763  PMID: 22900046
15.  In Vitro Echinocandin Susceptibility of Aspergillus Isolates from Patients Enrolled in the Transplant-Associated Infection Surveillance Network▿ 
We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin.
PMCID: PMC3147660  PMID: 21670187
16.  Invasive Non-Aspergillus Mold Infections in Transplant Recipients, United States, 2001–2006 
Emerging Infectious Diseases  2011;17(10):1855-1864.
PMCID: PMC3311117  PMID: 22000355
Mucorales; Fusarium; Scedosporium; mucormycosis; non-Aspergillus; fungi; organ transplant; epidemiology; invasive mold infections; zygomycosis; fusariosis; surveillance; United States; research
17.  Factors Associated with Mortality in Transplant Patients with Invasive Aspergillosis 
Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA.
Transplant patients from 23 U.S. centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network (TRANSNET). IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression.
Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT (239/415, 57.5%) when compared to SOT patients (78/227, 34.4%; p<0.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition and CNS disease were poor prognostic indicators; whereas, prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death.
There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.
PMCID: PMC2874071  PMID: 20450350
Aspergillosis; transplant; Aspergillus; mortality
18.  Impact of Aspergillus fumigatus in allergic airway diseases 
For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I-mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA), known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF). The goal of this review is to discuss new understandings of host-pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.
PMCID: PMC3294627  PMID: 22410255
19.  Differential Aspergillus lentulus Echinocandin Susceptibilities Are Fksp Independent ▿  
Antimicrobial Agents and Chemotherapy  2010;54(12):4992-4998.
The recently described species Aspergillus lentulus exhibits differential and reduced susceptibilities to echinocandins and other antifungal drugs in vitro. A. lentulus isolates overall are less susceptible to caspofungin, although they maintain susceptibility to anidulafungin and micafungin. Mutations or polymorphisms in fks, the gene encoding the catalytic subunit of β-1,3-glucan synthase, are known to confer decreased susceptibility to echinocandins in Candida spp. and Aspergillus fumigatus. The analysis of the A. lentulus fks sequence did not reveal a polymorphism at any of the known hot-spot regions of the gene. Caspofungin and micafungin kinetic inhibition profiles of the A. lentulus glucan synthase were comparable to those from susceptible A. fumigatus enzymes. Although the basal cell wall chitin levels in A. lentulus averaged 60% of those in A. fumigatus, echinocandin treatment promoted the increase of cell wall chitin in both organisms, indicating that A. lentulus displays a compensatory chitin response similar to that of A. fumigatus. The data suggest that differential echinocandin susceptibilities in A. lentulus are independent of the echinocandin target, Fksp, and they emphasize the potential that the drugs' capacity to inhibit the target enzyme is unequal at the cellular level.
PMCID: PMC2981225  PMID: 20855747
20.  Reduced mortality after allogeneic hematopoietic cell transplantation 
The New England journal of medicine  2010;363(22):2091-2101.
We tested the hypothesis that changes in our transplant practice have improved outcomes over the last decade. To explore correlates of improved outcomes, we analyzed the frequency and severity of graft-versus-host disease and hepatic, renal, pulmonary and infectious complications.
During 1993–1997 and 2003–2007, 1418 and 1148 patients received their first allogeneic transplants at our Center. Outcome measures included non-relapse mortality, recurrent malignancy, overall mortality, and the frequency and severity of major complications across this decade. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for severity of illness at the time of transplantation.
In comparing outcomes during 1993–1997 and 2003–2007, we observed statistically significant decreases in the hazards of day -200 non-relapse mortality (by 60%), overall non-relapse mortality (by 52%), relapse or progression of malignancy (by 21%), and overall mortality (by 41%), after adjusting for components of the PAM score. Similar results were seen when the analyses were confined to patients receiving myeloablative conditioning therapy. We found statistically significant declines in the risk of more severe GVHD, disease caused by infections (viral, bacterial, and fungal), and damage to the liver, kidneys, and lungs.
We document a substantial reduction in the hazard of death related to allogeneic hematopoietic cell transplantation as well as improved long-term survival over the last decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD.
PMCID: PMC3017343  PMID: 21105791
Marrow transplantation; hematopoietic cell transplantation; liver disease; kidney disease; pulmonary disease; infectious complications; graft-vs.-host disease; ursodiol; mortality; survival; comparative outcomes research
21.  Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study 
The Lancet infectious diseases  2010;10(8):521-526.
There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants.
We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of χ2 tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis.
We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3.6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22.4%) given antivirals later (p=0.007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar.
Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009–10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation.
PMCID: PMC3045703  PMID: 20620116
22.  Microarray and Molecular Analyses of the Azole Resistance Mechanism in Candida glabrata Oropharyngeal Isolates▿  
DNA microarrays were used to analyze Candida glabrata oropharyngeal isolates from seven hematopoietic stem cell transplant recipients whose isolates developed azole resistance while the recipients received fluconazole prophylaxis. Transcriptional profiling of the paired isolates revealed 19 genes upregulated in the majority of resistant isolates compared to their paired susceptible isolates. All seven resistant isolates had greater than 2-fold upregulation of C. glabrata PDR1 (CgPDR1), a master transcriptional regulator of the pleiotropic drug resistance (PDR) network, and all seven resistant isolates showed upregulation of known CgPDR1 target genes. The altered transcriptome can be explained in part by the observation that all seven resistant isolates had acquired a single nonsynonymous mutation in their CgPDR1 open reading frame. Four mutations occurred in the regulatory domain (L280P, L344S, G348A, and S391L) and one in the activation domain (G943S), while two mutations (N764I and R772I) occurred in an undefined region. Association of azole resistance and the CgPDR1 mutations was investigated in the same genetic background by introducing the CgPDR1 sequences from one sensitive isolate and five resistant isolates into a laboratory azole-hypersusceptible strain (Cgpdr1 strain) via integrative transformation. The Cgpdr1 strain was restored to wild-type fluconazole susceptibility when transformed with CgPDR1 from the susceptible isolate but became resistant when transformed with CgPDR1 from the resistant isolates. However, despite the identical genetic backgrounds, upregulation of CgPDR1 and CgPDR1 target genes varied between the five transformants, independent of the domain locations in which the mutations occurred. In summary, gain-of-function mutations in CgPDR1 contributed to the clinical azole resistance, but different mutations had various degrees of impact on the CgPDR1 target genes.
PMCID: PMC2916311  PMID: 20547810
23.  Geoclimatic Influences on Invasive Aspergillosis after Hematopoietic Stem Cell Transplantation 
Aspergillus species are ubiquitous. We hypothesized that climatic variables that affect airborne mold counts affect the incidence of invasive aspergillosis (IA).
Patients who received hematopoietic stem cell transplants (HSCTs) in geographically and climatically diverse regions (Seattle, WA, and Houston, TX) were examined. Cumulative incidence function, Kaplan-Meier analysis, and Cox proportional hazards regression were performed to examine the association between IA and season. Poisson regression analysis was performed to evaluate the seasonal patterns in IA rates and association with spore counts and climate.
In Seattle, the 3-month incidence of IA was 4.6% (5.7% in allograft recipients and 0.8% in autograft recipients). During the 10-year study period, there was a decrease in the incidence of IA among allogeneic HSCT recipients, corresponding to decreased risks during the nonsummer months; receipt of HSCTs during the summer months was associated with an increased hazard for IA (hazard ratio, 1.87; 95% confidence interval, 1.25–2.81) after adjustment for other known risks. The person-month IA rate in Seattle was positively associated with environmental spore counts, which increased with high temperature and low precipitation. No seasonal effect on IA was observed in Houston, where total spore counts were lower and not variable by climate.
Climatic variables differentially affect airborne spore counts and IA risk in geographically disparate centers.
PMCID: PMC3024009  PMID: 20450414
24.  Patterns of Susceptibility of Aspergillus Isolates Recovered from Patients Enrolled in the Transplant-Associated Infection Surveillance Network▿  
Journal of Clinical Microbiology  2009;47(10):3271-3275.
We analyzed antifungal susceptibilities of 274 clinical Aspergillus isolates from transplant recipients with proven or probable invasive aspergillosis collected as part of the Transplant-Associated Infection Surveillance Network (TRANSNET) and examined the relationship between MIC and mortality at 6 or 12 weeks. Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth dilution method for amphotericin B (AMB), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), and ravuconazole (RAV). The isolate collection included 181 Aspergillus fumigatus, 28 Aspergillus niger, 27 Aspergillus flavus, 22 Aspergillus terreus, seven Aspergillus versicolor, five Aspergillus calidoustus, and two Aspergillus nidulans isolates and two isolates identified as Aspergillus spp. Triazole susceptibilities were ≤4 μg/ml for most isolates (POS, 97.6%; ITR, 96.3%; VOR, 95.9%; RAV, 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were ≥4 μg/ml. AMB inhibited 93.3% of isolates at an MIC of ≤1 μg/ml. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 μg/ml. One of 181 isolates of A. fumigatus showed resistance (MIC ≥ 4 μg/ml) to two of three azoles tested. Although there appeared to be a correlation of higher VOR MICs with increased mortality at 6 weeks, the relationship was not statistically significant (R2 = 0.61; P = 0.065). Significant relationships of in vitro MIC to all-cause mortality at 6 and 12 weeks for VOR or AMB were not found.
PMCID: PMC2756905  PMID: 19692558
25.  Molecular Identification of Aspergillus Species Collected for the Transplant-Associated Infection Surveillance Network▿  
Journal of Clinical Microbiology  2009;47(10):3138-3141.
A large aggregate collection of clinical isolates of aspergilli (n = 218) from transplant patients with proven or probable invasive aspergillosis was available from the Transplant-Associated Infection Surveillance Network, a 6-year prospective surveillance study. To determine the Aspergillus species distribution in this collection, isolates were subjected to comparative sequence analyses by use of the internal transcribed spacer and β-tubulin regions. Aspergillus fumigatus was the predominant species recovered, followed by A. flavus and A. niger. Several newly described species were identified, including A. lentulus and A. calidoustus; both species had high in vitro MICs to multiple antifungal drugs. Aspergillus tubingensis, a member of the A. niger species complex, is described from clinical specimens; all A. tubingensis isolates had low in vitro MICs to antifungal drugs.
PMCID: PMC2756904  PMID: 19675215

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