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Biomedical subjects

John R Wingard

Publications and source records attributed to John R Wingard.

At least 19 recordsLinked to original sources
PubMed2007

Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts.

Invasive fungal infection (IFI) is a leading cause of infection-related mortality among patients with cancer and prolonged neutropenia and among allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease. Invasive candidiasis was the principal IFI in the period predating fluconazole prophylaxis, whereas today, invasive aspergillosis and other mold infections cause the majority of deaths from fungal infection in this patient population. The changing epidemiology of IFI, in addition to advances made in antifungal therapeutics and early diagnosis of IFI, warrant a reevaluation of earlier strategies aimed at prevention and early treatment of IFI that were developed several years ago. Here, we propose that persistent neutropenic fever is nonspecific for an IFI and should not be used as the sole criterion for empirical modification in the antifungal regimen in a patient receiving mold-active prophylaxis. We explore the potential benefits and gaps in knowledge associated with employing chest CT scans and laboratory markers as diagnostic adjuncts for IFI. Finally, we discuss the implications of newer antifungal agents and diagnostic adjuncts in the design of future clinical trials to evaluate prophylaxis and early prevention strategies.

Antifungal Agents↗
PubMed2006

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

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

Adolescent↗
PubMed2006

Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy.

BACKGROUND: Little is known about the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy. METHODS: An in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells, was developed. An Aspergillus fumigatus strain expressing green fluorescent protein was used. Invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, polymerase chain reaction, and galactomannan were determined. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed, and results were bridged to humans. RESULTS: A. fumigatus penetrated the cellular bilayer 14-16 h after inoculation. Galactomannan levels were inextricably tied to fungal invasion and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress the growth of A. fumigatus; rather, the combination was required. Monte Carlo simulations showed that human dosages of amphotericin B of at least 0.6 mg/kg were required to achieve adequate drug exposure. CONCLUSIONS: This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood.

Amphotericin B↗
PubMed2006

New strategies of antifungal therapy in hematopoietic stem cell transplant recipients and patients with hematological malignancies.

Invasive fungal infections (IFIs) are associated with considerable morbidity and mortality among high-risk individuals. Outcomes for IFI historically have been suboptimal and associated with a high mortality rate, hence global prophylaxis strategies have been applied to at-risk populations. Among certain populations, fluconazole prophylaxis has reduced systemic and superficial infections caused by Candida species. Newer azoles are currently being evaluated as prophylaxis and have the potential to provide protection against mould pathogens that are more troublesome to treat once they occur. Global prophylaxis strategies have the shortcoming of subjecting patients to therapy that ultimately will not need it. Targeted prophylaxis has the advantage of treating only patients at highest risk using some parameter of greater host susceptibility. Prophylaxis strategies are most suitable in patients at the highest risk for IFI. For patient groups whose risk is somewhat lower or when suspicion of IFI occurs in patients receiving prophylaxis, empirical antifungal therapy is often employed following a predefined period of fever. Again this approach subjects many non-infected patients to unnecessary and toxic therapy. A more refined approach such as presumptive or pre-emptive therapy whereby treatment is only initiated upon positive identification of a surrogate marker of infection in combination with clinical and radiological signs will subject fewer patients to toxic and expensive treatments.

Algorithms↗
PubMed2006

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.

More than 40000 hematopoietic cell transplants (HCTs) are performed worldwide each year. With improvements in transplant technology, larger numbers of transplant recipients survive free of the disease for which they were transplanted. However, there are late complications that can cause substantial morbidity. Many survivors are no longer under the care of transplant centers, and many community health care providers may be unfamiliar with health matters relevant to HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Bone Marrow Transplantation (ASBMT) have developed these recommendations to offer care providers suggested screening and prevention practices for autologous and allogeneic HCT survivors.

Community Health Centers↗
PubMed2006

Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic stem cell transplant recipients.

A single-institution, open-label prospective pharmacokinetic evaluation of the interaction between intravenous itraconazole and intravenous cyclosporin A and tacrolimus was conducted in allogeneic hematopoietic stem cell transplant recipients. The study was conducted in 2 phases, with patients acting as their own controls. In phase 1, steady-state concentrations and clearance of cyclosporin A and tacrolimus administered alone were evaluated. Phase 2 evaluated serum concentrations and clearance of cyclosporin A and tacrolimus under the influence of itraconazole therapy. Among 17 patients who completed both phases of the study, the mean increase in the serum tacrolimus concentration was 83% (P<.0001), and the mean increase in the serum cyclosporin A concentration was 80% (P=.0001). There was no correlation between serum itraconazole concentrations and the serum concentrations of tacrolimus or cyclosporin A. The drug interaction between itraconazole and calcineurin inhibitors is predictable and occurs within 48 hours of concomitant drug administration. The data suggest that dose reductions of tacrolimus and cyclosporin A in the range of 50% to 100% are necessary when itraconazole therapy is initiated and that subsequent close monitoring of serum concentrations is necessary to guide further dose modifications.

Adult↗
PubMed2006

Preparing for the unthinkable: emergency preparedness for the hematopoietic cell transplant program.

Emergencies come at the most inopportune times. Some are totally unexpected, others come with short warnings. Although rare, an emergency comes with the potential to wreak disaster and pose serious risk to the services provided to hematopoietic cell transplant (HCT) patients. Yet, the consequences of an emergency can be mitigated by thinking the unthinkable and having a plan for emergency preparedness in place. Each HCT center should develop a plan containing steps of mitigation, preparedness, response and recovery. This report provides the framework for a HCT-specific emergency preparedness plan that can be used by individual centers to develop customized guidelines on preparing for, responding to, and recovering from an emergency.

Disaster Planning↗
PubMed2006

Is combination antifungal therapy for invasive aspergillosis a necessity in hematopoietic stem-cell transplant recipients?

PURPOSE OF REVIEW: The use of combination antifungal therapy in hematopoietic stem-cell transplantation patients is controversial and limited by a paucity of controlled data. The recent literature is reviewed and the relative arguments for and against combination antifungal therapy are outlined with summative recommendations to assist practitioners in decision-making. RECENT FINDINGS: There is an abundance of in-vitro and murine in-vivo combination antifungal literature, whereas clinical data are less abundant and controlled. Of the published case series there is a suggested benefit to combination therapy over monotherapy, although there are limitations to the available literature. Other issues in the combination debate that are addressed include the following: improved response rates and a survival advantage have been demonstrated in recent monotherapy studies; response rates in most published combination therapy studies do not suggest large gains over monotherapy; the lack of sustained survival advantage to combination therapy studies; and finally the consideration of host defenses in treatment responses. SUMMARY: Based on available data, combination therapy is not warranted at the initial diagnosis of invasive aspergillosis. Randomized, controlled trials with rigorous study design are needed.

Animals↗
PubMed2006

Factors associated with parameters of engraftment potential of umbilical cord blood.

BACKGROUND: Umbilical cord blood (UCB) is an acceptable source of hematopoietic cells for transplantation with success being associated with the nucleated cell count (NCC), CD34+ cells, and colony-forming unit-granulocyte-macrophage (CFU-GM) content infused. A total of 1033 UCB samples with neonatal and paternal characteristics that might influence hematopoietic content were examined. STUDY DESIGN AND METHODS: UCB samples were screened, processed, and reevaluated for the above cell counts. These parameters of engraftment potential were analyzed for associations with neonatal and parental characteristics. RESULTS: Postprocessed NCCs (median, 6.53 x 10(8)+/- 2.80 x 10(8) SD; mean 7.30 x 10(8)), CD34+ counts (median, 2.02 x 10(6) +/- 2.20 x 10(6) SD; mean, 2.65 x 10(6); r = 0.66; p < 0.001), and CFU-GM content (median, 2.65 x 10(5) +/- 3.16 x 10(5) SD; mean, 3.54 x 10(5); r = 0.61; p < 0.001) all were strongly interrelated. Both initial volume (median, 77.5 +/- 26.2 mL SD; mean, 81.9 mL) and initial NCC (median, 9.75 x 10(8) +/- 4.88 x 10(8) SD; mean, 10.9 x 10(8)) correlated well with postprocessed NCC (r = 0.60; r = 0.90; p < 0.01), CD34+ count (r = 0.40; r = 0.63; p < 0.01), and CFU-GM content (r = 0.38; r = 0.59; p < 0.01), with a stronger relationship seen with initial NCC. Infant birth weight (specifically, >3000 g), but not sex, gestational age, or cytomegalovirus status correlated strongly with collection volume and UCB cell counts. Units from minority volunteers contained relatively smaller volumes and hematopoietic content. CONCLUSION: UCB banks should emphasize selecting the heaviest infants and processing large-volume units with high NCCs to optimize hematopoietic potential. Minority recruitment should be encouraged with consideration given to inherent racial differences in cell counts. There does not appear to be a significant relationship between other neonatal and parental characteristics and that of engraftment potential.

Antigens, CD34↗
PubMed2005

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

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

Amphotericin B↗
PubMed2005

Study of renal safety in amphotericin B lipid complex-treated patients.

To investigate the renal safety of amphotericin B lipid complex (ABLC), records from 3514 ABLC-treated patients with fungal infections were reviewed. The median change in predicted creatinine clearance (CCr) from baseline to the end of therapy was -3 mL/min (range, -119 to 118 mL/min); doubling of serum creatinine (S-Cr) level occurred in 13% of patients, and new dialysis was needed for 3% of patients. Patients with underlying renal disease who had received prior antifungal therapy demonstrated a median CCr of 0.5 mL/min (range, -107 to 52 mL/min). Despite increased risk for renal impairment in allogeneic hematopoietic stem-cell transplant recipients, only 17% of patients demonstrated end-of-therapy doubling of S-Cr levels, and the median change in CCr was -10 mL/min (range, -107 to 108 mL/min). In ABLC-treated patients, concomitant treatment with potentially nephrotoxic agents and a baseline S-Cr level of <2 mg/dL were factors predisposing for the development of nephrotoxicity. These data provide evidence that ABLC may be used safely to treat patients who are at increased risk for renal impairment.

Adolescent↗
PubMed2005

Long-term health-related quality of life, growth, and spiritual well-being after hematopoietic stem-cell transplantation.

PURPOSE: To examine health-related quality of life (HRQOL) and growth, and spiritual well-being in adult survivors of hematopoietic stem-cell transplantation (HSCT) for a malignant disease. METHODS: HSCT survivors (n = 662) were recruited through the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry and were drawn from 40 transplantation centers. HSCT survivors completed a telephone interview and a set of questionnaires a mean of 7.0 years post-HSCT (range, 1.8 to 22.6 years). Study measures included a variety of standardized measures of HRQOL and growth and spiritual well-being. An age- and sex-matched healthy comparison (HC) group (n = 158) was recruited using a peer nomination method. The HC group completed a parallel telephone interview and set of questionnaires. RESULTS: Multivariate analysis of variance analyses found the HSCT survivor group reported poorer status relative to the HC group for all HRQOL outcome clusters including physical health, physical functioning, social functioning, psychological adjustment, and dyadic adjustment. In contrast, the HSCT survivor group reported more psychological and interpersonal growth. Mean effect size for the 24 outcome indices examined was 0.36 standard deviations, an effect size often considered clinically meaningful or important. The largest group differences were found for measures of general health, physical function and well-being, depression, cognitive function, and fatigue. CONCLUSION: The experience of HSCT for a malignant disease has a wide-ranging, longstanding, and profound impact on adult recipients. Relative to healthy controls, HSCT survivors reported poorer physical, psychological, and social functioning but, conversely, more psychological and interpersonal growth, differences that appeared to persist many years after HSCT.

Adult↗
PubMed2005

An assay for human hematopoietic stem cells based on transplantation into nonobese diabetic recombination activating gene-null perforin-null mice.

Abstract Nonobese diabetic recombination activating gene-null perforin-null (NOD- Rag1 null Prf1 null ) mice, which totally lack mature T and B cells and natural killer cell cytotoxic function, survive longer and are easier to breed than NOD-severe combined immunodeficiency ( scid ) or NOD- scid /beta 2 -microglobulin null mice. We have tested the use of NOD- Rag1 null Prf1 null mice as recipients in a long-term xenograft assay for human hematopoietic stem cells (HSCs) by adopting Yoder and colleagues' method of conditioned newborn mice, with minor modifications. Pregnant NOD- Rag1 null Prf1 null dams were treated with busulfan 22.5 mg/kg. On the day of delivery, the busulfan-exposed pups underwent transplantation with 4 to 5 million T cell--depleted human cord blood mononuclear cells via the facial vein. At 2 months after transplantation, all 11 transplanted mice showed human hematopoietic engraftment in the peripheral blood. At 6 months after transplantation, human cells were detected in 5 mice, which showed higher than 0.9% human cell engraftment at 2 months. The mean percentage of human CD45 + cells in the bone marrow of engrafted mice was 43.9% +/- 36.5% (range, 2.0%-79.9%). Next, we tested the usefulness of conditioned newborn NOD- Rag1 null Prf1 null mice for applications to characterize the dye efflux capability and phenotypic features of human HSCs. Given that cord blood HSCs have the ability to efflux rhodamine 123 (Rho), we attempted transplantations of sorted cells that retained a low level (Rho low ) or high level (Rho high ) of Rho. Six-month engraftment was found only with the Rho low cells, which contained high percentages of CD34 + CD38 - cells and side population cells with Hoechst 33324 efflux activity. These observations suggest that Rho low cells are highly enriched for primitive hematopoietic cells. Accordingly, conditioned newborn NOD- Rag1 null Prf1 null mice provide a desirable model for an assay of long-term transplantable human HSCs.

Animals↗
PubMed2005

Increased levels of tumor necrosis factor alpha are associated with an increased risk of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Tumor necrosis factor-alpha (TNF) has been implicated in the reactivation of cytomegalovirus (CMV) at a cellular level. We therefore hypothesized that increased posttransplantation TNF levels may be associated with the development of CMV antigenemia (CMV-Ag). We studied 134 patients undergoing allogeneic hematopoietic stem cell transplantation. After excluding CMV-negative donor and recipient pairs, 94 patients were evaluable. By cluster analysis, 2 groups were designated by TNF levels obtained between days 4 and 7 after transplantation: 58 patients had low levels (median, 0 pg/mL; range, 0-5.5 pg/mL), and 36 patients had high levels (median, 43.75 pg/mL; range, 7.5-1756 pg/mL). To determine the independent effect of TNF on the development of CMV-Ag and acute graft-versus-host disease and on survival, Kaplan-Meier and Cox models stratified by TNF patient groups were evaluated. High TNF levels were associated with a more rapid onset of CMV-Ag (P < .001) and with the occurrence of the composite end point of CMV-Ag or death (P < .001). Factors independently associated with CMV-Ag in multivariate analysis were a high TNF level (hazard ratio [HR], 2.57; P = .003) and acute graft-versus-host disease (as a time-dependent covariate; HR, 2.30; P = .010). Factors independently associated with the composite end point of CNV-Ag or death were a high TNF level (HR, 2.42; P < .001) and patient age (per year; HR, 1.93; P = .017). In conclusion, a high posttransplantation TNF level is significantly associated with the risk for developing CMV infection. Early detection of high levels of TNF may be used to identify patients at high risk for developing CMV-Ag.

Adult↗
PubMed2005

Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Interleukin (IL)-12 has antitumor effects in murine studies. To evaluate this clinically, we investigated whether high levels of circulating IL-12 in patients after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with improved relapse-free survival. We prospectively studied 134 patients undergoing HSCT. Median follow-up was 1158 days (range, 70-1792 days). Plasma IL-12 levels were measured before transplantation and on days 0, +4, +7, and +14 after transplantation. The highest levels were seen on days +4 and +7 and were categorized by a cluster analysis of the logarithmically transformed IL-12 concentrations, which were then correlated with relapse-free survival. Forty-six patients had low levels of IL-12 (median, 2 pg/mL; range, 0-6.5 pg/mL), 49 patients had medium levels (median, 20.5 pg/mL; range, 7-75.5 pg/mL), and 25 patients had high levels (median, 181 pg/mL; range, 84-623 pg/mL). Patients with high IL-12 levels before transplantation had the highest increase after transplantation. With a multivariate Cox model for relapse onset, with the low IL-12 level as the reference, patients in the high-IL-12 group had an adjusted hazard ratio of 0.27 (95% confidence interval, 0.09-0.79), and medium group patients had a hazard ratio of 0.65 (95% confidence interval, 0.31-1.36). The incidences of relapse at 500 days by Kaplan-Meier analysis by IL-12 group were 23.0% (high group), 40.3% (medium group), and 48.8% (low group). There was no association between IL-12 levels and the risk of acute graft-versus-host disease (GVHD; P = .51) or chronic GVHD (P = .28). In conclusion, high IL-12 levels after HSCT are associated with improved relapse-free survival without increasing the risk for GVHD. Patients with high pretransplantation IL-12 levels have an increased likelihood of higher posttransplantation IL-12 levels, possibly because of a host-graft interaction, and this may predispose to better clinical outcomes.

Acute Disease↗
PubMed2005

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.

This consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis of chronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) that describes the extent and severity of chronic GVHD for each organ or site at any given time, taking functional impact into account. Third, it proposes new guidelines for global assessment of chronic GVHD severity that are based on the number of organs or sites involved and the degree of involvement in affected organs (mild, moderate, or severe). Diagnosis of chronic GVHD requires the presence of at least 1 diagnostic clinical sign of chronic GVHD (e.g., poikiloderma or esophageal web) or the presence of at least 1 distinctive manifestation (e.g., keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests (e.g., Schirmer test) in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories of GVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic or distinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days after transplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond 100 days, often during withdrawal of immune suppression). The broad category of chronic GVHD includes (1) classic chronic GVHD (without features or characteristics of acute GVHD) and (2) an overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currently recommended that systemic therapy be considered for patients who meet criteria for chronic GVHD of moderate to severe global severity.

Chronic Disease↗