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Biomedical subjects

J R Wingard

Publications and source records attributed to J R Wingard.

At least 91 records · Page 5Linked to original sources

Early detection of human cytomegalovirus viremia in bone marrow transplant recipients by DNA amplification.

Surveillance blood cultures for human cytomegalovirus (HCMV) are commonly used to identify the bone marrow transplant (BMT) recipients with the highest risk of serious HCMV disease and for whom early interventional ganciclovir therapy would be beneficial. We monitored 36 allogeneic BMT recipients weekly for the presence of HCMV in the blood from 0 to 100 days posttransplantation. Viable HCMV in leukocytes (WBC) was detected by shell vial and tube culture methods. HCMV DNA in WBC and plasma was detected by PCR and DNA hybridization using primers and a probe from the EcoRI fragment D region of HCMV AD169. A uracil-N-glycosylase-dUTP PCR protocol was used to prevent false-positive results due to amplicon carryover. Seventeen patients had multiple consecutive positive samples containing HCMV DNA in plasma or WBC. In 14 of 17 patients, HCMV was also detected by blood culture. HCMV DNA was detected sporadically in six patients, none of whom had positive cultures. One patient had HCMV viremia detected by WBC culture only. The remaining 12 patients had no positive PCR assays or blood cultures. For the patients with positive blood cultures, PCR detection of HCMV DNA in plasma preceded detection of HCMV in culture by a mean of 8 days and detection in WBC preceded detection in culture by 6 days. HCMV disease (interstitial pneumonia) was documented for two patients with viremia (blood culture and PCR positive) and one patient without viremia (blood culture and PCR negative). The earlier recognition of high-risk patients provided by detection of HCMV DNA in plasma or WBC may improve the efficacy of early interventional antiviral therapy.

Bone Marrow Transplantation↗

Thrombotic thrombocytopenic purpura associated with FK506 following bone marrow transplantation.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) have been observed after bone marrow transplantation (BMT), typically occurring 1-6 months following BMT. We describe two patients who developed TTP very early after BMT while receiving intravenous FK506. They were treated with platelet support and plasma exchange (PE) using either fresh frozen plasma (FFP) or cryosupernatant fraction of plasma (CFP), resulting in remission of TTP activity.

Adult↗

Viral infections in severely immunocompromised cancer patients.

Immunocompromised cancer patients are susceptible to infection by many viral pathogens. The most serious morbidity results from active infection by members of the herpes virus family. Reactivation of latent virus occurs as a sequela of cytotoxic therapy and deficiency of cell-mediated immunity, especially cytotoxic responses, the major host protective defense. Herpes simplex virus and varicella zoster virus infections are problematic in patients with all types of cancer; cytomegalovirus infections cause life-threatening morbidity in bone marrow transplant patients. Several antiviral agents are highly active against these pathogens and different strategies of using them have resulted in reduced morbidity and mortality. Ultimately, the resolution of these infections is dependent on the control of the malignancy and the ability of the patient to mount an adequate immune response.

Chickenpox↗

Infections due to resistant Candida species in patients with cancer who are receiving chemotherapy.

The apparent increase in the prevalence of candidal infections among patients with cancer and the changes in the spectrum of Candida pathogens infecting these patients are associated with a number of factors. Selection of less-susceptible organisms occurs because antibacterial and antifungal agents alter microbial flora, and the use of these agents can lead to mutations that confer antibiotic resistance to initially susceptible organisms. Candida organisms that are resistant to polyenes and azoles have been increasingly isolated from specimens from oncology patients, and outbreaks of infections due to these less-susceptible organisms have been reported in several centers. Antifungal resistance has largely been observed among non-albicans Candida species, especially Candida parapsilosis, Candida lusitaniae, and Candida krusei. However, there also has been an increase in the isolation of resistant Candida albicans, the more prevalent and more virulent species of Candida, from specimens from other patients. Isolation of resistant C. albicans from oncology patients has been rare, although the potential for further problems exists. These observations emphasize the importance of the selective pressure exerted by antifungal agents on the microbiological flora of patients and the influence of these agents on the prevalence and spectrum of fungal pathogens in clinical settings.

Antifungal Agents↗

Predictors of acute respiratory failure after bone marrow transplantation in children.

OBJECTIVE: To determine factors associated with acute respiratory failure after bone marrow transplantation which can be identified before the onset of lung disease. DESIGN: Population-based, retrospective study. SETTING: A referral-based pediatric intensive care unit and bone marrow transplant center. PATIENTS: Thirty-nine patients with lung disease (abnormal chest radiograph or a need for supplemental oxygen) were identified from a group of 318 pediatric bone marrow transplant patients from 1978 to 1988. Thirty-four of 39 patients with complete data were further classified into patients with mild lung disease (recovery without needing endotracheal intubation, n = 16) and patients with acute respiratory failure (requirement for endotracheal intubation, n = 18). INTERVENTIONS: Regression analyses were performed to define risk factors for development of respiratory failure (multivariate logistic regression) and for a shortened interval between the identification of lung disease and respiratory failure (Cox proportional hazards analysis). MEASUREMENTS AND MAIN RESULTS: Ninety-three percent (15/16) of patients with mild lung disease survived. Conversely, only 9% (2/23) of patients with respiratory failure survived. Predictors of respiratory failure included graft vs. host disease (odds ratio 28.3, 95% confidence interval 1.9-421, p = .015), a prelung disease (baseline) circulating creatinine concentration of > 1.5 mg/dL (> 132.6 mumol/L) (odds ratio 28.4, 95% confidence interval 1.4-577, p = .029), and male gender (odds ratio 14.6, 95% confidence interval 1-210, p = .049). Predictors of a shortened time to onset of respiratory failure included baseline serum creatinine value of > 1.5 mg/dL (> 132.6 mumol/L) (hazard ratio 6.2, 95% confidence interval 1.5-26.5, p = .013) and baseline total bilirubin concentration > 1.4 mg/dL (> 23.9 mumol/L) (hazard ratio 4.5, 95% confidence interval 0.98-20.7, p = .053). The median time to onset of respiratory failure was 4 days in patients with baseline creatinine values > or = 1.5 mg/dL (> 132.6 mumol/L) and 5 days in patients with baseline bilirubin concentrations > or = 1.4 mg/dL (> 23.9 mumol/L) vs. > 26 days in patients with creatinine < 1.5 mg/dL (< 132.6 mumol/L) and > 29 days in patients with bilirubin < 1.4 mg/dL (< 23.9 mumol/L) (Kaplan-Meier analysis). CONCLUSIONS: Renal and liver dysfunction preceded clinical evidence of lung disease in bone marrow transplant patients who developed respiratory failure. Lung disease leading to respiratory failure and adult respiratory distress syndrome appears to develop as one component of the multiple organ failure syndrome in pediatric bone marrow transplant patients.

Acute Disease↗

Functional ability and quality of life of patients after allogeneic bone marrow transplantation.

In recent years, increasing attention has focused on the quality of life of long-term survivors of bone marrow transplantation. Most survivors appear to have good health and high levels of functional capacity, exhibit little psychological distress and achieve social adaptation and resumption of valued roles. In addition, they conduct educational and employment pursuits and experience satisfaction with their lives at levels comparable to the general population. However, some survivors, especially those with chronic graft-versus-host disease, report low levels of these parameters. Challenges for future studies are to identify the various changes that occur over time, the tempo at which they occur, how the changes interact, and what parameters predict for positive and adverse outcomes. Such investigations will provide the basis of strategies to optimize good outcomes.

Adult↗

Quality of life of bone marrow transplant long-term survivors.

Adult survivors of bone marrow transplantation not in life threatening relapse were surveyed with a mailed questionnaire 6-149 months after transplant. Of 171 eligible patients, 157 were contacted and 135 (86%) responded. Survivors showed a high degree of overall satisfaction with major life domains but were least satisfied with their bodies, level of physical strength and ability to attain sexual satisfaction. Positive and negative affect were higher than general population samples and less tension, fatigue, confusion and depression were displayed than comparison groups. Multiple regression analyses showed that self-esteem and level of current physical functioning made significant contributions to predicting multiple quality-of-life outcomes. Previous graft-versus-host disease was predictive of low satisfaction with life domains. Lack of social support was predictive of anger and Negative Affect. Transplantation at a younger age was related to overall life satisfaction, vigor and Positive Affect. Women showed more Negative Affect than men. Time since transplant related to level of confusion among patients. Most survivors reported high levels of perceived quality of life on multiple indicators. Self-esteem, current level of physical functioning, social support and age at bone marrow transplantation were predictive of quality of life outcomes.

Adolescent↗

Personal changes, dispositional optimism, and psychological adjustment to bone marrow transplantation.

We investigated the number and direction of personal changes experienced by long-term survivors of bone marrow transplantation (BMT) and the relationships of those changes and dispositional optimism to psychological adjustment (current and future life satisfaction and mood). Surveys were returned by 86.0% (N = 135) of all eligible long-term survivors; respondents primarily were young males who were 6 to 149 months post-BMT. Subjects reported more positive changes in the relationship and existential/psychological domains and more negative changes in the physical health domain; there was no difference on the plans/activities domain. Negative changes were more strongly related to adjustment than were positive changes. The number of negative changes reported was significantly related to current and future life satisfaction and negative mood after controlling for demographic and illness variables and dispositional optimism. The interaction term for negative and positive changes was significantly related to future life satisfaction after controlling for all other variables.

Adaptation, Psychological↗

Chromosome abnormalities in patients treated with 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation.

Autologous bone marrow transplantation (ABMT) offers potentially curative therapy for patients with acute leukemia and lymphoma, yet little information exists about the chromosome abnormalities observed in ABMT recipients. Clonal abnormalities of chromosome 1 were reported by van den Akker. We report the cytogenetic results of 55 patients who underwent ABMT between November 1987 and July 1990: acute nonlymphocytic leukemia (ANLL, 22), acute lymphocytic leukemia (ALL, eight), Hodgkin's disease (seven), lymphoma (16), other (two). ANLL patients received busulfan and cytoxan, and the others received cytoxan and total body irradiation as their preparative regimen before transplant. BM was purged ex vivo with 4-hydroperoxycyclophosphamide (4-HC) at 30-100 micrograms/ml before reinfusion to kill tumor cells. Cytogenetic analysis was performed before and after transplant. Between one and four posttransplant specimens of BM were analyzed per patient (range 36-921 days). Chromosome abnormalities were observed in 14 of 55 patients after transplant. Seven had clonal abnormalities; all were in leukemic relapse, and one karyotype had complex rearrangements. Clonal abnormalities of chromosome 1 were not observed. Seven patients had nonclonal changes, and three of these have had overt clinical relapse. Our data suggest that clonal abnormalities observed posttransplant are best explained by clinical relapse of tumor and that ex vivo marrow purging with 4-HC is not likely to induce clonal chromosome abnormalities in normal cells. Long-term observation of these patients will be required to answer that question definitively, however.

Adolescent↗

Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients.

Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.

Amphotericin B↗

Viral infections in leukemia and bone marrow transplant patients.

Infections by herpesviruses are common phenomena in patients being treated for acute leukemia and those undergoing bone marrow transplantation. Reactivation of endogenous latent virus caused by the immunosuppressive and cytotoxic effects of cytoreductive therapies is a common mechanism of infection. With cytomegalovirus (CMV), acquisition of exogenous virus by transfusion of blood products containing virus and from the bone marrow graft in the case of bone marrow transplantation can occur. Serious morbidity can result and occasional mortality. CMV infections in allogeneic BMT recipients have high case fatality rates. Treatment and preventive strategies for herpes simplex virus (HSV), CMV, and varicella zoster virus (VZV) have been developed to reduce morbidity. Acyclovir, either given prophylactically or as treatment of active infection, has been highly successful in reducing illness from HSV and VZV infection. For CMV, provision of CMV-seronegative blood products is the mainstay of prevention of morbidity in seronegative patients and is especially important in the care of patients undergoing allogeneic BMT. Ganciclovir given either prophylactically or as early therapy for patients detected to be shedding CMV appears to be a promising strategy. Bolstering host immunity through augmentation of anti-CMV cytotoxic T-cell responses appears to be an exciting candidate therapy under development.

Bone Marrow Transplantation↗

Infections in allogeneic bone marrow transplant recipients.

Remarkable strides have been made in the management of infectious complications after bone marrow transplantation. Improved understanding of patterns of infection, the introduction of new antimicrobials, the advent of cytokines to enhance immune recovery, the development of better strategies to control graft-versus-host disease, and the availability of more accurate and rapid diagnostic assays have all contributed to reducing the morbidity and mortality from infection after allogeneic marrow transplantation.

Bacterial Infections↗

Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis.

To assess the efficacy of immune globulin in preventing CMV infection, interstitial pneumonia, GVHD and death after BMT, we reviewed and synthesized data from 12 published studies (with 1282 patients) in which immune globulin was used prophylactically in BMT patients, controls were included and clinical outcomes were assessed. Data synthesis indicates that immune globulin significantly reduces fatal CMV infection (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.23-0.99), CMV pneumonia (OR 0.61, CI 0.42-0.89), non-CMV interstitial pneumonia (OR 0.57, CI 0.35-0.95) and total mortality (OR 0.74, CI 0.55-0.99). The reduction in acute GVHD was not quite significant (OR CI 0.45-1.02). Complications decrease with both hyperimmune and conventional immune globulin. For CMV-negative transplant recipients, immune globulin decreases symptomatic CMV infection (OR 0.55, CI 0.31-0.94) and interstitial pneumonia (OR 0.34, CI 0.15-0.77). For CMV-positive recipients, immune globulin prevents interstitial pneumonia (OR 0.45, CI 0.26-0.80) but not symptomatic CMV infection (CI 0.41-2.80). We conclude that immune globulin is efficacious in preventing major complications of BMT in both CMV-negative and CMV-positive recipients.

Adult↗

New preparative regimens with diaziquone or cytarabine in combination with busulfan and cyclophosphamide.

Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.

Antineoplastic Combined Chemotherapy Protocols↗

Factors influencing third party payer costs for allogeneic BMT.

To assess how payer costs for allogeneic BMT relate to patient characteristics and clinical complications, a retrospective cohort study of 402 persons undergoing allogeneic BMT between 1980 and 1987 at a university-based BMT center was designed to determine total inpatient payer costs, including hospital and physician costs, and number of days hospitalized during the first 180 days following BMT. The average total inpatient payer cost (in 1990 dollars) during the first 180 days following BMT was $208,410. Inflation-adjusted inpatient payer costs increased from $227,806 in 1980 to $308,545 in 1983, and then decreased to $156,163 by 1987. In multivariate analysis, inpatient payer costs were strongly associated with occurrence of CMV infection (increase of $53,517; p = 0.0001) or acute GVHD (increase of $46,500; p = 0.001), and significantly associated with malignant (versus non-malignant) disease (decrease of $36,633; p = 0.05), even after adjusting for length of survival and year of BMT. Inpatient payer costs were not related to patient age, sex or race. Despite recent reductions in inpatient payer costs for BMT, CMV infection and acute GVHD continue to be associated with tremendous costs to third party payers. Further reductions in the costs of BMT may require improved prevention of CMV infection and GVHD.

Adolescent↗

Thalidomide for the treatment of chronic graft-versus-host disease.

BACKGROUND: Allogeneic bone marrow transplantation is an accepted therapy for hematologic cancer, aplastic anemia, and inherited immunodeficiencies. Chronic graft-versus-host disease (GVHD) is the principal complication in patients surviving more than 100 days. Thalidomide has been shown experimentally to be effective in treating GVHD. METHODS: We treated 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with "high-risk" chronic GVHD (identified as having at least two of the following three risk factors: chronic GVHD that has evolved from acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction. Such patients have a high mortality rate.) with thalidomide in a dose that produced a plasma level of 5 micrograms per milliliter two hours after administration. Therapy was continued for three months after a complete response or for six months after a partial response. RESULTS: The overall actuarial survival of all enrolled patients was 64 percent. Survival was 76 percent among the patients receiving salvage therapy for refractory GVHD and 48 percent among those with high-risk GVHD. A complete response was observed in 14 patients, a partial response in 12 patients, and no response in 18. Side effects were minor, most notably sedation in almost all patients. CONCLUSIONS: In this preliminary trial, thalidomide appeared to be safe and effective for the treatment of chronic GVHD. A trial comparing thalidomide with prednisone in patients with newly diagnosed chronic GVHD will be required to demonstrate its relative efficacy.

Adolescent↗