Current practices for treatment of respiratory syncytial virus and other non-influenza respiratory viruses in high-risk patient populations: a survey of institutions in the Midwestern Respiratory Virus Collaborative.

BACKGROUND: The optimal treatment for respiratory syncytial virus (RSV) infection in adult immunocompromised patients is unknown. We assessed the management of RSV and other non-influenza respiratory viruses in Midwestern transplant centers. METHODS: A survey assessing strategies for RSV and other non-influenza respiratory viral infections was sent to 13 centers. RESULTS: Multiplex polymerase chain reaction assay was used for diagnosis in 11/12 centers. Eight of 12 centers used inhaled ribavirin (RBV) in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience. Six of 12 used intravenous immunoglobulin (IVIG), mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post-stem cell transplant population, patients with lower respiratory tract infection (LRTI), graft-versus-host disease, and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, 6/10 treated upper respiratory tract infection (URTI). No center treated non-lung solid organ transplant (SOT) recipients with URTI; 7/11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancy without hematopoietic stem cell transplantation were treated with RBV at a similar frequency to non-lung SOT recipients. Three of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1/12 treated coronavirus. CONCLUSIONS: Treatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV, or the use of IVIG. The presence of such heterogeneity demonstrates the need for further studies defining optimal treatment of RSV in immunocompromised hosts.

Serial testing for latent tuberculosis infection in transplant candidates: a retrospective review.

BACKGROUND: Accurately identifying latent tuberculosis (TB) infection (LTBI) in liver and renal transplant candidates is important because of the risks associated with both treatment of LTBI and reactivation of disease in this population. Many programs advocate yearly screening of patients awaiting organ transplantation. The reproducibility of serial interferon-gamma release assay (IGRA) testing in transplant candidates has not been studied. METHODS: We conducted a retrospective longitudinal study of patients listed for liver or kidney transplantation between January 1, 2005 and February 1, 2012 at the University of Illinois Medical Center at Chicago. Data collected included demographics, transplant type, IGRA results, treatment received, and mortality. RESULTS: The study population was comprised of 795 adults; 79 (10%) had at least 1 indeterminate result; indeterminate results were less common in men (P = 0.01) and more common in liver transplant candidates (P < 0.001). The reversion frequency was 27% with a rate of 158.1 reversions in 1000 person-years. A higher magnitude of initial TB response values was predictive of consistently positive results (P < 0.001). The conversion frequency was 15% with a rate of 82.6 conversions in 1000 person-years. Among those who converted, the values of the IGRA varied, with 48% having a TB response of <1 IU/mL, 41% 1-5 IU/mL, and only 10% >5 IU/mL. CONCLUSIONS: A significant number of conversions and reversions occur during serial IGRA testing of transplant candidates. Delineating true-positive converters from false-positives is an issue that warrants further study.

Latent tuberculosis in kidney and liver transplant patients: a review of treatment practices and outcomes.

BACKGROUND: The standard treatment of latent tuberculosis infection (LTBI) is associated with toxicities and data are limited on tolerability among patients with advanced organ disease listed for transplant. Alternate options are available, but they have yet to be studied in this population. METHODS: A retrospective review of the treatment of LTBI among kidney and/or liver transplant candidates was conducted to assess factors impacting therapy initiation, tolerability, and completion of therapy. RESULTS: Of 174 eligible patients, treatment of LTBI was initiated in 129, of which 91 were listed for kidney transplant and 38 were listed for liver or liver/kidney transplant. Infectious Diseases consultation was independently associated with treatment initiation when controlling for waitlisted organ and receipt of hemodialysis (odds ratio [OR] 81.14, 95% confidence interval [CI] 23.94-274.94, P < 0.001). Documented completion of first-line therapy was 47% overall, and 49% and 39%, respectively, among kidney and liver/kidney candidates (P = not significant). On multivariable analysis, controlling for baseline aspartate aminotransferase and waitlisted organ, first-line receipt of rifampin was associated with lower rates of treatment completion (OR 0.19, 95% CI 0.05-0.77, P = 0.02). CONCLUSION: Based on medical record documentation, completion of first-line therapy was <50% in this cohort, although this is likely an underestimate, as 34% of patients had no chart documentation that therapy was completed. Approximately 20% of patients did not complete first-line therapy because of adverse effects.

A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.

AIM: A review of the clinical presentation, diagnosis, treatment and outcomes of 30 solid organ transplant recipients (SOTRs) with histoplasmosis or blastomycosis from 3 Midwestern academic medical centers. BACKGROUND: The endemic fungal pathogens, Histoplasma capsulatum and Blastomyces dermatitidis, may cause severe infection in SOTRs. In this report, we describe the clinical presentation, diagnosis, treatment, and outcomes of these endemic fungal infections (EFIs) among SOTRs at 3 academic transplant centers. METHODS: A retrospective review was conducted of SOTRs with histoplasmosis or blastomycosis from 3 Midwestern medical centers in the United States. Data collected included demographics, immunosuppression, clinical presentation, method of diagnosis, antifungal treatment, response to therapy, and patient and graft survival. RESULTS: Between 1996 and 2008, 30 transplant recipients with histoplasmosis or blastomycosis were identified, giving a cumulative incidence of infection of 0.50% (30/5989); 73% of the study patients were renal transplant recipients, and the median time to disease onset after transplantation was 10.5 months. The lungs were the most common site of infection (83%), and 60% had disseminated disease. Urine antigen testing was positive in all patients in whom it was performed (23/23). Initial antifungal therapy consisted of amphotericin B in 70%, and 87% received azoles, typically itraconazole (83%). Two patients developed relapsed infection and 7 patients had graft failure after EFI. Overall mortality was 30%, with an attributable mortality of 13%. CONCLUSIONS: As in several previous single-center studies, the incidence of post-transplant histoplasmosis and blastomycosis was <1%, but often resulted in disseminated infection. In this cohort, EFI was associated with a high rate of allograft loss and overall mortality.

Gastrointestinal tuberculosis in renal transplant recipients: case report and review of the literature.

Mycobacterium tuberculosis is an important opportunistic pathogen following renal transplantation and is often associated with adverse outcomes. Gastrointestinal tuberculosis (GITB) is an infrequent manifestation of TB but a potentially lethal one. We present a case of a renal allograft recipient with GITB 18 months after transplant and review other published cases to identify the typical presenting symptoms, risk factors, and natural history. Treatment of GITB is also discussed.

Unusual presentation of cytomegalovirus enteritis after liver and kidney transplantation.

Cytomegalovirus (CMV) is a cause of significant morbidity and mortality in solid organ transplant recipients. Gastrointestinal (GI) tract infection by CMV in this population can cause symptomatic disease, which typically manifests as fever, abdominal pain, nausea, and bloody diarrhea. Erosive lesions of the GI mucosa are often evident on endoscopic exam. We report an unusual presentation of CMV enteritis in a kidney and liver transplant recipient with the development of acute onset voluminous watery diarrhea in the absence of other typical symptoms and subsequent progression to hypovolemic shock and acute renal failure. This case emphasizes the atypical presentations of common opportunistic infections that may occur in immunosuppressed hosts.

Risk factors for wound healing complications in sirolimus-treated renal transplant recipients.

Impaired surgical site healing occurs in 20% to 50% of sirolimus (SRL)-treated renal transplant (RT) recipients, with most patients having received concomitant corticosteroids. We determined the incidence of surgical site complications among RT recipients receiving SRL with mycophenolate mofetil (MMF), with most patients on a steroid-avoidance protocol. SRL/MMF patients with complications within 3 months of transplantation were compared with 1) SRL/MMF patients without them and 2) matched RT recipients receiving tacrolimus (FK)/MMF. Between January 2002 and March 2005, 44 of 300 (15%) RT recipients received SRL within 6 weeks of transplantation. Fourteen (31.8%) developed lymphocele, bladder leak, wound dehiscence, cellulitis, or an abscess. Obesity (BMI > or =30 kg/m2) was significantly associated with problems: the mean BMI of SRL cases with complications was 29.9 kg/m2 vs 25.4 kg/m2 for SRL patients without them (P = .047). Seventy-one percent of obese SRL patients experienced complications compared with 24.3% (P = .025) of non-obese SRL patients. Surgical treatment was required in 29% of patients. Rates of maintenance steroid use were similar in SRL complicated cases compared with SRL patients without them. The FK control group showed a lower rate of complications (14.3%; P = .163) despite similar BMI, rejection rates, and chronic steroid use as the SRL group. Obesity and graft rejection were independent predictors of complications. Thus, among a group of predominantly steroid-free recipients on SRL, the rates of wound complications were similar to those seen previously, but the highest risk for them was observed in obese recipients and in those with acute rejection episodes. Wound complications were associated with significant morbidity.

Anti-capsular antibodies activate killing of Escherichia coli O8:K87 by the alternate complement pathway in porcine serum.

Enterotoxigenic Escherichia coli (ETEC) strains that produce K88 (F4)+ fimbria are important causes of diarrhea and post-diarrheal septicemia in swine. ETEC O8:K87, a serotype represented by a number of these strains, is typically serum resistant. Strain-specific antibodies are known to activate alternative C pathway-mediated killing of other serum-resistant E. coli [Hill, A.W., Shears, A.L., Hibbitt, K.G., 1978. The requirement of specific antibody for the killing of E. coli by the alternate complement pathway in bovine serum. Immunology 34, 131-136], but their antigenic targets have not been determined. We tested the hypothesis that anti-K87 antibodies activate alternative pathway-mediated killing of ETEC O8:K87. Pigs were immunized with ETEC O8:K87 strain 2534-86 cells or purified K87 polysaccharide. Post-, but not pre-immunization sera killed 2534-86 cells, and absorption with 2534-86 cells or by K87 affinity chromatography eliminated bactericidal activity. Complementation of absorbed serum with anti-K87 antibodies restored bactericidal activity, confirming the ability of these antibodies to activate C-mediated serum killing. Serum from age-matched, non-vaccinated control pigs also killed 2534-86. This activity was eliminated by absorption with 2534-86 cells, but not K87 affinity chromatography, indicating that specific non-capsular antibodies are also able to activate C-mediated killing. In all cases, Mg-EGTA-treated serum was as effective as non-treated serum in killing, suggesting that bactericidal activity was mediated predominantly if not exclusively via the alternative C pathway.

Limitations of current antiretroviral agents and opportunities for development.

Significant progress has been made in the field of human immunodeficiency virus (HIV) pharmacotherapy. This is a remarkable achievement given that the virus was first recognized in the United States in 1981 and the first antiretroviral (ARV) agent became available in 1987. There are now 20 medications in 4 different classes approved by the Food and Drug Administration (FDA) for the treatment of HIV and the carefully orchestrated use of these agents has dramatically decreased HIV mortality. However, the currently available agents have concerning limitations. These include potentially life-threatening side effects, drug interactions, loss of effectiveness over time due to resistance and the need for an extremely high level of medication adherence to achieve viral suppression. In the following review, important features of the presently available agents are described, and the characteristics of an ideal ARV agent defined.

Educational interventions for asthma in children.

BACKGROUND: Self-management education programs have been developed for children with asthma, but it is unclear whether such programs improve outcomes. OBJECTIVES: To determine the efficacy of asthma self-management education on health outcomes in children. SEARCH STRATEGY: Systematic search of the Cochrane Airways Group's and Cochrane Schizophrenia Group's Special Registers of Controlled Trials and hand searches of the reference lists of relevant review articles. SELECTION CRITERIA: Randomized and controlled clinical trials of asthma self-management education programs in children and adolescents aged 2 -18 years. DATA COLLECTION AND ANALYSIS: All studies were assessed independently by two reviewers. Disagreements were settled by consensus. Study authors were contacted for missing data or to verify methods. Subgroup analyses examined the impact of type and intensity of educational intervention, self-management strategy, trial type, asthma severity, adequacy of follow-up, and study quality. MAIN RESULTS: Of 45 trials identified, 32 studies involving 3706 patients were eligible. Asthma education programs were associated with moderate improvement in measures of airflow (standardized mean difference [SMD] 0.50, 95% confidence interval [CI] 0.25 to 0.75) and self-efficacy scales (SMD 0.36, 95% CI 0.15 to 0.57). Education programs were associated with modest reductions in days of school absence (SMD -0.14, 95% CI -0.23 to -0.04), days of restricted activity (SMD -0.29, 95% CI -0.49 to -0.08), and emergency room visits (SMD -0.21, 95% CI -0.33 to -0.09). There was a reduction in nights disturbed by asthma when pooled using a fixed-effects but not a random-effects model. Effects of education were greater for most outcomes in moderate-severe, compared with mild-moderate asthma, and among studies employing peak flow versus symptom-based strategies. Effects were evident within the first 6 months, but for measures of morbidity and health care utilization, were more evident by 12 months. REVIEWER'S CONCLUSIONS: Asthma self-management education programs in children improve a wide range of measures of outcome. Self-management education directed to prevention and management of attacks should be be incorporated into routine asthma care. Conclusions about the relative effectiveness of the various components are limited by the lack of direct comparisons. Future trials of asthma education programs should focus on morbidity and functional status outcomes, including quality of life, and involve direct comparisons of the various components of interventions.

A model of self-regulation for control of chronic disease.

Chronic disease poses increasing threat to individual and community health. The day-to-day manager of disease is the patient who undertakes actions with the guidance of a clinician. The ability of the patient to control the illness through an effective therapeutic plan is significantly influenced by social and behavioral factors. This article presents a model of patient management of chronic disease that accounts for intrapersonal and extemal influences on management and emphasizes the central role of self-regulatory processes in disease control. Asthma serves as a case for exploration of the model. Findings from a 5-year study of 637 children with asthma and their care-taking parents supported that the self-regulation elements of the model were reasonably stable over time and baseline values were predictive of important disease management outcomes.

Can children teach their parents about asthma?

The Open Airways for Schools (OAS) program has been shown to improve the self-management skills and health outcomes of students with asthma in Grades 3 to 5. This report examines the impact of OAS on students' parents. Because pilot studies showed that parental attendance at school-based sessions was low, the authors held six sessions at school for children and gave children homework assignments to complete with parents at home to teach parents about asthma and build support for children's self-management efforts. Analysis of 1-year follow-up data showed that children's participation in OAS was a significant predictor of parental self-management skills (p <.03) and that OAS children's communication was more strongly associated than controls' with parents' self-management (p = .05). The findings show that health education activities brought home from school by children can positively influence parents' self-management of a complex chronic disease such as asthma.

Factors influencing quality of life in older women with heart disease.

BACKGROUND: Better understanding of factors influencing the quality of life (QOL) of cardiac patients can guide treatment decisions. OBJECTIVES: To describe the impact of clinical and psychosocial factors on the QOL of older women with heart disease. RESEARCH DESIGN: Baseline and 12-month data from women participating in an intervention study. SUBJECTS: Eligible participants, identified from medical records, were female, > or = 60 years of age, and diagnosed with cardiac disease. A volunteer sample of 570 women (87% white) completed baseline interviews, with 485 women completing the 12-month assessment. MEASURES: Utilizing Wilson and Cleary's conceptual framework (1995), measures of clinical, psychosocial, and functional status were examined for their associations with QOL. RESULTS: At baseline, General Health Perceptions and Symptom Status accounted for 38% and 26%, respectively, of the variation in the QOL rating. Using logistic regression models, seven measures were significant predictors (P < 0.05) of maintenance/improvement versus decline in QOL over 12 months: baseline QOL rating; baseline value and change in satisfaction with social activities over 12 months; change in satisfaction with physical activities; change in satisfaction with mental activities; and baseline value and change in perceived stress. For women who maintained or improved their satisfaction with social activities, the odds for also maintaining or improving QOL were 4.5 times the odds for women whose satisfaction with social activities deteriorated. CONCLUSIONS: Satisfaction with social activities and perceived stress are important predictors of subsequent QOL. Consideration of the impact of treatments on these factors may help to prevent deterioration of QOL among older female cardiac patients.

GLI-2 modulates retroviral gene expression.

GLI proteins are involved in the development of mice, humans, zebrafish, Caenorhabditis elegans, Xenopus, and Drosophila. While these zinc finger-containing proteins bind to TG-rich promoter elements and are known to regulate gene expression in C. elegans and Drosophila, mechanistic understanding of how regulation is mediated through naturally occurring transcriptional promoters is lacking. One isoform of human GLI-2 appears to be identical to a factor previously called Tax helper protein (THP), thus named due to its ability to interact with a TG-rich element in the human T-lymphotropic virus type 1 (HTLV-1) enhancer thought to mediate transcriptional stimulation by the Tax protein of HTLV-1. We now demonstrate that, working through its TG-rich binding site and adjacent elements, GLI-2/THP actually suppresses gene expression driven by the HTLV-1 promoter. GLI-2/THP has no effect on the HTLV-2 promoter, activates expression from the promoters of human immunodeficiency virus types 1 and (HIV-1 and -2), and stimulates HIV-1 replication. Both effective suppression and activation of gene expression and viral replication require the first of the five zinc fingers, which is not necessary for DNA binding, to be intact. Thus, not only can GLI-2/THP either activate or suppress gene expression, depending on the promoter, but the same domain (first zinc finger) mediates both effects. These findings suggest a role for GLI-2 in retroviral gene regulation and shed further light on the mechanisms by which GLI proteins regulate naturally occurring promoters.

Human GLI-2 is a tat activation response element-independent Tat cofactor.

Zinc finger-containing GLI proteins are involved in the development of Caenorhabditis elegans, Xenopus, Drosophila, zebrafish, mice, and humans. In this study, we show that an isoform of human GLI-2 strongly synergizes with the Tat transactivating proteins of human immunodeficiency virus types 1 and 2 (HIV-1 and -2) and markedly stimulates viral replication. GLI-2 also synergizes with the previously described Tat cofactor cyclin T1 to stimulate Tat function. Surprisingly, GLI-2/Tat synergy is not dependent on either a typical GLI DNA binding site or an intact Tat activation response element but does require an intact TATA box. Thus, GLI-2/Tat synergy results from a mechanism of action which is novel both for a GLI protein and for a Tat cofactor. These findings link the GLI family of transcriptional and developmental regulatory proteins to Tat function and HIV replication.

Gender differences in the associations of self esteem, stress and social support with functional health status among older adults with heart disease.

This study explored and compared the role of self esteem, stress and social support in maintenance or improvement in physical and psychosocial functioning over 12 months in older men and women with cardiovascular disease. Data from 502 adults over 60 years of age showed that self esteem and stress were both significantly associated with functioning when demographic and clinical factors were controlled. Men were significantly more likely than women to maintain or improve in functioning. Self esteem, stress, compliance with medication regimens, and marital status were significantly associated with maintenance or improvement of functioning among women. Only age and stress were significantly associated with maintenance or improvement in functioning among men. Findings indicated that: (1) stress and self esteem were stronger predictors of functioning, especially among women, than demographic and clinical factors; and (2) women in the highest quartile of the self esteem distribution were approximately five times as likely to maintain or improve their functioning as women in the lowest quartile.

Increasing asthma knowledge and changing home environments for Latino families with asthmatic children.

We tested an asthma education program in 204 underserved Latino families with an asthmatic child. The education program consisted of one or two sessions delivered in each family's home in the targeted participant's preferred language by a bilingual, bicultural educator. We encouraged, but did not require, attendance by the child. The curriculum was culturally-tailored, and all participants received education on understanding asthma, preventing asthma attacks, and managing asthma. Outcomes included change in asthma knowledge and change in home environment asthma management procedures. Asthma knowledge increased significantly (39 to 50% correct from pre- to post-test, P < 0.001) and participants made significant changes to the child's bedroom environment (mean number of triggers decreased from 2.4 to 1.8, P < 0.001; mean number of controllers increased from 0.7 to 0.9, P < 0.001). The results support the value of asthma education and its importance in the national agenda to reduce health disparities among minorities.