Christopher R. Ensor

De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation

BACKGROUND The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. METHODS We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). RESULTS We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). CONCLUSIONS Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.

Generic maintenance immunosuppression in solid organ transplant recipients.

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immuno‐suppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.

Prophylaxis and Treatment of Respiratory Syncytial Virus in Adult Immunocompromised Patients

Objective: To review the literature regarding current strategies and strategies under active development for the prevention and treatment of respiratory syncytial virus (RSV) infections in immunocompromised adults. Data Sources: The MEDLINE/PubMed, EMBASE, and Cochrane databases were queried from January 1980 to December 2011 for articles in English using these associated search terms: respiratory syncytial virus, ribavirin, intravenous immunoglobulin, IVIG, palivizumab, motavizumab, lung, pneumonia, transplantation, bone marrow, cancer, malignancy, and vaccine. Study Selection and Data Extraction: All relevant original studies, metaanalyses, systematic reviews, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. Data Synthesis: RSV in the immunocompromised adult can lead to significant morbidity and mortality. Treatment of RSV-infected adults is limited to antiviral therapy with ribavirin (aerosolized, oral, intravenous) and immunomodulation with intravenous immunoglobulins, corticosteroids, and palivizumab. Existing literature is predominantly case reports, small trials, and retrospective reviews of patients infected with RSV who have undergone lung or hematopoietic stem cell transplantation (HSCT). Palivizumab may be a viable option for prophylaxis against RSV in high-risk adults. Ribavirin is the most studied treatment option and should remain the backbone of multidrug regimens. Of the routes of administration, aerosolized ribavirin carries the preponderance of evidence and, though challenging, is preferred to limit systemic toxicities in the infected patient. Addition of an immunomodulator to ribavirin may provide a survival benefit over ribavirin alone; however, this has only been studied in a subset of HSCT patients with lower respiratory tract RSV infection. Conclusions: Research most strongly supports the use of aerosolized ribavirin as the treatment strategy for immunocompromised adults with RSV. Addition of an immunomodulator may provide a survival benefit over ribavirin alone. Strategies and supportive data for the prevention of RSV infection in the high-risk adult are critically needed.

Pharmacist-managed international normalized ratio patient self-testing is associated with increased time in therapeutic range in patients with left ventricular assist devices at an academic medical center.

Patients with left ventricular assist devices (LVADs) are at increased risk of bleeding and thrombotic complications making warfarin therapy particularly challenging. Patient self-testing (PST) using point-of-care international normalized ratio (INR) devices has shown favorable outcomes in other populations, but the use of PST in LVAD patients has not been well described. The purpose of this study was to evaluate the effectiveness of pharmacist-managed INR PST versus usual care (UC) in patients with LVADs at a single center. We performed a retrospective cohort study of adult patients (in a 1:4 ratio PST versus UC) implanted with an LVAD (HeartMate II or HVAD) treated with warfarin from January 1, 2007, to January 31, 2013. We reviewed all INRs and bleeding/thrombotic events in LVAD patients whose anticoagulation was managed by clinical pharmacists via INR PST versus UC and calculated a percent time in therapeutic range (%TTR) by Rosendaal method. Fifty-five patients were studied. Demographic data were generally similar between the cohorts. Mean %TTR was higher in the PST cohort versus UC (44.4% vs. 30.6%, p = 0.026). There was no difference in the rate per patient-year of bleeding (0.23 vs. 0.33, p = 0.55) or thrombotic events (0.12 vs. 0.13, p = 0.88). Pharmacist-managed INR PST is associated with an increased %TTR in patients with LVADs.

Streamlining the process for initial review of pharmacy residency applications: An analytic approach

PURPOSE An analytics-driven process for improving the efficiency of initial candidate screening by pharmacy residency programs is described. METHODS In an initiative to streamline pharmacy resident selection at Johns Hopkins Hospital, retrospective analyses of materials submitted by prospective residents during two application periods (n = 277) were conducted to identify the applicant characteristics most strongly associated with the ultimate extension of an invitation to interview. Multiple two-member teams of pharmacist reviewers independently scored each application on 13 variables, with the resultant item scores tallied to derive rank sum scores. Univariate and multivariate logistic regression analyses were performed to identify the factors most important in distinguishing candidates invited for an interview from those not invited. RESULTS Univariate analysis indicated that all 13 evaluated applicant characteristics correlated with the likelihood of an interview invitation, but some were relatively less determinative; these factors were excluded from a final multivariate logistic regression model containing only the 7 factors most strongly predictive of an invitation to interview: grade point average, pharmacy work experience, professional association involvement, rotation experiences, presentations, publications, and skills and certifications. The final model was found to be highly explanatory (r(2) = 0.66) of variances in interview-invitation decisions and has been adopted as a guide to future initial screening of candidate applications. CONCLUSION By analyzing the relative importance of specific residency applicant characteristics and focusing on those deemed most useful in determining which candidates are invited for interviews, a large teaching institution streamlined preliminary application screening while maintaining an equitable candidate selection process.

Intravenous Neostigmine for Postoperative Acute Colonic Pseudo-Obstruction

Objective: To review the literature on the safety and effectiveness of neostigmine for the treatment of postoperative acute colonic pseudo-obstruction. Data Sources: The MEDLINE/PubMed, EMBASE, and Cochrane databases from November 1969 to November 2011 were queried for articles published in English, using the search terms neostigmine, acute colonic pseudo-obstruction, postoperative, surgery, and Ogilvie syndrome. Study Selection and Data Extraction: All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. Data Synthesis: Neostigmine may provide an effective treatment option for postoperative acute colonic pseudo-obstruction (ACPO) after conservative treatment measures have failed. One randomized controlled trial, 8 prospective and 3 retrospective observational studies, and 9 case reports evaluated neostigmine for ACPO. Included studies were limited by small sample sizes and heterogeneous populations not focused on postoperative patients, use of adjuvant agents, and lack of a consistent neostigmine regimen. Conclusions: Neostigmine may be a safe and effective treatment option for postoperative ACPO; however, current data do not support its use as a first-line intervention. Prospective and retrospective studies have demonstrated improvement in clinical symptoms, reduction in time to resolution, and reduction of recurrence for patients who failed conservative management. Prospective clinical trial data that evaluate early neostigmine versus conservative management are critically needed to determine neostigmines role as a first-line therapy for ACPO.

Pharmacotherapy for Mechanical Circulatory Support: A Comprehensive Review

Objective To provide a comprehensive review of the pharmacotherapy associated with the provision of mechanical circulatory support (MCS) to patients with end-stage heart failure and guidance regarding the selection, assessment, and optimization of drug therapy for this population. Data Sources: The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched from 1960 to July 2010 for articles published in English using the search terms mechanical circulatory support, ventricular assist system, ventricular assist device, left ventricular assist device, right ventricular assist device, biventricular assist device, total artificial heart, pulsatile, positive displacement, axial, centrifugal, hemostasis, bleeding, hemodynamic, blood pressure, thrombosis, antithrombotic therapy, anticoagulant, antiplatelet, right ventricular failure, ventricular arrhythmia, anemia, arteriovenous malformation, stroke, infection, and clinical pharmacist. Study Selection And Data Extraction: All relevant original studies, metaanalyses, systematic reviews, guidelines, and reviews were assessed for inclusion. References from pertinent articles were examined for content not found during the initial search. Data Synthesis: MCS has advanced significantly since the first left ventricular assist device was implanted in 1966. Further advancements in MCS technology that occurred in the tatter decade are changing the overall management of end-stage heart failure care and cardiac transplantation. These pumps allow for improved bridge-to-transplant rates, enhanced survival, and quality of life. Pharmacotherapy associated with MCS devices may optimize the performance of the pumps and improve patient outcomes, as well as minimize morbidity related to their adverse effects. This review highlights the knowledge needed to provide appropriate clinical pharmacy services for patients supported by MCS devices. Conclusions: The HeartMate II clinical investigators called for the involvement of pharmacists in MCS patient assessment and optimization. Pharmacotherapeutic management of patients supported with MCS devices requires individualized care, with pharmacists as part of the team, based on the characteristics of each pump and recipient.

Induction immunosuppression for orthotopic heart transplantation: a review

Objectives To describe the appropriateness and safety of induction immunosuppression for patients at risk for fatal rejection, and to describe the safety and effectiveness profiles of the induction regimens available in the United States. Data Sources MEDLINE/PubMed database, EMBASE database, Google Scholar; references from pertinent articles were also reviewed to identify additional data. Study Selection A systematic literature review from January 1, 1980, through June 30, 2008, was performed. Included articles ranged from case series to prospective randomized controlled double-blind placebo-controlled trials that detailed the following topics with respect to induction immunosuppression: risk of fatal rejection, renal sparing, malignancy, OKT3, rabbit or equine antithymocyte globulin, daclizumab, basiliximab, and alemtuzumab. Results Patients at highest risk for fatal rejection experienced a survival benefit from induction immunosuppression, whereas all other patients experienced no benefit or harm. Most of the early data detail positive experiences with polyclonal antibody regimens. Several newer trials compare the use of polyclonal strategies with the use of anti-CD25 targeted monoclonal antibodies. Few researchers have assessed the usefulness of an anti-CD52 approach. Overall, induction therapy remains a poorly studied and widely variable practice among the major US heart transplant centers. Conclusion At present, the unrestricted use of induction for all patients does not seem prudent. Induction should be individualized for each patient on the basis of a well-designed protocol, careful analysis of the transplant centers demographics, and the effectiveness and safety profiles of the regimens used.

Characterization, prophylaxis, and treatment of infectious complications in craniomaxillofacial and upper extremity allotransplantation: a multicenter perspective.

Background: Vascularized composite allotransplants consist of heterogeneous tissues from different germ layers, which include skin, muscle, bone, fat, nerves, and lymph nodes. The antigenic diversity of these tissues, particularly of the highly immunogenic skin component, necessitates potent immunosuppressive regimens similar to that of some solid organ transplants. Indeed, the lifelong, high-dose, multidrug immunosuppressive protocols expose vascularized composite allotransplant recipients to considerable risk of infectious, metabolic, and neoplastic sequelae. In this article, the authors review the infectious risk to patients after vascularized composite allotransplantation, with special attention to the somewhat limited experience with the prophylaxis and treatment of infections after this innovative reconstructive surgery. Methods: A review of the literature was undertaken to elucidate the characterization, prophylaxis, and treatment of all documented infectious complications. Results: Infections in face and hand vascularized composite allotransplants follow a course similar to that of solid organ transplants. Several differences exist, including the unique flora of craniomaxillofacial transplants, the increased risk of donor-derived infections, and the alteration of the risk-to-benefit ratio for cytomegalovirus infections. Conclusions: The patient with a face or limb transplant has many of the same infectious risks as a lung transplant recipient, which include bacterial, viral, and fungal infections. Because of the anatomy, mucosal exposure, and differing donor flora, however, the face or limb transplant is susceptible to invasive diseases from a variety of microbes.

Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings

We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)‐based therapy for antibody‐mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement‐1q (C1q)‐fixing ability of their immunodominant (ID) donor‐specific anti‐human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230–11 874) to 1878 (653–7791) after therapy (p = 0.001) and to 1400 (850–8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714–14 405) to <30 after therapy (p = 0.01) and <30 2 weeks later (p = 0.02). Forced expiratory volume in 1s ( FEV1) fell from mean 2.11 L pre‐AMR to 1.92 L at AMR (p = 0.04). FEV1 was unchanged after CFZ (1.91 L) and subsequently rose to a maximum of 2.13 L (p = 0.01). Mean forced expiratory flow during mid forced vital capacity (25–75) (FEF25–75) fell from mean 2.5 L pre‐AMR to 1.95 L at AMR (p = 0.01). FEF25–75 rose after CFZ to 2.54 L and reached a maximum of 2.91 L (p = 0.01). Responders had less chronic lung allograft dysfunction or progression versus nonresponders (25% vs. 83%, p = 0.04). No deaths occurred within 120 days and 7 patients died post CFZ therapy of allograft failure. Larger prospective interventional studies are needed to further describe the benefit of CFZ‐based therapy for pulmonary AMR.