Background Most studies of solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) focus on outcomes within 1 month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been... more
Background Most studies of solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) focus on outcomes within 1 month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. Methods We used data from a multicenter registry to calculate mortality by 90 days following initial acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional hazards models to compare risk factors for death by days 28 and 90. Results Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19; 190 of 936 (20%) died by 28 days, and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included age >65 years (adjusted hazard ratio [aHR], 1.8 [1.3–2.4]; P <.001), lung transplant (vs nonlung transplant; aHR, 1.5 [1.0–2.3]; P = .05), heart fail...
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Background Rapidly growing mycobacteria (RGM) have high rates of antibiotic resistance and require prolonged therapy with considerable toxicity. Less toxic and more effective therapies are needed. One promising agent is clofazimine (CFZ),... more
Background Rapidly growing mycobacteria (RGM) have high rates of antibiotic resistance and require prolonged therapy with considerable toxicity. Less toxic and more effective therapies are needed. One promising agent is clofazimine (CFZ), an antibiotic with favorable in vitro data but limited clinical data in RGM. Methods We performed a retrospective cohort study to assess outcomes of adult patients treated with CFZ for RGM infection. Primary outcome was cure, defined as no evidence of clinical, radiographic, or microbiologic recurrence within 1 year of follow-up after stopping treatment. If a patient was retreated for infection, only the index treatment was included in the analysis. Results We treated 55 adults for RGM infection with CFZ in combination with a median of 5 other antibiotic classes over the entire course of treatment. Of these patients, 58% had pulmonary infection (81% nodular-bronchiectatic and 19% cavitary); 100% of pulmonary infections were M. abscessus. Non-pulmon...
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Purpose Outcomes of lung transplant recipients (LTR) hospitalized for COVID-19 and comparisons to non-lung solid organ transplant recipients (SOTR) are incompletely described. Methods Using a multicenter prospective registry of SOTR, we... more
Purpose Outcomes of lung transplant recipients (LTR) hospitalized for COVID-19 and comparisons to non-lung solid organ transplant recipients (SOTR) are incompletely described. Methods Using a multicenter prospective registry of SOTR, we examined 28-day outcomes (mortality [primary outcome], intensive care unit (ICU) admission, mechanical ventilation, and bacterial pneumonia) among both LTR and non-lung SOTR hospitalized with laboratory-confirmed COVID-19 diagnosed between March 1, 2020 and September 21, 2020. Data were analyzed using Stata (StataCorp, College Station, TX); chi-square tests were used to compare categorical variables and multivariable logistic regression was used to assess risk factors for mortality. Results The cohort included 72 LTR and 392 non-lung SOTR (Table 1). Overall, 28-day mortality trended higher in LTR vs. non-lung SOTR (27.8% vs. 19.9%, P=0.136). Other 28-day outcomes were similar between LTR and non-lung SOTR: ICU admission (45.8% vs. 39.1%, P=0.28), mechanical ventilation (32.9% vs. 31.1%, P=0.78), and bacterial pneumonia (15.3% vs. 8.2%, P=0.063). Congestive heart failure, diabetes, age >65 years, and obesity (BMI >= 30) were independently associated with mortality in non-lung SOTR, but not in LTR (Table 2). Conclusion In this large prospective cohort comparing lung and non-lung SOTR hospitalized for COVID-19, there were high but not significantly different rates of short-term morbidity and mortality. Baseline comorbidities appeared to drive mortality in non-lung SOTR but not LTR. Further studies are needed to identify risk factors for mortality among LTR.
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Background Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of... more
Background Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. Methods We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. Results Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 live...
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Background The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients.... more
Background The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described. Methods We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. Results Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46–57), median time post-transplant was 5 years (IQR 2–10), 61% were male, and 92% ha...
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Supplemental Digital Content is available in the text. Background. Infection remains a leading cause of death in kidney transplant recipients. This study aimed to assess the scope and consistency of infection outcomes reported in... more
Supplemental Digital Content is available in the text. Background. Infection remains a leading cause of death in kidney transplant recipients. This study aimed to assess the scope and consistency of infection outcomes reported in contemporary trials conducted in kidney transplant recipients. Methods. A literature review of all randomized trials and trial protocols reporting infection outcomes in adult kidney transplant recipients was identified in the Cochrane Kidney and Transplant Specialized Register from January 2014 to July 2019. Characteristics and infection outcomes from the trials were analyzed. Results. From 102 included trials, 772 outcome measures were extracted and categorized into 216 unique measures with a median of 3.2 outcome measures per trial (range: 1–9). Measures were further grouped into 32 outcomes based on site of infection (14 outcomes) and organism (18 outcomes). The most commonly reported site-specific outcome and organism-specific outcome were systemic infection (71% trials) and cytomegalovirus infection (62% trials), respectively. Outcome metric and methods of aggregation included mean, median, proportion, proportional change, and number of patients with at least 1 episode. Across all trials, measures were assessed at 55 different time points with a range of 1–11 time points per trial. Conclusions. Infection outcomes in kidney transplant recipients were frequently reported by site and organism but varied widely in terms of outcome, metrics, method of aggregation, and time point of measurement. Establishment of core outcomes for infection based on the shared priorities of patients/caregivers and health professionals may improve the consistency, comparability, and usefulness of trial evidence
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Coronavirus Disease 2019 (COVID-19) remains a global health emergency with limited treatment options, lagging vaccine rates and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune... more
Coronavirus Disease 2019 (COVID-19) remains a global health emergency with limited treatment options, lagging vaccine rates and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses. To test whether a short course of treatment was safe in COVID-19 patients, we treated 10 hospitalized, oxygen requiring, non-critically ill patients with CSA at a starting dose of 9mg/kg/day. Five patients experienced adverse events, none were serious, and transaminitis was most common. No subject enrolled in this trial required intensive care unit (ICU)-level care and all patients were discharged alive from the hospital. Further, CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyper-inflammation, including CXC...
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Donor‐derived infections with multidrug‐resistant gram‐negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor‐derived, disseminated infection with... more
Donor‐derived infections with multidrug‐resistant gram‐negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor‐derived, disseminated infection with colistin‐resistant, carbapenemase‐producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug‐resistant infections in immunocompromised hosts.
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Transplant recipients are uniquely susceptible to infectious diseases due to the nature of their underlying conditions and their immunosuppressed status; consequently infections in solid organ transplantation may be associated with... more
Transplant recipients are uniquely susceptible to infectious diseases due to the nature of their underlying conditions and their immunosuppressed status; consequently infections in solid organ transplantation may be associated with significant morbidity and mortality. These patients are not only vulnerable to a broad range of infectious organisms including those not normally considered to be pathogenic, but also prone to unusual presentations and more severe manifestations of infection. Chapter 7 is an introduction to the risks and epidemiology of infections in solid organ transplantation. It provides an overview of pre-transplantation donor and candidate screening, reviews the classic timeline for infection, and discusses methods for disease prevention including immunizations, environmental control, and post-transplantation prophylaxis.
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The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in... more
The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in detail. Two study populations were examined retrospectively to assess the survival of liver grafts procured from HCV+ donors. First, we evaluated the survival of all 13 HCV+ and 103 HCV- grafts that were transplanted at our institution to HCV+ recipients from January 1, 1995 to December 31, 1999. In parallel, we analyzed a subset of the United Network for Organ Sharing (UNOS) liver transplant database from the same 5-year time period that was comprised of 14,195 adult patients for whom donor and recipient HCV serologies were known. Kaplan-Meier graft survival for both patient populations was calculated based on donor and recipient HCV serologic status. A Cox proportional hazards analysis was performed on UNOS data to identify variables independently predicting graft survival. For transplants performed at our institution, we found no statistically significant difference in the Kaplan-Meier graft survival of HCV+ and HCV- grafts transplanted to HCV+ recipients (P=0.68). The incidence of biopsy-proven, recurrent HCV posttransplant was similar in recipients receiving either HCV+ or HCV- grafts (4/13 vs. 18/103, chi-square P=0.211). Analysis of UNOS data revealed that the survival of HCV+ grafts in HCV+ recipients was equivalent to the survival of HCV- grafts in HCV+ recipients. Unexpectedly, the survival of grafts in HCV+ recipients in general was significantly inferior to that of grafts in HCV- recipients. Multivariate analysis of all patients found recipient but not donor HCV status to be independently predictive of graft survival. Analysis of data from a single center and the national UNOS database suggests that transplantation of liver allografts from HCV+ donors to HCV+ recipients results in graft survival comparable to HCV- grafts transplanted to HCV+ recipients. In contrast, recipient HCV positivity is an independent predictor of graft failure compared with patients transplanted for other causes of liver disease.
Research Interests: Survival Analysis, Treatment Outcome, Medicine, Hepatitis C, Transplantation, and 12 morePopulation, Humans, Internal Medicine, Hepatitis C Virus, Liver Transplantation, Time Factors, Proportional hazards model, Survival Rate, Retrospective Studies, Proportional Hazards Models, Medical and Health Sciences, and Tissue and organ procurement
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The detection and management of potential donor-derived infections is challenging, in part due to the complexity of communications between diverse labs, organ procurement organizations (OPOs), and recipient transplant centers. We sought... more
The detection and management of potential donor-derived infections is challenging, in part due to the complexity of communications between diverse labs, organ procurement organizations (OPOs), and recipient transplant centers. We sought to determine if communication delays or errors occur in the reporting and management of donor-derived infections and if these are associated with preventable adverse events in recipients. All reported potential donor-derived transmission events reviewed by the Organ Procurement and Transplantation Network Ad Hoc Disease Transmission Advisory Committee from January 2008 to June 2010 were evaluated for communication gaps between the donor center, OPO and transplant centers. The impact on recipient outcomes was then determined. Fifty-six infection events (IEs; involving 168 recipients) were evaluated. Eighteen IEs (48 recipients) were associated with communication gaps, of which 12 resulted in adverse effects in 69% of recipients (20/29), including six ...
Research Interests: Health Sciences, Communication, Medicine, Quality of Care, Humans, and 12 moreClinical research, Practice, Infectious Disease, Organ Transplantation, Psychological Intervention, General medicine, Prognosis, Care Delivery, Organ procurement, Adverse effect, Medical and Health Sciences, and Tissue and organ procurement
BACKGROUND Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and... more
BACKGROUND Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. METHODS In an international online survey, participants rated the absolute importance of 16 infections and 8 severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. RESULTS 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, 8 who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5 respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1) and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top 3 most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top 3 severity dimensions. Relative importance (best-worst) scores were consistent. CONCLUSIONS Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes. This article is protected by copyright. All rights reserved.
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M.G.I. received research support, paid to Northwestern University, from AiCuris, Janssen, and Shire; he is a paid consultant for Adagio, AlloVir, Celltrion, Cidara, Genentech, Roche, Janssen, Shionogi, and Viracor Eurofins; he is also a... more
M.G.I. received research support, paid to Northwestern University, from AiCuris, Janssen, and Shire; he is a paid consultant for Adagio, AlloVir, Celltrion, Cidara, Genentech, Roche, Janssen, Shionogi, and Viracor Eurofins; he is also a paid member of DSMBs from Janssen, Merck, SAB Biotherapeutics, Sequiris, Takeda, and Vitaeris. R.A. received research support, paid to Johns Hopkins University, from Aicuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, and Takeda/Shire. E.B. received research support, paid to the University of Pennsylvania, from Merck and Takeda and has served on DSMB for Amplyx and has served as an unpaid scientific advisor for Merck and Takeda. D.K. received research support, paid to the University of Michigan, from AstraZenica and Janssen. S.P. has participated in clinical trials with Chimerix and Merck and receives research support from Global Life Technologies. N.M.T. received research support, paid to UMass Memorial Medical Center, from Incyte. C.R.W. is a paid consultant for Enzychem; he is also member of DSMBs from Atea and Biogen. The other authors declare no conflicts of interest.
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Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases... more
Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases Society of America Training Program Directors’ Committee focused the 2018 National Fellowship Program Directors’ Meeting at IDWeek on “Remediation of the Struggling Fellow.” Small group discussions addressed 7 core topics, including feedback and evaluations, performance management and remediation, knowledge deficits, fellow well-being, efficiency and time management, teaching skills, and career development. This manuscript synthesizes those discussions around a competency-based framework to provide program directors and other educators with a roadmap for addressing common contemporary remediation challenges.
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A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and... more
A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P =...
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We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D... more
We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic uti...
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Research Interests: Gastroenterology, Kidney transplantation, Medicine, Prevention, Humans, and 15 moreInternal Medicine, Cytomegalovirus, Prodrug, CMV, Association, Prophylaxis, Cytomegalovirus Infections, Long Term, Likelihood Functions, Predictive value of tests, Antiviral Agents, immunoglobulin G, Ganciclovir, immunoglobulin M, and Medical and Health Sciences
Novel influenza A/H1N1 virus has caused significant illness worldwide. In response to this global crisis, the American Society of Transplantation (AST) Infectious Diseases Community of Practice and the Transplant Infectious Diseases... more
Novel influenza A/H1N1 virus has caused significant illness worldwide. In response to this global crisis, the American Society of Transplantation (AST) Infectious Diseases Community of Practice and the Transplant Infectious Diseases section of The Transplantation Society (TTS) developed a guidance document for novel H1N1. In this paper, we discuss current guidance for H1N1 as it relates to solid organ transplantation. We include discussion around clinical presentation, diagnosis, therapy and prevention specifically addressing areas such as chemoprophylaxis, immunization and donor-derived infection. Although this document addresses conditions specific to novel H1N1, many principles could be applied to future pandemics. As new information emerges about novel H1N1, updates will be made to the electronic version of the document posted on the websites of the AST and TTS.
Research Interests: Surgery, Treatment, Public Health, Medicine, Transplantation, and 15 moreHumans, Society, Child, influenza A, Organ Transplantation, Infant, American, Immunocompromised host, Intensive Care Medicine, Transplants, Pandemic, Antiviral Agents, Child preschool, Medical and Health Sciences, and Influenza vaccines
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Certain endocrinopathies and metabolic abnormalities such as adrenal insufficiency and hyponatremia may be clues to the diagnosis of tuberculosis while, at the same time, complicating its management; others, such as prolonged therapy with... more
Certain endocrinopathies and metabolic abnormalities such as adrenal insufficiency and hyponatremia may be clues to the diagnosis of tuberculosis while, at the same time, complicating its management; others, such as prolonged therapy with pharmacologic doses of glucocorticoids, can reactivate and disseminate tuberculosis in the susceptible patient. This enhancement of susceptibility to reactivation of tuberculosis by prolonged, high-dose glucocorticoid therapy is the more important problem, clinically. Of lesser importance, but of considerable pathophysiologic interest, are the phenomena of hyponatremia and hypercalcemia. Individual endocrine glandular deficiency due to tuberculous destruction is rare, with the exception of involvement of the internal genitalia (see Chapter 13).
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Background With the ongoing opioid epidemic in the US, there has been an increase in the proportion of deceased organ donors with a history of injection drug use (IDU), raising concern for additional infectious risks to transplantation.We... more
Background With the ongoing opioid epidemic in the US, there has been an increase in the proportion of deceased organ donors with a history of injection drug use (IDU), raising concern for additional infectious risks to transplantation.We sought to determine how recent IDU among deceased organ donors impacted donor culture results. Methods A retrospective cohort study was conducted at four transplant centers in Philadelphia between 1/1/2015 and 6/30/2016. All deceased organ donors who donated ≥ 1 organ to one of the centers were included. Exposed donors were those with a recent history of IDU (defined by use in the prior 12 months based on donor chart review). Unexposed donors were those with no recent history of IDU. The primary outcome was any positive donor culture (taken during the terminal hospitalization or at the time of organ procurement) for bacteria or Candida. Multivariable logistic regression was used to determine the association between recent IDU and donor culture posi...
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Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a... more
Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.
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End-organ disease has become a major cause of morbidity and mortality in HIV-infected patients due to increased life expectancy, increasing the demand for organ transplantation in these patients. The care of HIV-infected transplant... more
End-organ disease has become a major cause of morbidity and mortality in HIV-infected patients due to increased life expectancy, increasing the demand for organ transplantation in these patients. The care of HIV-infected transplant recipients warrants a multidisciplinary team approach, including the transplant team, pharmacists, infectious disease specialists, nurses, and patients and their families. The immunosuppression of HIV-infected recipients post-transplant does not appear to further advance HIV disease. The post-transplant risk for HIV-infected recipients of opportunistic infections does not appear to be increased by immunosuppression. However, the overall rate of infections is high, and it is even higher in hepatitis C virus (HCV) co-infected transplant recipients. HIV/HCV co-infected recipients have worse outcomes compared to both liver and kidney HIV-infected recipients.
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The impact of pre‐transplant (SOT) carbapenem‐resistant Enterobacterales (CRE) colonization or infection on post‐SOT outcomes is unclear. We conducted a multi‐center, international, cohort study of SOT recipients, with microbiologically... more
The impact of pre‐transplant (SOT) carbapenem‐resistant Enterobacterales (CRE) colonization or infection on post‐SOT outcomes is unclear. We conducted a multi‐center, international, cohort study of SOT recipients, with microbiologically diagnosed CRE colonization and/or infection pre‐SOT. Sixty adult SOT recipients were included (liver n = 30, hearts n = 17). Klebsiella pneumoniae (n = 47, 78%) was the most common pre‐SOT CRE species. Median time from CRE detection to SOT was 2.32 months (IQR 0.33–10.13). Post‐SOT CRE infection occurred in 40% (n = 24/60), at a median of 9 days (IQR 7–17), and most commonly due to K pneumoniae (n = 20/24, 83%). Of those infected, 62% had a surgical site infection, and 46% had bloodstream infection. Patients with post‐SOT CRE infection more commonly had a liver transplant (16, 67% vs. 14, 39%; p =.0350) or pre‐SOT CRE BSI (11, 46% vs. 7, 19%; p =.03). One‐year post‐SOT survival was 77%, and those with post‐SOT CRE infection had a 50% less chance of survival vs. uninfected (0.86, 95% CI, 0.76–0.97 vs. 0.34, 95% CI 0.08–1.0, p =.0204). Pre‐SOT CRE infection or colonization is not an absolute contraindication to SOT and is more common among abdominal SOT recipients, those with pre‐SOT CRE BSI, and those with early post‐SOT medical and surgical complications.
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Despite clinical and laboratory screening of potential donors for transmissible disease, unexpected transmission of disease from donor to recipient remains an inherent risk of organ transplantation. The Disease Transmission Advisory... more
Despite clinical and laboratory screening of potential donors for transmissible disease, unexpected transmission of disease from donor to recipient remains an inherent risk of organ transplantation. The Disease Transmission Advisory Committee (DTAC) was created to review and classify reports of potential disease transmission and use this information to inform national policy and improve patient safety. From January 1, 2008 to December 31, 2017, the DTAC received 2185 reports; 335 (15%) were classified as a proven/probable donor transmission event. Infections were transmitted most commonly (67%), followed by malignancies (29%), and other disease processes (6%). Forty‐six percent of recipients receiving organs from a donor that transmitted disease to at least 1 recipient developed a donor‐derived disease (DDD). Sixty‐seven percent of recipients developed symptoms of DDD within 30 days of transplantation, and all bacterial infections were recognized within 45 days. Graft loss or death occurred in about one third of recipients with DDD, with higher rates associated with malignancy transmission and parasitic and fungal diseases. Unexpected DDD was rare, occurring in 0.18% of all transplant recipients. These findings will help focus future efforts to recognize and prevent DDD.
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The advent of therapies for successful treatment of hepatitis C virus has allowed the heart and lung transplant community to re-explore the use of hepatitis C virus-positive donors for organ transplantation, with a benefit for many... more
The advent of therapies for successful treatment of hepatitis C virus has allowed the heart and lung transplant community to re-explore the use of hepatitis C virus-positive donors for organ transplantation, with a benefit for many terminally ill patients. The consensus statements provided herein represent the current state of knowledge and expertise in this area, which we expect will continue to rapidly evolve over the next few years.
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Introduction In transplant recipients, CMV infection RR to prior antiviral Tx is associated with significant morbidity and mortality. Existing antivirals are not approved for RR CMV infection and are limited by their toxicities. A prior... more
Introduction In transplant recipients, CMV infection RR to prior antiviral Tx is associated with significant morbidity and mortality. Existing antivirals are not approved for RR CMV infection and are limited by their toxicities. A prior Phase 2 dose-ranging study of MBV for RR CMV (67% of patients [pts] achieved undetectable CMV DNA within 6 wks) motivated initiation of a Phase 3 trial with the concept of an investigator-assigned (IA) Tx comparator arm. Objective To assess the efficacy and safety of MBV compared with IA anti-CMV therapies in HSCT/SOT recipients with RR CMV infection. Methods In this Phase 3, randomized, open-label, multicenter, active-controlled study (NCT02931539), HSCT/SOT recipients (≥12 years old) with RR CMV infection are randomized 2:1 to MBV (400 mg BID) or IA Tx (ganciclovir [GCV], valganciclovir [VGC], foscarnet [FSC], cidofovir [CDV]) for 8 wks. Pts in the IA Tx group discontinuing Tx early (lack of response and/or intolerance; investigator discretion) are assessed Wks 3–7 to enter MBV rescue arm. Pts are followed for 12 wks after the 8-wk Tx period. Inclusion criteria include: documented CMV infection with screening value ≥2730 IU/mL / ≥910 IU/mL (whole blood / plasma) in 2 consecutive tests ≥1 day apart; current refractory CMV infection: documented failure to achieve >1 log10 decrease in CMV DNA after ≥14 days of the same anti-CMV Tx. Pts with ≥1 genetic mutation associated with GCV/VGC, FSC or CDV resistance must also meet refractory criteria. Pts with tissue invasive CMV disease with CNS involvement including the retina, eg CMV retinitis, are excluded. A central specialty laboratory quantifies plasma CMV DNA (COBAS ‘AmpliPrep/TaqMan’ CMV test). The primary efficacy endpoint is confirmed CMV viremia clearance (defined as plasma CMV DNA concentrations Results Planned enrollment is 351 pts across ∼140 sites (North America, Europe, Asia Pacific). Study start, Dec 2016; completion ∼Sep 2020. Conclusions The comparator arm of this Phase 3 study is valid for evaluating efficacy and safety of MBV for RR CMV compared with available anti-CMV Tx, whilst allowing for personalized Tx for pts in the comparator group.
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The quality of the papers published in Transplant Infectious Disease depends on both the authors and the expert peer reviewers, who help the Editors choose the best papers and help the authors to improve their presentation and to make... more
The quality of the papers published in Transplant Infectious Disease depends on both the authors and the expert peer reviewers, who help the Editors choose the best papers and help the authors to improve their presentation and to make their papers the best they can be. Careful timely reviews are what make the peerreview journal system function. We are very grateful for the efforts of all our reviewers who have helped our Journal achieve high standards of quality again this year. We express our thanks to those who have reviewed manuscripts for our Journal this past year. The Editors are deeply grateful for their assistance and could not produce this journal without their time and expertise. – The Editors
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Background Transplant guidelines recommend exercising caution when considering organs that may be infected or colonized with multidrug-resistant organisms (MDROs) and treating the organ recipient with perioperative antibiotics active... more
Background Transplant guidelines recommend exercising caution when considering organs that may be infected or colonized with multidrug-resistant organisms (MDROs) and treating the organ recipient with perioperative antibiotics active against the donor MDRO. Unfortunately, donor MDROs are often identified only after transplantation. We developed a clinical prediction tool to stratify donors’ MDRO risk at the time of donor evaluation. Methods A retrospective cohort study was conducted at four transplant centers in Philadelphia between January1, 2015 and June 30, 2016. All deceased organ donors who donated ≥1 organ to one of the centers were included. Multivariate logistic regression was used to determine predictors of donor MDROs, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci, extended-spectrum cephalosporin-resistant (ESC-R) or carbapenem-resistant Enterobacteriaceae, multidrug-resistant (MDR) P. aeruginosa, or MDR Acinetobacter species. Manual fo...
Background CDI is an important cause of morbidity and mortality in SOT and HCT patients (pts). In retrospective single-center analyses, severe disease and relapse were common. We undertook a multicenter prospective observational study to... more
Background CDI is an important cause of morbidity and mortality in SOT and HCT patients (pts). In retrospective single-center analyses, severe disease and relapse were common. We undertook a multicenter prospective observational study to evaluate outcomes of CDI among both SOT and HCT patients. Methods Adults with a first episode of CDI, defined as 3 liquid stools/24 h with the detection of C. difficile toxin in stool, within the first 2 years of SOT or HCT were recruited from 12 centers internationally in the INSIGHT network. At enrollment, demographics, comorbidities, medication histories and outcomes were collected prospectively over 90 days to assess clinical cure, recurrences and complications and to define baseline risk factors for clinical cure and recurrent CDI. Results 132 patients (81 SOT, 51 HCT (32 allogeneic)) were enrolled: median age 56 years, 62.1% were males, 97% were hospitalized. 80.3% were diagnosed by DNA assay. CDI occurred a median of 20 days post transplant (...
Background Valganciclovir (VGCV) and ganciclovir (GCV) are commonly used to prevent CMV in at-risk lung transplant recipients (LTRs). Because renal function changes frequently in the post-transplant setting, antiviral under-dosing may... more
Background Valganciclovir (VGCV) and ganciclovir (GCV) are commonly used to prevent CMV in at-risk lung transplant recipients (LTRs). Because renal function changes frequently in the post-transplant setting, antiviral under-dosing may occur. We sought to determine the frequency of GCV/VGCV under-dosing and its impact on CMV-related outcomes among LTRs. Methods We conducted a retrospective cohort study of all adult LTRs with a CMV seropositive donor (D+) between 2014 and 2016 at the Hospital of the University of Pennsylvania. Exposed patients were those with exposure to inappropriately low-dose GCV/VGCV. Unexposed patients were those whose antiviral dosing was consistently appropriate for their creatinine clearance. We employed a multivariable Cox proportional hazard analysis to determine the impact of low-dose prophylaxis on time to CMV infection post-transplant; prophylaxis dosing was incorporated as a time-varying covariate in this survival analysis. Results 108 adults underwent C...
Research Interests: Medicine()
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PURPOSE OF REVIEW The purpose of this review is to highlight novel advances in prophylaxis against and treatment of CMV in kidney transplant recipients. Current options include intravenous ganciclovir and oral valganciclovir, but use of... more
PURPOSE OF REVIEW The purpose of this review is to highlight novel advances in prophylaxis against and treatment of CMV in kidney transplant recipients. Current options include intravenous ganciclovir and oral valganciclovir, but use of these agents is limited by side effects, such as myelosuppression as well as evolving resistance in CMV strains. RECENT FINDINGS Advances in the field include novel drugs that have shown promise in preliminary studies and are now being tested in large-scale clinical trials. Moreover, there is a developing focus in enhancing host immune responses to better protect against viral infection using anti-CMV vaccines. Studying host immune responses to CMV has also led to improved monitoring strategies, such as the QuantiFERON assay, which will allow for improved risk stratification and targeted therapies in transplant recipients. SUMMARY In summary, although options for prophylaxis and treatment against CMV have been somewhat limited to date, a number of new strategies are currently under development with several drugs in phase 3 trials. Therefore, the landscape of CMV management in kidney transplant recipients will be changing significantly in the coming years with the ultimate goal of safer and more effective therapies to combat CMV.
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Hepatitis C virus (HCV) seroconversion among HCV‐uninfected transplant recipients from HCV‐infected (NAT+/Antibody+) or HCV‐exposed (NAT−/Antibody+) donors has been reported. However, the origin of anti‐HCV antibody and the implications... more
Hepatitis C virus (HCV) seroconversion among HCV‐uninfected transplant recipients from HCV‐infected (NAT+/Antibody+) or HCV‐exposed (NAT−/Antibody+) donors has been reported. However, the origin of anti‐HCV antibody and the implications of seroconversion remain unknown. We longitudinally tested plasma from HCV‐uninfected kidney (n = 31) or heart transplant recipients (n = 9) of an HCV NAT+ organ for anti‐HCV antibody (both IgG and IgM isotypes). Almost half of all participants had detectable anti‐HCV antibody at any point during follow‐up. The majority of antibody‐positive individuals became positive within 1‐3 days of transplantation, and 6 recipients had detectable antibody on the first day posttransplant. Notably, all anti‐HCV antibody was IgG, even in samples collected posttransplant day 1. Late seroconversion was uncommon (≈20%‐25% of antibody+ recipients). Early antibody persisted over 30 days in kidney recipients, whereas early antibody dropped below detection in 50% of heart recipients within 2 weeks after transplant. Anti‐HCV antibody is common in HCV‐uninfected recipients of an HCV NAT+ organ. The IgG isotype of this antibody and the kinetics of its appearance and durability suggest that anti‐HCV antibody is donor derived and is likely produced by a cellular source. Our data suggest that transfer of donor humoral immunity to a recipient may be much more common than previously appreciated.
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These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the management of transplantation in HIV‐infected individuals. Transplantation has become the standard of care... more
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the management of transplantation in HIV‐infected individuals. Transplantation has become the standard of care for patients with HIV and end‐stage kidney or liver disease. Although less data exist for thoracic organ and pancreas transplantation, it is likely that transplantation is also safe and effective for these recipients as well. Despite what is typically a transient decline in CD4+ T lymphocytes, HIV remains well controlled and infection risks are similar to those of HIV‐uninfected transplant recipients. The availability of effective directly active antivirals for the treatment of Hepatitis C is likely to improve outcomes in HIV and HCV co‐infected individuals, a population previously noted to have decreased survival. Drug interactions remain an important consideration, and integrase inhibitor‐based regimens are preferred due to the absence of interactions with calcineurin and mTOR inhibitors. Additionally, despite the use of more potent immunosuppression, rejection rates exceed those found in HIV‐uninfected recipients. Ongoing research evaluating HIV‐positive organ donors may provide support for utilizing these donors for HIV‐positive patients in need of transplantation.
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Purpose of ReviewIn addition to the infectious risk associated with all solid organ transplants, pancreas transplantation poses some unique risks associated with surgical technique and host risk factors. This review highlights several key... more
Purpose of ReviewIn addition to the infectious risk associated with all solid organ transplants, pancreas transplantation poses some unique risks associated with surgical technique and host risk factors. This review highlights several key areas of infectious diseases that physicians must consider in patients undergoing pancreas transplantation.Recent FindingsSurgical site infections are common after pancreas transplantation, and empiric antimicrobials, including antifungal coverage, are often needed to reduce the risk of these infections. Cytomegalovirus and Epstein-Barr virus (EBV) infections require close monitoring post-transplant, and we are just beginning to understand risk factors for post-transplant lymphoproliferative disorder, which is often associated with EBV infection in these patients.SummaryPancreas transplantation can be a successful cure for diabetes, if post-transplant complications, including rejection and infection, can be appropriately managed. Recent use of pancreata from HIV- and HCV-positive donors has increased the pool of possible donors, and ideally, more centers will begin to use these organs. Islet cell transplantation and xenotransplantation are exciting new avenues of research for potential diabetes cures.
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Influenza is responsible for significant morbidity after transplantation. We evaluated Th1/Th2 cytokines and IL-10 levels during influenza infection in the post-transplant setting. Sera from 277 transplant recipients were analyzed at... more
Influenza is responsible for significant morbidity after transplantation. We evaluated Th1/Th2 cytokines and IL-10 levels during influenza infection in the post-transplant setting. Sera from 277 transplant recipients were analyzed at influenza diagnosis and 28 days later for IFN-γ, IL-4, IL-13 and IL-10. IL-13 levels were associated with protection against pneumonia and ICU admission, whereas the IFN-γ/IL-13 ratio and IL-10 levels were associated with an increased risk of pneumonia and ICU admission. This association was independent of viral load. A skewing of immune responses towards Th2 in transplant patients appears to confer protection from severe influenza infection, independently of viral load.
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Organs from hepatitis C virus (HCV)-infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected... more
Organs from hepatitis C virus (HCV)-infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected kidneys could be safely transplanted into HCV-negative patients. However, intermediate-term data on quality of life and renal function are needed to counsel patients about risk. To describe 12-month HCV treatment outcomes, estimated glomerular filtration rate (eGFR), and quality of life for the 10 kidney recipients in THINKER-1 and 6-month data on 10 additional recipients. Open-label, nonrandomized trial. (ClinicalTrials.gov: NCT02743897). Single center. 20 HCV-negative transplant candidates. Participants underwent transplant with kidneys infected with genotype 1 HCV and received elbasvir-grazoprevir on posttransplant day 3. The primary outcome was HCV cure. Exploratory outcomes included 1) RAND-36 Physical Component Summary (PCS) and Mental Componen...