Razonable, Raymund R.

AbstractThis study of 64 solid organ and hematopoietic stem cell transplant recipients found that peripheral blood absolute lymphocyte count of <610 and <830/µL, respectively, correlated with cytomegalovirus infection. In an era when sophisticated measures of CMV-specific T cells are emerging, we emphasize the utility of the inexpensive and readily-available absolute lymphocyte count.

AbstractBackgroundTacrolimus is a cornerstone of immunosuppression after transplantation but is highly susceptible to changes from interacting variables and has a narrow therapeutic index. Clotrimazole troches are commonly used as a non‐systemic antifungal to prevent oral candidiasis. Studies suggest that clotrimazole troches, though minimally absorbed systemically, may affect tacrolimus concentrations by inhibition of metabolic enzyme activity in the intestines. However, the magnitude of the impact of clotrimazole on tacrolimus dosing requirements to maintain goal levels is not well described.MethodsTo assess this, tacrolimus dose adjustments and trough concentrations were retrospectively examined in 95 heart transplant recipients before and after the discontinuation of clotrimazole.ResultsThe median percent tacrolimus dose change was an increase of 66.7% (IQR28.6%, 100%) after clotrimazole discontinuation, and the median trough concentration percent change from baseline to the first trough after clotrimazole discontinuation (in the absence of a dose change) was −42.5% (IQR−52.3%, −30.9%). Five cases of allograft rejection were observed.ConclusionIn conclusion, clotrimazole troches exert a meaningful interaction with tacrolimus that requires close monitoring and dose adjustment. The data from this single‐center study provide novel information that could guide providers on the degree of tacrolimus dose adjustment needed when discontinuing clotrimazole prophylaxis after heart transplantation.

Abstract Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed “resistant/refractory CMV” and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of “resistant” and “refractory” CMV. These definitions have emerged from the Working Group’s review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies.

Background. Control of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) requires a functional immune system. We assessed the association between quantitation and function of CMV-specific CD8+ T cells and CMV infection in SOT recipients. Methods. During a 10-year period, selected kidney, heart, lung, pancreas, liver, and composite tissue recipients were tested for CMV-specific CD8+ T cells immune competence (CMV-CD8+), as measured by enumeration, interferon-gamma production, and CD107a/b degranulation. Quantitative and functional data were used to assemble T-cell immune competence (TIC) score. CMV infection was diagnosed by polymerase chain reaction in blood and other samples or histopathology. Results. Of 130 patients tested, 59 had CMV infection or disease. The median onset to CMV infection was 10.5 months (interquartile range [IQR], 5.5–18.7). Gastrointestinal disease (28.8%), pneumonia (20.3%), and CMV syndrome (17%) were most common presentation. An impaired nonspecific or CMV-CD8+ TIC score was associated with tissue-invasive disease (hazard risk, 2.84, 95% confidence interval, 1.03–11.81; P = 0.04). Patients with impaired CMV-CD8+ TIC score had longer viremia duration (42.4 days vs 18.8 d; P < 0.001). Patients with impaired nonspecific or CMV-CD8+ TIC score had higher risk of relapse (68.8% vs 27.9%; hazard risk, 2.56; 95% confidence interval, 1.09–5.89; P = 0.03). Patients with CMV infection or disease had lower median absolute lymphocyte count (380 [IQR, 240–540] vs 940 [IQR, 551–1210] cells/mm 3 ; P < 0.0001) and CD4+ T cell count (29 cells/mm 3 [IQR, 1.3–116.0] vs 325.5 cells/mm 3 [IQR, 151.5–589.8]; P < 0.0001). Conclusions. Nonspecific and CMV-specific CD8+ T-cell function correlated with the course of CMV after SOT, and measuring these has the potential to assist in its clinical management.

AbstractBackgroundMycobacterium tuberculosis may be transmitted via the allograft to cause a morbid and potentially fatal infection after solid organ transplantation (SOT). We reviewed all reported cases of donor‐derived tuberculosis (DDTB) to provide an update on its epidemiology, clinical course, and outcome after SOT.MethodsMEDLINE, OVID, and EMBASE were reviewed from its inception until December 31, 2016 using key words donor‐derived infection, tuberculosis and solid organ transplant or transplantation.ResultsWe retrieved 36 cases of proven (n = 17), probable (n = 8), and possible (n = 11) DDTB among 16 lung, 13 kidney, 6 liver, and 1 heart recipients. Most patients were male (21/35, 60%) with median age of 48 (range 23‐68) years. Median time to clinical presentation or diagnosis was 2.7 months (range 0.2‐29). The most common donor risk factor was residence in a TB‐endemic area (13/28, 46.4%). Fever was the most frequent presenting symptom (20/36, 56.5%). Diagnosis of tuberculosis was mostly made via AFB smear or mycobacterial culture (30/36, 83.3%). Allograft involvement was expectedly common; there were almost equal proportions of pulmonary (36%), extra‐pulmonary (28%) and disseminated (36%) cases. All cases of pulmonary TB were identified only among lung transplant recipients. The median duration of TB treatment was 10.5 (range 3‐24) months. Graft loss occurred in four (4/22, 18.2%) patients. All‐cause mortality was 25% (9/36); four of nine deaths were attributed to TB.ConclusionsDonor‐derived TB presents early after SOT, most commonly as fever, and carries a high mortality risk. Donors should be screened, with particular attention to TB risk factors. Fever during the early post‐operative period should prompt a thorough evaluation for DDTB in endemic regions and among patients with “at‐risk” donors.

Abstract Background Mycobacterium tuberculosis ( TB ) is a common pathogen worldwide, and it may cause significant infection after solid organ transplantation ( SOT ). We reviewed all reported TB cases to provide an update on its epidemiology, clinical presentation, management, and outcome after SOT . Methods MEDLINE , EMBASE , and OVID were reviewed from January 1, 1998, to December 31, 2016, using keywords tuberculosis and solid organ transplant or transplantation. Results There were 187 publications reporting 2082 cases of TB among kidney (n = 1719), liver (n = 253), heart (n = 77), lung (n = 25), and kidney‐pancreas (n = 8) recipients. Among cohort studies, the median incidence was 2.37% (range, 0.05%‐13.27%) overall. Most TB disease was considered reactivation of latent infection, occurring beyond the first year after SOT . Early‐onset cases were seen among donor‐derived TB cases. Fever was the most common symptom. Radiologic findings were highly variable. Extrapulmonary and disseminated TB occurred 29.84% and 15.96%, respectively. Multidrug‐resistant TB was rare. Treatment using 4 or 5 drugs was commonly associated with hepatotoxicity and graft dysfunction. All‐cause mortality was 18.84%. Conclusions This large review highlights the complexity of TB after SOT . Reactivation TB , donor‐transmitted infection, extrapulmonary involvement, and disseminated disease are common occurrences. Treatment of TB is commonly associated with hepatotoxicity and graft dysfunction.

AbstractCytomegalovirus (CMV) pneumonia causes major morbidity and mortality. Its diagnosis requires demonstration of viral cytopathic changes in tissue, entailing risks of lung biopsy. This study aimed to determine CMV viral load (VL) thresholds in bronchoalveolar lavage fluid (BALF) for diagnosis of CMV pneumonia in immunocompromised patients. CMV VL in BALF was studied in 17 patients (83% transplant recipients) and 21 control subjects with and without CMV pneumonia, respectively, using an FDA‐approved PCR assay (Cobas® AmpliPrep/Cobas TaqMan® CMV Test, Roche Molecular Systems, Inc.) calibrated to the WHO International Standard for CMV DNA (NIBSC: 09/162). Receiver operating characteristic curve analysis produced a BALF CMV VL threshold of 34 800, IU/mL with 91.7% sensitivity and 100.0% specificity for diagnosis of possible, probable, and proven CMV pneumonia in transplant patients, while a threshold of 656 000 IU/mL yielded 100% sensitivity and specificity among biopsy‐proven cases. For all immunocompromised patients, a VL threshold of 274 IU/mL was selected. VL thresholds also were normalized to BALF cell count yielding a threshold of 0.32 IU/106 cells with 91.7% sensitivity and 90.5% specificity for possible, probable, and proven CMV pneumonia in transplant recipients. Monitoring CMV VL in BALF may be a less invasive method for diagnosing CMV pneumonia in immunocompromised patients.

Abstract Background Quantification of cytomegalovirus (CMV) deoxyribonucleic acid (DNA) has important diagnostic, prognostic, and therapeutic implications in the management of transplant recipients. We aimed to assess a viral load in plasma and whole blood that distinguishes CMV disease from asymptomatic infection in a cohort of solid organ and hematopoietic stem cell transplantation. Methods We prospectively measured and compared CMV viral load in paired plasma and whole blood samples collected from transplant recipients with CMV infection and disease. Cytomegalovirus viral loads were determined by a commercially available US Food and Drug Administration-approved quantitative assay (COBAS AmpliPrep/COBAS TaqMan CMV Test [CAP/CTM CMV]) calibrated to the first World Health Organization International Standard for CMV DNA quantification. Results Moderate agreement of CMV viral load was observed between plasma and whole blood, with 31% of samples having discordant findings, particularly among samples with low DNA levels. Among the subset of samples where both paired samples had quantifiable levels, we observed a systematic bias that reflected higher viral load in whole blood compared with plasma. Based on receiver operating curve analysis, an initial plasma CMV viral load threshold of 1700 IU/mL in solid organ transplant recipients (sensitivity 80%, specificity 74%) and 1350 IU/mL in allogeneic hematopoietic stem cell transplant recipients (sensitivity 87%, specificity 87%) distinguished CMV disease and asymptomatic infection. Conclusions This study identifies standardized viral load thresholds that distinguish CMV disease from asymptomatic infection using CAP/CTM CMV assay. We propose these thresholds as potential triggers to be evaluated in prospective studies of preemptive therapy. Plasma was better than whole blood for measuring viral load using the CAP/CTM CMV assay.

AbstractHuman herpesvirus 6 (HHV‐6A and HHV‐6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV‐6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate histopathological effects of HHV‐6 remains the gold standard for diagnosis of end‐organ disease. HHV‐6 reactivation may be restricted to the infected organ with no evidence of active infection in the blood. HHV‐6 infections in liver transplant patients are mostly asymptomatic, but clinically significant tissue‐invasive infections have been treated successfully with ganciclovir, foscarnet or cidofovir. Inherited chromosomally integrated HHV‐6 (ciHHV‐6), in either the recipient or the donor organ, may create confusion about systemic HHV‐6 infection. Recipients with inherited ciHHV‐6 may have an increased risk of opportunistic infection and graft rejection. This article reviews the current scientific data on the clinical effects, risk factors, pathogenesis, diagnosis and treatment of HHV‐6 infections in liver transplant recipients.